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WO 2021/154761
PCIUUS2021/015143
METHODS FOR TREATMENT OF CANCER WITH AN ANTI-TIGIT ANTAGONIST ANTIBODY
CROSS-REFERENCES TO RELATED APPLICATIONS
This application claims priority to U.S. Patent Application No. 62/966,448,
filed on January 27,
2020; U.S. Patent Application No. 62/985,822, filed on March 5, 2020; U.S.
Patent Application No.
62/994,272, filed on March 24, 2020; International Application No.
PCT/U52020/024526, filed on March
24, 2020; U.S. Patent Application No. 63/059,054, filed on July 30, 2020; U.S.
Patent Application No.
63/059,960, filed on July 31, 2020; U.S. Patent Application No. 63/074,807,
filed on September 4, 2020;
U.S. Patent Application No. 63/074,827, filed on September 4, 2020;
International Application No.
PCT/US2020/049415, filed on September 4, 2020; U.S. Patent Application No.
63/085,890, filed on
September 30, 2020; U.S. Patent Application No. 63/105,198, filed on October
23, 2020; U.S. Patent
Application No. 63/114,517, filed on November 16, 2020; U.S. Patent
Application No. 63/124,693, filed on
December 11,2020; and U.S. Patent Application No. 63/127,109, filed on
December 17, 2020, the entire
contents of each of which are incorporated herein by reference in their
entirety.
SEQUENCE LISTING
The instant application contains a Sequence Listing which has been submitted
electronically in
ASCII format and is hereby incorporated by reference in its entirety. Said
ASCII copy, created on
January 25, 2021, is named 50474-206W02_Sequence_Listing_1_25_2021_5125 and is
30,641 bytes in
size.
FIELD OF THE INVENTION
The present invention relates to methods, uses, and compositions for the
treatment of cancer.
More specifically, the invention concerns the treatment of patients having
cancer with an anti-TIGIT
antagonist antibody (e.g., treatment with an anti-TIGIT antagonist antibody as
a monotherapy or a
combination therapy).
BACKGROUND OF THE INVENTION
Cancers are characterized by the uncontrolled growth of cell subpopulations.
Cancers are the
leading cause of death in the developed world and the second leading cause of
death in developing
countries, with over 14 million new cancer cases diagnosed and over eight
million cancer deaths
occurring each year. Cancer care thus represents a significant and ever-
increasing societal burden.
Thus, there is an unmet need in the field for the development of efficacious
immunotherapies and
methods of dosing the same for the treatment of cancers.
SUMMARY OF THE INVENTION
In one aspect, the invention provides a method of treating a subject having a
cancer, the method
comprising administering to the subject a dosing regimen comprising one or
more dosing cycles of an
anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every
three weeks, a PD-1
axis binding antagonist at a dose of about 900 mg to about 1500 mg every three
weeks, a platinum-based
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chemotherapeutic agent every three weeks, and a non-platinum-based
chemotherapeutic agent every
three weeks.
In another aspect, the invention provides a method of treating a subject
having a cancer, the
method comprising administering to the subject a dosing regimen comprising one
or more dosing cycles
of an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000
mg every four weeks and a
PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every four
weeks.
In another aspect, the invention provides a method of treating a subject
having a cancer, the
method comprising administering to the subject a dosing regimen comprising one
or more dosing cycles
of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg
every two weeks and a
PD-1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every
two weeks.
In another aspect, the invention provides a kit comprising an anti-TIGIT
antagonist antibody for
use in combination with a PD-1 axis binding antagonist for treating a subject
having a cancer according to
the methods provided herein.
In another aspect, the invention provides an anti-TIGIT antagonist antibody
and a PD-1 axis
.. binding antagonist for use in a method of treating a subject having a
cancer, wherein the method is
according to the methods provided herein.
In another aspect, the invention provides use of an anti-TIGIT antagonist
antibody in the
manufacture of a medicament for treating a subject having a cancer in
combination with a PD-1 axis
binding antagonist, wherein the treatment is according to the methods provided
herein.
In another aspect, the invention provides a method of treating a subject
having a cancer, the
method comprising administering to the subject a dosing regimen comprising one
or more dosing cycles
of an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000
mg every four weeks and a
PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every four
weeks.
In another aspect, the invention provides a method of treating a subject
having a cancer, the
method comprising administering to the subject a dosing regimen comprising one
or more dosing cycles
of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg
every two weeks and a
PD-1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every
two weeks.
In another aspect, the invention provides a method of treating a subject
having a cancer, the
method comprising administering to the subject a dosing regimen comprising one
or more dosing cycles
of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg
every three weeks, a
PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every
three weeks, a platinum-
based chemotherapeutic agent every three weeks, and a non-platinum-based
chemotherapeutic agent
every three weeks.
In another aspect, the invention provides a method of treating a subject
having a cancer, the
method comprising administering to the subject a dosing regimen comprising one
or more dosing cycles
of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg
every three weeks and
an anti-PD-1 antagonist antibody at a dose of about 100 mg to about 300 mg
every three weeks, wherein
the anti-PD-1 antagonist antibody is pembrolizumab.
In another aspect, the invention provides a method of treating a subject
having a cancer, the
method comprising administering to the subject a dosing regimen comprising one
or more dosing cycles
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of tiragolumab and pembrolizumab, wherein the pembrolizumab is administered at
a dose of between
about 300 mg to about 500 mg every six weeks.
In another aspect, the invention provides a method for treating a subject
having a cancer, the
method comprising administering to the subject a dosing regimen comprising one
or more dosing cycles
of an anti-TIGIT antagonist antibody at a dose of between about 500 mg to
about 700 mg every three
weeks, a PD-1 axis binding antagonist at a dose of between about 900 mg to
about 1500 mg every three
weeks, and an antimetabolite at a dose of between about 10 mg/m2 to about
10000 mg/m2 twice a day
orally every three weeks for 2-weeks on/1-week off.
In another aspect, the invention provides a method of treating a subject
having a cancer, the
method comprising administering to the subject a dosing regimen comprising one
or more dosing cycles
of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg
every three weeks, a
PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every
three weeks,
gemcitabine, and nab-paclitaxel.
In another aspect, the invention provides a method for treating a subject
having a cancer, the
method comprising administering to the subject a dosing regimen comprising one
or more dosing cycles
of an anti-TIGIT antagonist antibody at a dose of between about 500 mg to
about 700 mg every three
weeks, a PD-1 axis binding antagonist at a dose of between about 900 mg to
about 1500 mg every three
weeks, and a VEGF antagonist at a dose of between about 1 mg/kg to about 35
mg/kg every three
weeks.
In another aspect, the invention provides a method of treating a subject
having a cancer, the
method comprising administering to the subject a dosing regimen comprising an
induction phase and a
maintenance phase, wherein (a) the induction phase comprises one or more
dosing cycles of an anti-
TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every
three weeks, a PD-1 axis
binding antagonist at a dose of about 900 mg to about 1500 mg every three
weeks, a platinum-based
chemotherapeutic agent every three weeks, and a non-platinum-based
chemotherapeutic agent every
three weeks; and (b) the maintenance phase comprises one or more additional
dosing cycles of the anti-
TIGIT antagonist antibody every three weeks, the PD-1 axis binding antagonist
every three weeks, and
the non-platinum-based chemotherapeutic agent every three weeks, and wherein
the maintenance phase
does not comprise administration of the platinum-based chemotherapeutic agent.
In another aspect, the invention provides a method of treating a subject
having a cancer, the
method comprising administering to the subject a dosing regimen comprising an
induction phase and a
maintenance phase, wherein (a) the induction phase comprises one or more
dosing cycles of an anti-
TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every
three weeks, a PD-1 axis
binding antagonist at a dose of about 900 mg to about 1500 mg every three
weeks, a platinum-based
chemotherapeutic agent every three weeks, and a non-platinum-based
chemotherapeutic agent every
three weeks; and (b) the maintenance phase comprises one or more additional
dosing cycles of the anti-
TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every
four weeks and the PD-1
axis binding antagonist at a dose of about 1400 mg to 2000 mg every four
weeks, wherein the
maintenance phase does not comprise administration of the platinum-based
chemotherapeutic agent or
non-platinum-based chemotherapeutic agent.
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In another aspect, the invention provides a method of treating a subject or
population of subjects
having a lung cancer, the method comprising administering to the subject or
population of subjects a
dosing regimen comprising one or more dosing cycles of an effective amount of
an anti-TIGIT antagonist
antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic
agent, and a
topoisomerase II inhibitor, wherein the treatment extends progression-free
survival (PFS) of the subject
as compared to treatment with the PD-1 axis binding antagonist, the platinum-
based chemotherapeutic
agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist
antibody.
In another aspect, the invention provides a method of treating a population of
subjects having a
lung cancer, the method comprising administering to the population of subjects
a dosing regimen
comprising one or more dosing cycles of an effective amount of an anti-TIGIT
antagonist antibody, a PD-
1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a
topoisomerase II inhibitor,
wherein the treatment results in a median PFS of the population of subjects of
about 8.2 months to about
9.2 months.
In another aspect, the invention provides a method of treating a subject or
population of subjects
having a lung cancer, the method comprising administering to the subject or
population of subjects a
dosing regimen comprising one or more dosing cycles of an effective amount of
an anti-TIGIT antagonist
antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic
agent, and a
topoisomerase ll inhibitor, wherein the treatment extends OS of the subject as
compared to treatment
with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic
agent, and the
topoisomerase ll inhibitor without the anti-TIGIT antagonist antibody.
In another aspect, the invention provides a method of treating a population of
subjects having a
lung cancer, the method comprising administering to the population of subjects
a dosing regimen
comprising one or more dosing cycles of an effective amount of an anti-TIGIT
antagonist antibody, a PD-
1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a
topoisomerase II inhibitor,
wherein the treatment results in a median OS of the population of subjects of
about 15.3 months to about
17.6 months.
In another aspect, the invention provides a method for treating a subject or
population of subjects
having SCLC, the method comprising administering to the subject or population
of subjects one or more
21-day dosing cycles of an anti-TIGIT antagonist antibody at a dose of about
500 mg to about 700 mg on
Day 1 of each dosing cycle, atezolizumab at a dose of about 900 mg to about
1500 mg on Day 1 of each
dosing cycle, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min on
Day 1 of each dosing
cycle, and etoposide at a dose of 100 mg/m2on each of Days 1, 2, and 3 of each
dosing cycle, wherein
the treatment extends PFS and/or OS of the subject or population of subjects
as compared to treatment
with atezolizumab, carboplatin, and etoposide without the anti-TIGIT
antagonist antibody.
In another aspect, the invention provides a method for treating a subject or
population of subjects
having ES-SCLC, the method comprising administering to the subject or
population of subjects four initial
dosing cycles followed by one or more additional dosing cycles, wherein (a)
the four initial dosing cycles
comprise administering tiragolumab at a dose of about 600 mg on Day 1 of each
initial dosing cycle,
atezolizumab at a dose of about 1200 mg on Day 1 of each initial dosing cycle,
carboplatin at a dose
sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each initial dosing cycle,
and etoposide at a dose of
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100 mg/m2on each of Days 1, 2, and 3 of each initial dosing cycle; and (b) the
one or more additional
dosing cycles comprise administering tiragolumab at a dose of about 600 mg on
Day 1 of each additional
dosing cycle and atezolizumab at a dose of about 1200 mg on Day 1 of each
additional dosing cycle,
wherein the four initial dosing cycles and the one or more additional dosing
cycles are each 21-day
dosing cycles, and wherein the treatment extends PFS and/or OS of the subject
or population of subjects
as compared to treatment with atezolizumab, carboplatin, and etoposide without
the tiragolumab.
In another aspect, the invention provides a method of treating a subject or
population of subjects
having a lung cancer, the method comprising administering to the subject or
population of subjects a
dosing regimen comprising one or more dosing cycles of an anti-TIGIT
antagonist antibody, a PD-1 axis
binding antagonist, a first chemotherapeutic agent which is a platinum-based
chemotherapeutic agent,
and a second chemotherapeutic agent which is a non-platinum-based
chemotherapeutic agent.
In another aspect, the invention provides a method of treating a subject or
population of subjects
having an advanced non-squamous NSCLC, the method comprising administering to
the subject or
population of subjects a dosing regimen comprising four 21-day dosing cycles
of tiragolumab,
atezolizumab, carboplatin or cisplatin, and pemetrexed, wherein the
tiragolumab is administered at a
dose of about 600 mg every three weeks, the atezolizumab is administered at a
dose of about 1200 mg
every three weeks, the carboplatin is administered at a dose sufficient to
achieve an AUC = 5 mg/ml/min
every three weeks or the cisplatin is administered at a dose of 75 mg/m2 every
three weeks, and the
pemetrexed is administered at a dose of about 500 mg/m2 every three weeks on
Day 1 of each of the four
21-day dosing cycles.
In another aspect, the invention provides a method of treating a subject or
population of subjects
having an advanced non-squamous NSCLC, the method comprising administering to
the subject or
population of subjects (i) four induction phase dosing cycles of tiragolumab
at a dose of about 600 mg
every three weeks, atezolizumab at a dose of about 1200 mg every three weeks,
carboplatin at a dose
sufficient to achieve an AUC = 5 mg/ml/min every three weeks, and pemetrexed
at a dose of about 500
mg/m2 every three weeks; and (ii) one or more maintenance phase dosing cycles
of tiragolumab at a
dose of about 600 mg every three weeks, atezolizumab at a dose of about 1200
mg every three weeks,
and pemetrexed at a dose of about 500 mg/m2 every three weeks, wherein the one
or more 21-day
dosing cycles of the maintenance phase do not comprise administration of the
carboplatin, wherein the
subject or population of subjects have received no prior systemic therapy for
the advanced non-
squamous NSCLC.
In another aspect, the invention provides a method for treating a subject
having a resectable
lung cancer, the method comprising administering to the subject one or more
dosing cycles of an anti-
TIGIT antagonist antibody at a dose of between about 500 mg to about 700 mg
every three weeks and a
PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500
mg every three weeks.
In another aspect, the invention provides a method for treating a subject
having a lung cancer,
the method comprising administering to the subject one or more dosing cycles
of an anti-TIGIT antagonist
antibody and a PD-1 axis binding antagonist, wherein at least one of the
dosing cycles comprises
administering to the subject the anti-TIGIT antagonist antibody at a dose of
between about 500 mg to
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about 700 mg every three weeks and the PD-1 axis binding antagonist at a dose
of between about 900
mg to about 1500 mg every three weeks as a neoadjuvant treatment.
In another aspect, the invention provides a method for treating a subject
having a resectable lung
cancer, the method comprising administering to the subject one or more dosing
cycles of tiragolumab at a
dose of about 600 mg every three weeks, atezolizumab at a dose of about 1200
mg every three weeks,
and (a) (i) carboplatin at a dose targeted to achieve an AUG of 5 mg/mL/min or
an AUG of 6 mg/mUmin
every three weeks; or (ii) cisplatin at a dose of about 75 mg/m2 every three
weeks; and (b) (i) pemetrexed
at a dose of about 500 mg/m2 every three weeks or gemcitabine at a dose of
about 1000 mg/m2 or about
1250 mg/m2 on Days 1 and 8 of each dosing cycle; or (ii) paclitaxel at a dose
of about 175 mg/m2 or
about 200 mg/m2 every three weeks.
In another aspect, the invention provides a method for treating a subject
having a lung cancer,
the method comprising administering to the subject one or more dosing cycles
of tiragolumab and
atezolizumab, wherein (I) at least one of the dosing cycles is a neoadjuvant
treatment and comprises
administering to the subject (a) tiragolumab at a dose of about 1200 mg every
three weeks; (b)
atezolizumab at a dose of about 1200 mg every three weeks as a neoadjuvant
treatment; and (c) (i)
carboplatin at a dose targeted to achieve an AUC of 5 mg/mUmin every three
weeks and gemcitabine at
a dose of about 1000 mg/m2 on Days 1 and 8 of each dosing cycle; (ii)
carboplatin at a dose targeted to
achieve an AUG of 6 mg/mUmin every three weeks and paclitaxel at a dose of
about 175 mg/m2 or about
200 mg/m2 every three weeks; or (iii) cisplatin at a dose of about 75 mg/m2
every three weeks and
gemcitabine at a dose of about 1250 mg/m2 on Days 1 and 8 of each dosing
cycle; and (II) at least one of
the dosing cycles comprises administering to the subject tiragolumab at a dose
of between about 500 mg
to about 700 mg every three weeks and atezolizumab at a dose of between about
900 mg to about 1500
mg every three weeks as an adjuvant treatment.
In another aspect, the invention provides a method for treating a subject or
population of subjects
having a cervical cancer with a detectable expression level of PD-L1, the
method comprising
administering to the subject or population of subjects one or more dosing
cycles of an anti-TIGIT
antagonist antibody at a dose of between about 500 mg to about 700 mg every
three weeks and a PD-1
axis binding antagonist at a dose of between about 900 mg to about 1500 mg
every three weeks.
In another aspect, the invention provides a method of selecting a therapy for
a subject having a
cervical cancer, the method comprising (a) detecting the protein expression
level of PD-L1 on tumor cells
from a tumor sample from the subject by an INC assay using an anti-PD-L1
antibody suitable for staining;
and (b) selecting for the subject having a detectable expression level of PD-
L1 a therapy comprising one
or more dosing cycles of an anti-TIGIT antagonist antibody administered at a
dose of between about 500
mg to about 700 mg every three weeks and a PD-1 axis binding antagonist
administered at a dose of
between about 900 mg to about 1500 mg every three weeks based on PD-L1
expression on tumor cells
having been detected.
In another aspect, the invention provides a method for treating a subject
having a cervical cancer
with a detectable expression level of PD-L1, the method comprising
administering to the subject one or
more dosing cycles of tiragolumab at a dose of about 600 mg every three weeks
and atezolizumab at a
dose of about 1200 mg every three weeks.
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In another aspect, the invention provides a method of treating a subject or
population of subjects
having a breast cancer, the method comprising administering to the subject or
population of subjects a
dosing regimen comprising one or more dosing cycles of tiragolumab at a dose
of about 840 mg every
four weeks, atezolizumab at a dose of about 1680 mg every four weeks, and nab-
paclitaxel at a dose of
about 100 mg/m2 for 3-weeks on/1 -week off.
In another aspect, the invention provides a method of treating a subject
having an early triple-
negative breast cancer (eTNBC), the method comprising administering to the
subject a dosing regimen
comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a
dose of about 300 mg to
about 600 mg every two weeks and a PD-1 axis binding antagonist at a dose of
about 600 mg to about
1200 mg every two weeks.
In another aspect, the invention provides a method of treating a subject
having an eTNBC, the
method comprising administering to the subject a dosing regimen comprising
tiragolumab at a dose of
about 420 mg every two weeks, atezolizumab at a dose of about 840 mg every two
weeks, and (a) (i)
nab-paclitaxel at a dose of about 125 mg/m2 every week and carboplatin at a
dose targeted to achieve an
AUC of 5 mg/mUmin every three weeks for the first 12 weeks of the dosing
regimen; and (ii) doxorubicin
at a dose of about 60 mg/m2 every two weeks, cyclophosphamide at a dose of
about 600 mg/m2 every
two weeks, and G-CSF or GM-CSF every two weeks for weeks 13-19 of the dosing
regimen; or (b) (i)
nab-paclitaxel at a dose of about 125 mg/m2 every week for the first 12 weeks
of the dosing regimen; and
(ii) doxorubicin at a dose of about 60 mg/m2 every two weeks, cyclophosphamide
at a dose of about 600
mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks for weeks 13-19 of
the dosing regimen;
wherein the method further comprises surgery between two and six weeks after
the last dose of the
dosing regimen.
In another aspect, the invention provides a method for treating a subject or
population of subjects
having an SCCHN with a detectable expression level of PD-L1, the method
comprising administering to
the subject or population of subjects one or more dosing cycles of an anti-
TIGIT antagonist antibody at a
dose of between about 500 mg to about 700 mg every three weeks and a PD-1 axis
binding antagonist at
a dose of between about 900 mg to about 1 500 mg every three weeks.
In another aspect, the invention provides a method of selecting a therapy for
a subject or
population of subjects having an SCCHN, the method comprising: (a) detecting a
protein expression level
.. of PD-L1 in a tumor sample from the subject or population of subjects by an
IHC assay using an anti-PD-
L1 antibody suitable for staining; and (b) selecting for the subject or
population of subjects having a
detectable expression level of PD-L1 a therapy comprising one or more dosing
cycles of a PD-1 axis
binding antagonist at a dose of between about 900 mg to about 1500 mg every
three weeks and an anti-
TIGIT antagonist antibody at a dose of between about 500 mg to about 700 mg
every three weeks based
on PD-L1 expression having been detected.
In another aspect, the invention provides a method for treating a subject
having an SCCHN with a
detectable expression level of PD-L1, the method comprising administering to
the subject one or more
dosing cycles of tiragolumab at a dose of about 600 mg every three weeks and
atezolizumab at a dose of
about 1200 mg every three weeks.
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In another aspect, the invention provides a method of treating a subject or
population of subjects
having a hepatocellular carcinoma (HOC), the method comprising administering
to the subject or
population of subjects one or more dosing cycles of an anti-TIGIT antagonist
antibody and a PD-1 axis
binding antagonist, wherein the subject or population of subjects have
received no prior systemic treatment
for HCC.
In another aspect, the invention provides a method of treating a subject or
population of subjects
having an HOC, the method comprising administering to the subject or
population of subjects one or more
dosing cycles of an anti-TIGIT antagonist antibody, a PD-1 axis binding
antagonist, and a VEGF
antagonist.
In another aspect, the invention provides a method of treating a subject or
population of subjects
having an HCC, the method comprising administering to the subject one or more
dosing cycles of
tiragolumab at a dose of about 600 mg every three weeks, atezolizumab at a
dose of about 1200 mg
every three weeks, and bevacizumab at a dose of about 15 mg/kg every three
weeks.
In another aspect, the invention provides a method for treating a subject or
population of subjects
having an MIBC, the method comprising administering to the subject one or more
dosing cycles of an
anti-TIGIT antagonist antibody at a dose of between about 500 mg to about 700
mg every three weeks
and a PD-1 axis binding antagonist at a dose of between about 900 mg to about
1500 mg every three
weeks, wherein the subject is ineligible for treatment with a platinum-based
chemotherapeutic agent.
In another aspect, the invention provides a method for treating a subject or
population of subjects
having an MIBC, the method comprising administering to the subject one or more
dosing cycles of an
anti-TIGIT antagonist antibody at a dose of between about 500 mg to about 700
mg every three weeks
and a PD-1 axis binding antagonist at a dose of between about 900 mg to about
1500 mg every three
weeks, wherein the treatment is a perioperative treatment.
In another aspect, the invention provides a method for treating a subject or
population of subjects
having an MIBC, the method comprising administering to the subject or
population of subjects one or
more dosing cycles of tiragolumab at a dose of about 600 mg every three weeks
and atezolizumab at a
dose of about 1200 mg every three weeks, wherein the subject or subjects are
cisplatin ineligible.
In another aspect, the invention provides a method for treating a subject or
population of subjects
having an !MSC, the method comprising administering to the subject or
population of subjects one or
more dosing cycles of tiragolumab at a dose of about 600 mg every three weeks
and atezolizumab at a
dose of about 1200 mg every three weeks, wherein the treatment is a
perioperative treatment.
In another aspect, the invention provides a method for treating a subject or
population of subjects
having an mUC, the method comprising administering to the subject or
population of subjects a dosing
regimen comprising one or more dosing cycles of an anti-TIGIT antagonist
antibody at a dose of between
about 500 mg to about 700 mg every three weeks and a PD-1 axis binding
antagonist at a dose of
between about 900 mg to about 1500 mg every three weeks.
In another aspect, the invention provides a method for treating a subject or
population of subjects
having an mUC, the method comprising administering to the subject or
population of subjects one or
more dosing cycles of tiragolumab at a dose of about 600 mg every three weeks
and atezolizumab at a
dose of about 1200 mg every three weeks.
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In another aspect, the invention provides a method for treating a subject or
population of subjects
having an mUC, the method comprising administering to the subject or
population of subjects a first
dosing regimen followed by a second dosing regimen, wherein (a) the first
dosing regimen comprises one
or more dosing cycles of tiragolumab at a dose of about 600 mg every three
weeks and atezolizumab at a
dose of about 1200 mg every three weeks; and (b) the second dosing regimen
comprises one or more
dosing cycles of atezolizumab at a dose of about 1200 mg every three weeks and
(i) enfortumab vedotin
is administered at a dose of 1.25 mg/kg every week for 2-weeks on/1 week off
or (ii) sacituzumab
govitecan is administered at a dose of 10 mg/kg every week for 2-weeks on/1
week off, wherein the
second dosing regimen is administered to the subject or population of subjects
after the subject or
population of subjects have experienced disease progression or unacceptable
toxicity during the first
dosing regimen.
In another aspect, the invention provides a method of treating a subject or
population of subjects
having a pancreatic cancer, the method comprising administering to the subject
or population of subjects
a dosing regimen comprising one or more 28-day dosing cycles of tiragolumab at
a dose of about 420 mg
on Days 1 and 15 of each 28-day dosing cycle, atezolizumab at a dose of about
840 mg on Days 1 and
15 of each 28-day dosing cycle, gemcitabine at a dose of about 1000 mg/m2 on
Days 1, 8, and 15 of each
28-day dosing cycle, and nab-paclitaxel at a dose of about 125 mg/m20n Days 1,
8, and 15 of each 28-
day dosing cycle.
In another aspect, the invention provides a method for treating a subject or
population of subjects
having an advanced or metastatic esophageal cancer, the method comprising
administering to the
subject or population of subjects a dosing regimen comprising one or more 21-
day dosing cycles of an
anti-TIGIT antagonist antibody at a dose of between about 500 mg to about 700
mg on Day 1 of each
dosing cycle and a PD-1 axis binding antagonist at a dose of between about 900
mg to about 1500 mg on
Day 1 of each dosing cycle.
In another aspect, the invention provides a method for treating a subject or
population of subjects
having an esophageal cancer, the method comprising administering to the
subject or population of
subjects a dosing regimen comprising one or more 21-day dosing cycles of an
anti-TIGIT antagonist
antibody at a dose of between about 500 mg to about 700 mg on Day 1 of each
dosing cycle and a PD-1
axis binding antagonist at a dose of between about 900 mg to about 1500 mg on
Day 1 of each dosing
cycle, wherein the subject or subjects have been previously treated with a
platinum-based
chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.
In another aspect, the invention provides a method for treating a subject or
population of subjects
having an advanced or metastatic esophageal cancer, the method comprising
administering to the
subject or population of subjects a dosing regimen comprising one or more 21-
day dosing cycles of
tiragolumab at a dose of about 600 mg on Day 1 of each dosing cycle,
atezolizumab at a dose of about
1200 mg on Day 1 of each dosing cycle, cisplatin at a dose of about 80 mg/m2
on Day 1 of each dosing
cycle, and 5-fluorouracil at a dose of 800 mg/m2 /24 hours on Days 1-5 of each
21-day cycle, wherein
cisplatin is omitted from the dosing regimen after six doses.
In another aspect, the invention provides a method for treating a subject or
population of subjects
having an advanced or metastatic esophageal cancer, the method comprising
administering to the
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subject or population of subjects a first dosing regimen and a second dosing
regimen, wherein (a) the first
dosing regimen comprises one or more 21-day dosing cycles of cisplatin at a
dose of about 80 mg/m2 on
Day 1 of each dosing cycle and 5-fluorouracil at a dose of 800 mg/m2 /24 hours
on Days 1-5 of each 21-
day cycle, wherein cisplatin is omitted from the dosing regimen after six
doses; and (b) the second dosing
regimen comprises one or more 21-day dosing cycles of tiragolumab at a dose of
about 600 mg on Day 1
of each dosing cycle and atezolizumab at a dose of about 1200 mg on Day 1 of
each dosing cycle.
In another aspect, the invention provides a kit comprising a PD-1 axis binding
antagonist and/or
an anti-TIGIT antagonist antibody for treating a subject having a cancer
according to the methods
provided herein.
In another aspect, the invention provides a kit comprising a PD-1 axis binding
antagonist for use
in combination with an anti-TIGIT antagonist antibody for treating a subject
having a cancer according to
the methods provided herein.
In another aspect, the invention provides a kit comprising an anti-TIGIT
antagonist antibody for
use in combination with a PD-1 axis binding antagonist for treating a subject
having a cancer according to
the methods provided herein.
In another aspect, the invention provides an anti-TIGIT antagonist antibody
and a PD-1 axis
binding antagonist for use in a method of treating a subject or population of
subjects having a cancer,
wherein the method is according to the methods provided herein.
In another aspect, the invention provides use of an anti-TIGIT antagonist
antibody in the
manufacture of a medicament for treating a subject or population of subjects
having a cancer in
combination with a PD-1 axis binding antagonist, wherein the treatment is
according to the methods
provided herein.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a flow chart showing the Phase lb chemotherapy expansion and Phase
lb 04W dosing
expansion).
FIG. 2 is a flow chart of a phase lb trial schema. EOCG = Eastern Cooperative
Oncology Group;
IHC = immunohistochemistry; PD-L1+ = programmed death-ligand 1 positive; Q4W =
every 4 weeks;
RECIST v1.1 = Response Criteria in Solid Tumors, Version 1.1; TFI = treatment-
free interval; TNBC =
triple-negative breast cancer.
FIG. 3 is a flow chart of a phase la study design. CRC = colorectal cancer,
DLT = dose-limiting
toxicity, GC = gastric cancer, HNSCC = head and neck squamous cell carcinoma,
IV = intravenous, MAD
= maximum administered dose, MSI = microsatellite instability, MSS =
microsatellite-stable, MTD =
maximum tolerated dose, NSCLC = non¨small cell lung cancer, OC = ovarian
cancer, PD = progression
of disease, PK = pharmacokinetic, RCC = renal cell carcinoma, TNBC = triple-
negative breast cancer,
UBC = urothelial bladder cancer.
FIG. 4 is a flow chart of the phase lb tiragolumab and atezolizumab expansion
cohorts, serial
biopsy cohort, and 04W dosing expansion cohort study design. CIT = cancer
immunotherapy; DLT =
dose-limiting toxicity; HNSCC = head and neck squamous cell carcinoma, IV =
intravenous, MAD =
maximum administered dose, MSI = microsatellite instability, MSS =
microsatellite-stable, N/ITD =
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maximum tolerated dose, NSCLC = non-small cell lung cancer, PD = progression
of disease; PD 1 =
programmed death-1; PD-L1 = programmed death ligand 1; PK = pharmacokinetic,
TIGIT = 1-cell
Immunoreceptor with Ig and ITIM domains. Note: Limited to patients with PD-L1
selected and/or TIGIT-
selected tumors, aAdvanced, incurable, refractory tumors. Tiragolumab IV and
atezolizumab 1200 mg IV
every 3 weeks. Will only enroll following IMC review of safety data from Phase
la. 3+3 dose escalation
with DLT window of 21 days. Other intermediate doses of tiragolumab may be
studied if they do not
exceed the MTD. To gain further safety, PK, and PD data, patients may be
backfill-enrolled if they
consent to optional serial biopsies. Evaluation of dose levels exceeding 1200
mg tiragolumab will require
a protocol amendment with a supporting rationale. bExpansion may begin at
doses MID or MAD. GUp
to approximately half of patients in each cohort will be those who consent to
optional serial biopsies.
Patients with tumors for which anti-PD-L1/PD-1 agents are approved by local
regulatory authorities (e.g.,
NSCLC melanoma, renal cell carcinoma) may only be enrolled in an expansion
cohort (indication-specific
or serial biopsy) if a clinical trial of an investigational agent in
combination with an anti-PD-L1 is
considered an acceptable treatment option. dLimited to patients who consent to
optional serial biopsies
(acceptable samples include core needle, excisional, incisional, punch, and/or
foreceps biopsies). eln the
04W dosing expansion cohort, a safety run-in of approximately 3 patients will
be completed. All relevant
safety data from the safety run-in will be thoroughly reviewed by an IMC and
by the investigators before
enrollment is continued.
FIG. 5 is a flow chart of the phase lb chemotherapy expansion cohorts study
design.
FIG. 6 is a flow chart of the phase lb non-chemotherapy expansion cohorts
study design.
FIG. 7 is a flow chart showing the conditions for continuing study treatment
beyond progression.
ECOG = Eastern Cooperative Oncology Group; RECIST = Response Evaluation
Criteria in Solid Tumors.
FIG. 8 is a flow chart showing crossover from phase la to phase lb. AE =
adverse event, DLT =
dose-limiting toxicity, PD = progression of disease.
FIG. 9 is a graph showing the pharmacokinetics of tiragolumab.
FIG. 10 is a series of graphs showing the pharmacodynamics of tiragolumab.
FIG. 11 is a graph showing all adverse events 10% in a phase la tiragolumab
dose-escalation
study. *Grade 5 AEs were malignant neoplasm progression (n=3), not related to
tiragolumab.
FIG. 12 is a graph showing all adverse events 10% in phase lb tiragolumab and
atezolizumab
dose-escalation study. *Grade 5 AEs were malignant neoplasm progression (n=12)
and pulmonary
embolism (n=2), not related to study drug(s).
FIG. 13 is a graph showing tumor size reduction in phase la tiragolumab dose-
escalation study.
FIG. 14 is a graph showing tumor size reduction in phase lb tiragolumab and
atezolizumab dose-
escalation study.
FIG. 15 is a graph showing CIT-naive PD-L1-positive NSCLC tumor size reduction
in phase lb
tiragolumab and atezolizumab dose-escalation study.
FIG. 16 is a graph showing CIT-naive PD-L1-positive NSCLC tumor size reduction
over time in
phase lb tiragolumab and atezolizumab dose-escalation study.
FIG. 17 is a flow chart of a phase III trial schema. 1L = first-line; CE =
carboplatin and etoposide;
ECOG PS = Eastern Cooperative Oncology Group performance status; ES-SCLC =
extensive-stage
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small cell lung cancer; LDH = lactase dehydrogenase; RECIST = Response
Evaluation Criteria in Solid
Tumors; ITT= intent-to-treat; PP = primary population.
FIG. 18 is a schematic diagram of the study design showing the parameters for
the selection of
subjects, stratification criteria, randomization into treatment arms, and
treatment endpoints.
FIG. 19 is a schematic diagram showing the design of the G042501 Phase II
clinical trial.
Patients with resectable Stage II, IIIA, or select IIIB (T3N2) non-small cell
lung cancer (NSCLC) who do
not have an activating EGFR mutation (EGFR-), do not have an ALKfusion
oncogene (ALK-), and have
an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, are
selected. Cohort A
consists of PD-L1 high patients. Patients in Cohort A are treated with
atezolizumab (Atezo) and
tiragolumab (Tira) every three weeks (Q3W) for 4 cycles. Cohort B consists of
patients having any PD-L1
status. Patients in Cohort B are treated with Atezo, Tira, and platinum-based
doublet chemotherapy
(Chemo) Q3W for 4 cycles. Chest computed tomography (CT) is performed after
Cycle 2 and Cycle 4.
Surgery is performed for patients in both cohorts, and major pathological
response (MPR) and
pathological complete response (pCR) are assessed. Following surgery, patients
in Cohort A are treated
with Atezo and Tira 03W for 16 cycles or Chemo 03W for 4 cycles. Patients in
Cohort B are treated with
Atezo and Tira 03W for 16 cycles. Postoperative radiotherapy (PORT) is
optional for R1/R2 resections
and/or ypN2 prior to adjuvant administration. Survival follow-up is performed.
FIG. 20 is a flow chart showing patient enrollment in the G042501 Phase II
clinical trial. For
Cohort A (PD-L1 high patients; PD-L1 tumor proportion score (TPS) 50%), a
safety lead-in is performed
using 6 patients. If surgical safety criteria are not met, enrollment of
Cohort A is halted. If surgical safety
criteria are met, enrollment of Cohort A is continued. For Cohort B (patients
with any PD-L1 status), a
safety lead-in is performed using 6 patients with PD-L1 TPS < 50%. If surgical
safety criteria are not met,
enrollment of Cohort B is halted. If surgical safety criteria are met,
enrollment of Cohort B is continued,
and patients having PD-L1 TPS < 50% and PD-L1 TPS 50% are enrolled. After 8
patients with tumors
expressing PD-L1 50% have been enrolled into Cohort B, enrollment of patients
having PD-L1 TPS
50% into Cohort A is continued.
FIG. 21 is a flow chart of a phase ll trial schema. 1L = first line; CDx =
companion diagnostic;
ECOG PS = Eastern Cooperative Oncology Group performance status; IHC =
immunohistochemistry;
IRC = independent review committee; PD-L1 = programmed death-ligand 1; 03W =
every 3 weeks; R =
randomization; sip = status-post; IV = intravenous.
FIG. 22 is a flow chart of a Phase lb trial schema. TNBC = triple-negative
breast cancer; G-CSF
= granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage
colony-stimulating factor;
Rand. = randomization, pCR = pathologic complete response, OW = once a week,
02W = every two
weeks, 03W = every three weeks.
FIG. 23 is a flow chart of a Phase II trial schema. HPV = Human
papillomavirus; IHC =
immunohistochemistry; IV = intravenous; 03W = every 3 weeks; PD-L1 low = TIC
10%-49%; PD-L1 high
= TIC 50%; SCCHN = squamous cell carcinoma of head and neck; RECIST = Response
Evaluation
Criteria in Solid Tumors.
FIG. 24 is a schematic diagram showing the design of the muscle-invasive
bladder cancer
(MIBC) cohorts of the W039613 Phase 113/11 clinical trial. At the screening
stage, patients having MIBC
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who are cisplatin ineligible and either PD-L1 positive (+) (top) or PD-L1
negative (-) (bottom) are
identified. Following randomization (R), patients are treated with
atezolizumab (Atezo; control) or
atezolizumab and tiragolumab (Tira).
FIG. 25 is a schematic diagram showing the design of the metastatic urothelial
carcinoma (mUC)
cohorts of the W039613 Phase lb/II clinical trial. At the screening stage,
patients having second-line
locally advanced or metastatic UC who have progressed during or following
platinum-containing therapy
and who are cancer immunotherapy (CIT) naïve are identified. Following
randomization (R), patients are
treated with atezolizumab (Atezo; control); atezolizumab and enfortumab
vedotin (EV); atezolizumab and
niraparib (Nira); atezolizumab and Hu5F9-G4; atezolizumab and tiragolumab
(Tira); atezolizumab and
sacituzumab govitecan (SG); atezolizumab and tocilizumab (TCZ); atezolizumab
and R07122290 (FAP-
4-1BBL); or R07121661 (PD1/TIM-3) during Stage 1. aDuring Stage 1, patients
who experience loss of
clinical benefit, as determined by the investigator, or unacceptable toxicity
may be eligible to receive a
different treatment combination during Stage 2, provided they meet the
eligibility criteria. bThe Atezo+Nira
arm has 40 patients. Patients who received enfortumab vedotin in Stage 1 do
not receive enfortumab
vedotin in Stage 2, and patients who received sacituzumab govitecan in Stage 1
do not receive
sacituzumab govitecan in Stage 2; other patients who are eligible for more
than one treatment arm are
assigned a treatment arm by the investigator. Once the Atezo+SG arm opens,
enrollment in the
Atezo+EV arm is closed. dThe Atezo+R07122290 (FAP-4-1BBL) arm is only opened
in ex-U.S.
countries.
FIG. 26 is a diagram showing the objective response rate (ORR) (complete
response/partial
response (CR/PR); stable disease/progressive disease (SD/PD); or not evaluable
(NE)) in patients from
the CITYSCAPE trial having low or high PD-L1 TPS as assessed by the pharmDx
22C3 IHC assay (high
TPS ?...50 /0; low TPS 1-49%) or low or high PD-L1 tumor content (TC) as
assessed by the CE-IVD
VENTANA SP263 IHC assay (high TC 50%; low TC 1-49%).
FIG. 27A is a bar graph showing the response rate (95% confidence interval
(Cl)) for patients
from the CITYSCAPE trial having a TPS A, as measured using the 22C3 IHC
assay.
FIG. 27B is a bar graph showing the response rate (95% CI) for patients from
the CITYSCAPE
trial having a TC '1 /0 as measured using the 5P263 IHC assay (and TPS % as
measured using the
22C3 IHC assay).
FIG. 28A is a graph showing progression-free survival (percent) for patients
from the
CITYSCAPE trial who were treated with tiragolumab and atezolizumab (tira +
atezo) or placebo + atezo
and had a TPS -1 /0 as measured using the 22C3 IHC assay. The inset table
shows median PFS in
months (mo) and hazard ratio (HR).
FIG. 28B is a graph showing progression-free survival (percent) for patients
from the
CITYSCAPE trial who were treated with tiragolumab and atezolizumab (tira +
atezo) or placebo + atezo
and had a TC 1 /0 as measured using the 5P263 IHC assay (and TPS 1 /c, as
measured using the 22C3
IHC assay). The inset table shows median PFS in months and HR.
FIG. 29A is a bar graph showing the response rate (95% confidence interval
(Cl)) for patients
from the CITYSCAPE trial having a TPS ?..50% as measured using the 22C3 IHC
assay.
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FIG. 29B is a bar graph showing the response rate (95% Cl) for patients from
the CITYSCAPE
trial having a TC .?.50 /0 as measured using the SP263 IHC assay.
FIG. 30A is a graph showing progression-free survival (percent) for patients
from the
CITYSCAPE trial who were treated with tiragolumab and atezolizumab (tira +
atezo) or placebo + atezo
and had a TPS 50 /µ, as measured using the 22C3 IHC assay. The inset table
shows median PFS in
months and HR.
FIG. 30B is a graph showing progression-free survival (percent) for patients
from the
CITYSCAPE trial who were treated with tiragolumab and atezolizumab (tira +
atezo) or placebo + atezo
and had a TC 50 /0 as measured using the 513263 IHC assay. The inset table
shows median PFS in
months and HR.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides therapeutic methods and compositions for
treatment of cancer
(e.g., a lung cancer (e.g., an early stage lung cancer (e.g., a resectable
lung cancer), a SCLC (e.g., an
ES-SCLC), a NSCLC (e.g., a squamous NSCLC or a non-squamous NSCLC, a locally
advanced
unresectable NSCLC, a Stage IIIB NSCLC, a recurrent or metastatic NSCLC (e.g.,
a locally advanced
unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous
NSCLC)), or a Stage IV
NSCLC (e.g., wherein the subject has not been previously treated for Stage IV
NSCLC))); a cervical
cancer (e.g., a Stage IVB, metastatic, recurrent, or persistent cervical
cancer, e.g., a metastatic and/or
recurrent PD-L1-positive cervical carcinoma); a breast cancer (e.g., a TNBC
(e.g., an early TNBC
(eTNBC))) or a HER2-positive breast cancer); a head and neck cancer (e.g.,
SCCHN, e.g.,
recurrent/metastatic PD-L1-positive SCCHN); a liver cancer (e.g., HCC, e.g.,
locally advanced or
metastatic HOC and/or unresectable HCC); a bladder cancer (e.g., MIBC, locally
advanced UC, or m UC);
an esophageal cancer; a pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC);
a kidney or renal cancer
(e.g., a RCC); a melanoma; an ovarian cancer; a gastric cancer (e.g., a
gastroesophageal junction
cancer); or a CRC (e.g., MSS or MSI-Low CRC)). The invention is based, at
least in part, on the
discovery that immunotherapies including an anti-TIGIT antibody (e.g., an anti-
TIGIT antagonist antibody,
such as tiragolumab) in combination with a PD-1 axis binding antagonist, a
VEGF antagonist, and/or a
chemotherapeutic agent can be useful in the treatment of cancer. Compositions,
uses, and kits involving
such combinations and/or dosing regimens are also provided herein.
I. GENERAL TECHNIQUES
The techniques and procedures described or referenced herein are generally
well understood
and commonly employed using conventional methodology by those skilled in the
art, such as, for
example, the widely utilized methodologies described in Sambrook et al.,
Molecular Cloning: A Laboratory
Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring
Harbor, N.Y.; Current
Protocols in Molecular Biology (F.M. Ausubel, et al. eds., (2003)); the series
Methods in Enzymology
(Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D.
Flames and G.R. Taylor
eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual,
and Animal Cell Culture
(R.I. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984);
Methods in Molecular
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Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed.,
1998) Academic Press;
Animal Cell Culture (R.I. Freshney), ed., 1987); Introduction to Cell and
Tissue Culture (J.P. Mather and
P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory
Procedures (A. Doyle, J.B.
Griffiths, and D.G. Newell, eds., 1993-8) J. Wiley and Sons; Handbook of
Experimental Immunology
(D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian
Cells (J.M. Miller and M.P.
Cabs, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds.,
1994); Current Protocols in
Immunology (J.E. Coligan et al., eds., 1991); Short Protocols in Molecular
Biology (Wiley and Sons,
1999); lmmunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P.
Finch, 1997); Antibodies: A
Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal
Antibodies: A Practical Approach
(P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using
Antibodies: A Laboratory Manual
(E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The
Antibodies (M. Zanotti and J.
D. Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and
Practice of Oncology
(V.T. DeVita et al., eds., J.B. Lippincott Company, 1993).
II. DEFINITIONS
It is to be understood that aspects and embodiments of the invention described
herein include
"comprising," "consisting," and "consisting essentially of" aspects and
embodiments. As used herein, the
singular form "a," "an," and "the" includes plural references unless indicated
otherwise.
The term "about" as used herein refers to the usual error range for the
respective value readily
known to the skilled person in this technical field. Reference to "about" a
value or parameter herein
includes (and describes) aspects that are directed to that value or parameter
per se. For example,
description referring to "about X" includes description of "X."
The terms "level of expression" or "expression level" in general are used
interchangeably and
generally refer to the amount of a biomarker in a biological sample.
"Expression" generally refers to the
process by which information (e.g., gene-encoded and/or epigenetic
information) is converted into the
structures present and operating in the cell. Therefore, as used herein,
"expression" may refer to
transcription into a polynucleotide, translation into a polypeptide, or even
polynucleotide and/or
polypeptide modifications (e.g., posttranslational modification of a
polypeptide). Fragments of the
transcribed polynucleotide, the translated polypeptide, or polynucleotide
and/or polypeptide modifications
(e.g., posttranslational modification of a polypeptide) shall also be regarded
as expressed whether they
originate from a transcript generated by alternative splicing or a degraded
transcript, or from a post-
translational processing of the polypeptide, e.g., by proteolysis. "Expressed
genes" include those that are
transcribed into a polynucleotide as mRNA and then translated into a
polypeptide, and also those that are
transcribed into RNA but not translated into a polypeptide (for example,
transfer and ribosomal RNAs).
An "amount" or "level" (e.g., expression level) of a biomarker can be measured
by methods known to one
skilled in the art and also disclosed herein. The amount or level of a
biomarker associated with an
increased clinical benefit to an individual can, for example, be a detectable
level in a biological sample. In
some aspects, the expression level or amount of a biomarker can be used to
identify/characterize a
subject having a cancer who may be likely to respond to, or benefit from, a
particular therapy (e.g., a
therapy comprising one or more dosing cycles of a PD-1 axis binding antagonist
and an anti-TIGIT
WO 2021/154761
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antagonist antibody or a therapy comprising one or more dosing cycles of an
anti-TIGIT antagonist
antibody).
"Increased expression," "increased expression level," "increased levels,"
"elevated expression,"
"elevated expression levels," or "elevated levels" refers to an increased
expression or increased levels of
a biomarker in an individual relative to a control, such as an individual or
individuals who are not suffering
from the disease or disorder (e.g., cancer) or an internal control (e.g., a
housekeeping biomarker).
"Decreased expression," "decreased expression level," "decreased levels,"
"reduced expression,"
"reduced expression levels," or "reduced levels" refers to a decrease
expression or decreased levels of a
biomarker in an individual relative to a control, such as an individual or
individuals who are not suffering
from the disease or disorder (e.g., cancer) or an internal control (e.g., a
housekeeping biomarker). In
some aspects, reduced expression is little or no expression.
The presence and/or expression level/amount of various biomarkers described
herein in a
sample can be analyzed by a number of methodologies, many of which are known
in the art and
understood by the skilled artisan, including, but not limited to,
immunohistochemistry ("IHC"), Western blot
analysis, immunoprecipitation, molecular binding assays, ELISA, ELIFA, flow
cytometry, fluorescence
activated cell sorting ("FACS"), MassARRAY, proteomics, quantitative blood
based assays (e.g., Serum
ELISA), biochemical enzymatic activity assays, in situ hybridization (ISH),
fluorescence in situ
hybridization (FISH), Southern analysis, Northern analysis, whole genome
sequencing, massively parallel
DNA sequencing (e.g., next-generation sequencing), NANOSTRINGe, polymerase
chain reaction (PCR)
including quantitative real time PCR (qRT-PCR) and other amplification type
detection methods, such as,
for example, branched DNA, SISBA, TMA and the like, RNA-seq, microarray
analysis, gene expression
profiling, and/or serial analysis of gene expression ("SAGE"), as well as any
one of the wide variety of
assays that can be performed by protein, gene, and/or tissue array analysis.
Typical protocols for
evaluating the status of genes and gene products are found, for example in
Ausubel et al., eds., 1995,
Current Protocols In Molecular Biology, Units 2 (Northern Blotting), 4
(Southern Blotting), 15
(Immunoblotting) and 18 (PCR Analysis). Multiplexed immunoassays such as those
available from Rules
Based Medicine or IVleso Scale Discovery ("MSD") may also be used.
By "correlate" or "correlating" is meant comparing, in any way, the
performance and/or results of
a first analysis or protocol with the performance and/or results of a second
analysis or protocol. For
example, one may use the results of a first analysis or protocol in carrying
out a second protocol and/or
one may use the results of a first analysis or protocol to determine whether a
second analysis or protocol
should be performed. With respect to the aspect of polypeptide analysis or
protocol, one may use the
results of the polypeptide expression analysis or protocol to determine
whether a specific therapeutic
regimen should be performed. With respect to the aspect of polynucleotide
analysis or protocol, one may
use the results of the polynucleotide expression analysis or protocol to
determine whether a specific
therapeutic regimen should be performed.
The phrase "substantially reduced" or "substantially different," as used
herein, denotes a
sufficiently high degree of difference between two numeric values (generally
one associated with a
molecule and the other associated with a reference/comparator molecule) such
that one of skill in the art
would consider the difference between the two values to be of statistical
significance within the context of
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the biological characteristic measured by said values (e.g., KD values). The
difference between said two
values is, for example, greater than about 10%, greater than about 20%,
greater than about 30%, greater
than about 40%, and/or greater than about 50% as a function of the value for
the reference/comparator
molecule.
The term "substantially similar" or "substantially the same," as used herein,
denotes a sufficiently
high degree of similarity between two numeric values (for example, one
associated with an antibody of
the invention and the other associated with a reference/comparator antibody),
such that one of skill in the
art would consider the difference between the two values to be of little or no
biological and/or statistical
significance within the context of the biological characteristic measured by
said values (e.g., KD values).
The difference between said two values is, for example, less than about 50%,
less than about 40%, less
than about 30%, less than about 20%, and/or less than about 10% as a function
of the
reference/comparator value.
The phrase "based on" when used herein means that the information about one or
more
biomarkers is used to inform a treatment decision, information provided on a
package insert, or
marketing/promotional guidance, and the like.
The term "TIGIT" or "T-cell immunoreceptor with Ig and ITIM domains" as used
herein refers to
any native TIGIT from any vertebrate source, including mammals such as
primates (e.g., humans) and
rodents (e.g., mice and rats), unless otherwise indicated. TIGIT is also known
in the art as
DKFZp667A205, FLJ39873, V-set and immunoglobulin domain-containing protein 9,
V-set and
transmembrane domain-containing protein 3, VSIG9, VSTM3, and WUCAM. The term
encompasses
"full-length," unprocessed TIGIT (e.g., full-length human TIGIT having the
amino acid sequence of SEQ
ID NO: 30), as well as any form of TIGIT that results from processing in the
cell (e.g., processed human
TIGIT without a signal sequence, having the amino acid sequence of SEQ ID NO:
31). The term also
encompasses naturally occurring variants of TIGIT, e.g., splice variants or
allelic variants. The amino
acid sequence of an exemplary human TIGIT may be found under UniProt Accession
Number Q495A1.
The terms "programmed death ligand 1" and "PD-L1" refer herein to native
sequence human PD-
L1 polypeptide. Native sequence PD-L1 polypeptides are provided under Uniprot
Accession No.
Q9NZQ7 (SEQ ID NO: 32). For example, the native sequence PD-L1 may have the
amino acid
sequence as set forth in Uniprot Accession No. Q9NZQ7-1 (isoform 1). In
another example, the native
sequence PD-L1 may have the amino acid sequence as set forth in Uniprot
Accession No. Q9NZQ7-2
(isoform 2). In yet another example, the native sequence PD-L1 may have the
amino acid sequence as
set forth in Uniprot Accession No. Q9NZQ7-3 (isoform 3). The term also
encompasses naturally
occurring variants of PD-L1, e.g., splice variants, or allelic variants. PD-L1
is also referred to in the art as
"programmed cell death 1 ligand 1," "PDCD1LG1," "CD274," "B7-H," and "PDL1."
The term "PD-1" or "Programmed Cell Death protein 1" refers herein to any
native PD-1 from any
vertebrate source, including mammals such as primates (e.g., humans) and
rodents (e.g., mice and rats),
unless otherwise indicated. PD-1 is also known in the art as CD279, PDCD1, and
programmed cell death
1. The term also encompasses naturally occurring variants of PD-1, e.g.,
splice variants, or allelic
variants. The amino acid sequence of an exemplary human PD-1 may be found
under UniProt Accession
Number Q15116.
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The term "PD-L2" or "Programmed Cell Death 1 Ligand 2" refers herein to any
native PD-L2 from
any vertebrate source, including mammals such as primates (e.g., humans) and
rodents (e.g., mice and
rats), unless otherwise indicated. PD-L2 is also known in the art as CD273
molecule, B7DC, and
PDCD1L2. The term also encompasses naturally occurring variants of PD-L2,
e.g., splice variants, or
allelic variants. The amino acid sequence of an exemplary human PD-L2 may be
found under UniProt
Accession Number Q9BQ51.
The term "antagonist" is used in the broadest sense, and includes any molecule
that partially or
fully blocks, inhibits, or neutralizes a biological activity of a native
polypeptide disclosed herein. Suitable
antagonist molecules specifically include antagonist antibodies or antibody
fragments (e.g., antigen-
binding fragments), fragments or amino acid sequence variants of native
polypeptides, peptides,
antisense oligonucleotides, small organic molecules, etc. Methods for
identifying antagonists of a
polypeptide may comprise contacting a polypeptide with a candidate antagonist
molecule and measuring
a detectable change in one or more biological activities normally associated
with the polypeptide.
The term "PD-1 axis binding antagonist" refers to a molecule that inhibits the
interaction of a PD-1
axis binding partner with either one or more of its binding partners, so as to
remove T-cell dysfunction
resulting from signaling on the PD-1 signaling axis, with a result being to
restore or enhance T-cell
function (e.g., proliferation, cytokine production, and/or target cell
killing). As used herein, a PD-1 axis
binding antagonist includes a PD-L1 binding antagonist, a PD-1 binding
antagonist, and a PD-L2 binding
antagonist. In some instances, the PD-1 axis binding antagonist includes a PD-
L1 binding antagonist or a
PD-1 binding antagonist. In one aspect, the PD-1 axis binding antagonist is a
PD-L1 binding antagonist.
In another aspect, the PD-1 axis binding antagonist is a PD-1 binding
antagonist. In another aspect, the
PD-1 axis binding antagonist is a PD-L2 binding antagonist.
The term "PD-1 binding antagonist" refers to a molecule that decreases,
blocks, inhibits,
abrogates or interferes with signal transduction resulting from the
interaction of PD-1 with one or more of
its binding partners, such as PD-L1 and/or PD-L2. PD-1 (programmed death 1) is
also referred to in the
art as "programmed cell death 1," "PDCD1," "CD279," and "SLEB2." An exemplary
human PD-1 is shown
in UniProtKB/Swiss-Prot Accession No. Q15116. In some instances, the PD-1
binding antagonist is a
molecule that inhibits the binding of PD-1 to one or more of its binding
partners. In a specific aspect, the
PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2.
For example, PD-1 binding
antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof,
immunoadhesins, fusion
proteins, oligopeptides, and other molecules that decrease, block, inhibit,
abrogate or interfere with signal
transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2.
In one instance, a PD-1
binding antagonist reduces the negative co-stimulatory signal mediated by or
through cell surface
proteins expressed on T lymphocytes mediated signaling through PD-1 so as
render a dysfunctional T-
cell less dysfunctional (e.g., enhancing effector responses to antigen
recognition). In some instances, the
PD-1 binding antagonist binds to PD-1. In some instances, the PD-1 binding
antagonist is an anti-PD-1
antibody (e.g., an anti-PD-1 antagonist antibody). Exemplary anti-PD-1
antagonist antibodies include
nivolumab, pembrolizumab, MEDI-0680 (AMP 514), PDR001 (spartalizumab),
REGN2810 (cemiplimab),
BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab,
dostarlimab, retifanlimab,
sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab,
genolimzumab, BI
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754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, OX-188, JTX-
4014, 609A,
Sym021, LZMO09, F520, S0001, AM0001, ENUM 24408, ENUM 388D4, STI-1110, AK-103,
and hAb21.
In a specific aspect, a PD-1 binding antagonist is MDX-1106 (nivolumab). In
another specific aspect, a
PD-1 binding antagonist is MK-3475 (pembrolizumab, previously known as
lambrolizumab). In another
specific aspect, a PD-1 binding antagonist is a PD-L2 Fc fusion protein, e.g.,
AMP-224. In another
specific aspect, a PD-1 binding antagonist is MEDI-0680. In another specific
aspect, a PD-1 binding
antagonist is PDR001 (spartalizumab). In another specific aspect, a PD-1
binding antagonist is
REGN2810 (cemiplimab). In another specific aspect, a PD-1 binding antagonist
is BGB-108. In another
specific aspect, a PD-1 binding antagonist is prolgolimab. In another specific
aspect, a PD-1 binding
antagonist is camrelizumab. In another specific aspect, a PD-1 binding
antagonist is sintilimab. In
another specific aspect, a PD-1 binding antagonist is tislelizumab. In another
specific aspect, a PD-1
binding antagonist is toripalimab. Other additional exemplary PD-1 binding
antagonists include BION-
004, CB201, AUNP-012, ADG104, and LBL-006.
The term "anti-PD-1 antagonist antibody" refers to an antibody or an antigen-
binding fragment or
variant thereof that is capable of binding PD-1 with sufficient affinity such
that it substantially or
completely inhibits the biological activity of PD-1. For example, an anti-PD-1
antagonist antibody may
decrease, block, inhibit, abrogate or interfere with signal transduction
resulting from the interaction of PD-
1 with either one or more of its binding partners, such as PD-L1 and/or PD-L2.
It will be understood by
one of ordinary skill in the art that in some instances, an anti-PD-1
antagonist antibody may antagonize
one PD-1 activity without affecting another PD-1 activity. For example, an
anti-PD-1 antagonist antibody
for use in certain of the methods or uses described herein is an anti-PD-1
antagonist antibody that
antagonizes PD-1 activity in response to one of its binding partners (e.g., PD-
L1 or PD-L2) without
affecting or minimally affecting any of the other PD-1 interactions. In one
aspect, the extent of binding of
an anti-PD-1 antagonist antibody to an unrelated, non-PD-1 protein is less
than about 10% of the binding
of the antibody to PD-1 as measured, e.g., by a radioimmunoassay (RIA). In
certain aspects, an anti-PD-
1 antagonist antibody that binds to PD-1 has a dissociation constant (KD) of 5
1pM, 5 100 nM, 5 10 nM,
5. 1 nM, 5. 0.1 nM, 5. 0.01 nM, or 5 0.001 nM (e.g., 10-8M or less, e.g., from
10-8M to 1013 M, e.g., from 10-
9 M to 10-13 M). In certain aspects, an anti-PD-1 antagonist antibody binds to
an epitope of PD-1 that is
conserved among PD-1 from different species or an epitope on PD-1 that allows
for cross-species
reactivity. In one aspect, the anti-PD-1 antagonist antibody is pembrolizumab
(previously known as
lambrolizumab). In one aspect, the anti-PD-1 antagonist antibody is nivolumab.
The term "PD-L1 binding antagonist" refers to a molecule that decreases,
blocks, inhibits,
abrogates, or interferes with signal transduction resulting from the
interaction of PD-L1 with either one or
more of its binding partners, such as PD-1 and/or B7-1. In some instances, a
PD-L1 binding antagonist is
a molecule that inhibits the binding of PD-L1 to its binding partners. In a
specific aspect, the PD-L1
binding antagonist inhibits binding of PD-L1 to PD-1 and/or B7-1. In some
instances, the PD-L1 binding
antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof,
immunoadhesins, fusion
proteins, oligopeptides and other molecules that decrease, block, inhibit,
abrogate or interfere with signal
transduction resulting from the interaction of PD-L1 with one or more of its
binding partners, such as PD-1
and/or B7-1. In one instance, a PD-L1 binding antagonist reduces the negative
co-stimulatory signal
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mediated by or through cell surface proteins expressed on T lymphocytes
mediated signaling through PD-
L1 so as to render a dysfunctional 1-cell less dysfunctional (e.g., enhancing
effector responses to antigen
recognition). In some instances, the PD-L1 binding antagonist binds to PD-L1.
In some instances, a PD-
L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1
antagonist antibody). Exemplary
anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1105, MEDI4736
(durvalumab),
MSB0010718C (avelumab), SHR-1316, CS1001, envafolimab, 1OB2450, ZKAB001, LP-
002, CX-072,
IMC-001, KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501, BGB-
A333, BCD-135, AK-
106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, and
HS-636. In
some aspects, the anti-PD-L1 antibody is atezolizumab, MDX-1105, MEDI4736
(durvalumab), or
MSB0010718C (avelumab). In one specific aspect, the PD-L1 binding antagonist
is MDX-1105. In
another specific aspect, the PD-L1 binding antagonist is MEDI4736
(durvalumab). In another specific
aspect, the PD-L1 binding antagonist is MSB0010718C (avelumab). In other
aspects, the PD-L1 binding
antagonist may be a small molecule, e.g., GS-4224, INCB086550, MAX-10181,
INCB090244, CA-170, or
ABSK041, which in some instances may be administered orally. Other exemplary
PD-L1 binding
antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003, and JS-003. In a
preferred aspect,
the PD-L1 binding antagonist is atezolizumab, marketed as TECENTRIQTm.
Atezolizumab is described in
WHO Drug Information (International Nonproprietary Names for Pharmaceutical
Substances), Proposed
INN: List 112, Vol. 28, No. 4, published January 16, 2015 (see page 485). In
another specific aspect, an
anti PD-L1 antibody is MSB0015718C.
The term "anti-PD-L1 antagonist antibody" refers to an antibody or an antigen-
binding fragment or
variant thereof that is capable of binding PD-L1 with sufficient affinity such
that it substantially or
completely inhibits the biological activity of PD-L1. For example, an anti-PD-
L1 antagonist antibody may
decrease, block, inhibit, abrogate or interfere with signal transduction
resulting from the interaction of PD-
L1 with either one or more of its binding partners, such as PD-1 and/or B7-1.
It will be understood by one
.. of ordinary skill in the art that in some instances, an anti-PD-L1
antagonist antibody may antagonize one
PD-L1 activity without affecting another PD-L1 activity. For example, an anti-
PD-L1 antagonist antibody
for use in certain of the methods or uses described herein is an anti-PD-L1
antagonist antibody that
antagonizes PD-L1 activity in response to one of its binding partners (e.g.,
PD-1 or B7-1) without affecting
or minimally affecting any of the other PD-L1 interactions. In one aspect, the
extent of binding of an anti-
PD-L1 antagonist antibody to an unrelated, non-PD-L1 protein is less than
about 10% of the binding of
the antibody to PD-L1 as measured, e.g., by a radioimmunoassay (RIA). In
certain aspects, an anti-PD-
L1 antagonist antibody that binds to PD-L1 has a dissociation constant (Ka) of
5 1pM, 5 100 nM, 5 10 nM,
5 1 nM, 5 0.1 nM, 5 0.01 nM, or 5. 0.001 nM (e.g., 10-8M or less, e.g., from
10-8M to 10-13M, e.g., from 10-
9 M to 10-13 M). In certain aspects, an anti-PD-L1 antagonist antibody binds
to an epitope of PD-L1 that is
conserved among PD-L1 from different species or an epitope on PD-L1 that
allows for cross-species
reactivity. In one aspect, the anti-PD-L1 antagonist antibody is atezolizumab.
The term "PD-L2 binding antagonist" refers to a molecule that decreases,
blocks, inhibits,
abrogates or interferes with signal transduction resulting from the
interaction of PD-L2 with either one or
more of its binding partners, such as PD-1. PD-L2 (programmed death ligand 2)
is also referred to in the
art as "programmed cell death 1 ligand 2," "PDCD1LG2," "CD273," "B7-DC,"
"Btdc," and "PDL2." An
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exemplary human PD-L2 is shown in UniProtKB/Swiss-Prot Accession No. Q9BQ51.
In some instances,
a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to
one or more of its binding
partners. In a specific aspect, the PD-L2 binding antagonist inhibits binding
of PD-L2 to PD-1.
Exemplary PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding
fragments thereof,
immunoadhesins, fusion proteins, oligopeptides and other molecules that
decrease, block, inhibit,
abrogate or interfere with signal transduction resulting from the interaction
of PD-L2 with either one or
more of its binding partners, such as PD-1. In one aspect, a PD-L2 binding
antagonist reduces the
negative co-stimulatory signal mediated by or through cell surface proteins
expressed on T lymphocytes
mediated signaling through PD-L2 so as render a dysfunctional T-cell less
dysfunctional (e.g., enhancing
effector responses to antigen recognition). In some aspects, the PD-L2 binding
antagonist binds to PD-
L2. In some aspects, a PD-L2 binding antagonist is an immunoadhesin.
Further examples of PD-1 axis binding antagonists include cemiplimab,
prolgolimab,
camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab,
retifanlimab, spartalizumab, sasanlimab,
penpulimab, CS1003, HLX10, SCT-I10A, SHR-1316, CS1001, envafolimab, 1QB2450,
ZKAB001, LP-
002, zimberelimab, balstilimab, genolimzumab, BI 754091, cetrelimab, YBL-006,
BAT1306, HX008, CX-
072, IMC-001, KL-A167, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021,
LZMO09, F520,
SG001, APL-502, cosibelimab, lodapolimab, GS-4224, INCB086550, FAZ053, TG-
1501, BGB-A333,
BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, MAX-10181, RC98, BION-004,
AM0001, CB201,
ENUM 244C8, ENUM 388D4, AUNP-012, STI-1110, ADG104, AK-103, LBL-006, hAb21,
AVA-004, PDL-
GEX, INCB090244, KD036, KY1003, LYN192, MT-6035, VXM10, YBL-007, ABSK041,
GB7003, JS-003,
and HS-636.
For the purposes herein, "atezolizumab" is an Fc-engineered, humanized, non-
glycosylated IgG1
kappa immunoglobulin that binds PD-L1 and comprises the heavy chain sequence
of SEQ ID NO: 28 and
the light chain sequence of SEQ ID NO: 29. Atezolizumab comprises a single
amino acid substitution
(asparagine to alanine) at position 297 on the heavy chain (N297A) using EU
numbering of Fc region
amino acid residues, which results in a non-glycosylated antibody that has
minimal binding to Fc
receptors. Atezolizumab is also described in WHO Drug Information
(International Nonproprietary Names
for Pharmaceutical Substances), Proposed INN: List 112, Vol. 28, No. 4,
published January 16, 2015 (see
page 485).
As used herein, "pembrolizumab" is a recombinant humanized monoclonal IgG4
antibody
directed against human cell surface receptor PD-1. Pembrolizumab is also
described in WHO Drug
Information (International Nonproprietary Names for Pharmaceutical
Substances), Proposed INN: List 72,
Vol. 28, No. 3, published 2014 (see page 407).
As used herein, "tiragolumab" is a fully human IgG1/kappa MAb-derived in Open
Monoclonal
Technology (OMT) rats that binds TIGIT and comprises the heavy chain sequence
of SEQ ID NO: 33 and
the light chain sequence of SEQ ID NO: 34. Tiragolumab comprises two N-linked
glycosylation sites
(N306) in the Fc domain. Tiragolumab is also described in WHO Drug Information
(International
Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 117,
Vol. 31, No. 2,
published July 7, 2017 (see page 343).
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As used herein, "bevacizumab" is a recombinant humanized monoclonal antibody
that recognizes
all isoforms of VEGF, which is described in WHO Drug Information
(International Nonproprietary Names
for Pharmaceutical Substances), Proposed INN: List 83, Vol. 14, No. 2,
published 2000 (see page 107).
Bevacizumab comprises the heavy chain variable region sequence of SEQ ID NO: X
and the light chain
variable region sequence of SEQ ID NO: X.
The term "anti-TIGIT antagonist antibody" refers to an antibody or an antigen-
binding fragment or
variant thereof that is capable of binding TIGIT with sufficient affinity such
that it substantially or
completely inhibits the biological activity of TIGIT. For example, an anti-
TIGIT antagonist antibody may
block signaling through PVR, PVRL2, and/or PVRL3 so as to restore a functional
response by T-cells
(e.g., proliferation, cytokine production, target cell killing) from a
dysfunctional state to antigen stimulation.
For example, an anti-TIGIT antagonist antibody may block signaling through PVR
without impacting PVR-
CD226 interaction. It will be understood by one of ordinary skill in the art
that in some instances, an anti-
TIGIT antagonist antibody may antagonize one TIGIT activity without affecting
another TIGIT activity. For
example, an anti-TIGIT antagonist antibody for use in certain of the methods
or uses described herein is
an anti-TIGIT antagonist antibody that antagonizes TIGIT activity in response
to one of PVR interaction,
PVRL3 interaction, or PVRL2 interaction, e.g., without affecting or minimally
affecting any of the other
TIGIT interactions. In one aspect, the extent of binding of an anti-TIGIT
antagonist antibody to an
unrelated, non-TIGIT protein is less than about 10% of the binding of the
antibody to TIGIT as measured,
e.g., by a radioimmunoassay (RIA). In certain aspects, an anti-TIGIT
antagonist antibody that binds to
TIGIT has a dissociation constant (KD) of 5 1pM, _5 100 nM, _5 10 nM, _5 1 nM,
_5 0.1 nM, _5 0.01 nM, or
5 0.001 nM (e.g., 10-8M or less, e.g., from 10-8M to 10-13M, e.g., from 10-9M
to 10-13 M). In certain
aspects, an anti-TIGIT antagonist antibody binds to an epitope of TIGIT that
is conserved among TIGIT
from different species or an epitope on TIGIT that allows for cross-species
reactivity. In some aspects,
the anti-TIGIT binding antibody has intact Fc-mediated effector function
(e.g., tiragolumab, vibostolimab,
etigilimab, E0S084448, or TJ-T6). In some aspects, the anti-TIGIT binding
antibody has enhanced Fc-
mediated effector function (e.g., SGN-TGT). In other aspects, the anti-TIGIT
binding antibody lacks Fc-
mediated effector function (e.g., domvanalimab, BMS-986207, ASP8374, or
C0M902). In some aspects,
the anti-TIGIT binding antibody is an IgG1 class antibody (e.g., tiragolumab,
vibostolimab, domvanalimab,
BMS-986207, etigilimab, BGB-A1217, SGN-TGT, E0S084448 (E0S-448), TJ-T6, or
AB308). In other
aspects, the anti-TIGIT binding antibody is an IgG4 class antibody (e.g.,
ASP8374 or C0M902). In one
aspect, the anti-TIGIT antagonist antibody is tiragolumab.
As used herein, "administering" is meant a method of giving a dosage of a
compound (e.g., an
anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-
PD-L1 antibody), a VEGF
antagonist, or a chemotherapeutic agent (e.g., a platinum-based
chemotherapeutic agent (e.g.,
carboplatin or cisplatin) and/or one or more non-platinum-based
chemotherapeutic agents (e.g., an
alkylating agent (e.g., cyclophosphamide), a taxane (e.g., paclitaxel, e.g.,
nab-paclitaxel), and/or a
topoisomerase II inhibitor (e.g., doxorubicin))) or a composition (e.g., a
pharmaceutical composition, e.g.,
a pharmaceutical composition including an anti-TIGIT antagonist antibody, a PD-
1 axis binding antagonist
(e.g., an anti-PD-L1 antibody), a chemotherapeutic agent (e.g., a platinum-
based chemotherapeutic agent
(e.g., carboplatin or cisplatin) and/or one or more non-platinum-based
chemotherapeutic agents (e.g., an
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alkylating agent (e.g., cyclophosphamide), a taxane (e.g., paclitaxel, e.g.,
nab-paclitaxel), and/or a
topoisomerase II inhibitor (e.g., doxorubicin)), an antibody-drug conjugate
(ADC) (e.g., enfortumab
vedotin or sacituzumab govitecan), and/or a colony stimulating factor (CSF)
(e.g., pegfilgrastim, filgrastim,
or sargramostim)) to a subject. The compounds and/or compositions utilized in
the methods described
herein can be administered, for example, intravenously (e.g., by intravenous
infusion), subcutaneously,
intramuscularly, intradermally, percutaneously, intraarterially,
intraperitoneally, intralesionally,
intracranially, intraarticularly, intraprostatically, intrapleurally,
intratracheally, intranasally, intravitreally,
intravaginally, intrarectally, topically, intratumorally, peritoneally,
subconjunctivally, intravesicularlly,
mucosally, intrapericardially, intraumbilically, intraocularly, orally,
topically, locally, by inhalation, by
injection, by infusion, by continuous infusion, by localized perfusion bathing
target cells directly, by
catheter, by lavage, in cremes, or in lipid compositions. The method of
administration can vary
depending on various factors (e.g., the compound or composition being
administered and the severity of
the condition, disease, or disorder being treated).
A "fixed" or "flat" dose of a therapeutic agent (e.g., an anti-TIGIT
antagonist antibody, a PD-1 axis
binding antagonist (e.g., an anti-PD-L1 antibody), a VEGF antagonist, a
chemotherapeutic agent (e.g., a
platinum-based chemotherapeutic agent or non-platinum-based chemotherapeutic
agent), an ADC (e.g.,
enfortumab vedotin or sacituzumab govitecan), or a CSF (e.g., pegfilgrastim,
filgrastim, or sargramostim))
refers to a dose that is administered to a patient without regard for the
weight or body surface area (BSA)
of the patient. The fixed or flat dose is therefore not provided as a mg/kg
dose or a mg/m2 dose, but
rather as an absolute amount of the therapeutic agent (e.g., absolute amount
of the therapeutic agent in
mg).
As used herein, the term "treatment" or "treating" refers to clinical
intervention designed to alter
the natural course of the individual or cell being treated during the course
of clinical pathology. Desirable
effects of treatment include delaying or decreasing the rate of disease
progression, ameliorating or
palliating the disease state, and remission or improved prognosis. For
example, an individual is
successfully "treated" if one or more symptoms associated with cancer are
mitigated or eliminated,
including, but are not limited to, reducing the proliferation of (or
destroying) cancerous cells, decreasing
symptoms resulting from the disease, increasing the quality of life of those
suffering from the disease,
decreasing the dose of other medications required to treat the disease,
delaying the progression of the
disease, and/or prolonging survival of individuals. For example, treating
comprises effective cancer
treatment with an effective amount of a therapeutic agent (e.g., an anti-TIGIT
antagonist antibody, a PD-1
axis binding antagonist, a VEGF antagonist, a chemotherapeutic agent (e.g., a
platinum-based
chemotherapeutic agent or non-platinum-based chemotherapeutic agent), an ADC
(e.g., enfortumab
vedotin or sacituzumab govitecan), and/or a CSF (e.g., pegfilgrastim,
filgrastim, or sargramostim)) or
combination of therapeutic agents. Treating herein includes, inter alia,
adjuvant therapy, neoadjuvant
therapy, non-metastatic cancer therapy (e.g., locally advanced cancer
therapy), and metastatic cancer
therapy. The treatment may be first-line treatment (e.g., the patient may be
previously untreated or not
have received prior systemic therapy), or second line or later treatment.
As used herein, "in combination with" or "in conjunction with" refers to
administration of one
treatment modality in addition to another treatment modality, for example, a
treatment regimen that
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includes administration of a PD-1 axis binding antagonist (e.g.,
atezolizumab), a VEGF antagonist, a
chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent or non-
platinum-based
chemotherapeutic agent), an ADC (e.g., enfortumab vedotin or sacituzumab
govitecan), and/or a CSF
(e.g., pegfilgrastim, filgrastim, or sargramostim) and an anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab). As such, "in
combination with" refers to
administration of one treatment modality before, during, or after
administration of the other treatment
modality to the patient.
A drug that is administered "concurrently" with one or more other drugs is
administered during the
same treatment cycle, on the same day of treatment, as the one or more other
drugs, and, optionally, at
the same time as the one or more other drugs. For instance, for cancer
therapies given every 3 weeks,
the concurrently administered drugs are each administered on day 1 of a 3-week
cycle.
As used herein, the term "perioperative treatment" refers to a treatment that
is administered
before and after a surgery. A perioperative treatment may include
administration of a neoadjuvant
therapy prior to a surgery (e.g., a cystectomy) and a therapy (e.g., an
adjuvant therapy) following the
surgery. For example, a perioperative treatment may include a neoadjuvant
therapy (e.g., an anti-TIGIT
antagonist antibody and a PD-1 axis binding antagonist neoadjuvant therapy)
that is administered after
diagnosis and before (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13, 14, 15
weeks or more before) a surgery
(e.g., a cystectomy) and a therapy (e.g., an adjuvant therapy (e.g., an anti-
TIGIT antagonist antibody and
a PD-1 axis binding antagonist adjuvant therapy)) following the surgery (e.g.,
about 1, 2, 3, 4, 5, 6, 7, 8, 9,
12, 13, 14, 15 weeks or more following the surgery).
A "disorder" or "disease" is any condition that would benefit from treatment
including, but not
limited to, disorders that are associated with some degree of abnormal cell
proliferation, e.g., cancer.
The term "dysfunction," in the context of immune dysfunction, refers to a
state of reduced immune
responsiveness to antigenic stimulation.
The term "dysfunctional," as used herein, also includes refractory or
unresponsive to antigen
recognition, specifically, impaired capacity to translate antigen recognition
into downstream T-cell effector
functions, such as proliferation, cytokine production (e.g., gamma interferon)
and/or target cell killing.
The terms "cancer" and "cancerous" refer to or describe the physiological
condition in mammals
that is typically characterized by unregulated cell growth. Cancers include
solid tumor cancers and non-
solid tumor cancers and locally advanced or metastatic cancers (e.g., locally
advanced or metastatic
tumors). Examples of cancer include but are not limited to, carcinoma,
lymphoma, blastoma, sarcoma,
and leukemia or lymphoid malignancies. More particular examples of such
cancers include, but are not
limited to urothelial carcinoma (UC), including locally advanced and
metastatic UC (mUC), bladder cancer
(e.g., muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder
cancer (NMIBC), e.g.,
BCG-refractory NMIBC), MIBC urothelial bladder cancer (UBC); kidney or renal
cancer (e.g., renal cell
carcinoma (RCC)); cancer of the urinary tract; lung cancer, such as small cell
lung cancer (SCLC), which
includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC),
which includes
squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable
NSCLC (e.g.,
Stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC),
adenocarcinoma of the
lung, or squamous cell cancer (e.g., epithelial squamous cell cancer (e.g.,
squamous carcinoma of the
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lung); pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC), e.g.,
metastatic PDAC)); head
and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1-positive SCCHN,
and head and neck
squamous cell cancer (HNSCC); ovarian cancer (OC); esophageal cancer; cancer
of the peritoneum;
hepatocellular cancer; gastric cancer (GC) (e.g., gastroesophageal junction
(GEJ) cancer) or stomach
cancer, including gastrointestinal cancer and gastrointestinal stromal cancer;
glioblastoma; cancer of the
urinary tract; hepatoma; breast cancer (e.g., HER2+ breast cancer and triple-
negative breast cancer
(TNBC (e.g., early TNBC (eTNBC)), which are estrogen receptors (ER-),
progesterone receptors (PgR-),
and HER2 (HER2-) negative); prostate cancer, such as castration-resistant
prostate cancer (CRPC);
cancer of the peritoneum; hepatocellular cancer; gastric or stomach cancer,
including gastrointestinal
cancer and gastrointestinal stromal cancer; pancreatic cancer (e.g.,
pancreatic ductal adenocarcinoma
(PDAC)); glioblastoma; cervical cancer (e.g., a Stage IVB, metastatic,
recurrent, or persistent cervical
cancer, e.g., a metastatic and/or recurrent PD-L1-positive cervical
carcinoma); ovarian cancer; liver
cancer (e.g., hepatocellular carcinoma (HCC), e.g., locally advanced or
metastatic HCC and/or
unresectable HCC); hepatoma; colon cancer; rectal cancer; colorectal cancer
(CRC; e.g., CRC with
microsatellite-stable (MSS) and microsatellite instability (MSI) low (MSI-
Low)),; endometrial or uterine
carcinoma; salivary gland carcinoma; prostate cancer; vulval cancer; thyroid
cancer; hepatic carcinoma;
anal carcinoma; penile carcinoma; melanoma, including superficial spreading
melanoma, lentigo maligna
melanoma, acral lentiginous melanomas, and nodular melanomas; multiple myeloma
and B-cell
lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL)); small
lymphocytic (SL) NHL;
intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade
immunoblastic NHL; high
grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease
NHL; mantle cell
lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia); chronic
lymphocytic
leukemia (CLL); acute lymphoblastic leukemia (ALL); acute myologenous leukemia
(AML); hairy cell
leukemia; chronic myeloblastic leukemia (CML); post-transplant
lymphoproliferative disorder (PTLD); and
myelodysplastic syndromes (MDS), as well as abnormal vascular proliferation
associated with
phakomatoses, edema (such as that associated with brain tumors), Meigs'
syndrome, brain cancer, head
and neck cancer, and associated metastases.
The term "persistent cervical cancer" as used herein refers to a cervical
cancer that has not been
rendered undetectable or benign after previous therapy.
As used herein, "Stage IVB cervical cancer" refers to a cervical cancer that
is classified as such
using a cervical cancer staging system (e.g., International Federation of
Gynecology and Obstetrics
(FIGO) staging system). In some aspects, a cervical cancer is classified as
Stage IVB if it has
metastasized to distant organs (including the parenchyma of the spleen or
liver) or to the inguinal and
extra-abdominal lymph nodes.
As used herein, the term "recurrent cervical cancer" refers to a cervical
cancer that has been
detected or has returned following an initial treatment with surgery,
radiation therapy, and/or
chemotherapy.
The term "TNBC" refers to breast cancer that lacks expression of ER, PR, and
HER2. The term
"eTNBC" refers to T2-4d TNBC (e.g., cT2-cT4, cN0-cN3, and cM0).
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Head and neck cancers include cancers that begin in the mucosal surfaces of
the upper
aerodigestive tract and affect the oral cavity, oropharynx, larynx,
hypopharynx, and nasopharynx.
As used herein, "urothelial carcinoma" and "UC" refer to a type of cancer that
typically occurs in
the urinary system, and includes muscle-invasive bladder cancer (MIBC) and
muscle-invasive urinary
tract urothelial cancer (UTUC). UC is also referred to in the art as
transitional cell carcinoma (TCC).
The term "tumor" refers to all neoplastic cell growth and proliferation,
whether malignant or
benign, and all pre-cancerous and cancerous cells and tissues. The terms
"cancer," "cancerous," "cell
proliferative disorder," "proliferative disorder," and "tumor" are not
mutually exclusive as referred to herein.
A "tumor cell" as used herein, refers to any tumor cell present in a tumor or
a sample thereof.
Tumor cells may be distinguished from other cells that may be present in a
tumor sample, for example,
stromal cells and tumor-infiltrating immune cells, using methods known in the
art and/or described herein.
"Tumor immunity" refers to the process in which tumors evade immune
recognition and
clearance. Thus, as a therapeutic concept, tumor immunity is "treated" when
such evasion is attenuated,
and the tumors are recognized and attacked by the immune system. Examples of
tumor recognition
include tumor binding, tumor shrinkage, and tumor clearance.
As used herein, "metastasis" is meant the spread of cancer from its primary
site to other places in
the body. Cancer cells can break away from a primary tumor, penetrate into
lymphatic and blood vessels,
circulate through the bloodstream, and grow in a distant focus (metastasize)
in normal tissues elsewhere
in the body. Metastasis can be local or distant. Metastasis is a sequential
process, contingent on tumor
cells breaking off from the primary tumor, traveling through the bloodstream,
and stopping at a distant
site. At the new site, the cells establish a blood supply and can grow to form
a life-threatening mass.
Both stimulatory and inhibitory molecular pathways within the tumor cell
regulate this behavior, and
interactions between the tumor cell and host cells in the distant site are
also significant.
The term "cytotoxic agent" as used herein refers to any agent that is
detrimental to cells (e.g.,
causes cell death or destruction, inhibits proliferation, or otherwise
inhibits or prevents a cellular function).
Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g.,
At211, 1131, 1125, yso, Reis, Rem,
srn1535 131212, p32, pb212 and radioactive isotopes of Lu); chemotherapeutic
agents or drugs (e.g.,
methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine,
etoposide), doxorubicin, melphalan,
mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth
inhibitory agents; enzymes
and fragments thereof such as nucleolytic enzymes; antibiotics; and toxins
such as small molecule toxins
or enzymatically active toxins of bacterial, fungal, plant or animal origin,
including fragments and/or
variants thereof; and the various antitumor or anti-cancer agents disclosed
below. Exemplary cytotoxic
agents can be selected from anti-microtubule agents, platinum coordination
complexes, alkylating agents,
topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors,
hormones and hormonal
analogues, signal transduction pathway inhibitors, non-receptor tyrosine
kinase angiogenesis inhibitors,
immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A, inhibitors
of fatty acid biosynthesis,
cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and
inhibitors of cancer
metabolism. In one instance, the cytotoxic agent is a platinum-based
chemotherapeutic agent (e.g.,
carboplatin or cisplatin). In one instance, the cytotoxic agent is an
antagonist of EGFR, e.g., N-(3-
ethynylphenyI)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (e.g., erlotinib).
In one instance the cytotoxic
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agent is a RAF inhibitor, e.g., a BRAF and/or CRAF inhibitor. In one instance
the RAF inhibitor is
vemurafenib. In one instance, the cytotoxic agent is a PI3K inhibitor.
"Chemotherapeutic agent" includes chemical compounds useful in the treatment
of cancer.
Examples of chemotherapeutic agents include erlotinib (TARCEVA0, Genentech/OSI
Pharm.),
bortezomib (VELCADE , Millennium Pharm.), disulfiram, epigallocatechin
gallate, salinosporamide A,
carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-
A), fulvestrant
(FASLODEX , AstraZeneca), sunitinib (SUTENT , Pfizer/Sugen), letrozole (FEMARA
, Novartis),
imatinib mesylate (GLEEVECe, Novartis), finasunate (VATALANIBe, Novartis),
oxaliplatin (ELOXATINe,
Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirolimus, RAPAMUNEe,
Wyeth), Lapatinib
(TYKERB , GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib
(NEXAVAR , Bayer
Labs), gefitinib (IRESSA0, AstraZeneca), AG1478, alkylating agents such as
thiotepa and CYTOXANe
cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and
piposulfan; aziridines such as
benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and
methylamelamines including
altretamine, triethylenemelamine, triethylenephosphoramide,
triethylenethiophosphoramide and
trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a
camptothecin (including
topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its
adozelesin, carzelesin and
bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and
cryptophycin 8);
adrenocorticosteroids (including prednisone and prednisolone); cyproterone
acetate; 5a-reductases
including finasteride and dutasteride); vorinostat, romidepsin, panobinostat,
valproic acid, mocetinostat
dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-
2189 and CB1-TM1);
eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards
such as chlorambucil,
chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine,
mechlorethamine oxide
hydrochloride, melphalan, novembichin, phenesterine, prednimustine,
trofosfamide, uracil mustard;
nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine,
nimustine, and ranimnustine;
antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially
calicheamicin y1I and
calicheamicin w1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186); dynemicin,
including dynemicin A;
bisphosphonates, such as clodronate; an esperamicin; as well as
neocarzinostatin chromophore and
related chromoprotein enediyne antibiotic chromophores), aclacinomysins,
actinomycin, authramycin,
azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin,
chromomycinis,
dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine,
ADRIAMYCINe (doxorubicin),
morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin
and deoxydoxorubicin),
epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as
mitomycin C, mycophenolic acid,
nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin,
rodorubicin, streptonigrin,
streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites
such as methotrexate and 5-
fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate,
pteropterin, trimetrexate; purine
analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;
pyrimidine analogs such as
ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine,
doxifluridine, enocitabine,
floxuridine; androgens such as calusterone, dromostanolone propionate,
epitiostanol, mepitiostane,
testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane;
folic acid replenisher such as
frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid;
eniluracil; amsacrine;
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bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone;
elfomithine; elliptinium acetate;
an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine;
maytansinoids such as
maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol;
nitraerine; pentostatin;
phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide;
procarbazine; PSKe
.. polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane;
rhizoxin; sizofuran;
spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine;
trichothecenes (especially 1-
2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine;
dacarbazine; mannomustine;
mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C");
cyclophosphamide; thiotepa;
taxanes (taxoids), e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology,
Princeton, N.J.),
ABRAXANE (Cremophor-free), albumin-engineered nanoparticle formulations of
paclitaxel (e.g.,
nanoparticle albumin-engineered paclitaxel (nab-paclitaxel)) (American
Pharmaceutical Partners,
Schaumberg, Ill.), and TAXOTERE (docetaxel, doxetaxel; Sanofi-Aventis);
chloranmbucil; GEMZARe
(gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs
such as cisplatin and
carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone;
vincristine; NAVELBINE0
(vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin;
capecitabine (XELODAe);
ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine
(DMF0); retinoids such
as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives
of any of the above.
Chemotherapeutic agents also include (i) anti-hormonal agents that act to
regulate or inhibit
hormone action on tumors such as anti-estrogens and selective estrogen
receptor modulators (SERMs),
including, for example, tamoxifen (including NOLVADEX ; tamoxifen citrate),
raloxifene, droloxifene,
iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone,
and FARESTONe
(toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme
aromatase, which regulates estrogen
production in the adrenal glands, such as, for example, 4(5)-imidazoles,
aminoglutethimide, MEGASE
(megestrol acetate), AROMASIN (exemestane; Pfizer), formestanie, fadrozole,
RIVISOR (vorozole),
FEMARA (letrozole; Novartis), and ARIMIDEX (anastrozole; AstraZeneca); (iii)
anti-androgens such as
flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin,
tripterelin, medroxyprogesterone
acetate, diethylstilbestrol, premarin, fluoxymesterone, all trans retionic
acid, fenretinide, as well as
troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein
kinase inhibitors (e.g., an
anaplastic lymphoma kinase (Alk) inhibitor, such as AF-802 (also known as CH-
5424802 or alectinib)); (v)
lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those
which inhibit expression of genes
in signaling pathways implicated in aberrant cell proliferation, such as, for
example, PKC-alpha, Ralf and
H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME0)
and HER2 expression
inhibitors; (viii) vaccines such as gene therapy vaccines, for example,
ALLOVECTIN , LEUVECTIN , and
VAXIDe; PROLEUKINe, rIL-2; a topoisomerase 1 inhibitor such as LURTOTECANe;
ABARELIXe rmRH;
and (ix) pharmaceutically acceptable salts, acids and derivatives of any of
the above.
Chemotherapeutic agents also include "platinum-based" chemotherapeutic agents,
also referred
to herein as "platinum agents," which comprise an organic compound which
contains platinum as an
integral part of the molecule. Typically, platinum-based chemotherapeutic
agents are coordination
complexes of platinum. Platinum-based chemotherapeutic agents are sometimes
called "platins" in the
art. Examples of platinum-based chemotherapeutic agents include, but are not
limited to, cisplatin,
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carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate,
phenanthriplatin, picoplatin, lipoplatin, and
satraplatin. Platinum-based chemotherapeutic agents (e.g., cisplatin or
carboplatin) may be administered
in combination with one or more additional chemotherapeutic agents, e.g., a
nucleoside analog (e.g.,
gemcitabine), an antimetabolite (e.g., pemetrexed or gemcitabine), or a taxane
(e.g., paclitaxel or nab-
paclitaxel).
The term "eligible for treatment with a platinum-based chemotherapy" means
that the subject is
eligible for treatment with a platinum-based chemotherapy, either in the
attending clinician's judgment or
according to standardized criteria for eligibility for platinum-based
chemotherapy that are known in the art.
Chemotherapeutic agents also include "non-platinum-based chemotherapeutic
agents," which, as
used herein, refer to chemotherapeutic agents that are not "platinum-based."
As used herein, the terms
"non-platinum-based chemotherapeutic agents" and "non-platinum agents" are
used interchangeably.
Exemplary non-platinum-based chemotherapeutic agents include antimetabolites
(e.g., pemetrexed and
gemcitabine), topoisomerase II inhibitors (e.g., etoposide, teniposide,
doxorubicin, daunorubicin,
mitoxantrone, amsacrine, an ellipticine, aurintricarboxylic acid, or HU-331),
taxanes (e.g., paclitaxel (e.g.,
albumin-engineered paclitaxel, also referred to as nanoparticle-albumin-bound
paclitaxel (nab-paclitaxel)),
docetaxel, larotaxel, cabazitaxel, milataxel, tesetaxel, and/or orataxel).
Exemplary non-platinum-based
chemotherapeutic agents also include alkylating agents (e.g.,
cyclophosphamide).
A "nucleoside analog," as used herein, refers to a nucleoside that includes a
nucleic acid analog
and a sugar. Nucleoside analogs may function as antimetabolites. Exemplary
nucleoside analogues
include but are not limited to gemcitabine, cytarabine, fludarabine, and
cladribine.
A "taxane" as used herein is a diterpene which may bind to tubulin, promoting
microtubule
assembly and stabilization and/or prevent microtubule depolymerization.
Taxanes included herein
include taxoid 10-deacetylbaccatin Ill and/or derivatives thereof. Exemplary
taxanes include, but are not
limited to, paclitaxel (i.e., TAXOL", CAS # 33069-62-4), docetaxel (i.e.,
TAXOTERE , CAS # 114977-28-
5), larotaxel, cabazitaxel, milataxel, tesetaxel, and/or orataxel. In some
aspects, the taxane is an
albumin-coated nanoparticle (e.g., nab-paclitaxel, i.e., ABRAXANE" and/or nab-
docetaxel, ABI-008). In
some aspects, the taxane is nab-paclitaxel (ABRAXANE"). In some aspects, the
taxane is formulated in
CREMAPHOR" (e.g., TAXOL") and/or in Tween such as polysorbate 80 (e.g.,
TAXOTERE"). In some
aspects, the taxane is liposome-encapsulated taxane. In some aspects, the
taxane is a prodrug form
and/or conjugated form of taxane (e.g., DHA covalently conjugated to
paclitaxel, paclitaxel poliglumex,
and/or linoleylcarbonate-paclitaxel). In some aspects, the paclitaxel is
formulated with substantially no
surfactant (e.g., in the absence of CREMAPHOR and/or Tween-such as TOCOSOL"
paclitaxel).
An "antimetabolite" as used herein is a chemotherapeutic agent that interferes
with and inhibits
(wholly or partially) an endogenous (normal) metabolic process within a cell
(e.g., a cancer cell).
Antimetabolites include gemcitabine, pemetrexed, capecitabine, hydroxyurea,
methotrexate, fluorouracil,
cladribine, mercaptopurine, and pralatrexate.
Chemotherapeutic agents also include dexamethasone, interferons, colchicine,
metoprine,
cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin,
allopurinol, amifostine, arsenic
trioxide, asparaginase, BCG live, bevacizumab, bexarotene, cladribine,
clofarabine, darbepoetin alfa,
denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin
acetate, ibritumomab, interferon alfa-
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2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen,
nandrolone, nelarabine,
nofetumomab, oprelvekin, paliferm in, pamidronate, pegademase, pegaspargase,
pegfilgrastim,
pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase,
sargramostim,
temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin,
zoledronate, and zoledronic acid,
and pharmaceutically acceptable salts thereof.
Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate,
cortisone acetate,
tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol,
mometasone, amcinonide,
budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone,
betamethasone sodium
phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone,
hydrocortisone-17-
butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone
valerate,
betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-
17-propionate,
fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate;
immune selective anti-
inflammatory peptides (1mSAIDs) such as phenylalanine-glutamine-glycine (FEG)
and its D-isomeric form
(feG) (IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such as
azathioprine, ciclosporin
(cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine,
leflunomideminocycline, sulfasalazine,
tumor necrosis factor alpha (TNFa) blockers such as etanercept (Enbrel),
infliximab (Remicade),
adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi),
Interleukin 1 (IL-1) blockers
such as anakinra (Kineret), T cell costimulation blockers such as abatacept
(Orencia), Interleukin 6 (IL-6)
blockers such as tocilizumab (ACTEMERA0); Interleukin 13 (IL-13) blockers such
as lebrikizumab;
Interferon alpha (IFN) blockers such as Rontalizumab; Beta 7 integrin blockers
such as rhuMAb Beta7;
IgE pathway blockers such as Anti-M1 prime; Secreted homotrimeric LTa3 and
membrane bound
heterotrimer LTa1/132 blockers such as Anti-lymphotoxin alpha (LTa);
radioactive isotopes (e.g., At211,
1131,1125, Y90, Re186, Re188, 5m153, Bi212, P32, Pb212 and radioactive
isotopes of Lu);
miscellaneous investigational agents such as thioplatin, PS-341,
phenylbutyrate, ET-18- OCH3, or
farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as
quercetin, resveratrol,
piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins,
betulinic acid and derivatives
thereof; autophagy inhibitors such as chloroquine; delta-9-
tetrahydrocannabinol (dronabinol,
MARINOLO); beta-lapachone; lapachol; colchicines; betulinic acid;
acetylcamptothecin, scopolectin, and
9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL0); bexarotene
(TARGRETINO);
bisphosphonates such as clodronate (for example, BONEFOSO or OSTAC0),
etidronate (DIDROCAL0),
NE-58095, zoledronic acid/zoledronate (ZOMETA8), alendronate (FOSAMAX0),
pamidronate
(AREDIA0), tiludronate (SKELIDO), or risedronate (ACTONEL0); and epidermal
growth factor receptor
(EGF-R); vaccines such as THERATOPE vaccine; perifosine, COX-2 inhibitor
(e.g., celecoxib or
etoricoxib), proteosome inhibitor (e.g., PS341); CCI-779; tipifarnib (R11577);
orafenib, ABT510; BcI-2
inhibitor such as oblimersen sodium (GENASENSE0); pixantrone;
farnesyltransferase inhibitors such as
lonafarnib (SCH 6636, SARASARTM); and pharmaceutically acceptable salts, acids
or derivatives of any
of the above; as well as combinations of two or more of the above such as
CHOP, an abbreviation for a
combined therapy of cyclophosphamide, doxorubicin, vincristine, and
prednisolone; and FOLFOX, an
abbreviation for a treatment regimen with oxaliplatin (ELOXATINTM) combined
with 5-FU and leucovorin.
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Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs
with analgesic,
antipyretic and anti-inflammatory effects. NSAIDs include non-selective
inhibitors of the enzyme
cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid
derivatives such as
ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen,
acetic acid derivatives such as
indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as
piroxicam, meloxicam,
tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as
mefenamic acid,
meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such
as celecoxib, etoricoxib,
lumiracoxib, parecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicated for
the symptomatic relief of
conditions such as rheumatoid arthritis, osteoarthritis, inflammatory
arthropathies, ankylosing spondylitis,
psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic
bone pain, headache and
migraine, postoperative pain, mild-to-moderate pain due to inflammation and
tissue injury, pyrexia, ileus,
and renal colic.
Chemotherapeutic agents also include "EGFR inhibitors," which refers to
compounds that bind to
or otherwise interact directly with EGFR and prevent or reduce its signaling
activity, and is alternatively
referred to as an "EGFR antagonist." Examples of such agents include small
molecules that bind to
EGFR. EGFR antagonists include small molecules such as compounds described in
US Patent Nos:
5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410,
6,455,534, 6,521,620,
6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459,
6,602,863, 6,391,874,
6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT
publications: W098/14451,
W098/50038, W099/09016, and W099/24037. Particular small molecule EGFR
antagonists include
OSI-774 (CP-358774, erlotinib, TARCEVA Genentech/OSI Pharmaceuticals); PD
183805 (Cl 1033, 2-
propenamide, Ni4-[(3-chloro-4-fluorophenyl)amino]-743-(4-morpholinyppropoxy]-6-
quinazolinyli-,
dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA6) 4-(3'-Chloro-4'-
fluoroanilino)-7-methoxy-6-(3-
morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-
methylphenyl-amino)-
quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-pheny1)-N2-(1-methyl-
piperidin-4-y1)-
pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Inge!helm); PKI-166 ((R)-4-
[4-[(1-phenylethyl)amino]-
1H-pyrrolo[2,3-d]pyrimidin-6-y1]-phenol); (R)-6-(4-hydroxypheny1)-4-[(1-
phenylethyl)amino]-7H-pyrrolo[2,3-
d]pyrimidine); CL-387785 (N44-[(3-bromophenyl)amino]-6-quinazoliny1]-2-
butynamide); EKB-569 (N-[4-
[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinoliny1]-4-
(dimethylamino)-2-butenamide)
(Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/HER2 tyrosine
kinase inhibitors such
as lapatinib (TYKERI36, GSK572016 or N-[3-chloro-4-[(3
fluorophenyl)methoxy]pheny1]-
6[5[[[2methylsulfonypethyl]aminoimethyl]-2-furany11-4-quinazolinamine).
Chemotherapeutic agents also include "tyrosine kinase inhibitors" including
the EGFR-targeted
drugs noted in the preceding paragraph; inhibitors of insulin receptor
tyrosine kinases, including
anaplastic lymphoma kinase (Alk) inhibitors, such as AF-802 (also known as CH-
5424802 or alectinib),
ASP3026, X396, LDK378, AP26113, crizotinib (XALKORI8), and ceritinib
(ZYKADIA8); small molecule
HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-
724,714, an oral selective
inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER
inhibitors such as EKB-569
(available from Wyeth) which preferentially binds EGFR but inhibits both HER2
and EGFR-
overexpressing cells; lapatinib (G5K572016; available from Glaxo-SmithKline),
an oral HER2 and EGFR
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tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER
inhibitors such as canertinib (CI-
1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available
from ISIS
Pharmaceuticals which inhibit Raf-1 signaling; non-HER targeted TK inhibitors
such as imatinib mesylate
(GLEEVEC , available from Glaxo SmithKline); multi-targeted tyrosine kinase
inhibitors such as sunitinib
(SUTENT , available from Pfizer); VEGF receptor tyrosine kinase inhibitors
such as vatalanib
(PTK787/ZK222584, available from Novartis/Schering AG); MAPK extracellular
regulated kinase I
inhibitor CI-1040 (available from Pharmacia); quinazolines, such as PD
153035,4-(3-chloroanilino)
quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such
as CGP 59326, CGP 60261
and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]
pyrimidines; curcumin (diferuloyl
methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing
nitrothiophene moieties; PD-
0183805 (Warner-Lamber); antisense molecules (e.g., those that bind to HER-
encoding nucleic acid);
quinoxalines (US Patent No. 5,804,396); tryphostins (US Patent No. 5,804,396);
ZD6474 (Astra Zeneca);
PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer);
Affinitac (ISIS 3521;
Isis/Lilly); imatinib mesylate (GLEEVEC0); PKI 166 (Novartis); GW2016 (Glaxo
SmithKline); CI-1033
(Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787
(Novartis/Schering AG);
INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE ); or as described in any
of the following patent
publications: US Patent No. 5,804,396; WO 1999/09016 (American Cyanamid); WO
1998/43960
(American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner
Lambert); WO
1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978
(Zeneca); WO 1996/3397
(Zeneca) and WO 1996/33980 (Zeneca).
The term "anthracycline" relates to a chemotherapeutic agent, an anticancer
agent for inducing
apoptosis, preferably by inhibiting the rebinding of DNA in topoisomerase II.
Examples include
doxorubicin (adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin,
rhodomycin, pyrarubicin,
valrubicin, N-trifluoro-acetyl doxorubicin-14-valerate, aclacinomycin,
morpholinodoxorubicin (morpholino-
DOX), cyanomorpholino-doxorubicin (cyanomorpholino-DOX), 2-pyrrolino-
doxorubicin (2-PDOX), 5-
iminodaunomycin, mitoxantrone and aclacinomycin A (aclarubicin). In some
aspects, the anthracycline is
administered in combination with an alkylating agent, e.g., doxorubicin in
combination with
cyclophosphamide (treatment with AC).
An "alkylating agent" as used herein is a chemotherapeutic agent which causes
DNA damage by
attaching an alkyl group to DNA. Alkylating agents include cyclophosphamide
and N,I\l',N"-
triethylenethiophosphoramide.
An "effective amount" of a compound, for example, an anti-TIGIT antagonist
antibody, a PD-1
axis binding antagonist (e.g., anti-PD-L1 antibody), a VEGF antagonist, a
chemotherapeutic agent (e.g., a
platinum-based chemotherapeutic agent or non-platinum-based chemotherapeutic
agent), an ADC (e.g.,
enfortumab vedotin or sacituzumab govitecan), or a CSF (e.g., pegfilgrastim,
filgrastim, or sargramostim),
is at least the minimum amount required to achieve the desired therapeutic
result, such as a measurable
increase in overall survival or progression-free survival of a particular
disease or disorder (e.g., a cancer).
An effective amount herein may vary according to factors such as the disease
state, age, sex, and weight
of the patient, and the ability of the antibody to elicit a desired response
in the subject. An effective
amount is also one in which any toxic or detrimental effects of the treatment
are outweighed by the
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therapeutically beneficial effects. For prophylactic use, beneficial or
desired results include results such
as eliminating or reducing the risk, lessening the severity, or delaying the
onset of the disease, including
biochemical, histological and/or behavioral symptoms of the disease, its
complications, and intermediate
pathological phenotypes presenting during development of the disease. For
therapeutic use, beneficial or
desired results include clinical results such as decreasing one or more
symptoms resulting from the
disease (e.g., reduction or delay in cancer-related pain, symptomatic skeletal-
related events (SSE),
reduction in symptoms per the European Organization for Research and Treatment
of Cancer Quality-of-
Life Questionnaire (EORTC QLQ-C30, e.g., fatigue, nausea, vomiting, pain,
dyspnea, insomnia, appetite
loss, constipation, diarrhea, or general level of physical emotional,
cognitive, or social functioning),
reduction in pain as measured by, e.g., the 10-point pain severity (measured
at its worst) numerical rating
scale (NRS), increasing the quality of life of those suffering from the
disease, decreasing the dose of
other medications required to treat the disease, enhancing effect of another
medication such as via
targeting, delaying the progression of the disease (e.g., progression-free
survival or radiographic
progression-free survival (rPFS); delay of unequivocal clinical progression
(e.g., cancer-related pain
progression, symptomatic skeletal-related event, deterioration in Eastern
Cooperative Group Oncology
Group (ECOG) Performance Status (PS) (e.g., how the disease affects the daily
living abilities of the
patient), and/or initiation of next systemic anti-cancer therapy), and/or
prolonging survival. In the case of
cancer or tumor, an effective amount of the drug may have the effect in
reducing the number of cancer
cells; reducing the tumor size; inhibiting (i.e., slow to some extent or
desirably stop) cancer cell infiltration
into peripheral organs; inhibit (i.e., slow to some extent and desirably stop)
tumor metastasis; inhibiting to
some extent tumor growth; and/or relieving to some extent one or more of the
symptoms associated with
the disorder. An effective amount can be administered in one or more
administrations. For purposes of
this invention, an effective amount of drug, compound, or pharmaceutical
composition is an amount
sufficient to accomplish prophylactic or therapeutic treatment either directly
or indirectly. As is understood
in the clinical context, an effective amount of a drug, compound, or
pharmaceutical composition may or
may not be achieved in conjunction with another drug, compound, or
pharmaceutical composition. Thus,
an "effective amount" may be considered in the context of administering one or
more therapeutic agents,
and a single agent may be considered to be given in an effective amount if, in
conjunction with one or
more other agents, a desirable result may be or is achieved. In some aspects,
beneficial or desired
results are reduction in symptoms associated with lung cancer per the health-
related quality of life
(HROoL) questionnaire as assessed by symptoms in lung cancer (SILC) scale
(e.g., time to deterioration
(TTD) in cough dyspnea and chest pain) and/or delaying time to lung-specific
antigen progression).
"Immunogenicity" refers to the ability of a particular substance to provoke an
immune response.
Tumors are immunogenic and enhancing tumor immunogenicity aids in the
clearance of the tumor cells
by the immune response. Examples of enhancing tumor immunogenicity include but
are not limited to
treatment with a TIGIT and/or PD-L1 antagonist (e.g., anti-TIGIT antagonist
antibodies and/or anti-PD-L1
antibodies).
"Individual response" or "response" can be assessed using any endpoint
indicating a benefit to
the subject, including, without limitation, (1) inhibition, to some extent, of
disease progression (e.g.,
progression of cancer, e.g., a lung cancer (e.g., small cell lung cancer
(SCLC), which includes extensive
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stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes
squamous NSCLC or non-
squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage
IIIB NSCLC), or
recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the
lung), a UC, e.g., a
bladder cancer (e.g., an MIBC), a urothelial bladder cancer (UBC), a
pancreatic cancer (e.g., a pancreatic
ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal
cancer (e.g., a renal cell
carcinoma (RCC)), a melanoma, a head and neck cancer (e.g., a head and neck
squamous cell cancer
(HNSCC)), an ovarian cancer (OC), a gastric cancer (GC) (e.g., a
gastroesophageal junction (GEJ)
cancer), a hepatocellular carcinoma (HCC), a colorectal cancer (CRC; e.g., CRC
with microsatellite-
stable (MSS) and microsatellite instability (MSI) low (MSI-Low)), or a breast
cancer (e.g., HER2+ breast
cancer and triple-negative breast cancer (TNBC), which are estrogen receptors
(ER-), progesterone
receptors (PgR-), and HER2 (HER2-) negative))), including slowing down and
complete arrest; (2) a
reduction in tumor size; (3) inhibition (i.e., reduction, slowing down or
complete stopping) of cancer cell
infiltration into adjacent peripheral organs and/or tissues; (4) inhibition
(i.e. reduction, slowing down or
complete stopping) of metastasis; (5) relief, to some extent, of one or more
symptoms associated with the
disease or disorder (e.g., cancer); (6) increase or extend in the length of
survival, including overall
survival and progression-free survival; and/or (9) decreased mortality at a
given point of time following
treatment.
As used herein, "pathological complete response" (pCR) is defined as the
proportion of patients
with an absence of residual invasive cancer of the complete resected specimen.
In the context of breast
cancer, "pathological complete response" or "pCR" refers to eradication of
tumor from both breast and
lymph nodes (ypTO/is ypN0).
As used herein in the context of urothelial carcinoma (UC), "pathological
downstaging rate" is
defined as the proportion of patients that reach pT1pN0 at the time of
cystectomy.
As used herein, "complete response" or "CR" refers to disappearance of all
target lesions.
As used herein, "partial response" or "PR" refers to at least a 30% decrease
in the sum of the
longest diameters (SLD) of target lesions, taking as reference the baseline
SLD.
As used herein, "objective response rate" (ORR) refers to the sum of complete
response (CR)
rate and partial response (PR) rate.
As used herein, "duration of objective response" (DOR) is defined as the time
from the first
occurrence of a documented objective response to disease progression, or death
from any cause within
30 days of the last dose of a treatment, whichever occurs first.
"Sustained response" refers to the sustained effect on reducing tumor growth
after cessation of a
treatment. For example, the tumor size may remain to be the same or smaller as
compared to the size at
the beginning of the administration phase. In some aspects, the sustained
response has a duration at
least the same as the treatment duration, at least 1.5x, 2.0x, 2.5x, or 3.0x
length of the treatment
duration.
An "effective response" of a subject or a subject's "responsiveness" to
treatment with a
medicament and similar wording refers to the clinical or therapeutic benefit
imparted to a subject as risk
for, or suffering from, a disease or disorder, such as cancer. In one aspect,
such benefit includes any one
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or more of: extending survival (including overall survival and progression
free survival); resulting in an
objective response (including a CR or a PR); or improving signs or symptoms of
cancer.
A subject who "does not have an effective response" to treatment refers to a
subject who does
not have any one of extending survival (including overall survival and
progression free survival); resulting
.. in an objective response (including a CR or a PR); or improving signs or
symptoms of cancer.
As used herein, "survival" refers to the patient remaining alive, and includes
overall survival as
well as progression-free survival.
As used herein, "overall survival" and "OS" refer to the length of time from
either the date of
diagnosis or the start of treatment for a disease (e.g., cancer) that the
patient is still alive. For example,
OS may be defined as the time from randomization to death from any cause.
As used herein, "overall survival rate" refers to the percentage of subjects
in a group who are
alive after a particular duration of time, e.g., six months, 1 year, or 5
years from the time of diagnosis or
treatment.
As used herein, "recurrence-free survival" (RFS) is defined as the time from
Day 1 in the first
cycle after surgery to the first documented recurrence of disease or death
from any cause.
As used herein, "event-free survival" (EFS) is defined as the time from
randomization to any of
the following events (whichever occurs first): disease progression (e.g.,
progression that precludes
surgery, as assessed by the investigator); local or distant disease
recurrence; or death from any cause.
As used herein, "progression-free survival" (PFS) refers to the length of time
during and after
treatment during which the disease being treated (e.g., cancer) does not get
worse. Progression-free
survival may include the amount of time patients have experienced a CR or a
PR, as well as the amount
of time patients have experienced stable disease.
As used herein, "stable disease" or "SD" refers to neither sufficient
shrinkage of target lesions to
qualify for CR or PR, nor sufficient increase to qualify for PD, taking as
reference the smallest SLD since
the treatment started.
As used herein, "progressive disease" or "PD" refers to at least a 20%
increase in the sum of the
longest diameters (SLD) of target lesions, taking as reference the smallest
SLD recorded since the
treatment started or the presence of one or more new lesions.
As used herein, "major pathological response" (MPR) is defined as 10% residual
viable tumor
at the time of surgical resection in the primary tumor.
As used herein, "delaying progression" of a disorder or disease means to
defer, hinder, slow,
retard, stabilize, and/or postpone development of the disease or disorder
(e.g., cancer). This delay can
be of varying lengths of time, depending on the history of the disease and/or
subject being treated. As is
evident to one skilled in the art, a sufficient or significant delay can, in
effect, encompass prevention, in
that the subject does not develop the disease. For example, in a late stage
cancer, development of
central nervous system (CNS) metastasis, may be delayed.
As used herein, the term "reducing or inhibiting cancer relapse" means to
reduce or inhibit tumor
or cancer relapse, or tumor or cancer progression.
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By "reduce or inhibit" is meant the ability to cause an overall decrease of
20%, 30%, 40%, 50%,
60%, 70%, 75%, 80%, 85%, 90%, 95%, or greater. Reduce or inhibit can refer to
the symptoms of the
disorder being treated (e.g., cancer), the presence or size of metastases, or
the size of the primary tumor.
By "extending survival" is meant increasing overall or progression free
survival in a treated patient
relative to an untreated patient (e.g., relative to a patient not treated with
the medicament), or relative to a
patient who does not express a biomarker at the designated level, and/or
relative to a patient treated with
an approved anti-tumor agent. An objective response refers to a measurable
response, including CR or
PR.
The terms "detecting" and "detection" are used herein in the broadest sense to
include both
qualitative and quantitative measurements of a target molecule. Detecting
includes identifying the mere
presence of the target molecule in a sample as well as determining whether the
target molecule is
present in the sample at detectable levels. Detecting may be direct or
indirect.
As used herein, a "PD-L1-positive tumor cell fraction" is the percentage of
viable tumor cells
showing partial or complete membrane staining (exclusive of cytoplasmic
staining) at any intensity
relative to all viable tumor cells present in a sample, following staining of
the sample in the context of an
immunohistochemical (IHC) assay, e.g., an IHC assay staining for PD-L1 using
the antibody SP142,
SP263, 22C3, or 28-8. Accordingly, a PD-L1-positive tumor cell fraction may be
calculated using the PD-
L1 IHC SP263 (Ventana) assay, for example, by the formula PD-L1-positive tumor
cell fraction = (number
of PD-L1-positive tumor cells)/(total number of PD-L1-positive and PD-L1
negative tumor cells), wherein
PD-L1 cytoplasmic staining of tumor cells and all non-tumor cells (e.g., tumor-
infiltrating immune cells,
normal cells, necrotic cells, and debris) are excluded from evaluation and
scoring. It will be appreciated
that any given diagnostic PD-L1 antibody may correspond with a particular IHC
assay protocol and/or
scoring terminology that can be used to derive a PD-L1-positive tumor cell
fraction. For example, a PD-
L1-positive tumor cell fraction can be derived from a tumor cell sample
stained with SP263, 22C3, SP142,
or 28-8 using OPTIVIEW detection on Benchmark ULTRA, EnVision Flex on
AutostainerLink 48,
OPTIVIEWO detection and amplification on Benchmark ULTRA, or EnVision Flex on
AutostainerLink 48,
respectively. In another example, a PD-L1-positive tumor cell fraction may be
calculated using the PD-L1
IHC 22C3 pharmDx assay (Dako) according to the formula above. A skilled
artisan will appreciate that
the sensitivities can vary between different PD-L1 antibodies used in IHC
assays. For example, only
about 64% of samples that meet a 1% TC or 25% TC threshold, as defined
respectively by staining with
28-8 or 22C3 and SP263, meet the threshold when stained using SP142. Hirsch et
al., Journal of
Thoracic Oncology 2016, 12(2): 208-222. As used herein, the terms PD-L1-
positive tumor cell fraction
and "tumor proportion score" (TPS) are used interchangeably.
As used herein, the "Ventana SP142 IHC assay" is conducted according to the
Ventana PD-L1
(SP142) Assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.),
which is incorporated
herein by reference in its entirety.
As used herein, the "Ventana 5P263 IHC assay" is conducted according to the
Ventana PD-L1
(5P263) Assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.),
which is incorporated
herein by reference in its entirety.
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As used herein, the "pharmDx 22C3 IHC assay" is conducted according to the PD-
L1 IHC 22C3
pharmDx package insert (Carpinteria, CA: Dako, Agilent Pathology Solutions),
which is incorporated
herein by reference in its entirety.
As used herein, the "pharmDx 28-8 IHC assay" is conducted according to the PD-
L1 IHC 28-8
pharmDx package insert (Carpinteria, CA: Dako, Agilent Pathology Solutions),
which is incorporated
herein by reference in its entirety.
A "tumor-infiltrating immune cell," as used herein, refers to any immune cell
present in a tumor or
a sample thereof. Tumor-infiltrating immune cells include, but are not limited
to, intratumoral immune
cells, peritumoral immune cells, other tumor stroma cells (e.g., fibroblasts),
or any combination thereof.
Such tumor-infiltrating immune cells can be, for example, T lymphocytes (such
as CD8+ T lymphocytes
and/or CD4+ T lymphocytes), B lymphocytes, or other bone marrow-lineage cells,
including granulocytes
(e.g., neutrophils, eosinophils, and basophils), monocytes, macrophages,
dendritic cells (e.g.,
interdigitating dendritic cells), histiocytes, and natural killer cells.
The term "biomarker," as used herein, refers to an indicator, e.g.,
predictive, diagnostic, and/or
prognostic, which can be detected in a sample, for example, PD-L1, ctDNA, or
cytokines (e.g., cytokines
associated with T-cell activation and/or lymphocyte subpopulations). The
biomarker may serve as an
indicator of a particular subtype of a disease or disorder (e.g., cancer)
characterized by certain,
molecular, pathological, histological, and/or clinical features. In some
aspects, a biomarker is a gene.
Biomarkers include, but are not limited to, polypeptides, polynucleotides
(e.g., DNA (e.g., ctDNA), and/or
RNA), polynucleotide copy number alterations (e.g., DNA copy numbers),
polypeptide and polynucleotide
modifications (e.g., posttranslational modifications), carbohydrates, and/or
glycolipid-based molecular
markers. In some aspects, the biomarker is PD-L1. In some aspects, the
biomarker is ctDNA. In some
aspects, the biomarker is one or more cytokines (e.g., one or more cytokines
associated with T-cell
activation and/or lymphocyte subpopulations). In some aspects, the biomarker
is a cell (e.g., an immune
cell, e.g., a T cell, e.g., a T cell subset, e.g., an activated T cell). In
some aspects, the biomarker is a
direct or indirect indicator of human papillomavirus (HPV) status. In some
aspects, the biomarker is p16.
In some aspects, the biomarker is an HPV protein or nucleic acid.
The term "housekeeping biomarker" refers to a biomarker or group of biomarkers
(e.g.,
polynucleotides and/or polypeptides) which are typically similarly present in
all cell types. In some
aspects, the housekeeping biomarker is a "housekeeping gene." A "housekeeping
gene" refers herein to
a gene or group of genes which encode proteins whose activities are essential
for the maintenance of cell
function and which are typically similarly present in all cell types.
As used herein, "circulating tumor DNA" and "ctDNA" refer to tumor-derived DNA
in the
circulatory system that is not associated with cells. ctDNA is a type of cell-
free DNA (cfDNA) that may
originate from tumor cells or from circulating tumor cells (CTCs). ctDNA may
be found, e.g., in the
bloodstream of a patient, or in a biological sample (e.g., blood, serum,
plasma, or urine) obtained from a
patient. In some aspects, ctDNA may include aberrant mutations (e.g., patient-
specific variants) and/or
methylation patterns.
The term "antibody" includes monoclonal antibodies (including full-length
antibodies which have
an immunoglobulin Fc region), polyclonal antibodies, antibody compositions
with polyepitopic specificity,
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multispecific antibodies (e.g., bispecific antibodies), diabodies, and single-
chain molecules, as well as
antibody fragments, including antigen-binding fragments, such as Fab, F(ab')2,
and Fv, so long as they
exhibit the desired biological activity. The term "immunoglobulin" (Ig) is
used interchangeably with
"antibody" herein. In one instance, the antibody is a full-length monoclonal
antibody.
The term IgG "isotype" or "subclass" as used herein is meant any of the
subclasses of
immunoglobulins defined by the chemical and antigenic characteristics of their
constant regions.
Depending on the amino acid sequences of the constant domains of their heavy
chains,
antibodies (immunoglobulins) can be assigned to different classes. There are
five major classes of
immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be
further divided into
subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy
chain constant domains
that correspond to the different classes of immunoglobulins are called a, y,
e, y, and p, respectively. The
subunit structures and three-dimensional configurations of different classes
of immunoglobulins are well
known and described generally in, for example, Abbas et al. Cellular and Mot.
Immunology, 401 ed. (W.B.
Saunders, Co., 2000). An antibody may be part of a larger fusion molecule,
formed by covalent or non-
covalent association of the antibody with one or more other proteins or
peptides.
The basic 4-chain antibody unit is a heterotetrameric glycoprotein composed of
two identical light
(L) chains and two identical heavy (H) chains. An IgM antibody consists of 5
of the basic heterotetramer
units along with an additional polypeptide called a J chain, and contains 10
antigen binding sites, while
IgA antibodies comprise from 2-5 of the basic 4-chain units which can
polymerize to form polyvalent
assemblages in combination with the J chain. In the case of IgGs, the 4-chain
unit is generally about
150,000 Da!tons. Each L chain is linked to an H chain by one covalent
disulfide bond, while the two H
chains are linked to each other by one or more disulfide bonds depending on
the H chain isotype. Each
H and L chain also has regularly spaced intrachain disulfide bridges. Each H
chain has at the N-
terminus, a variable domain (VH) followed by three constant domains (CH) for
each of the a and y chains
and four CH domains for p. and c isotypes. Each L chain has at the N-terminus,
a variable domain (VL)
followed by a constant domain at its other end. The VL is aligned with the VH
and the CL is aligned with
the first constant domain of the heavy chain (CH1). Particular amino acid
residues are believed to form an
interface between the light chain and heavy chain variable domains. The
pairing of a VH and VL together
forms a single antigen-binding site. For the structure and properties of the
different classes of antibodies,
see, e.g., Basic and Clinical Immunology, 8th Edition, Daniel P. Sties, Abba
I. Terr and Tristram G.
Parsolw (eds), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6. The
L chain from any
vertebrate species can be assigned to one of two clearly distinct types,
called kappa and lambda, based
on the amino acid sequences of their constant domains. Depending on the amino
acid sequence of the
constant domain of their heavy chains (CH), immunoglobulins can be assigned to
different classes or
isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG and
IgM, having heavy chains
designated a, 6, c, y, and po, respectively. The y and a classes are further
divided into subclasses on the
basis of relatively minor differences in the CH sequence and function, e.g.,
humans express the following
subclasses: IgG1, IgG2A, IgG2B, IgG3, IgG4, IgA1 and IgA2.
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The term "hypervariable region" or "HVR" as used herein refers to each of the
regions of an
antibody variable domain which are hypervariable in sequence and which
determine antigen binding
specificity, for example "complementarity determining regions" ("CDRs").
Generally, antibodies comprise six CDRs: three in the VH (CDR-H1, CDR-H2, CDR-
H3), and
three in the VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs herein include:
(a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52
(L2), 91-96 (L3), 26-
32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. MoL Biol. 196:901-
917 (1987));
(b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3),
31-35b (H1), 50-
65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological
Interest, 5th Ed. Public
Health Service, National Institutes of Health, Bethesda, MD (1991)); and
(c) antigen contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2),
89-96 (L3), 30-35b
(H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. MoL Biol. 262: 732-745
(1996)).
Unless otherwise indicated, the CDRs are determined according to Kabat et al.,
supra. One of
skill in the art will understand that the CDR designations can also be
determined according to Chothia,
supra, McCallum, supra, or any other scientifically accepted nomenclature
system.
"Framework" or "FR" refers to variable domain residues other than
complementary determining
regions (CDRs). The FR of a variable domain generally consists of four FR
domains: FR1, FR2, FR3,
and FR4. Accordingly, the CDR and FR sequences generally appear in the
following sequence in VH (or
VL): FR1-CDR-H1(CDR-L1)-FR2- CDR-H2(CDR-L2)-FR3- CDR-H3(CDR-L3)-FR4.
The term "variable-domain residue-numbering as in Kabat" or "amino-acid-
position numbering as
in Kabat," and variations thereof, refers to the numbering system used for
heavy-chain variable domains
or light-chain variable domains of the compilation of antibodies in Kabat
etal., supra. Using this
numbering system, the actual linear amino acid sequence may contain fewer or
additional amino acids
corresponding to a shortening of, or insertion into, a FR or HVR of the
variable domain. For example, a
heavy-chain variable domain may include a single amino acid insert (e.g.,
residue 52a according to
Kabat) after residue 52 of H2 and inserted residues (e.g., residues 82a, 82b,
and 82c, etc. according to
Kabat) after heavy-chain FR residue 82. The Kabat numbering of residues may be
determined for a
given antibody by alignment at regions of homology of the sequence of the
antibody with a "standard"
Kabat numbered sequence.
The Kabat numbering system is generally used when referring to a residue in
the variable domain
(approximately residues 1-107 of the light chain and residues 1-113 of the
heavy chain) (e.g., Kabat et al.,
Sequences of Immunological Interest. 5th Ed. Public Health Service, National
Institutes of Health,
Bethesda, Md. (1991)). The "EU numbering system" or "EU index" is generally
used when referring to a
residue in an immunoglobulin heavy chain constant region (e.g., the EU index
reported in Kabat et al.,
supra). The "EU index as in Kabat" refers to the residue numbering of the
human IgG1 EU antibody.
The term "variable" refers to the fact that certain segments of the variable
domains differ
extensively in sequence among antibodies. The V domain mediates antigen
binding and defines the
specificity of a particular antibody for its particular antigen. However, the
variability is not evenly
distributed across the entire span of the variable domains. Instead, it is
concentrated in three segments
called hypervariable regions (HVRs) both in the light-chain and the heavy
chain variable domains. The
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more highly conserved portions of variable domains are called the framework
regions (FR). The variable
domains of native heavy and light chains each comprise four FR regions,
largely adopting a beta-sheet
configuration, connected by three HVRs, which form loops connecting, and in
some cases forming part of,
the beta-sheet structure. The HVRs in each chain are held together in close
proximity by the FR regions
and, with the HVRs from the other chain, contribute to the formation of the
antigen binding site of
antibodies (see Kabat eta!,, Sequences of Immunological Interest, Fifth
Edition, National Institute of
Health, Bethesda, MD (1991)). The constant domains are not involved directly
in the binding of antibody
to an antigen, but exhibit various effector functions, such as participation
of the antibody in antibody-
dependent cellular toxicity.
The "variable region" or "variable domain" of an antibody refers to the amino-
terminal domains of
the heavy or light chain of the antibody. The variable domains of the heavy
chain and light chain may be
referred to as "VH" and "VL", respectively. These domains are generally the
most variable parts of the
antibody (relative to other antibodies of the same class) and contain the
antigen binding sites.
"Framework" or "FR" refers to variable domain residues other than
hypervariable region (HVR)
residues. The FR of a variable domain generally consists of four FR domains:
FR1, FR2, FR3, and FR4.
Accordingly, the HVR and FR sequences generally appear in the following
sequence in VH (or VL): FR1-
H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.
The terms "full-length antibody," "intact antibody," and "whole antibody" are
used interchangeably
to refer to an antibody in its substantially intact form, as opposed to an
antibody fragment. Specifically,
whole antibodies include those with heavy and light chains including an Fc
region. The constant domains
may be native sequence constant domains (e.g., human native sequence constant
domains) or amino
acid sequence variants thereof. In some cases, the intact antibody may have
one or more effector
functions.
A "naked antibody" refers to an antibody that is not conjugated to a
heterologous moiety (e.g., a
cytotoxic moiety) or radiolabel. The naked antibody may be present in a
pharmaceutical composition.
An "antibody fragment" comprises a portion of an intact antibody, preferably
the antigen-binding
and/or the variable region of the intact antibody. Examples of antibody
fragments include Fab, Fab',
F(a1.3)2 and Fv fragments; diabodies; linear antibodies (see U.S. Patent
5,641,870, Example 2; Zapata et
al., Protein Eng. 8(10): 1057-1062 [1995]); single-chain antibody molecules
and multispecific antibodies
formed from antibody fragments. Papain digestion of antibodies produced two
identical antigen-binding
fragments, called "Fab" fragments, and a residual "Fc" fragment, a designation
reflecting the ability to
crystallize readily. The Fab fragment consists of an entire L chain along with
the variable region domain
of the H chain (VH), and the first constant domain of one heavy chain (CH1).
Each Fab fragment is
monovalent with respect to antigen binding, i.e., it has a single antigen-
binding site. Pepsin treatment of
an antibody yields a single large F(a1:02 fragment which roughly corresponds
to two disulfide linked Fab
fragments having different antigen-binding activity and is still capable of
cross-linking antigen. Fab'
fragments differ from Fab fragments by having a few additional residues at the
carboxy terminus of the
CH1 domain including one or more cysteines from the antibody hinge region.
Fab'-SH is the designation
herein for Fab' in which the cysteine residue(s) of the constant domains bear
a free thiol group. F(a1.3')2
WO 2021/154761
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antibody fragments originally were produced as pairs of Fab' fragments which
have hinge cysteines
between them. Other chemical couplings of antibody fragments are also known.
The Fc fragment comprises the carboxy-terminal portions of both H chains held
together by
disulfides. The effector functions of antibodies are determined by sequences
in the Fc region, the region
which is also recognized by Fc receptors (FcR) found on certain types of
cells.
"Functional fragments" of the antibodies of the invention comprise a portion
of an intact antibody,
generally including the antigen binding or variable region of the intact
antibody or the Fc region of an
antibody which retains or has modified FcR binding capability. Examples of
antibody fragments include
linear antibody, single-chain antibody molecules and multispecific antibodies
formed from antibody
fragments.
"Fv" is the minimum antibody fragment which contains a complete antigen-
recognition and -
binding site. This fragment consists of a dimer of one heavy- and one light-
chain variable region domain
in tight, non-covalent association. From the folding of these two domains
emanate six hypervariable
loops (3 loops each from the H and L chain) that contribute the amino acid
residues for antigen binding
and confer antigen binding specificity to the antibody. However, even a single
variable domain (or half of
an Fv comprising only three HVRs specific for an antigen) has the ability to
recognize and bind antigen,
although at a lower affinity than the entire binding site.
"Single-chain Fv" also abbreviated as "sFv" or "scFv" are antibody fragments
that comprise the VH
and VL antibody domains connected into a single polypeptide chain. Preferably,
the sFv polypeptide
further comprises a polypeptide linker between the VH and VL domains which
enables the sFv to form the
desired structure for antigen binding. For a review of the sFv, see Pluckthun
in The Pharmacology of
Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag,
New York, pp. 269-315
(1994).
The term "Fc region" herein is used to define a C-terminal region of an
immunoglobulin heavy
chain that contains at least a portion of the constant region. The term
includes native sequence Fc
regions and variant Fc regions. In one aspect, a human IgG heavy chain Fc
region extends from Cys226,
or from Pro230, to the carboxyl-terminus of the heavy chain. However,
antibodies produced by host cells
may undergo post-translational cleavage of one or more, particularly one or
two, amino acids from the C-
terminus of the heavy chain. Therefore, an antibody produced by a host cell by
expression of a specific
nucleic acid molecule encoding a full-length heavy chain may include the full-
length heavy chain, or it
may include a cleaved variant of the full-length heavy chain. This may be the
case where the final two C-
terminal amino acids of the heavy chain are glycine (G446) and lysine (K447).
Therefore, the C-terminal
lysine (Lys447), or the C-terminal glycine (31y446) and lysine (Lys447), of
the Fc region may or may not
be present. Amino acid sequences of heavy chains including an Fc region are
denoted herein without the
C-terminal lysine (Lys447) if not indicated otherwise. In one aspect, a heavy
chain including an Fc region
as specified herein, comprised in an antibody disclosed herein, comprises an
additional C-terminal
glycine-lysine dipeptide (G446 and K447). In one aspect, a heavy chain
including an Fc region as
specified herein, comprised in an antibody disclosed herein, comprises an
additional C-terminal glycine
residue (G446). In one aspect, a heavy chain including an Fc region as
specified herein, comprised in an
antibody disclosed herein, comprises an additional C-terminal lysine residue
(K447). In one aspect, the
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Fc region contains a single amino acid substitution N297A of the heavy chain.
Unless otherwise specified
herein, numbering of amino acid residues in the Fe region or constant region
is according to the EU
numbering system, also called the EU index, as described in Kabat et al.,
Sequences of Proteins of
Immunological Interest, 5th Ed. Public Health Service, National Institutes of
Health, Bethesda, MD, 1991.
"Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an
antibody. The
preferred FcR is a native sequence human FcR. Moreover, a preferred FcR is one
which binds an IgG
antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and
FcyRIII subclasses,
including allelic variants and alternatively spliced forms of these receptors,
FcyRII receptors include
FcyRIIA (an "activating receptor") and FcyRIIB (an "inhibiting receptor"),
which have similar amino acid
sequences that differ primarily in the cytoplasmic domains thereof. Activating
receptor FcyRIIA contains
an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic
domain. Inhibiting receptor
FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in
its cytoplasmic domain (see
M. Daeron, Annu. Rev. Immunol. 15:203-234 (1997). FcRs are reviewed in Ravetch
and Kinet, Annu.
Rev. Immunol. 9: 457-92 (1991); Capel etal., Immunomethods 4: 25-34 (1994);
and de Haas et al., J.
.. Lab. Clin. Med. 126: 330-41 (1995). Other FcRs, including those to be
identified in the future, are
encompassed by the term "FcR" herein.
The term "diabodies" refers to small antibody fragments prepared by
constructing sFy fragments
(see preceding paragraph) with short linkers (about 5-10) residues) between
the VH and VL domains such
that inter-chain but not intra-chain pairing of the V domains is achieved,
thereby resulting in a bivalent
fragment, i.e., a fragment having two antigen-binding sites. Bispecific
diabodies are heterodimers of two
"crossover" sFy fragments in which the VH and VL domains of the two antibodies
are present on different
polypeptide chains. Diabodies are described in greater detail in, for example,
EP 404,097; WO 93/11161;
Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993).
The monoclonal antibodies herein specifically include "chimeric" antibodies
(immunoglobulins) in
which a portion of the heavy and/or light chain is identical with or
homologous to corresponding
sequences in antibodies derived from a particular species or belonging to a
particular antibody class or
subclass, while the remainder of the chain(s) is (are) identical with or
homologous to corresponding
sequences in antibodies derived from another species or belonging to another
antibody class or subclass,
as well as fragments of such antibodies, so long as they exhibit the desired
biological activity (U.S. Patent
No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855
(1984)). Chimeric antibodies of
interest herein include PRIMATIZED antibodies wherein the antigen-binding
region of the antibody is
derived from an antibody produced by, e.g., immunizing macaque monkeys with an
antigen of interest.
As used herein, "humanized antibody" is used a subset of "chimeric
antibodies."
The "class" of an antibody refers to the type of constant domain or constant
region possessed by
its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE,
IgG, and IgM, and several of
these may be further divided into subclasses (isotypes), e.g., IgGi, IgG2,
IgG3, !gat, IgAi, and IgA2. The
heavy chain constant domains that correspond to the different classes of
immunoglobulins are called a, 6,
e, y, and 11, respectively.
"Affinity" refers to the strength of the sum total of non-covalent
interactions between a single
binding site of a molecule (e.g., an antibody) and its binding partner (e.g.,
an antigen, e.g., TIGIT, PD-L1,
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or VEGF). Unless indicated otherwise, as used herein, "binding affinity"
refers to intrinsic binding affinity
which reflects a 1:1 interaction between members of a binding pair (e.g.,
antibody and antigen). The
affinity of a molecule X for its partner Y can generally be represented by the
dissociation constant (KO.
Affinity can be measured by common methods known in the art, including those
described herein.
Specific illustrative and exemplary aspects for measuring binding affinity are
described in the following.
A "human antibody" is an antibody that possesses an amino-acid sequence
corresponding to that
of an antibody produced by a human and/or has been made using any of the
techniques for making
human antibodies as disclosed herein. This definition of a human antibody
specifically excludes a
humanized antibody comprising non-human antigen-binding residues. Human
antibodies can be
produced using various techniques known in the art, including phage-display
libraries. Hoogenboom and
Winter, J. Mol. Biol., 227:381 (1991); Marks et aL, J. MoL Biol., 222:581
(1991). Also available for the
preparation of human monoclonal antibodies are methods described in Cole
eta!,, Monoclonal Antibodies
and Cancer Therapy, Alan R. Liss, p. 77(1985); Boerner etal., J. ImmunoL,
147(1):86-95 (1991). See
also van Dijk and van de Winkel, Curr. Opin. PharmacoL, 5:368-74 (2001). Human
antibodies can be
prepared by administering the antigen to a transgenic animal that has been
modified to produce such
antibodies in response to antigenic challenge, but whose endogenous loci have
been disabled, e.g.,
immunized xenomice (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584
regarding XENOMOUSETm
technology). See also, for example, Li etal., Proc. Natl. Acad. ScL USA,
103:3557-3562 (2006) regarding
human antibodies generated via a human B-cell hybridoma technology.
"Humanized" forms of non-human (e.g., murine) antibodies are chimeric
antibodies that contain
minimal sequence derived from non-human immunoglobulin. In one aspect, a
humanized antibody is a
human immunoglobulin (recipient antibody) in which residues from an HVR
(hereinafter defined) of the
recipient are replaced by residues from an HVR of a non-human species (donor
antibody) such as
mouse, rat, rabbit or non-human primate having the desired specificity,
affinity, and/or capacity. In some
instances, framework ("FR") residues of the human immunoglobulin are replaced
by corresponding non-
human residues. Furthermore, humanized antibodies may comprise residues that
are not found in the
recipient antibody or in the donor antibody. These modifications may be made
to further refine antibody
performance, such as binding affinity. In general, a humanized antibody will
comprise substantially all of
at least one, and typically two, variable domains, in which all or
substantially all of the hypervariable loops
correspond to those of a non-human immunoglobulin sequence, and all or
substantially all of the FR
regions are those of a human immunoglobulin sequence, although the FR regions
may include one or
more individual FR residue substitutions that improve antibody performance,
such as binding affinity,
isomerization, immunogenicity, etc. The number of these amino acid
substitutions in the FR are typically
no more than 6 in the H chain, and in the L chain, no more than 3. The
humanized antibody optionally
will also comprise at least a portion of an immunoglobulin constant region
(Fe), typically that of a human
immunoglobulin. For further details, see, e.g., Jones etal., Nature 321:522-
525 (1986); Riechmann et al.,
Nature 332:323-329 (1988); and Presta, Curr. Op. Struct Biol. 2:593-596
(1992). See also, for example,
Vaswani and Hamilton, Ann. Allergy, Asthma & Immunot 1:105-115(1998); Harris,
Biochem. Soc.
Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-
433 (1994); and U.S. Pat.
Nos. 6,982,321 and 7,087,409.
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The term an "isolated antibody" when used to describe the various antibodies
disclosed herein,
means an antibody that has been identified and separated and/or recovered from
a cell or cell culture
from which it was expressed. Contaminant components of its natural environment
are materials that
would typically interfere with diagnostic or therapeutic uses for the
polypeptide, and can include enzymes,
hormones, and other proteinaceous or non-proteinaceous solutes. In some
aspects, an antibody is
purified to greater than 95% or 99% purity as determined by, for example,
electrophoretic (e.g., SDS-
PAGE, isoelectric focusing (IEF), capillary electrophoresis) or
chromatographic (e.g., ion exchange or
reverse phase HPLC). For a review of methods for assessment of antibody
purity, see, e.g., Flatman et
al., J. Chromatogr. B 848:79-87 (2007). In preferred aspects, the antibody
will be purified (1) to a degree
sufficient to obtain at least 15 residues of N-terminal or internal amino acid
sequence by use of a spinning
cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or
reducing conditions using
Coomassie blue or, preferably, silver stain. Isolated antibody includes
antibodies in situ within
recombinant cells, because at least one component of the polypeptide natural
environment will not be
present. Ordinarily, however, isolated polypeptide will be prepared by at
least one purification step.
The term "monoclonal antibody" as used herein refers to an antibody obtained
from a population
of substantially homogeneous antibodies, i.e., the individual antibodies
comprising the population are
identical and/or bind the same epitope, except for possible variant
antibodies, e.g., containing naturally
occurring mutations or arising during production of a monoclonal antibody
preparation, such variants
generally being present in minor amounts. In contrast to polyclonal antibody
preparations, which typically
include different antibodies directed against different determinants
(epitopes), each monoclonal antibody
of a monoclonal antibody preparation is directed against a single determinant
on an antigen. Thus, the
modifier "monoclonal" indicates the character of the antibody as being
obtained from a substantially
homogeneous population of antibodies, and is not to be construed as requiring
production of the antibody
by any particular method. For example, the monoclonal antibodies in accordance
with the present
invention may be made by a variety of techniques, including but not limited to
the hybridoma method,
recombinant DNA methods, phage-display methods, and methods utilizing
transgenic animals containing
all or part of the human immunoglobulin loci.
As used herein, the term "binds," "specifically binds to," or is "specific
for" refers to measurable
and reproducible interactions such as binding between a target and an
antibody, which is determinative of
the presence of the target in the presence of a heterogeneous population of
molecules including
biological molecules. For example, an antibody that specifically binds to a
target (which can be an
epitope) is an antibody that binds this target with greater affinity, avidity,
more readily, and/or with greater
duration than it binds to other targets. In one aspect, the extent of binding
of an antibody to an unrelated
target is less than about 10% of the binding of the antibody to the target as
measured, for example, by a
radioimmunoassay (RIA). In certain aspects, an antibody that specifically
binds to a target has a
dissociation constant (KD) of 5. 1pM, .5. 100 nM, 5 10 nM, 5. 1 nM, or 5. 0.1
nM. In certain aspects, an
antibody specifically binds to an epitope on a protein that is conserved among
the protein from different
species. In another aspect, specific binding can include, but does not require
exclusive binding. The
term as used herein can be exhibited, for example, by a molecule having a KD
for the target of 10-4M or
lower, alternatively 10-5M or lower, alternatively 10-6 M or lower,
alternatively 10-7 M or lower, alternatively
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10-8 M or lower, alternatively 10-0 M or lower, alternatively 10-10 M or
lower, alternatively 10-1' M or lower,
alternatively 10-12 M or lower or a KD in the range of 10-4 M to 10-6 M or 10-
6 M to 10-10 M or 10-7 M to
10-0 M. As will be appreciated by the skilled artisan, affinity and KD values
are inversely related. A high
affinity for an antigen is measured by a low KD value. In one aspect, the term
"specific binding" refers to
binding where a molecule binds to a particular polypeptide or epitope on a
particular polypeptide without
substantially binding to any other polypeptide or polypeptide epitope.
"Percent (%) amino acid sequence identity" with respect to a reference
polypeptide sequence is
defined as the percentage of amino acid residues in a candidate sequence that
are identical with the
amino acid residues in the reference polypeptide sequence, after aligning the
sequences and introducing
gaps, if necessary, to achieve the maximum percent sequence identity, and not
considering any
conservative substitutions as part of the sequence identity. Alignment for
purposes of determining
percent amino acid sequence identity can be achieved in various ways that are
within the skill in the art,
for instance, using publicly available computer software such as BLAST, BLAST-
2, ALIGN or Megalign
(DNASTAR) software. Those skilled in the art can determine appropriate
parameters for aligning
sequences, including any algorithms needed to achieve maximal alignment over
the full length of the
sequences being compared. For purposes herein, however, % amino acid sequence
identity values are
generated using the sequence comparison computer program ALIGN-2. The ALIGN-2
sequence
comparison computer program was authored by Genentech, Inc., and the source
code has been filed with
user documentation in the U.S. Copyright Office, Washington D.C., 20559, where
it is registered under
U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly
available from
Genentech, Inc., South San Francisco, California, or may be compiled from the
source code. The
ALIGN-2 program should be compiled for use on a UNIX operating system,
including digital UNIX V4.0D.
All sequence comparison parameters are set by the ALIGN-2 program and do not
vary.
In situations where ALIGN-2 is employed for amino acid sequence comparisons,
the % amino
acid sequence identity of a given amino acid sequence A to, with, or against a
given amino acid
sequence B (which can alternatively be phrased as a given amino acid sequence
A that has or comprises
a certain A, amino acid sequence identity to, with, or against a given amino
acid sequence B) is
calculated as follows:
100 times the fraction X/Y
where X is the number of amino acid residues scored as identical matches by
the sequence alignment
program ALIGN-2 in that program's alignment of A and B, and where Y is the
total number of amino acid
residues in B. It will be appreciated that where the length of amino acid
sequence A is not equal to the
length of amino acid sequence B, the % amino acid sequence identity of A to B
will not equal the %
amino acid sequence identity of B to A. Unless specifically stated otherwise,
all ./0 amino acid sequence
identity values used herein are obtained as described in the immediately
preceding paragraph using the
ALIGN-2 computer program.
As used herein, "subject" or "individual" is meant a mammal, including, but
not limited to, a
human or non-human mammal, such as a bovine, equine, canine, ovine, or feline.
In some aspects, the
subject is a human. Patients are also subjects herein.
The term "patient" refers to a human patient. For example, the patient may be
an adult.
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The term "diagnosis" is used herein to refer to the identification or
classification of a molecular or
pathological state, disease or condition (e.g., cancer). For example,
"diagnosis" may refer to identification
of a particular type of cancer. "Diagnosis" may also refer to the
classification of a particular subtype of
cancer, for instance, by histopathological criteria, or by molecular features
(e.g., a subtype characterized
by expression of one or a combination of biomarkers (e.g., particular genes or
proteins encoded by said
genes)).
The term "sample," as used herein, refers to a composition that is obtained or
derived from a
subject and/or individual of interest that contains a cellular and/or other
molecular entity that is to be
characterized and/or identified, for example, based on physical, biochemical,
chemical, and/or
physiological characteristics. For example, the phrase "tumor sample",
"disease sample" and variations
thereof refers to any sample obtained from a subject of interest that would be
expected or is known to
contain the cellular and/or molecular entity that is to be characterized.
Samples include, but are not
limited to, tissue samples, primary or cultured cells or cell lines, cell
supernatants, cell lysates, platelets,
serum, plasma, vitreous fluid, lymph fluid, synovial fluid, follicular fluid,
seminal fluid, amniotic fluid, milk,
whole blood, blood-derived cells, urine, cerebro-spinal fluid, saliva, sputum,
tears, perspiration, mucus,
stool, tumor lysates, and tissue culture medium, tissue extracts such as
homogenized tissue, tumor
tissue, cellular extracts, and combinations thereof.
By "tissue sample" or "cell sample" is meant a collection of similar cells
obtained from a tissue of
a subject or individual. The source of the tissue or cell sample may be solid
tissue as from a fresh, frozen
and/or preserved organ, tissue sample, biopsy, and/or aspirate; blood or any
blood constituents such as
plasma; bodily fluids such as cerebral spinal fluid, amniotic fluid,
peritoneal fluid, or interstitial fluid; cells
from any time in gestation or development of the subject. The tissue sample
may also be primary or
cultured cells or cell lines. Optionally, the tissue or cell sample is
obtained from a disease tissue/organ.
For instance, a "tumor sample" is a tissue sample obtained from a tumor or
other cancerous tissue. The
tissue sample may contain a mixed population of cell types (e.g., tumor cells
and non-tumor cells,
cancerous cells and non-cancerous cells). The tissue sample may contain
compounds which are not
naturally intermixed with the tissue in nature such as preservatives,
anticoagulants, buffers, fixatives,
wax, nutrients, antibiotics, or the like. In some aspects, the sample is a
tumor tissue sample. In some
aspects, the tumor tissue sample is a UC tumor tissue sample (e.g., a bladder
cancer tumor tissue
sample (e.g., an MIBC tumor tissue sample)). In some aspects, the sample is a
transurethral resection of
bladder tumor (TURBT) sample. In some aspects, the sample is a cystectomy or
nephroureterectomy
sample. In other aspects, the tumor tissue sample is a lung cancer tumor
tissue sample (e.g., an early
stage lung cancer tissue sample (e.g., an NSCLC tumor tissue sample (e.g., a
stage II, IIIA, or IIIB
NSCLC tumor tissue sample), e.g., squamous or non-squamous NSCLC tumor tissue
sample, e.g., a
resectable NSCLC tumor tissue sample)). In some aspects, the sample is a
locally advanced
unresectable NSCLC tumor tissue sample (e.g., Stage IIIB NSCLC tumor tissue
sample), or recurrent or
metastatic NSCLC tumor tissue sample (e.g., Stage IV NSCLC tumor tissue
sample)), a pancreatic
cancer tumor tissue sample (e.g., a PDAC tumor tissue sample), e.g., a
metastatic PDAC tumor tissue
sample)), or a breast cancer tumor tissue sample (e.g., a H ER2+ breast cancer
tumor tissue sample or a
TNBC tumor tissue sample).
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For the purposes herein a "section" of a tissue sample is meant a single part
or piece of a tissue
sample, for example, a thin slice of tissue or cells cut from a tissue sample
(e.g., a tumor sample). It is to
be understood that multiple sections of tissue samples may be taken and
subjected to analysis, provided
that it is understood that the same section of tissue sample may be analyzed
at both morphological and
molecular levels, or analyzed with respect to polypeptides (e.g., by
immunohistochemistry) and/or
polynucleotides (e.g., by in situ hybridization).
A "reference sample," "reference cell," "reference tissue," "control sample,"
"control cell," or
"control tissue," as used herein, refers to a sample, cell, tissue, standard,
or level that is used for
comparison purposes. In one aspect, a reference sample, reference cell,
reference tissue, control
sample, control cell, or control tissue is obtained from a healthy and/or non-
diseased part of the body
(e.g., tissue or cells) of the same subject or individual. For example, the
reference sample, reference cell,
reference tissue, control sample, control cell, or control tissue may be
healthy and/or non-diseased cells
or tissue adjacent to the diseased cells or tissue (e.g., cells or tissue
adjacent to a tumor). In another
aspect, a reference sample is obtained from an untreated tissue and/or cell of
the body of the same
subject or individual. In yet another aspect, a reference sample, reference
cell, reference tissue, control
sample, control cell, or control tissue is obtained from a healthy and/or non-
diseased part of the body
(e.g., tissues or cells) of an individual who is not the subject or
individual. In even another aspect, a
reference sample, reference cell, reference tissue, control sample, control
cell, or control tissue is
obtained from an untreated tissue and/or cell of the body of an individual who
is not the subject or
individual.
The term "protein," as used herein, refers to any native protein from any
vertebrate source,
including mammals such as primates (e.g., humans) and rodents (e.g., mice and
rats), unless otherwise
indicated. The term encompasses "full-length," unprocessed protein as well as
any form of the protein
that results from processing in the cell. The term also encompasses naturally
occurring variants of the
protein, e.g., splice variants or allelic variants.
"Polynucleotide" or "nucleic acid," as used interchangeably herein, refers to
polymers of
nucleotides of any length, and include DNA and RNA. The nucleotides can be
deoxyribonucleotides,
ribonucleotides, modified nucleotides or bases, and/or their analogs, or any
substrate that can be
incorporated into a polymer by DNA or RNA polymerase, or by a synthetic
reaction. Thus, for instance,
polynucleotides as defined herein include, without limitation, single- and
double-stranded DNA, DNA
including single- and double-stranded regions, single- and double-stranded
RNA, and RNA including
single- and double-stranded regions, hybrid molecules comprising DNA and RNA
that may be single-
stranded or, more typically, double-stranded or include single- and double-
stranded regions. In addition,
the term "polynucleotide" as used herein refers to triple-stranded regions
comprising RNA or DNA or both
RNA and DNA. The strands in such regions may be from the same molecule or from
different molecules.
The regions may include all of one or more of the molecules, but more
typically involve only a region of
some of the molecules. One of the molecules of a triple-helical region often
is an oligonucleotide. The
terms "polynucleotide" and "nucleic acid" specifically includes mRNA and
cDNAs.
A polynucleotide may comprise modified nucleotides, such as methylated
nucleotides and their
analogs. If present, modification to the nucleotide structure may be imparted
before or after assembly of
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the polymer. The sequence of nucleotides may be interrupted by non-nucleotide
components. A
polynucleotide may be further modified after synthesis, such as by conjugation
with a label. Other types
of modifications include, for example, "caps," substitution of one or more of
the naturally-occurring
nucleotides with an analog, internucleotide modifications such as, for
example, those with uncharged
linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates,
carbamates, and the like) and
with charged linkages (e.g., phosphorothioates, phosphorodithioates, and the
like), those containing
pendant moieties, such as, for example, proteins (e.g., nucleases, toxins,
antibodies, signal peptides,
poly-L-lysine, and the like), those with intercalators (e.g., acridine,
psoralen, and the like), those
containing chelators (e.g., metals, radioactive metals, boron, oxidative
metals, and the like), those
containing alkylators, those with modified linkages (e.g., alpha anomeric
nucleic acids), as well as
unmodified forms of the polynucleotide(s). Further, any of the hydroxyl groups
ordinarily present in the
sugars may be replaced, for example, by phosphonate groups, phosphate groups,
protected by standard
protecting groups, or activated to prepare additional linkages to additional
nucleotides, or may be
conjugated to solid or semi-solid supports. The 5' and 3' terminal OH can be
phosphorylated or
substituted with amines or organic capping group moieties of from 1 to 20
carbon atoms. Other hydroxyls
may also be derivatized to standard protecting groups. Polynucleotides can
also contain analogous
forms of ribose or deoxyribose sugars that are generally known in the art,
including, for example, 2'-0-
methyl-, 2'-0-ally1-, 2'-fluoro-, or 2'-azido-ribose, carbocyclic sugar
analogs, a-anomeric sugars, epimeric
sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose
sugars, sedoheptuloses,
acyclic analogs, and abasic nucleoside analogs such as methyl riboside. One or
more phosphodiester
linkages may be replaced by alternative linking groups. These alternative
linking groups include, but are
not limited to, aspects wherein phosphate is replaced by P(0)S ("thioate"),
P(S)S ("dithioate"), "(0)NR2
("amidate"), P(0)R, P(0)OR', CO or CH2 ("formacetal"), in which each R or R'
is independently H or
substituted or unsubstituted alkyl (1-20 C) optionally containing an ether (-0-
) linkage, aryl, alkenyl,
cycloalkyl, cycloalkenyl or araldyl. Not all linkages in a polynucleotide need
be identical. The preceding
description applies to all polynucleotides referred to herein, including RNA
and DNA.
"Carriers" as used herein include pharmaceutically acceptable carriers,
excipients, or stabilizers
that are nontoxic to the cell or mammal being exposed thereto at the dosages
and concentrations
employed. Often the physiologically acceptable carrier is an aqueous pH
buffered solution. Examples of
.. physiologically acceptable carriers include buffers such as phosphate,
citrate, and other organic acids;
antioxidants including ascorbic acid; low molecular weight (less than about 10
residues) polypeptide;
proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic
polymers such as
polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine,
arginine or lysine;
monosaccharides, disaccharides, and other carbohydrates including glucose,
mannose, or dextrins;
chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol;
salt-forming counterions
such as sodium; and/or nonionic surfactants such as TWEENTm, polyethylene
glycol (PEG), and
PLURONICSTM.
The phrase "pharmaceutically acceptable" indicates that the substance or
composition must be
compatible chemically and/or toxicologically, with the other ingredients
comprising a formulation, and/or
the mammal being treated therewith.
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The term "pharmaceutical formulation" or "pharmaceutical composition" refers
to a preparation
which is in such form as to permit the biological activity of an active
ingredient contained therein to be
effective, and which contains no additional components which are unacceptably
toxic to a subject to
which the formulation would be administered.
The term "package insert" is used to refer to instructions customarily
included in commercial
packages of therapeutic products or medicaments that contain information about
the indications, usage,
dosage, administration, combination therapy, other medicaments to be combined
with the packaged
product, and/or contraindications and/or warnings concerning the use of such
therapeutic products or
medicaments.
As used herein, the term "induction phase" refers to a series of one or more
dosing cycles (e.g.,
about 4-6 cycles) of one or more therapeutic agents (e.g., an anti-TIGIT
antagonist antibody, a PD-1 axis
binding antagonist, and/or a chemotherapeutic agent) administered to a
subject, wherein the one or more
dosing cycles are optionally followed by a maintenance phase.
The term "maintenance phase" as used herein refers to a series of one or more
dosing cycles of
.. one or more therapeutic agents (e.g., an anti-TIGIT antagonist antibody, a
PD-1 axis binding antagonist,
and/or a chemotherapeutic agent) that are administered to a subject subsequent
to an induction
phase. In some instances, the maintenance phase is initiated only if the
subject did not experience
disease progression or unacceptable toxicity during the induction phase. The
induction phase and
maintenance phase may or may not comprise use of the same therapeutic agents.
For example, in some
instances, the induction phase includes use of an anti-TIGIT antagonist
antibody, a PD-1 axis binding
antagonist, a platinum-based chemotherapeutic agent, and a non-platinum-based
chemotherapeutic
agent, and the maintenance phase includes use of an anti-TIGIT antagonist
antibody and a PD-1 axis
binding antagonist.
In the context of bladder cancer, the term "ineligible for treatment with a
platinum-based
chemotherapy" or "unfit for treatment with a platinum-based chemotherapy"
means that the subject is
ineligible or unfit for treatment with a platinum-based chemotherapy, either
in the attending clinician's
judgment or according to standardized criteria for eligibility for platinum-
based chemotherapy that are
known in the art. For example, the criteria set forth in Galsky et al. Lancet
Oncol. 12(3):211-4, 2011,
which is incorporated herein by reference in its entirety, may be used to
determine whether a subject is
eligible for cisplatin-based chemotherapy. Galsky et al. describe a consensus
definition of patients with
metastatic UC (m UC) in which patients meeting at least one of the following
are considered unfit for
cisplatin-based chemotherapy: (i) a World Health Association (WHO) or Eastern
Cooperative Oncology
Group (ECOG) performance status of 2, or Karnofsky performance status of 60-
70%; (ii) creatinine
clearance (calculated or measured) less than 1 mils; (iii) National Cancer
Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE) v4.0 Grade 2 audiometric
hearing loss; (iv) CTCAE
v.4.0 Grade 2 peripheral neuropathy; and/or New York Heart Association (NYHA)
class III heart failure.
In one example, a patient is considered unfit for cisplatin-based chemotherapy
if they have one or more of
the following: impaired renal function (e.g., glomerular filtration rate (GFR)
>30 but <60 mUmin); GFR
may be assessed by direct measurement (i.e., creatinine clearance or
ethyldediaminetetra-acetate) or, if
.. not available, by calculation from serum/plasma creatinine (Cockcroft-Gault
formula)); hearing loss (e.g.,
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NCI CTCAE v4.0 Grade 2 2 audiometric hearing loss of 25 decibels at two
contiguous frequencies);
peripheral neuropathy (e.g., NCI CTCAE v4.0 Grade 2 peripheral neuropathy
(i.e., sensory alteration or
paresthesia, including tingling)); and/or ECOG performance status assessment
(see Oken et al. Am. J.
Clin. Oncol. 5:649-655, 1982, which is incorporated herein by reference in its
entirety) (e.g., an ECOG
performance status of 2). In some aspects, a subject having one of the
following may be eligible for
carboplatin-based chemotherapy: impaired renal function (e.g., GFR >30 but <60
mUmin); GFR may be
assessed by direct measurement (i.e., creatinine clearance or
ethyldediaminetetra-acetate) or, if not
available, by calculation from serum/plasma creatinine (Cockcroft-Gault
formula)); hearing loss (e.g.,
CTCAE v4.0 Grade 2 audiometric hearing loss of 25 decibels at two contiguous
frequencies); peripheral
neuropathy (e.g., NCI CTCAE v4.0 Grade 2 peripheral neuropathy (i.e., sensory
alteration or
paresthesia, including tingling)); and/or ECOG performance status assessment
(e.g., an ECOG
performance status of 2). For example, cisplatin ineligibility may be defined
by any one of the following
criteria: (i) impaired renal function (GFR <60 mL/min); GFR may be assessed by
direct measurement
(i.e., creatinine clearance or ethyldediaminetetra-acetate) or, if not
available, by calculation from
serum/plasma creatinine (Cockcroft Gault formula); (ii) a hearing loss
(measured by audiometry) of 25 dB
at two contiguous frequencies; (iii) Grade 2 or greater peripheral neuropathy
(i.e., sensory alteration or
parasthesis including tingling); and (iv) ECOG Performance Status of 2.
III. THERAPEUTIC AND DIAGNOSTIC METHODS AND USES
A. Therapeutic methods and uses relating to cancers
Therapeutic methods and uses
Provided herein are methods and uses for treating cancer (e.g., a solid tumor
and/or a locally
advanced or metastatic cancer, e.g., a lung cancer (e.g., an early stage lung
cancer (e.g., a resectable
lung cancer), a small cell lung cancer (SCLC) (e.g., an extensive stage (ES)-
SCLC), a non-small cell lung
cancer (NSCLC) (e.g., a squamous NSCLC or a non-squamous NSCLC, a locally
advanced unresectable
NSCLC, a Stage IIIB NSCLC, a recurrent or metastatic NSCLC (e.g., a locally
advanced unresectable or
metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)), or a Stage
IV NSCLC (e.g.,
wherein the subject has not been previously treated for Stage IV NSCLC))); a
cervical cancer (e.g., a
Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a
metastatic and/or recurrent PD-L1-
positive cervical carcinoma); a breast cancer (e.g., a triple-negative breast
cancer (TNBC) (e.g., an
estrogen receptor negative (ER-), progesterone receptor negative (PR-), and
HER2 negative (HER2-)
breast cancer, e.g., an early TNBC (eTNBC)) or a HER2-positive breast cancer);
a head and neck cancer
(e.g., squamous cell carcinoma of the head and neck (SCCHN), e.g.,
recurrent/metastatic PD-L1-positive
SCCHN); a liver cancer (e.g., hepatocellular carcinoma (HCC), e.g., locally
advanced or metastatic HCC
and/or unresectable HCC); a bladder cancer (e.g., muscle-invasive bladder
cancer (MIBC) or locally
advanced or metastatic urothelial carcinoma (mUC)); an esophageal cancer; a
pancreatic cancer (e.g., a
pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC); a kidney or
renal cancer (e.g., a
renal cell carcinoma (RCC)); a melanoma; an ovarian cancer; a gastric cancer
(e.g., a gastroesophageal
junction cancer); or a colorectal cancer (CRC; e.g., CRC with microsatellite-
stable (MSS) or microsatellite
instability (MSI) low (MSI-Low)) in a subject comprising administering to the
subject one or more dosing
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cycles of an effective amount of an anti-TIGIT antagonist antibody (e.g., an
anti-TIGIT antagonist
antibody, e.g., tiragolumab), or a combination of both an anti-TIGIT
antagonist antibody and a PD-1 axis
binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as
atezolizumab, or an anti-PD-1
antagonist antibody such as pembrolizumab).
The present invention includes methods and uses involving administration of an
effective amount
of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody
as disclosed herein, e.g.,
tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1
antagonist antibody, such as
atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g.,
pembrolizumab) to a subject in need
thereof every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some
instances, administration
of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-
TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist
(e.g., an anti-PD-L1 antagonist
antibody, such as atezolizumab) results in a complete response (CR) or a
partial response (PR). In some
instances, administration of the effective amount of the anti-TIGIT antagonist
antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis
binding antagonist (e.g., an
anti-PD-L1 antagonist antibody, such as atezolizumab) results in an increase
in progression-free survival
(PFS) or duration of objective response (DOR). In some instances,
administration of the effective amount
of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody
as disclosed herein, e.g.,
tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1
antagonist antibody, such as
atezolizumab) results in an increase in overall survival (OS). In some
instances, administration of the
effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist
(e.g., an anti-PD-L1 antagonist
antibody, such as atezolizumab) results in an increase in PFS of the subject,
e.g., as compared to
treatment with the PD-1 axis binding antagonist without the anti-TIGIT
antagonist antibody or as
compared to treatment with the anti-TIGIT antagonist antibody without the PD-1
axis binding antagonist.
In some instances, the effective amount of the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis
binding antagonist (e.g., an
anti-PD-L1 antagonist antibody, such as atezolizumab) extends OS of the
subject, e.g., as compared to
treatment with the PD-1 axis binding antagonist without the anti-TIGIT
antagonist antibody or as
compared to treatment with the anti-TIGIT antagonist antibody without the PD-1
axis binding antagonist.
The present invention includes methods and uses involving administration of an
effective amount
of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody
as disclosed herein, e.g.,
tiragolumab) to a subject in need thereof every four weeks (e.g., on Day 1 of
each 28-day dosing cycle).
In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) is administered every four weeks (e.g.,
on Day 1 of each 28-day
dosing cycle) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1
antagonist antibody, e.g.,
atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g.,
pembrolizumab) is administered every
two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three
weeks (e.g., on Day 1 of
each 21-day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day
dosing cycle). In some
instances, administration of the effective amount of the anti-TIGIT antagonist
antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) results in a CR or
a PR. In some instances,
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administration of the effective amount of the anti-TIC IT antagonist antibody
(e.g., an anti-TIGIT antagonist
antibody as disclosed herein, e.g., tiragolumab) results in an increase in PFS
of the subject compared to
a reference. In some instances, administration of the effective amount of the
anti-TIGIT antagonist
antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) results in an
increase in DOR. In some instances, administration of the effective amount of
the anti-TIGIT antagonist
antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) extends OS of
the subject.
The present invention includes methods and uses involving administration of an
effective amount
of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody
as disclosed herein, e.g.,
tiragolumab) to a subject in need thereof every two weeks (e.g., on Days 1 and
15 of each 28-day dosing
cycle). In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-
TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab) is administered every two weeks (e.g., on
Days 1 and 15 of each 28-
day dosing cycle) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1
antagonist antibody, e.g.,
atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g.,
pembrolizumab) is administered every
two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three
weeks (e.g., on Day 1 of
each 21-day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day
dosing cycle). The
present invention includes methods and uses involving administration of an
effective amount of an anti-
TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab)
and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody,
such as atezolizumab, or an
anti-PD-1 antagonist antibody, such as e.g., pembrolizumab) to a subject in
need thereof every two
weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle). In some instances,
administration of the
effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist
(e.g., an anti-PD-L1 antagonist
antibody, such as atezolizumab) results in a CR or a PR. In some instances,
administration of the
effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist
(e.g., an anti-PD-L1 antagonist
antibody, such as atezolizumab) results in an increase in PFS of the subject,
e.g., as compared to
treatment with the PD-1 axis binding antagonist without the anti-TIGIT
antagonist antibody or as
compared to treatment with the anti-TIGIT antagonist antibody without the PD-1
axis binding antagonist.
In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an
anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the
PD-1 axis binding
antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab)
extends OS of the subject,
e.g., as compared to treatment with the PD-1 axis binding antagonist without
the anti-TIGIT antagonist
antibody or as compared to treatment with the anti-TIGIT antagonist antibody
without the PD-1 axis
binding antagonist.
The present invention includes methods and uses involving administration of an
effective amount
of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody
as disclosed herein, e.g.,
tiragolumab) to a subject in need thereof every three weeks (e.g., on Day 1 of
each 21-day dosing cycle).
In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) is administered every three weeks (e.g.,
on Day 1 of each 21-day
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dosing cycle) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1
antagonist antibody, e.g.,
atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g.,
pembrolizumab) is administered every
two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three
weeks (e.g., on Day 1 of
each 21-day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day
dosing cycle). In certain
instances, the present invention includes methods and uses involving
administration of an effective
amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist
antibody as disclosed herein,
e.g., tiragolumab) to a subject in need thereof every three weeks (e.g., on
Day 1 of each 21-day dosing
cycle). In some instances, administration of the effective amount of the anti-
TIGIT antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) results in a CR or a PR. In
some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an
anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results
in an increase in PFS of the
subject compared to a reference. In some instances, administration of the
effective amount of the anti-
TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab)
extends OS of the subject. In some instances, the present invention includes a
method of treating a
subject having a cancer, the method comprising administering to the subject a
dosing regimen comprising
one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of
about 500 mg to about 700
mg every three weeks, a PD-1 axis binding antagonist at a dose of about 900 mg
to about 1500 mg every
three weeks, a platinum-based chemotherapeutic agent every three weeks, and a
non-platinum-based
chemotherapeutic agent every three weeks. In some instances, the method
comprises administering to
the subject a dosing regimen comprising one or more dosing cycles of an anti-
TIGIT antagonist antibody
at a dose of 500 mg to 700 mg every three weeks, a PD-1 axis binding
antagonist at a dose of 900 mg to
1500 mg every three weeks, a platinum-based chemotherapeutic agent every three
weeks, and a non-
platinum-based chemotherapeutic agent every three weeks.
In certain instances, the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody are
administered without a chemotherapeutic agent (e.g., without any
chemotherapeutic agent, e.g., the
entire dosing regimen is devoid of administration of a chemotherapeutic agent
to the subject).
In some embodiments, the subject has not been previously treated with a
therapy (e.g., a cancer
immunotherapy and/or a chemotherapeutic agent) for the cancer. In some
embodiments, the subject has
received prior treatment with a therapy (e.g., a cancer immunotherapy and/or a
chemotherapeutic agent)
for the cancer. In some instances, the subject has not received prior systemic
therapy (e.g., e.g., prior
systemic therapy with curative intent, e.g., chemotherapy) within at least the
month prior to the
administration with the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody (e.g., within
the two months prior, three months prior, four months prior, six months prior,
one year prior, two years
prior, three years prior, four years prior, five years prior, or ten years
prior to the administration with the
PD-1 axis binding antagonist and the anti-TIC IT antagonist antibody). In some
instances, the subject is
chemotherapy naïve.
In some embodiments, the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody
are administered in conjunction with a chemotherapy. For example, a once-every-
two-weeks (02W),
once-every-three-weeks (03W), or once-every-four-weeks (04W) dosing regimen of
the PD-1 axis
binding antagonist and/or the anti-TIGIT antagonist antibody can be
administered in conjunction with one
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or more chemotherapeutic agents. The one or more chemotherapeutic agents can
be administered at the
same frequency as the frequency of administration of the PD-1 axis binding
antagonist and the anti-TIGIT
antagonist antibody (02W, 03W, or 04W) or at a different frequency (e.g., 3-
weeks on/1-week off
schedule (e.g., Days 1, 8, and 15 of every 28-day cycle)). For example, in
some embodiments, the PD-1
axis binding antagonist and the anti-TIGIT antagonist antibody are
administered every two weeks and the
one or more chemotherapeutic agents is administered every week, 3-weeks on/1-
week off, every two
weeks, every three weeks, or every four weeks. Alternatively, the PD-1 axis
binding antagonist and the
anti-TIGIT antagonist antibody are administered every three weeks and the one
or more
chemotherapeutic agents is administered every week, two weeks, every three
weeks, or every four
weeks. Alternatively, the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody are
administered every four weeks and the one or more chemotherapeutic agents is
administered every
week, 3-weeks on/1-week off, every two weeks, every three weeks, or every four
weeks. In certain
instances, a chemotherapeutic agent is administered multiple times per week
(e.g., 2, 3, 4, 5, 6 or 7 times
per week (e.g., at Days 1, 2, and 3 of a dosing cycle).
In some embodiments, the dose of a chemotherapeutic agent is reduced after one
or more initial
doses (e.g., after one, two, three, four, or more initial doses). For example,
a subsequent dose of the
chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent (e.g.,
carboplatin or cisplatin)
and/or one or more non-platinum-based chemotherapeutic agents (e.g., an
alkylating agent (e.g.,
cyclophosphamide), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a
topoisomerase II inhibitor
(e.g., doxorubicin))) can be administered at about 95%, 90%, 85%, 80%, 75%,
70%, 65%, 60%, 55%,
50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the initial dose. For
example, an initial dose
of nab-paclitaxel of 125 mg/m2 can be reduced for a subsequent dose, e.g., to
100 mg/m2 or 75 mg/m2;
an initial dose of nab-paclitaxel of 100 mg/m2 can be reduced for a subsequent
dose, e.g., to 75 mg/m2;
an initial dose of paclitaxel of about 175 mg/m2 can be reduced for a
subsequent dose, e.g., to 150
mg/m2, 125 mg/m2, 100 mg/m2, or 75 mg/m2; an initial dose of paclitaxel of
about 200 mg/m2 can be
reduced for a subsequent dose, e.g., to 175 mg/m2, 150 mg/m2, 125 mg/m2, 100
mg/m2, or 75 mg/m2; an
initial dose of gemcitabine of about 1000 mg/m2 can be reduced for a
subsequent dose, e.g., to 900
mg/m2, 800 mg/m2, 750 mg/m2, 700 mg/m2, 600 mg/m2, or 500 mg/m2; an initial
dose of cisplatin of about
75 mg/m2 can be reduced for a subsequent dose, e.g., to 70 mg/m2, 65 mg/m2, 60
mg/m2, 55 mg/m2, 50
mg/m2, or 45 mg/m2; an initial dose of pemetrexed of about 500 mg/m2 can be
reduced for a subsequent
dose, e.g., to 450 mg/m2, 400 mg/m2, 350 mg/m2, 300 mg/m2, 250 mg/m2, or 200
mg/m2; and/or an initial
dose of carboplatin of a dose sufficient to achieve AUC = 6 mg/ml/min can be
reduced for a subsequent
dose, e.g., to a dose sufficient to achieve AUG = 5.5. mg/ml/mm, 5.0
mg/ml/min, 4.5 mg/ml/min, or 4.0
mg/ml/min. In some examples, an initial dose of nab-paclitaxel of 125 mg/m2
can be reduced for a
subsequent dose, e.g., to 100 mg/m2 or 75 mg/m2; an initial dose of nab-
paclitaxel of 100 mg/m2 can be
reduced for a subsequent dose, e.g., to 75 mg/m2; an initial dose of
paclitaxel of 175 mg/m2 can be
reduced for a subsequent dose, e.g., to 150 mg/m2, 125 mg/m2, 100 mg/m2, or 75
mg/m2; an initial dose
of paclitaxel of 200 mg/m2 can be reduced for a subsequent dose, e.g., to 175
mg/m2, 150 mg/m2, 125
mg/m2, 100 mg/m2, or 75 mg/m2; an initial dose of gemcitabine of 1000 mg/m2
can be reduced for a
subsequent dose, e.g., to 900 mg/m2, 800 mg/m2, 750 mg/m2, 700 mg/m2, 600
mg/m2, or 500 mg/m2; an
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initial dose of cisplatin of 75 mg/m2 can be reduced for a subsequent dose,
e.g., to 70 mg/m2, 65 mg/m2,
60 mg/m2, 55 mg/m2, 50 mg/m2, or 45 mg/m2; an initial dose of pemetrexed of
500 mg/m2 can be reduced
for a subsequent dose, e.g., to 450 mg/m2, 400 mg/m2, 350 mg/m2, 300 mg/m2,
250 mg/m2, or 200
mg/m2; and/or an initial dose of carboplatin of a dose sufficient to achieve
AUC = 6 mg/ml/min can be
reduced for a subsequent dose, e.g., to a dose sufficient to achieve AUC =
5.5. mg/ml/min, 5.0
mg/ml/min, 4.5 mg/ml/min, or 4.0 mg/ml/min.
The present invention includes methods and uses involving administration of an
effective amount
of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody
as disclosed herein, e.g.,
tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist
antibody, such as
.. atezolizumab, or an anti-PD-1 antagonist antibody such as pembrolizumab),
and a chemotherapy
combination to a subject in need thereof. In some embodiments, the anti-TIGIT
antagonist antibody (e.g.,
anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the
PD-1 axis binding
antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are
administered every two
weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three weeks
(e.g., on Day 1 of each
21-day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day
dosing cycle). In some
instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist
antibody as disclosed herein,
e.g., tiragolumab) is administered every four weeks (e.g., on Day 1 of each 28-
day dosing cycle) and the
PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g.,
atezolizumab) is administered
every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every
three weeks (e.g., on Day 1
of each 21-day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-
day dosing cycle). In some
instances, the chemotherapy combination includes an effective amount of a
first non-platinum-based
chemotherapeutic agent and an effective amount of a second non-platinum-based
chemotherapeutic
agent. In some instances, the first non-platinum-based chemotherapeutic agent
is an antimetabolite and
the second non-platinum-based chemotherapeutic agent is a taxane. In some
embodiments, the
chemotherapy combination (e.g., the antimetabolite (e.g., gemcitabine,
pemetrexed, or capecitabine) and
the taxane (e.g., nab-paclitaxel and paclitaxel)) is administered weekly,
biweekly, or three times every
four weeks (e.g., on Days 1, 8, and 15 of each 28-day dosing cycle).
In particular embodiments, the method involves administration of an effective
amount of an anti-
TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab),
a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g.,
atezolizumab), gemcitabine,
and paclitaxel to a subject in need thereof, wherein the anti-TIGIT antagonist
antibody (e.g., anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis
binding antagonist (e.g., an
anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every two
weeks (e.g., on Days 1
and 15 of each 28-day dosing cycle) and the chemotherapy combination (e.g.,
the antimetabolite and the
taxane (e.g., gemcitabine and paclitaxel)) is administered more frequently
(e.g., three times every four
weeks (e.g., on Days 1, 8, and 15 of each 28-day dosing cycle).
In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab), the PD-1 axis binding
antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the
antimetabolite (e.g.,
gemcitabine), and the taxane (e.g., paclitaxel) results in a CR or a PR. In
some instances, administration
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of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-
TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g.,
anti-PD-L1 antagonist
antibody, such as atezolizumab), the antimetabolite (e.g., gemcitabine), and
the taxane (e.g., paclitaxel)
results in an increase in PFS of the subject. In some instances,
administration of the effective amount of
the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g.,
tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist
antibody, such as
atezolizumab), the antimetabolite (e.g., gemcitabine), and the taxane (e.g.,
paclitaxel) extends OS of the
subject.
The present invention includes methods and uses involving administration of an
effective amount
of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody
as disclosed herein, e.g.,
tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist
antibody, such as
atezolizumab, or an anti-PD-1 antagonist antibody such as pembrolizumab), and
a chemotherapy
combination to a subject in need thereof, wherein the chemotherapy combination
includes an effective
amount of a platinum-based chemotherapeutic agent and an effective amount of a
non-platinum-based
chemotherapeutic agent. In some instances, the anti-TIGIT antagonist antibody
(e.g., anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis
binding antagonist (e.g., an
anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every two
weeks (e.g., on Days 1
and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each
21-day dosing cycle), or
every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some
instances, the platinum-based
.. chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-
based chemotherapeutic agent is
an antimetabolite (e.g., pemetrexed). In some embodiments, the chemotherapy
combination (e.g., the
platinum-based chemotherapeutic agent and the antimetabolite (e.g.,
pemetrexed)) are administered
weekly, every two weeks, every four weeks, or three times every four weeks
(e.g., on Days 1, 8, and 15
of each 28-day dosing cycle).
In particular embodiments, the method involves administration of an effective
amount of an anti-
TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab),
a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g.,
atezolizumab), a platinum-
based chemotherapeutic agent (e.g., carboplatin or cisplatin), and an
antimetabolite (e.g., pemetrexed) to
a subject in need thereof, wherein the anti-TIGIT antagonist antibody (e.g.,
anti-TIGIT antagonist antibody
as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist
(e.g., an anti-PD-L1
antagonist antibody, e.g., atezolizumab) are administered every three weeks
(e.g., on Day 1 of each 21-
day dosing cycle) and the chemotherapy combination (e.g., the platinum-based
chemotherapeutic agent
(e.g., carboplatin or cisplatin) and the antimetabolite (e.g., pemetrexed) are
administered at the same
frequency (e.g., every three weeks, e.g., on Day 1 of each 21-day dosing
cycle). In some instances, the
dosing continues for four-to-six induction dosing cycles (e.g., four induction
dosing cycles, five induction
dosing cycles, or six induction dosing cycles). After the induction dosing
cycles, maintenance therapy
can be administered in one or more subsequent (maintenance) dosing cycles. In
certain embodiments,
the one or more maintenance dosing cycles does not include the platinum-based
chemotherapeutic
agent.
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In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab), the PD-1 axis binding
antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the
platinum-based
chemotherapeutic agent (e.g., carboplatin or cisplatin), and the
antimetabolite (e.g., pemetrexed) results
in a CR or a PR. In some instances, administration of the effective amount of
the anti-TIGIT antagonist
antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab), the PD-1 axis
binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as
atezolizumab), the platinum-based
chemotherapeutic agent (e.g., carboplatin or cisplatin), and the
antimetabolite (e.g., pemetrexed) results
in an increase in PFS of the subject. In some instances, administration of the
effective amount of the
anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g.,
tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist
antibody, such as
atezolizumab), the platinum-based chemotherapeutic agent (e.g., carboplatin or
cisplatin), and the
antimetabolite (e.g., pemetrexed) extends OS of the subject.
In some instances, the subject receiving the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis
binding antagonist (e.g., anti-
PD-L1 antagonist antibody, such as atezolizumab), the platinum-based
chemotherapeutic agent (e.g.,
carboplatin or cisplatin), and the antimetabolite (e.g., pemetrexed) is being
treated for a solid tumor or a
locally advanced or metastatic cancer. Additionally or alternatively, the
cancer may be a lung cancer
(e.g., an early stage lung cancer (e.g., a resectable lung cancer), a SCLC
(e.g., an ES-SCLC), a NSCLC
(e.g., a squamous NSCLC or a non-squamous NSCLC, a locally advanced
unresectable NSCLC, a Stage
IIIB NSCLC, a recurrent or metastatic NSCLC (e.g., a locally advanced
unresectable or metastatic non-
squamous NSCLC (e.g., Stage IV non-squamous NSCLC)), or a Stage IV NSCLC
(e.g., wherein the
subject has not been previously treated for Stage IV NSCLC))); a cervical
cancer (e.g., a Stage IVB,
metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic
and/or recurrent PD-L1-positive
cervical carcinoma); a breast cancer (e.g., a TNBC (e.g., an early TNBC
(eTNBC))) or a HER2-positive
breast cancer); a head and neck cancer (e.g., SCCHN, e.g.,
recurrent/metastatic PD-L1-positive
SCCHN); a liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC
and/or unresectable HCC);
a bladder cancer (e.g., MIBC, locally advanced UC, or mUC); an esophageal
cancer; a pancreatic cancer
(e.g., PDAC, e.g., metastatic PDAC); a kidney or renal cancer (e.g., a RCC); a
melanoma; an ovarian
cancer; a gastric cancer (e.g., a gastroesophageal junction cancer); or a CRC
(e.g., MSS or MSI-Low
CRC).
The present invention also includes methods and uses involving administration
of an effective
amount of an anti-TIC IT antagonist antibody (e.g., an anti-TIGIT antagonist
antibody as disclosed herein,
e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1
antagonist antibody, such as
atezolizumab, or an anti-PD-1 antagonist antibody such as pembrolizumab), and
a chemotherapy (e.g., a
taxane (e.g., paclitaxel or nab-paclitaxel)) to a subject in need thereof. In
some instances, the anti-TIGIT
antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein,
e.g., tiragolumab) and the
PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g.,
atezolizumab) are
administered every two weeks (e.g., on Days 1 and 15 of each 28-day dosing
cycle), every three weeks
(e.g., on Day 1 of each 21-day dosing cycle), or every four weeks (e.g., on
Day 1 of each 28-day dosing
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cycle). In some instances, the anti-TIGIT antagonist antibody (e.g., anti-
TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist
(e.g., an anti-PD-L1 antagonist
antibody, e.g., atezolizumab) are administered every four weeks (e.g., on Day
1 of each 28-day dosing
cycle). In some embodiments, the chemotherapy is administered weekly, every
two weeks, every four
weeks, or three times every four weeks (e.g., on Days 1, 8, and 15 of each 28-
day dosing cycle). In
some embodiments, the chemotherapy is administered weekly.
In some instances, administration of an effective amount of an anti-TIGIT
antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab), a PD-1 axis binding
antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab, or
an anti-PD-1 antagonist
antibody such as pembrolizumab), and a chemotherapy (e.g., a taxane (e.g.,
paclitaxel or nab-paclitaxel))
results in a CR or a PR. In some instances, administration of an effective
amount of an anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed
herein, e.g., tiragolumab), a PD-
1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as
atezolizumab, or an anti-PD-1
antagonist antibody such as pembrolizumab), and a chemotherapy (e.g., a taxane
(e.g., paclitaxel or nab-
paclitaxel)) results in an increase in PFS of the subject compared to a
reference. In some instances,
administration of an effective amount of an anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT antagonist
antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding
antagonist (e.g., an anti-PD-L1
antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody
such as pembrolizumab),
and a chemotherapy (e.g., a taxane (e.g., paclitaxel or nab-paclitaxel))
results in an increase in DOR. In
some instances, administration of an effective amount of an anti-TIGIT
antagonist antibody (e.g., an anti-
TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis
binding antagonist (e.g., an
anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1
antagonist antibody such as
pembrolizumab), and a chemotherapy (e.g., a taxane (e.g., paclitaxel or nab-
paclitaxel)) extends OS of
the subject.
The present invention also includes methods and uses involving administration
of an effective
amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist
antibody as disclosed herein,
e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1
antagonist antibody, such as
atezolizumab, or an anti-PD-1 antagonist antibody such as pembrolizumab), and
a chemotherapy
combination to a subject in need thereof, wherein the chemotherapy combination
includes an effective
amount of a platinum-based chemotherapeutic agent and an effective amount of a
non-platinum-based
chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent
is a taxane (e.g.,
paclitaxel or nab-paclitaxel). In some instances, the anti-TIGIT antagonist
antibody (e.g., anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis
binding antagonist (e.g., an
anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every two
weeks (e.g., on Days 1
and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each
21-day dosing cycle), or
every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some
embodiments, the chemotherapy
combination (e.g., the platinum-based chemotherapeutic agent and the taxane
(e.g., paclitaxel or nab-
paclitaxel)) are administered weekly, every two weeks, every four weeks, or
three times every four weeks
(e.g., on Days 1, 8, and 15 of each 28-day dosing cycle).
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In particular embodiments, the method involves administration of an effective
amount of an anti-
TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab),
a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g.,
atezolizumab), a platinum-
based chemotherapeutic agent (e.g., carboplatin or cisplatin), and a taxane
(e.g., paclitaxel or nab-
.. paclitaxel) to a subject in need thereof, wherein the anti-TIGIT antagonist
antibody (e.g., anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis
binding antagonist (e.g., an
anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every
three weeks (e.g., on Day 1
of each 21-day dosing cycle) and the chemotherapy combination (e.g., the
platinum-based
chemotherapeutic agent (e.g., carboplatin or cisplatin) and the taxane (e.g.,
paclitaxel or nab-paclitaxel)
are administered at the same frequency (e.g., every three weeks, e.g., on Day
1 of each 21-day dosing
cycle). In some instances, the dosing continues for four-to-six induction
dosing cycles (e.g., four
induction dosing cycles, five induction dosing cycles, or six induction dosing
cycles). After the induction
dosing cycles, maintenance therapy can be administered in one or more
subsequent (maintenance)
dosing cycles. In certain embodiments, the one or more maintenance dosing
cycles does not include the
platinum-based chemotherapeutic agent.
In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab), the PD-1 axis binding
antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the
platinum-based
chemotherapeutic agent (e.g., carboplatin or cisplatin), and the taxane (e.g.,
paclitaxel or nab-paclitaxel)
results in a CR or a PR. In some instances, administration of the effective
amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed
herein, e.g., tiragolumab), the
PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as
atezolizumab), the platinum-
based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the taxane
(e.g., paclitaxel or nab-
paclitaxel) results in an increase in PFS of the subject. In some instances,
administration of the effective
amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist
antibody as disclosed herein,
e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1
antagonist antibody, such as
atezolizumab), the platinum-based chemotherapeutic agent (e.g., carboplatin or
cisplatin), and the taxane
(e.g., paclitaxel or nab-paclitaxel) extends OS of the subject.
In some instances, the subject receiving the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis
binding antagonist (e.g., anti-
PD-L1 antagonist antibody, such as atezolizumab), the platinum-based
chemotherapeutic agent (e.g.,
carboplatin or cisplatin), and the taxane (e.g., paclitaxel or nab-paclitaxel)
is being treated for a solid
tumor or a locally advanced or metastatic cancer. Additionally or
alternatively, the cancer may be a lung
cancer (e.g., an early stage lung cancer (e.g., a resectable lung cancer), a
SCLC (e.g., an ES-SCLC), a
NSCLC (e.g., a squamous NSCLC or a non-squamous NSCLC, a locally advanced
unresectable NSCLC,
a Stage IIIB NSCLC, a recurrent or metastatic NSCLC (e.g., a locally advanced
unresectable or
metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)), or a Stage
IV NSCLC (e.g.,
wherein the subject has not been previously treated for Stage IV NSCLC))); a
cervical cancer (e.g., a
Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a
metastatic and/or recurrent PD-L1-
positive cervical carcinoma); a breast cancer (e.g., a TNBC (e.g., an early
TNBC (eTNBC))) or a HER2-
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positive breast cancer); a head and neck cancer (e.g., SCCHN, e.g.,
recurrent/metastatic PD-L1-positive
SCCHN); a liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC
and/or unresectable HCC);
a bladder cancer (e.g., MIBC, locally advanced UC, or mUC); an esophageal
cancer; a pancreatic cancer
(e.g., PDAC, e.g., metastatic PDAC); a kidney or renal cancer (e.g., a RCC); a
melanoma; an ovarian
cancer; a gastric cancer (e.g., a gastroesophageal junction cancer); or a CRC
(e.g., MSS or MSI-Low
CRC).
Also provided herein are methods and uses involving administration of an
effective amount of an
anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g.,
tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist
antibody, such as
atezolizumab, or an anti-PD-1 antagonist antibody such as pembrolizumab), and
a chemotherapy
combination to a subject in need thereof, wherein the chemotherapy combination
includes an effective
amount of a platinum-based chemotherapeutic agent and an effective amount of a
non-platinum-based
chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent
is a topoisomerase II
inhibitor (e.g., etoposide). In some instances, the anti-TIGIT antagonist
antibody (e.g., anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis
binding antagonist (e.g., an
anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every two
weeks (e.g., on Days 1
and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each
21-day dosing cycle), or
every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some
embodiments, the chemotherapy
combination (e.g., the platinum-based chemotherapeutic agent and the
topoisomerase II inhibitor (e.g.,
etoposide)) are administered weekly, every two weeks, every four weeks, or
three times every four weeks
(e.g., on Days 1, 8, and 15 of each 28-day dosing cycle). In some embodiments,
the topoisomerase II
inhibitor (e.g., etoposide) is administered more frequently than the platinum-
based chemotherapeutic
agent (e.g., three times per week, e.g., on Days 1, 2, and 3 of each dosing
cycle).
In particular embodiments, the method involves administration of an effective
amount of an anti-
TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab),
a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g.,
atezolizumab), a platinum-
based chemotherapeutic agent (e.g., carboplatin or cisplatin), and a
topoisomerase II inhibitor (e.g.,
etoposide) to a subject in need thereof, wherein the anti-TIGIT antagonist
antibody (e.g., anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis
binding antagonist (e.g., an
anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered every
three weeks (e.g., on Day 1
of each 21-day dosing cycle) and the chemotherapy combination (e.g., the
platinum-based
chemotherapeutic agent (e.g., carboplatin or cisplatin) and the topoisomerase
II inhibitor (e.g., etoposide)
are administered at the same frequency (e.g., every three weeks, e.g., on Day
1 of each 21-day dosing
cycle). In some instances, the dosing continues for four-to-six induction
dosing cycles (e.g., four
induction dosing cycles, five induction dosing cycles, or six induction dosing
cycles). After the induction
dosing cycles, maintenance therapy can be administered in one or more
subsequent (maintenance)
dosing cycles. In certain embodiments, the one or more maintenance dosing
cycles does not include the
platinum-based chemotherapeutic agent or the topoisomerase II inhibitor (e.g.,
etoposide).
In some instances, the effective amount of the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis
binding antagonist (e.g., anti-
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PD-L1 antagonist antibody, such as atezolizumab), the platinum-based
chemotherapeutic agent (e.g.,
carboplatin or cisplatin), and the topoisomerase II inhibitor (e.g.,
etoposide) results in (a) a CR or a PR.
In some instances, the effective amount of the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis
binding antagonist (e.g., anti-
PD-L1 antagonist antibody, such as atezolizumab), the platinum-based
chemotherapeutic agent (e.g.,
carboplatin or cisplatin), and the topoisomerase II inhibitor (e.g.,
etoposide) results in an increase in PFS
of the subject. In some instances, the effective amount of the anti-TIGIT
antagonist antibody (e.g., an
anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-
1 axis binding antagonist
(e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum-
based chemotherapeutic
agent (e.g., carboplatin or cisplatin), and the topoisomerase II inhibitor
(e.g., etoposide) extends OS of the
subject.
In some instances, the subject receiving the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis
binding antagonist (e.g., anti-
PD-L1 antagonist antibody, such as atezolizumab), the platinum-based
chemotherapeutic agent (e.g.,
carboplatin or cisplatin), and the topoisomerase II inhibitor (e.g.,
etoposide) is being treated for a solid
tumor or a locally advanced or metastatic cancer. Additionally or
alternatively, the cancer may be a lung
cancer (e.g., an early stage lung cancer (e.g., a resectable lung cancer), a
SCLC (e.g., an ES-SCLC), a
NSCLC (e.g., a squamous NSCLC or a non-squamous NSCLC, a locally advanced
unresectable NSCLC,
a Stage IIIB NSCLC, a recurrent or metastatic NSCLC (e.g., a locally advanced
unresectable or
metastatic non-squamous NSCLC (e.g., Stage IV non-squamous NSCLC)), or a Stage
IV NSCLC (e.g.,
wherein the subject has not been previously treated for Stage IV NSCLC))); a
cervical cancer (e.g., a
Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a
metastatic and/or recurrent PD-L1-
positive cervical carcinoma); a breast cancer (e.g., a TNBC (e.g., an early
TNBC (eTNBC))) or a HER2-
positive breast cancer); a head and neck cancer (e.g., SCCHN, e.g.,
recurrent/metastatic PD-L1-positive
SCCHN); a liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC
and/or unresectable HCC);
a bladder cancer (e.g., MIBC, locally advanced UC, or mUC); an esophageal
cancer; a pancreatic cancer
(e.g., PDAC, e.g., metastatic PDAC); a kidney or renal cancer (e.g., a RCC); a
melanoma; an ovarian
cancer; a gastric cancer (e.g., a gastroesophageal junction cancer); or a CRC
(e.g., MSS or MSI-Low
CRC).
Also provided herein are methods and uses involving administration of an
effective amount of an
anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g.,
tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist
antibody, such as
atezolizumab, or an anti-PD-1 antagonist antibody such as pembrolizumab), and
a VEGF antagonist
(e.g., an anti-VEGF antibody (e.g., bevacizumab)) to a subject in need
thereof. In some instances, the
anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody as
disclosed herein, e.g.,
tiragolumab), the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist
antibody, e.g.,
atezolizumab), and the VEGF antagonist (e.g., an anti-VEGF antibody (e.g.,
bevacizumab)) are
administered every three weeks (e.g., on Day 1 of each 21-day dosing cycle).
In particular embodiments, the method involves administration of an effective
amount of an anti-
TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab),
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a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g.,
atezolizumab), and the
VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) to a subject
in need thereof, wherein
the anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody as
disclosed herein, e.g.,
tiragolumab), the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist
antibody, e.g.,
atezolizumab), and the VEGF antagonist (e.g., an anti-VEGF antibody (e.g.,
bevacizumab)) are
administered every three weeks (e.g., on Day 1 of each 21-day dosing cycle).
In some instances, the
effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g.,
anti-PD-L1 antagonist
antibody, such as atezolizumab), and the VEGF antagonist (e.g., an anti-VEGF
antibody (e.g.,
bevacizumab)) results in an increase in OS of the subject. In some instances,
the effective amount of the
anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g.,
tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist
antibody, such as
atezolizumab), and the VEGF antagonist (e.g., an anti-VEGF antibody (e.g.,
bevacizumab)) results in an
increase in PFS of the subject.
In some instances, the subject receiving the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis
binding antagonist (e.g., anti-
PD-L1 antagonist antibody, such as atezolizumab), and the VEGF antagonist
(e.g., an anti-VEGF
antibody (e.g., bevacizumab)) is being treated for a solid tumor or a locally
advanced or metastatic
cancer. Additionally or alternatively, the cancer may be a lung cancer (e.g.,
an early stage lung cancer
(e.g., a resectable lung cancer), a SCLC (e.g., an ES-SCLC), a NSCLC (e.g., a
squamous NSCLC or a
non-squamous NSCLC, a locally advanced unresectable NSCLC, a Stage IIIB NSCLC,
a recurrent or
metastatic NSCLC (e.g., a locally advanced unresectable or metastatic non-
squamous NSCLC (e.g.,
Stage IV non-squamous NSCLC)), or a Stage IV NSCLC (e.g., wherein the subject
has not been
previously treated for Stage IV NSCLC))); a cervical cancer (e.g., a Stage
IVB, metastatic, recurrent, or
.. persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-
positive cervical carcinoma); a breast
cancer (e.g., a TNBC (e.g., an eTNBC)) or a HER2-positive breast cancer); a
head and neck cancer (e.g.,
SCCHN, e.g., recurrent/metastatic PD-L1-positive SCCHN); a liver cancer (e.g.,
HCC, e.g., locally
advanced or metastatic HCC and/or unresectable HCC); a bladder cancer (e.g.,
MIBC, locally advanced
UC, or mUC); an esophageal cancer; a pancreatic cancer (e.g., PDAC, e.g.,
metastatic PDAC); a kidney
or renal cancer (e.g., a RCC); a melanoma; an ovarian cancer; a gastric cancer
(e.g., a gastroesophageal
junction cancer); or a CRC (e.g., MSS or MSI-Low CRC).
The present invention includes a method of treating cancer in a cancer patient
comprising
administering to the patient a combination of atezolizumab, bevacizumab, and
tiragolumab in an amount
effective to treat the cancer.
Also provided herein are methods and uses involving administration of an
effective amount of an
anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g.,
tiragolumab), an anti-PD-1 antagonist antibody, and a VEGF antagonist (e.g.,
an anti-VEGF antibody
(e.g., bevacizumab)) to a subject in need thereof, wherein the anti-PD-1
antagonist antibody is
pembrolizumab. In some instances, the anti-TIGIT antagonist antibody (e.g.,
anti-TIGIT antagonist
antibody as disclosed herein, e.g., tiragolumab), an anti-PD-1 antagonist
antibody, and a VEGF
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antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) are administered
every three weeks (e.g.,
on Day 1 of each 21-day dosing cycle), wherein the anti-PD-1 antagonist
antibody is pembrolizumab.
In particular embodiments, the method involves administration of an effective
amount of an anti-
TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab),
an anti-PD-1 antagonist antibody, and a VEGF antagonist (e.g., an anti-VEGF
antibody (e.g.,
bevacizumab)) to a subject in need thereof, wherein the anti-TIGIT antagonist
antibody (e.g., anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the anti-PD-1
antagonist antibody, and the
VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) are
administered every three weeks
(e.g., on Day 1 of each 21-day dosing cycle), wherein the anti-PD-1 antagonist
antibody is
pembrolizumab. In some instances, the effective amount of the anti-TIGIT
antagonist antibody (e.g., an
anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the
anti-PD-1 antagonist antibody,
and the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab))
results in an increase in OS
of the subject, wherein the anti-PD-1 antagonist antibody is pembrolizumab. In
some instances, the
effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab), the anti-PD-1 antagonist antibody, and
the VEGF antagonist (e.g., an
anti-VEGF antibody (e.g., bevacizumab)) results in an increase in PFS of the
subject, wherein the anti-
PD-1 antagonist antibody is pembrolizumab.
In some instances, the subject receiving the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab), the anti-PD-1
antagonist antibody, and the
VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is being
treated for a solid tumor or a
locally advanced or metastatic cancer, wherein the anti-PD-1 antagonist
antibody is pembrolizumab.
Additionally or alternatively, the cancer may be a lung cancer (e.g., an early
stage lung cancer (e.g., a
resectable lung cancer), a SCLC (e.g., an ES-SCLC), a NSCLC (e.g., a squamous
NSCLC or a non-
squamous NSCLC, a locally advanced unresectable NSCLC, a Stage IIIB NSCLC, a
recurrent or
metastatic NSCLC (e.g., a locally advanced unresectable or metastatic non-
squamous NSCLC (e.g.,
Stage IV non-squamous NSCLC)), or a Stage IV NSCLC (e.g., wherein the subject
has not been
previously treated for Stage IV NSCLC))); a cervical cancer (e.g., a Stage
IVB, metastatic, recurrent, or
persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive
cervical carcinoma); a breast
cancer (e.g., a TNBC (e.g., an eTNBC)) or a HER2-positive breast cancer); a
head and neck cancer (e.g.,
SCCHN, e.g., recurrent/metastatic PD-L1-positive SCCHN); a liver cancer (e.g.,
HCC, e.g., locally
advanced or metastatic HCC and/or unresectable HCC); a bladder cancer (e.g.,
MIBC, locally advanced
UC, or mUC); an esophageal cancer; a pancreatic cancer (e.g., PDAC, e.g.,
metastatic PDAC); a kidney
or renal cancer (e.g., a RCC); a melanoma; an ovarian cancer; a gastric cancer
(e.g., a gastroesophageal
junction cancer); or a CRC (e.g., MSS or MSI-Low CRC).
Also provided herein are methods and uses involving administration of an
effective amount of
tiragolumab and pembrolizumab to a subject in need thereof. In some instances,
tiragolumab is
administered every three weeks (e.g., on Day 1 and Day 22 of each 42-day
dosing cycle) and
pembrolizumab is administered every six weeks (e.g., on Day 1 of each 42-day
dosing cycle).
In particular embodiments, the method involves administration of an effective
amount of
tiragolumab and pembrolizumab to a subject in need thereof, wherein
tiragolumab is administered every
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three weeks (e.g., on Day 1 and Day 22 of each 42-day dosing cycle) and
pembrolizumab is administered
every six weeks (e.g., on Day 1 of each 42-day dosing cycle). In some
instances, the effective amount of
tiragolumab and pembrolizumab results in an increase in OS of the subject,
wherein the anti-PD-1
antagonist antibody is pembrolizumab. In some instances, the effective amount
of tiragolumab and
pembrolizumab results in an increase in PFS of the subject, wherein the anti-
PD-1 antagonist antibody is
pembrolizumab.
In some instances, the subject receiving tiragolumab and pembrolizumab is
being treated for a
solid tumor or a locally advanced or metastatic cancer, wherein the anti-PD-1
antagonist antibody is
pembrolizumab. Additionally or alternatively, the cancer may be a lung cancer
(e.g., an early stage lung
cancer (e.g., a resectable lung cancer), a SCLC (e.g., an ES-SCLC), a NSCLC
(e.g., a squamous NSCLC
or a non-squamous NSCLC, a locally advanced unresectable NSCLC, a Stage IIIB
NSCLC, a recurrent or
metastatic NSCLC (e.g., a locally advanced unresectable or metastatic non-
squamous NSCLC (e.g.,
Stage IV non-squamous NSCLC)), or a Stage IV NSCLC (e.g., wherein the subject
has not been
previously treated for Stage IV NSCLC))); a cervical cancer (e.g., a Stage
IVB, metastatic, recurrent, or
persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive
cervical carcinoma); a breast
cancer (e.g., a TNBC (e.g., an eTNBC)) or a HER2-positive breast cancer); a
head and neck cancer (e.g.,
SCCHN, e.g., recurrent/metastatic PD-L1-positive SCCHN); a liver cancer (e.g.,
HCC, e.g., locally
advanced or metastatic HCC and/or unresectable HCC); a bladder cancer (e.g.,
MIBC, locally advanced
UC, or mUC); an esophageal cancer; a pancreatic cancer (e.g., PDAC, e.g.,
metastatic PDAC); a kidney
or renal cancer (e.g., a RCC); a melanoma; an ovarian cancer; a gastric cancer
(e.g., a gastroesophageal
junction cancer); or a CRC (e.g., MSS or MSI-Low CRC).
Also provided herein are methods of treating a subject having a cancer, the
methods comprising
administering to the subject a dosing regimen comprising one or more dosing
cycles of an anti-TIGIT
antagonist antibody at a dose of about 500 mg to about 700 mg every three
weeks, a PD-1 axis binding
antagonist at a dose of about 900 mg to about 1500 mg every three weeks, a
platinum-based
chemotherapeutic agent every three weeks, and a non-platinum-based
chemotherapeutic agent every
three weeks. In some instances, the method comprises an induction phase and a
maintenance phase.
In some instances, the induction phase and maintenance phase each comprise one
or more dosing
cycles. In some instances, the maintenance phase does not comprise
administration of the platinum-
based chemotherapeutic agent. In some instances, the maintenance phase does
not comprise
administration of the non-platinum-based chemotherapeutic agent. In some
instances, the maintenance
phase comprises one or more dosing cycles of an anti-TIGIT antagonist antibody
at a dose of about 700
mg to about 1000 mg every four weeks and a PD-1 axis binding antagonist at a
dose of about 1400 mg to
2000 mg every four weeks.
Also provided herein are methods of treating a subject having a cancer, the
methods comprising
administering to the subject a dosing regimen comprising one or more dosing
cycles of an anti-TIGIT
antagonist antibody at a dose of about 500 mg to about 700 mg every three
weeks and an anti-PD-1
antagonist antibody at a dose of about 100 mg to about 300 mg every three
weeks, wherein the anti-PD-1
antagonist antibody is pembrolizumab.
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Also provided herein are an anti-TIGIT antagonist antibody and a PD-1 axis
binding antagonist
for use in a method of treating a subject or population of subjects having a
cancer, wherein the method is
according to a method provided herein.
Also provided herein is use of an anti-TIGIT antagonist antibody in the
manufacture of a
medicament for treating a subject or population of subjects having a cancer in
combination with a PD-1
axis binding antagonist, wherein the treatment is according to a method
provided herein. In some
aspects, the PD-1 axis binding antagonist are provided in separate
formulations. In other aspects, the
anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are
provided in a single formulation.
In some aspects, tiragolumab and atezolizumab are combined in an IV bag prior
to administration.
Dosing of agents
Dosing of anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists,
VEGF antagonists,
and chemotherapeutic agents is described in Section III(K).
Cancer characterization and selection
In any of the methods, uses, or compositions for use described herein, the
cancer may be solid
tumor or a locally advanced or metastatic cancer. In some instances, the
cancer is a lung cancer (e.g.,
an early stage lung cancer (e.g., a resectable lung cancer), a SCLC (e.g., an
ES-SCLC), a NSCLC (e.g.,
a squamous NSCLC or a non-squamous NSCLC, a locally advanced unresectable
NSCLC, a Stage IIIB
NSCLC, a recurrent or metastatic NSCLC (e.g., a locally advanced unresectable
or metastatic non-
squamous NSCLC (e.g., Stage IV non-squamous NSCLC)), or a Stage IV NSCLC
(e.g., wherein the
subject has not been previously treated for Stage IV NSCLC))); a cervical
cancer (e.g., a Stage IVB,
metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic
and/or recurrent PD-L1-positive
cervical carcinoma); a breast cancer (e.g., a TNBC (e.g., an early TNBC
(eTNBC))) or a HER2-positive
breast cancer); a head and neck cancer (e.g., SCCHN, e.g.,
recurrent/metastatic PD-L1-positive
.. SCCHN); a liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC
and/or unresectable HCC);
a bladder cancer (e.g., MIBC, locally advanced UC, or mUC); an esophageal
cancer; a pancreatic cancer
(e.g., PDAC, e.g., metastatic PDAC); a kidney or renal cancer (e.g., a RCC); a
melanoma; an ovarian
cancer; a gastric cancer (e.g., a gastroesophageal junction cancer); or a CRC
(e.g., MSS or MSI-Low
CRC). In some instances in which the subject has a breast cancer, the subject
has not received prior
systemic therapy for metastatic breast cancer.
In some instances, in any of the methods, uses, or compositions for use
described herein, the
subject has no epidermal growth factor receptor (EGFR) or anaplastic lymphoma
kinase (ALK) genomic
tumor aberrations. In some instances, in any of the methods, uses, or
compositions for use described
herein, the subject does not have a sensitizing EGFR gene mutation or ALK gene
rearrangement. In
some instances, the subject has an Eastern Cooperative Oncology Group (ECOG)
Performance Status
(PS) of 0 or 1.
Methods for detecting the mutational status EGFR and ALK are well known in the
art, and
include, but are not limited to, sequencing DNA from clinical samples (e.g.,
tumor biopsies or blood
samples (e.g., circulating tumor DNA in blood)) using a next-generation
sequencing method, such as the
.. targeted gene pulldown and sequencing method described in Frampton et al.
(Nature Biotechnology.
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31(11): 1023-1033, 2013), which is incorporated by reference herein in its
entirety. Such a next-
generation sequencing method can be used with any of the methods disclosed
herein to detect various
mutations (e.g., insertions, deletions, base substitutions, focal gene
amplifications, and/or homozygous
gene deletions), while enabling the use of small samples (e.g., from small-
core needle biopsies, fine-
needle aspirations, and/or cell blocks) or fixed samples (e.g., formalin-fixed
and paraffin-embedded
(FFPE) samples). Other methods for the detection of the mutational status of
EGFR and ALK include
fluorescence in situ hybridization (FISH) and immunohistochemical (INC)
methods. Exemplary methods
for the detection of the mutational status of ALK are disclosed in U.S. Patent
No: 9,651,555, which is
herein incorporated by reference in its entirety. In some instances, the
VENTANA anti-ALK(D5F3) IHC
assay is used to determine the mutational status of the ALKgene.
In some instances of any of the methods described herein, the mutation is a
sensitizing EGFR
mutation. Sensitizing EGFR mutations are well known in the art and include
those described in U.S.
Publication No: US 2018/0235968 and in Juan et al. (Therapeutic Advances in
Medical Oncology. 9(3):
201-216, 2017), which are incorporated by reference herein in their
entireties. In some instances, the
sensitizing EGFR mutation is a mutation in any one of exons 18-21 (e.g., a
mutation in exon 18, exon 19,
exon 20, and/or exon 21). In some instances, the sensitizing EGFR mutation is
a deletion of exon 19
(dell 9). In other instances, sensitizing EGFR mutation is a L858R point
mutation in exon 21. In some
instances, the sensitizing EGFR mutation is a G719X point mutation in exon 18,
wherein "X" is most
commonly C, A, or S. In some instances, the sensitizing EGFR mutation is a
G719S point mutation in
exon 18. In some instances, the sensitizing EGFR mutation is a G719A point
mutation in exon 18. In
some instances, the sensitizing EGFR mutation is a S720F point mutation in
exon 18. In some instances,
the sensitizing EGFR mutation is a L8610 point mutation in exon 21. In some
instances, the sensitizing
EGFR mutation is a L861R point mutation in exon 21. In other instances, the
sensitizing EGFR mutation
is a T790M point mutation. In some instances, the sensitizing EGFR mutation is
an E709X point
mutation, where "X" is most commonly K, A, or H. In some instances, the
sensitizing EGFR mutation is a
S768I point mutation.
In some instances of any of the methods described herein, the mutation is an
ALKgene
rearrangement. ALKgene rearrangements are well known in the art and include
those described in U.S.
Patent No: 9,651,555 and in Du et al. (Thoracic Cancer. 9: 423-430, 2018),
which are incorporated herein
by reference in their entireties. In some instances, the ALKgene rearrangement
results in the creation of
an oncogenic ALK tyrosine kinase that activates downstream signaling pathways
resulting in increased
cell proliferation and survival. In some instances, the ALKgene rearrangement
is an ALK rearrangement
with a gene selected from the group consisting of EML4, KIF5B, KLC1, TFG, TPR,
HIP1, STRN, DCTN1,
SOSTM1, NPM1, BCL11A, BIRC6, RANBP2, AT/C, CLTC, TMP4, and MSN resulting in
the formation of
.. a fusion oncogene. In some instances, the ALKgene rearrangement is an EML4
rearrangement with
ALK resulting in the formation of the fusion oncogene EML4-ALK.
In some instances, in any of the methods, uses, or compositions for use
described herein, the
subject does not have a pulmonary lymphoepithelioma-like carcinoma subtype of
NSCLC. Methods for
detecting the subtype of NSCLC are well known in the art, and include, but are
not limited to, methods of
determination by histopathological criteria, or by molecular features (e.g., a
subtype characterized by
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expression of one or a combination of biomarkers (e.g., particular genes or
proteins encoded by said
genes)). In some instances, the sample is selected from the group consisting
of a tissue sample, a whole
blood sample, a serum sample, and a plasma sample. In some instances, the
tissue sample is a tumor
sample.
In some instances, in any of the methods, uses, or compositions for use
described herein, the
subject does not have an active Epstein-Barr virus (EBV) infection or a known
or suspected chronic active
EBV infection. Indicators of active or chronic active EBV infections for use
in the methods described
herein can include, but are not limited to, EBV IgM, EBV IgG, Epstein-Barr
nuclear antigen (EBNA), and
Epstein-Barr viral particles detected in a sample from the subject (e.g., a
blood or serum sample).
Methods for detecting the presence of one or more indicators of active or
chronic active EBV infection,
including EBV IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-
Barr viral particles in a
sample from a subject are well known in the art, and include, but are not
limited to, methods involving
serological diagnosis (e.g., the detection of EBV DNA (e.g., by PCR analysis
of a blood sample for the
detection of EBV viral particles) or EBV antigens or anti-EBV antibodies
(e.g., detection of EBNA, EBV
.. IgM, or EBV IgG using heterophilic antibodies). In some instances, the
sample is selected from the group
consisting of a whole blood sample, a serum sample, and a plasma sample. In
some instances, the
subject is negative for EBV IgM and/or negative by EBV PCR. In some instances,
the subject is negative
for EBV IgM and/or negative by EBV PCR and is positive for EBV IgG and/or
positive for Epstein-Barr
nuclear antigen (EBNA). In other instances, the subject is negative for EBV
IgG and/or negative for
EBNA.
In some instances, in any of the methods, uses, or compositions for use
described herein, the
subject has a PD-L1 selected tumor (e.g., a tumor PD-L1 expression with a
minimum PD-L1-positive
tumor cell fraction or TPS ?..= 30% (e.g., 50%) as determined by an IHC with
the SP263 or 22C3 antibody
or a proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating
immune cells (ICs) is
greater than or equal to 1% in the tumor sample as determined by an IHC with
the SP142 antibody). In
some instances, the PD-L1 selected tumor is a tumor that has been determined
to have a PD-L1-positive
tumor cell fraction or PD-L1 TPS of greater than, or equal to, 30% (e.g.,
greater than, or equal to, 50%) by
an immunohistochemical (IHC) assay. In some instances, the PD-L1 selected
tumor is a tumor that has
been determined to have a proportion of tumor area occupied by PD-L1-
expressing immune cells (ICs)
greater than or equal to 1% by an immunohistochemical (IHC) assay. In some
instances, the IHC assay
uses the anti-PD-L1 antibody SP263, 22C3, SP142, or 28-8. In some instances,
the IHC assay uses anti-
PD-L1 antibody SP263. In some instances, the IHC assay uses anti-PD-L1
antibody SP142. In some
instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the
tumor sample has
been determined to have a TPS of greater than, or equal to, 50%. In some
instances, the PD-L1-positive
.. tumor cell fraction is greater than, or equal to, 50% (e.g., as determined
by positive staining with the anti-
PD-L1 antibody SP263 (e.g., using the Ventana assay), as determined by
positive staining with the anti-
PD-L1 antibody 22C3 (e.g., using the pharmDx assay), or as determined by
positive staining with the anti-
PD-L1 antibody 28-8). In some embodiments, the PD-L1-positive tumor cell
fraction is greater than, or
equal to, 30%, as determined by positive staining with the anti-PD-L1 antibody
SP142. In some
instances, the ICs has been determined to be greater than, or equal to, 1%
(e.g., as determined using the
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Ventana (SP142) PD-L1 IHC assay). In some instances, the ICs has been
determined to be greater than,
or equal to, 5% (e.g., as determined using the Ventana (5P142) PD-L1 IHC
assay). In some instances,
the ICs has been determined to be greater than, or equal to, 10% (e.g., as
determined using the Ventana
(SP142) PD-L1 IHC assay). In some instances, the ICs has been determined to be
greater than, or equal
to, 1% and less than 50% (e.g., as determined using the Ventana (SP142) PD-L1
IHC assay). In some
instances, the ICs has been determined to be greater than, or equal to, 1 ./0
and less than 30% (e.g., as
determined using the Ventana (SP142) PD-L1 IHC assay).
In some instances, in any of the methods, uses, or compositions for use
described herein, a
tumor sample obtained from the individual has a detectable protein expression
level of PD-L1. In some
instances, the detectable protein expression level of PD-L1 has been
determined by an IHC assay. In
some instances, the IHC assay uses anti-PD-L1 antibody SP142. In some
instances, the tumor sample
has been determined to have a detectable expression level of PD-L1 in greater
than, or equal to, 1 ./c, of
the tumor cells in the tumor sample. In some instances, the tumor sample has
been determined to have
a detectable expression level of PD-L1 in greater than, or equal to, 1% and
less than 5% of the tumor
cells in the tumor sample. In some instances, the tumor sample has been
determined to have a
detectable expression level of PD-L1 in greater than, or equal to, 5% and less
than 50% of the tumor cells
in the tumor sample. In some instances, the tumor sample has been determined
to have a detectable
expression level of PD-L1 in greater than, or equal to, 50% of the tumor cells
in the tumor sample. In
some instances, the tumor sample has been determined to have a detectable
expression level of PD-L1
in tumor-infiltrating immune cells that comprise greater than, or equal to, 1%
of the tumor sample. In
some instances, the tumor sample has been determined to have a detectable
expression level of PD-L1
in tumor-infiltrating immune cells that comprise greater than, or equal to,
1`)/0 and less than 5% of the
tumor sample. In some instances, the tumor sample has been determined to have
a detectable
expression level of PD-L1 in tumor-infiltrating immune cells that comprise
greater than, or equal to, 5%
and less than 10% of the tumor sample. In some instances, the tumor sample has
been determined to
have a detectable expression level of PD-L1 in tumor-infiltrating immune cells
that comprise greater than,
or equal to, 10% of the tumor sample.
In some instances, in any of the methods, uses, or compositions for use
described herein, a
tumor sample obtained from the individual has a detectable nucleic acid
expression level of PD-L1. In
some instances, the detectable nucleic acid expression level of PD-L1 has been
determined by RNA-seq,
RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY
technique, ISH,
or a combination thereof. In some instances, the sample is selected from the
group consisting of a tissue
sample, a whole blood sample, a serum sample, and a plasma sample. In some
instances, the tissue
sample is a tumor sample. In some instances, the tumor sample comprises tumor-
infiltrating immune
cells, tumor cells, stromal cells, and any combinations thereof.
Responses to Treatment
In some embodiments of any of the methods described herein, a subject's
response to the
therapy can be characterized by one or more measures. In some embodiments, the
treatment results in
a CR or a PR. In some embodiments, the treatment results in an increase in PFS
or DOR.
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In some instances, the treatment results in an increase in PFS of the subject,
e.g., as compared
to treatment with the PD-1 axis binding antagonist without the anti-TIGIT
antagonist antibody or as
compared to treatment with the anti-TIGIT antagonist antibody without the PD-1
axis binding antagonist.
For example, in embodiments in which no chemotherapeutic agent is administered
(e.g., only an anti-
TIGIT antagonist antibody (e.g., tiragolumab) in combination with a PD-1 axis
binding antagonist (e.g.,
atezolizumab) is administered), the treatment may result in an increase in PFS
of the subject, e.g., as
compared to treatment with the PD-1 axis binding antagonist without the anti-
TIGIT antagonist antibody
or as compared to treatment with the anti-TIGIT antagonist antibody without
the PD-1 axis binding
antagonist. In embodiments in which an anti-TIGIT antagonist antibody (e.g.,
tiragolumab) and a PD-1
axis binding antagonist (e.g., atezolizumab) are administered in combination
with one or more
chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g.,
carboplatin or cisplatin)
and/or one or more non-platinum-based chemotherapeutic agents (e.g., an
alkylating agent (e.g.,
cyclophosphamide), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a
topoisomerase II inhibitor
(e.g., doxorubicin))), the treatment may result in an increase in PFS of the
subject, e.g., as compared to
(i) treatment with the PD-1 axis binding antagonist and the one or more
chemotherapeutic agents without
the anti-TIGIT antagonist antibody; (ii) as compared to treatment with the
anti-TIGIT antagonist antibody
and the one or more chemotherapeutic agents without the PD-1 axis binding
antagonist; and/or (iii) as
compared to treatment with the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody
without the one or more chemotherapeutic agents.
In some instances, the treatment extends OS of the subject, e.g., as compared
to treatment with
the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or
as compared to treatment
with the anti-TIGIT antagonist antibody without the PD-1 axis binding
antagonist. For example, in
embodiments in which no chemotherapeutic agent is administered (e.g., only an
anti-TIGIT antagonist
antibody (e.g., tiragolumab) in combination with a PD-1 axis binding
antagonist (e.g., atezolizumab) is
.. administered), the treatment may result in an increase in OS of the
subject, e.g., as compared to
treatment with the PD-1 axis binding antagonist without the anti-TIGIT
antagonist antibody or as
compared to treatment with the anti-TIGIT antagonist antibody without the PD-1
axis binding antagonist.
In embodiments in which an anti-TIGIT antagonist antibody (e.g., tiragolumab)
and a PD-1 axis binding
antagonist (e.g., atezolizumab) are administered in combination with one or
more chemotherapeutic
agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or
cisplatin) and/or one or more
non-platinum-based chemotherapeutic agents (e.g., an antimetabolite (e.g.,
pemetrexed, gemcitabine, or
capecitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a
topoisomerase II inhibitor (e.g.,
etoposide))), the treatment may result in an increase in OS of the subject,
e.g., as compared to (i)
treatment with the PD-1 axis binding antagonist and the one or more
chemotherapeutic agents without
the anti-TIGIT antagonist antibody; (ii) as compared to treatment with the
anti-TIGIT antagonist antibody
and the one or more chemotherapeutic agents without the PD-1 axis binding
antagonist; and/or (iii) as
compared to treatment with the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody
without the one or more chemotherapeutic agents.
Progression-free survival of the subject can be measured according to RECIST
v1.1 criteria, as
described in Eisenhauer et al., Eur. J. Cancer. 2009, 45:228-47. In some
embodiments, PFS is
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measured as the period of time from the start of treatment to the first
occurrence of disease progression
as determined by RECIST v1.1 criteria. In some embodiments, PFS is measured as
the time from the
start of treatment to the time of death.
In some embodiments, a treatment described herein extends the PFS of the
subject by at least
about 2.4 months (e.g., by 2.4-120 months, by 2.5-100 months, by 3.0-80
months, by 4.0-60 months, by
5.0-48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12 months, e.g.,
by at least about 2.4
months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0
months, 3.1 months, 3.2
months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8
months, 3.9 months, 4.0
months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6
months, 4.7 months, 4.8
months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4
months, 5.5 months, 5.6
months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0
months, 7.5 months, 8.0
months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months,
11.5 months, 12
months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19
months, 20 months, 21
months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28
months, 29 months, 30
months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
In some
embodiments, the treatment extends the PFS of the subject by at least about 4
months (e.g., by 4-120
months, by 5-100 months, by 6-80 months, by 7-60 months, by 8-48 months, by 9-
36 months, or by 10-24
months, e.g., by at least about 4.0 months, 4.1 months, 4.2 months, 4.3
months, 4.4 months, 4.5 months,
4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2
months, 5.3 months, 5.4
months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0
months, 6.5 months, 7.0
months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months,
10.5 months, 11
months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17
months, 18 months,
19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months,
26 months, 27 months,
28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months,
35 months, or 36
months). In some embodiments, the treatment extends the PFS of the subject by
at least about 2 months
(e.g., by 2-120 months, by 3-100 months, by 4-80 months, by 6-60 months, by 8-
48 months, by 9-36
months, or by 10-24 months, e.g., by at least about 2.0 months, 2.1 months,
2.2 months, 2.3 months, 2.4
months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0
months, 3.1 months, 3.2
months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8
months, 3.9 months, 4.0
months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6
months, 4.7 months, 4.8
months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4
months, 5.5 months, 5.6
months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0
months, 7.5 months, 8.0
months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months,
11.5 months, 12
months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19
months, 20 months, 21
months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28
months, 29 months, 30
months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
In some embodiments, a treatment described herein extends the DOR of the
subject by at least
about 2.4 months (e.g., by 2.4-120 months, by 2.5-100 months, by 3.0-80
months, by 4.0-60 months, by
5.0-48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12 months, e.g.,
by at least about 2.4
months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0
months, 3.1 months, 3.2
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months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8
months, 3.9 months, 4.0
months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6
months, 4.7 months, 4.8
months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4
months, 5.5 months, 5.6
months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0
months, 7.5 months, 8.0
.. months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11
months, 11.5 months, 12
months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19
months, 20 months, 21
months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28
months, 29 months, 30
months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
In some
embodiments, the treatment extends the DOR of the subject by at least about 4
months (e.g., by 4-120
months, by 5-100 months, by 6-80 months, by 7-60 months, by 8-48 months, by 9-
36 months, or by 10-24
months, e.g., by at least about 4.0 months, 4.1 months, 4.2 months, 4.3
months, 4.4 months, 4.5 months,
4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2
months, 5.3 months, 5.4
months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0
months, 6.5 months, 7.0
months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months,
10.5 months, 11
months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17
months, 18 months,
19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months,
26 months, 27 months,
28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months,
35 months, or 36
months). In some embodiments, the treatment extends the DOR of the subject by
at least about 2
months (e.g., by 2-120 months, by 3-100 months, by 4-80 months, by 6-60
months, by 8-48 months, by 9-
36 months, or by 10-24 months, e.g., by at least about 2.0 months, 2.1 months,
2.2 months, 2.3 months,
2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0
months, 3.1 months, 3.2
months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8
months, 3.9 months, 4.0
months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6
months, 4.7 months, 4.8
months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4
months, 5.5 months, 5.6
months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0
months, 7.5 months, 8.0
months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months,
11.5 months, 12
months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19
months, 20 months, 21
months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28
months, 29 months, 30
months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
In some embodiments, OS is measured as the period of time from the start of
treatment to death.
In some instances, the treatment extends the OS of the subject by at least
about 2 months (e.g., by 2-120
months, by 3-110 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-
48 months, by 8-36
months, or by 10-24 months, e.g., by at least about 2 months, 2.1 months, 2.2
months, 2.3 months, 2.4
months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0
months, 3.1 months, 3.2
months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8
months, 3.9 months, 4.0
months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6
months, 4.7 months, 4.8
months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4
months, 5.5 months, 5.6
months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0
months, 7.5 months, 8.0
months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months,
11.5 months, 12
months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19
months, 20 months, 21
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months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28
months, 29 months, 30
months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
In some instances,
the treatment extends the OS of the subject by at least about 3.3 months
(e.g., by 3.3-120 months, by 4-
100 months, by 5-80 months, by 6-60 months, by 7-48 months, by 8-36 months, or
by 10-24 months, e.g.,
by at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months,
3.8 months, 3.9 months,
4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6
months, 4.7 months, 4.8
months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4
months, 5.5 months, 5.6
months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0
months, 7.5 months, 8.0
months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months,
11.5 months, 12
months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19
months, 20 months, 21
months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28
months, 29 months, 30
months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
In some instances,
the treatment extends the OS of the subject by at least about 5.3 months
(e.g., by 5.3-120, by 6-60
months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least
about 5.3 months, 5.5
.. months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5
months, 9.0 months, 9.5
months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months,
14 months, 15
months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22
months, 23 months, 24
months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31
months, 32 months, 33
months, 34 months, 35 months, or 36 months).
B. Therapeutic methods and uses relating to lung cancer
Lung cancer remains the leading cause of cancer deaths worldwide. In the
United States, it is
the most common cancer in both men and women and accounts for 12%-14% of all
new cancer cases.
In 2020, there will be an estimated 228,820 new cases of lung cancer,
resulting in 135,720 deaths in the
.. United States (Siegel et al. CA Cancer J Clin. 70:7-30 (2020)).
Non-small cell lung cancer
Non-small cell lung cancer (NSCLC) is the predominant subtype of lung cancer,
accounting for
approximately 85% of all cases.
Non-small cell lung cancer (NSCLC) is the predominant subtype of lung cancer,
accounting for
approximately 80%-85% of all cases (Osmani et al. Semin Cancer Biol. 52 (Pt
1):103-9 (2018)). NSCLC
can be divided into two major histologic types: adenocarcinoma and squamous
cell carcinoma (Travis et
al. 2011). Adenocarcinoma histology accounts for approximately 40%-50% of all
NSCLC, while
squamous cell histology accounts for approximately 20%-30% of NSCLC (Osmani et
al. Semin Cancer
.. Biol. 52 (Pt 1):103-9 (2018)). The remaining cases of NSCLC are represented
by large cell carcinoma,
neuroendocrine tumors, sarcomatoid carcinoma, and are of poorly differentiated
histology.
In its early stages, NSCLC is treated surgically with curative intent.
However, 30%-70% of
patients undergoing resection develop recurrence and die as a result of
disease progression (Siegel et al.
Cancer Statistics. CA Cancer J Clin. 70:7-30 (2020)). Therefore, there is a
high unmet need for improved
medical intervention for early-stage NSCLC.
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For advanced disease, the overall five-year survival rate is 2%-4%. Poor
prognostic factors for
survival in patients with NSCLC include advanced stage of disease at the time
of initial diagnosis, poor
performance status, and a history of unintentional weight loss. More than half
of the patients with NSCLC
are diagnosed with distant disease, which directly contributes to poor
survival prospects.
Despite improvements in the first-line treatment of patients with advanced
NSCLC that have
resulted in longer survival times and reduced disease-related symptoms, nearly
all patients experience
disease progression. Cancer immunotherapies, in particular, offer the
possibility of long-term disease
control. In the metastatic NSCLC setting, PD-L1/PD-1 blocking antibodies
(e.g., atezolizumab,
nivolumab, and pembrolizumab) provided clinically meaningful benefit in either
unselected or PD-L1-
selected advanced NSCLC patients; however, a substantial proportion of
patients still remained
unresponsive or progressed on anti-PD-L1/PD-1 treatment, and the escape
mechanisms to such
treatment are poorly understood.
Thus, there is an unmet need in the field for the development of efficacious
immunotherapies and
methods of dosing the same for the treatment (e.g., first-line treatment) of
lung cancer (e.g., NSCLC (e.g.,
.. non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-
squamous NSCLC (e.g.,
Stage IV non-squamous NSCLC)))) that achieve a more favorable benefit-risk
profile.
Small cell lung cancer
Small cell lung cancer (SCLC) accounts for approximately 15% of all cases of
lung cancer. The
majority (approximately 70%) of patients with SCLC are diagnosed with
extensive-stage disease (ES-
SCLC), which has poor survival prospects (median OS approximately 10-12
months). While
chemotherapy alone can palliate symptoms and prolong survival for patients
with ES-SCLC, long-term
survival is rare. The five-year relative survival rate for people with stage I
SCLC is approximately 31%.
At stage IV, the five-year relative survival rate declines to approximately
2%.
Thus, there is a need in the field for improved treatments for lung cancer
(e.g., SCLC, e.g., ES-
SCLC).
i. Methods and uses for treating lung cancer
Provided herein are methods of treating a population of subjects having a lung
cancer, the
method comprising administering to the population of subjects a dosing regimen
comprising one or more
dosing cycles of an effective amount of an anti-TIGIT antagonist antibody, a
PD-1 axis binding antagonist,
a platinum-based chemotherapeutic agent, and a topoisomerase ll inhibitor,
wherein the treatment results
in a median PFS of the population of subjects of at least about 6 months
(e.g., at least about 6 months
(e.g., between 6 months and 24 months (e.g., between about 6 months to about
15 months (e.g., 6
months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13
months, 14 months, or 15
months), e.g., between about 6 months to about 13 months (e.g., 6 months, 6.5
months, 7 months, 7.5
months, 8 months, 8.5 months, 9 months, 9.5 months, 10 months, 10.5 months, 11
months, 11.5 months,
12 months, 12.5 months, 13 months)),e.g., between about 8 months to about 10
months (e.g., 8.1
months, 8.2 months, 8.3 months, 8.4 months, 8.5 months, 8.6 months, 8.7
months, 8.8 months, 8.9
months, 9.0 months, 9.1 months, 9.2 months, 9.3 months, 9.4 months, 9.5
months, 9.6 months, 9.7
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months, 9.8 months, 9.9 months, 10.0 months)). In some instances, treatment
results in a median PFS of
the population of subjects of about 8.2 months to about 9.2 months (e.g.,
about 8.2, 8.4, 8.6, 8.8, 9.0, or
9.2 months, e.g., 8.2-8.4, 8.4-8.6, 8.6-8.8, 8.8-9.0, or 9.0-9.2 months).
Also provided herein are methods of treating a population of subjects having a
lung cancer, the
method comprising administering to the population of subjects a dosing regimen
comprising one or more
dosing cycles of an effective amount of an anti-TIGIT antagonist antibody, a
PD-1 axis binding antagonist,
a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor,
wherein the treatment results
in a median OS of the population of subjects of at least about 12 months
(e.g., between about 12 months
to about 40 months (e.g., between about 12 to about 30 months (e.g., 12
months, 13 months, 14 months,
months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22
months, 23 months,
24 months, 25 months, 26 months, 27 months, 28 months, 29 months, or 30
months), e.g., between
about 12 months to about 20 months (e.g., 12 months, 13 months, 14 months, 15
months, 16 months, 17
10 months, 18 months, 19 months, or 20 months))). In some instances, the
treatment results in a median
OS of the population of subjects of about 15.3 months to about 17.6 months
(e.g., about 15.5, 16, 16.5,
17, 17.5, or 17.6 months, e.g., 15.3-16 months, 16-17 months, or 17-17.6
months).
Methods and uses for treating small cell lung cancer
15 Provided herein are methods and uses for treating lung cancer (e.g.,
small cell lung cancer
(SCLC), e.g., extensive stage SCLC (ES-SCLC)) in a subject or population of
subjects comprising
administering to the subject or population of subjects one or more dosing
cycles of an effective amount of
an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g.,
tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist
antibody, such as
atezolizumab), a platinum-based chemotherapeutic agent (e.g., carboplatin or
cisplatin), and a
topoisomerase II inhibitor (e.g., etoposide).
Dosing Regimens, Administration, and Response to Treatment
The therapeutic methods and uses of the invention described herein include, in
one aspect,
administering to a subject or population of subjects having a lung cancer
(e.g., SCLC, e.g., ES-SCLC) an
effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an
anti-PD-L1 antagonist
antibody (e.g., atezolizumab)), a platinum-based chemotherapeutic agent, and a
topoisomerase II
inhibitor, wherein the treatment extends progression-free survival (PFS) of
the subject or population of
subjects as compared to treatment with the PD-1 axis binding antagonist, the
platinum-based
chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-
TIGIT antagonist antibody,
thereby treating the subject or population of subjects. In some instances, the
treatment extends OS of
the subject or population of subjects as compared to treatment with the PD-1
axis binding antagonist, the
platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor
without the anti-TIGIT
antagonist antibody.
In some embodiments, the PFS of the individual is measured according to RECIST
v1.1 criteria,
as described in Eisenhauer et al., Eur. J. Cancer. 2009, 45:228-47. In some
embodiments, PFS is
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measured as the period of time from the start of treatment to the first
occurrence of disease progression
as determined by RECIST v1.1 criteria. In some embodiments, PFS is measured as
the time from the
start of treatment to the time of death.
In some embodiments, the treatment extends the PFS of the subject or
population of subjects by
at least about 2.4 months (e.g., by 2.4-120 months, by 2.5-100 months, by 3.0-
80 months, by 4.0-60
months, by 5.0-48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12
months, e.g., by at least
about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months,
3.0 months, 3.1 months,
3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8
months, 3.9 months, 4.0
months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6
months, 4.7 months, 4.8
months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0
months, 7.5 months, 8.0
months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months,
11.5 months, 12
months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19
months, 20 months, 21
months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28
months, 29 months, 30
months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months)
as compared to
treatment with the PD-1 axis binding antagonist, the platinum-based
chemotherapeutic agent, and the
topoisomerase II inhibitor without the anti-TIG IT antagonist antibody. In
some embodiments, the
treatment extends the PFS of the subject or population of subjects by at least
about 4 months (e.g., by 4-
120 months, by 5-100 months, by 6-80 months, by 7-60 months, by 8-48 months,
by 9-36 months, or by
10-24 months, e.g., by at least about 4.0 months, 4.1 months, 4.2 months, 4.3
months, 4.4 months, 4.5
months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5
months, 6.0 months, 6.5
months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5
months, 10 months, 10.5
months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16
months, 17 months,
18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months,
25 months, 26 months,
27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months,
34 months, 35 months,
or 36 months) as compared to treatment with the PD-1 axis binding antagonist,
the platinum-based
chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-
TIG IT antagonist antibody. In
some embodiments, the treatment extends the PFS of the subject or population
of subjects by at least
about 2 months (e.g., by 2-120 months, by 3-100 months, by 4-80 months, by 6-
60 months, by 8-48
months, by 9-36 months, or by 10-24 months, e.g., by at least about 2.0
months, 2.1 months, 2.2 months,
2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9
months, 3.0 months, 3.1
months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7
months, 3.8 months, 3.9
months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5
months, 4.6 months, 4.7
months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5
months, 7.0 months, 7.5
months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5
months, 11 months, 11.5
months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18
months, 19 months, 20
months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27
months, 28 months, 29
months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or
36 months) as
compared to treatment with the PD-1 axis binding antagonist, the platinum-
based chemotherapeutic
agent, and the topoisomerase II inhibitor without the anti-TIG IT antagonist
antibody. In some aspects, the
treatment extends the PFS of the subject or population of subjects by at least
about 3 months to about 4
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months as compared to treatment with the PD-1 axis binding antagonist, the
platinum-based
chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-
TIG IT antagonist antibody.
In some instances, the methods and uses of treating a subject or population of
subjects having a
lung cancer (e.g., SCLC, e.g., ES-SCLC) include administering to the subject
or population of subjects an
effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an
anti-PD-L1 antagonist
antibody, such as atezolizumab), a platinum-based chemotherapeutic agent
(e.g., carboplatin or
cisplatin), and a topoisomerase II inhibitor (e.g., etoposide), wherein the
treatment extends OS of the
subject or population of subjects as compared to treatment with the PD-1 axis
binding antagonist, the
platinum-based chemotherapeutic agent, and the topoisomerase ll inhibitor
without the anti-TIGIT
antagonist antibody.
In some embodiments, OS is measured as the period of time from the start of
treatment to death.
In some instances, the treatment extends the OS of the subject or population
of subjects by at least about
2 months (e.g., by 2-120 months, by 3-110 months, by 4-100 months, by 5-80
months, by 6-60 months,
by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 2
months, 2.1 months, 2.2
months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8
months, 2.9 months, 3.0
months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6
months, 3.7 months, 3.8
months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4
months, 4.5 months, 4.6
months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2
months, 5.3 months, 5.4
months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0
months, 6.5 months, 7.0
months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months,
10.5 months, 11
months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17
months, 18 months,
19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months,
26 months, 27 months,
28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months,
35 months, or 36
months) as compared to treatment with the PD-1 axis binding antagonist, the
platinum-based
chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-
TIG IT antagonist antibody. In
some instances, the treatment extends the OS of the subject or population of
subjects by at least about
3.3 months (e.g., by 3.3-120 months, by 4-100 months, by 5-80 months, by 6-60
months, by 7-48 months,
by 8-36 months, or by 10-24 months, e.g., by at least about 3.3 months, 3.4
months, 3.5 months, 3.6
months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2
months, 4.3 months, 4.4
months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0
months, 5.5 months, 6.0
months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0
months, 9.5 months, 10
months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months,
15 months, 16
months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23
months, 24 months, 25
months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32
months, 33 months, 34
months, 35 months, or 36 months) as compared to treatment with the PD-1 axis
binding antagonist, the
platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor
without the anti-TIGIT
antagonist antibody. In some instances, the treatment extends the OS of the
subject or population of
subjects by at least about 5.3 months (e.g., by 5.3-120, by 6-60 months, by 7-
48 months, by 8-36 months,
or by 10-24 months, e.g., by at least about 5.3 months, 5.5 months, 6.0
months, 6.5 months, 7.0 months,
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7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5
months, 11 months, 11.5
months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18
months, 19 months, 20
months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27
months, 28 months, 29
months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or
36 months) as
compared to treatment with the PD-1 axis binding antagonist, the platinum-
based chemotherapeutic
agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist
antibody.
In some instances, the effective amount of the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g. a
fixed dose) of between about
30 mg to about 1200 mg (e.g., between about 30 mg to about 1100 mg, e.g.,
between about 60 mg to
about 1000 mg, e.g., between about 100 mg to about 900 mg, e.g., between about
200 mg to about 800
mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to
about 800 mg, e.g.,
between about 400 mg to about 750 mg, e.g., between about 450 mg to about 750
mg, e.g., between
about 500 mg to about 700 mg, e.g., between about 550 mg to about 650 mg,
e.g., 600 mg 10 mg, e.g.,
600 6 mg, e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600 1 mg, e.g., 600
0.5 mg, e.g., 600 mg) every
three weeks. In some instances, the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-
TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose
(e.g., a fixed dose) of between
about 30 mg to about 600 mg (e.g., between about 50 mg to about 600 mg, e.g.,
between about 60 mg to
about 600 mg, e.g., between about 100 mg to about 600 mg, e.g., between about
200 mg to about 600
mg, e.g., between about 200 mg to about 550 mg, e.g., between about 250 mg to
about 500 mg, e.g.,
between about 300 mg to about 450 mg, e.g., between about 350 mg to about 400
mg, e.g., about 375
mg) every three weeks. In some instances, the effective amount of the anti-
TIGIT antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) is a dose (e.g., a fixed
dose) of about 600 mg every three weeks.
In some instances, the effective amount of the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g. a
fixed dose) of between 30 mg
to 1200 mg (e.g., between 30 mg to 1100 mg, e.g., between 60 mg to 1000 mg,
e.g., between 100 mg to
900 mg, e.g., between 200 mg to 800 mg, e.g., between 300 mg to 800 mg, e.g.,
between 400 mg to 800
mg, e.g., between 400 mg to 750 mg, e.g., between 450 mg to 750 mg, e.g.,
between 500 mg to 700 mg,
e.g., between 550 mg to 650 mg, e.g., 600 mg 10 mg, e.g., 600 6 mg, e.g.,
600 5 mg, e.g., 600 3
mg, e.g., 600 1 mg, e.g., 600 0.5 mg, e.g., 600 mg) every three weeks. In
some instances, the
effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) is a dose (e.g., a fixed dose) of between
30 mg to 600 mg (e.g.,
between 50 mg to 600 mg, e.g., between 60 mg to 600 mg, e.g., between 100 mg
to 600 mg, e.g.,
between 200 mg to 600 mg, e.g., between 200 mg to 550 mg, e.g., between 250 mg
to 500 mg, e.g.,
between 300 mg to 450 mg, e.g., between 350 mg to 400 mg, e.g., 375 mg) every
three weeks. In some
instances, the effective amount of the anti-TIGIT antagonist antibody (e.g.,
an anti-TIGIT antagonist
antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a fixed
dose) of 600 mg every three
weeks.
In some instances, effective amount of the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a
fixed dose) dose of 600 mg
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every three weeks. In some instances, the dose (e.g., fixed dose) of the anti-
TIGIT antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) administered in a
combination therapy (e.g., a combination treatment with a PD-1 axis binding
antagonist (e.g., an anti-PD-
L1 antagonist antibody, e.g., atezolizumab)), topoisomerase II inhibitor
(e.g., etoposide), and/or a
platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) may be
reduced as compared to a
standard dose of the anti-TIGIT antagonist antibody administered as a
monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of
between about 80 mg to about
2000 mg (e.g., between about 100 mg to about 1600 mg, e.g., between about 200
mg to about 1600 mg,
e.g., between about 300 mg to about 1600 mg, e.g., between about 400 mg to
about 1600 mg, e.g.,
between about 500 mg to about 1600 mg, e.g., between about 600 mg to about
1600 mg, e.g., between
about 700 mg to about 1600 mg, e.g., between about 800 mg to about 1600 mg,
e.g., between about 900
mg to about 1500 mg, e.g., between about 1000 mg to about 1400 mg, e.g.,
between about 1050 mg to
about 1350 mg, e.g., between about 1100 mg to about 1300 mg, e.g., between
about 1150 mg to about
1250 mg, e.g., between about 1175 mg to about 1225 mg, e.g., between about
1190 mg to about 1210
mg, e.g., 1200 mg 5 mg, e.g., 1200 2.5 mg, e.g., 1200 1.0 mg, e.g., 1200
0.5 mg, e.g., 1200 mg)
every three weeks. In some instances, the effective amount of the PD-1 axis
binding antagonist (e.g.,
anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed
dose) of about 840 mg every
two weeks. In some instances, the effective amount of the PD-1 axis binding
antagonist (e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of
about 1200 mg every three
weeks. In some instances, the effective amount of the PD-1 axis binding
antagonist (e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of
between 80 mg to 2000 mg
(e.g., between 100 mg to 1600 mg, e.g., between 200 mg to 1600 mg, e.g.,
between 300 mg to 1600 mg,
e.g., between 400 mg to 1600 mg, e.g., between 500 mg to 1600 mg, e.g.,
between 600 mg to 1600 mg,
e.g., between 700 mg to 1600 mg, e.g., between 800 mg to 1600 mg, e.g.,
between 900 mg to 1500 mg,
e.g., between 1000 mg to 1400 mg, e.g., between 1050 mg to 1350 mg, e.g.,
between 1100 mg to 1300
mg, e.g., between 1150 mg to 1250 mg, e.g., between 1175 mg to 1225 mg, e.g.,
between 1190 mg to
1210 mg, e.g., 1200 mg 5 mg, e.g., 1200 2.5 mg, e.g., 1200 1.0 mg, e.g.,
1200 0.5 mg, e.g., 1200
mg) every three weeks. In some instances, the effective amount of the PD-1
axis binding antagonist
(e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a
fixed dose) of 840 mg every
two weeks.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of
about 1400 mg to 2000 mg
every four weeks. In some instances, the effective amount of the PD-1 axis
binding antagonist (e.g., anti-
.. PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed
dose) of 1400 mg to 2000 mg
every four weeks. In some instances, the effective amount of the PD-1 axis
binding antagonist (e.g., anti-
PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose)
of about 1680 mg every
four weeks. In some instances, the effective amount of the PD-1 axis binding
antagonist (e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of
1680 mg every four weeks. In
.. some instances, the dose (e.g., fixed dose) of the PD-1 axis binding
antagonist (e.g., anti-PD-L1
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antagonist antibody (e.g., atezolizumab)) administered in a combination
therapy (e.g., a combination
treatment with an anti-TIGIT antagonist antibody, such as an anti-TIGIT
antagonist antibody disclosed
herein, e.g., tiragolumab), a topoisomerase II inhibitor (e.g., etoposide),
and/or a platinum-based
chemotherapeutic agent (e.g., carboplatin or cisplatin) may be reduced as
compared to a standard dose
of the PD-1 axis binding antagonist administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01
mg/kg to about 50 mg/kg of the
subject's body weight (e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g.,
between about 0.1 mg/kg
to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g.,
between about 2.5 mg/kg to
about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between
about 10 mg/kg to about
mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., about 15 2
mg/kg, about 15 1
mg/kg, about 15 0.5 mg/kg, about 15 0.2 mg/kg, or about 15 0.1 mg/kg,
e.g., about 15 mg/kg) every
three weeks. In some instances, the effective amount of the PD-1 axis binding
antagonist (e.g., anti-PD-
L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01
mg/kg to about 15 mg/kg of
15 the subject's body weight (e.g., between about 0.1 mg/kg to about 15
mg/kg, e.g., between about 0.5
mg/kg to about 15 mg/kg, e.g., between about 1 mg/kg to about 15 mg/kg, e.g.,
between about 2.5 mg/kg
to about 15 mg/kg, e.g., between about 5 mg/kg to about 15 mg/kg, e.g.,
between about 7.5 mg/kg to
about 15 mg/kg, e.g., between about 10 mg/kg to about 15 mg/kg, e.g., between
about 12.5 mg/kg to
about 15 mg/kg, e.g., between about 14 mg/kg to about 15 mg/kg, e.g., about 15
1 mg/kg, e.g., about
20 15 0.5 mg/kg, e.g., about 15 0.2 mg/kg, e.g., about 15 0.1 mg/kg,
e.g., about 15 mg/kg) every three
weeks. In some instances, the effective amount of PD-1 axis binding antagonist
(e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab)) is a dose of about 15 mg/kg
administered every three weeks.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab)) is a dose of between 0.01 mg/kg to
50 mg/kg of the subject's
body weight (e.g., between 0.01 mg/kg to 45 mg/kg, e.g., between 0.1 mg/kg to
40 mg/kg, e.g., between
1 mg/kg to 35 mg/kg, e.g., between 2.5 mg/kg to 30 mg/kg, e.g., between 5
mg/kg to 25 mg/kg, e.g.,
between 10 mg/kg to 20 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., 15
2 mg/kg, 15 1 mg/kg,
15 0.5 mg/kg, 15 0.2 mg/kg, or 15 0.1 mg/kg, e.g., 15 mg/kg) every three
weeks. In some
instances, the effective amount of the PD-1 axis binding antagonist (e.g.,
anti-PD-L1 antagonist antibody
(e.g., atezolizumab)) is a dose of between 0.01 mg/kg to 15 mg/kg of the
subject's body weight (e.g.,
between 0.1 mg/kg to 15 mg/kg, e.g., between 0.5 mg/kg to 15 mg/kg, e.g.,
between 1 mg/kg to 15
mg/kg, e.g., between 2.5 mg/kg to 15 mg/kg, e.g., between 5 mg/kg to 15 mg/kg,
e.g., between 7.5 mg/kg
to 15 mg/kg, e.g., between 10 mg/kg to 15 mg/kg, e.g., between 12.5 mg/kg to
15 mg/kg, e.g., between
14 mg/kg to 15 mg/kg, e.g., 15 1 mg/kg, e.g., 15 0.5 mg/kg, e.g., 15 0.2
mg/kg, e.g., 15 0.1 mg/kg,
e.g., 15 mg/kg) every three weeks. In some instances, the effective amount of
PD-1 axis binding
antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a
dose of 15 mg/kg administered
every three weeks.
In some instances, the dose of the PD-1 axis binding antagonist (e.g., anti-PD-
L1 antagonist
antibody (e.g., atezolizumab)) administered in a combination therapy (e.g., a
combination treatment with
an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody
disclosed herein, e.g.,
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tiragolumab), a topoisomerase II inhibitor (e.g., etoposide), and/or a
platinum-based chemotherapeutic
agent (e.g., carboplatin or cisplatin) may be reduced as compared to a
standard dose of the PD-1 axis
binding antagonist administered as a monotherapy.
In some instances, the effective amount of the platinum-based chemotherapeutic
agent (e.g.,
carboplatin or cisplatin) is a dose sufficient to achieve an AUC from 1-50
mg/ml/min (e.g., 2-25
mg/ml/min, 3-15 mg/ml/min, 4-10 mg/ml/min, or 5 mg/ml/min, e.g., 2 mg/ml/min,
3 mg/1111/min, 4
mg/ml/min, 5 mg/ml/min, 6 mg/ml/min, 7 mg/ml/min, 8 mg/ml/min, 9 mg/ml/min, 10
mg/ml/min, 11
mg/ml/min, 12 mg/ml/min, 13 mg/ml/min, 14 mg/ml/min, 15 mg/ml/min, 20
mg/mVmin, 25 mg/ml/min, 30
mg/ml/min, 35 mg/ml/min, 40 mg/ml/min, 45 mg/mVmin, 50 mg/ml/min). In some
instances, the effective
amount of the platinum-based chemotherapeutic agent (e.g., carboplatin or
cisplatin) is a dose sufficient
to achieve AUC = 5 mg/ml/mm.
AUC can be calculated using the Calvert formula (Calvert et al., J. Clin.
Orval. 1989, 7:1748-56):
Total dose (mg) = (target AUC) x (glomerular filtration rate [GFR] + 25)
In some instances, for example, 1200 mg of atezolizumab is equivalent to an
average body
weight-based dose of 15 m/kg.
In some instances, the effective amount of the platinum-based chemotherapeutic
agent (e.g.,
carboplatin or cisplatin) is 200 mg-1500 mg (e.g., 300 mg-1200 mg, 400 mg-1100
mg, or 500 mg-1000
mg, e.g., 300 mg-400 mg, 400 mg-500 mg, 500 mg-600 mg, 600 mg-700 mg, 700 mg-
750 mg, 750 mg-
800 mg, 800 mg-900 mg, 900 mg-1000 mg, 1000 mg-1100 mg, or 1100 mg-1200 mg,
e.g., about 200 mg,
about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about
800 mg, about 900 mg,
about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, or
about 1500 mg). In
some instances, the effective amount of the platinum-based chemotherapeutic
agent (e.g., carboplatin or
.. cisplatin) is about 500 mg-1000 mg (e.g., about 500 mg, about 600 mg, about
700 mg, about 800 mg,
about 900 mg, or about 1000 mg).
In some instances, the effective amount of the topoisomerase ll inhibitor
(e.g., etoposide) is from
10-1000 mg/m2 (e.g., from 20-800 mg/m2, from 30-700 mg/m2, from 40-500 mg/m2,
from 50-300 mg/m2,
from 75-200 mg/m2, or from 80-150 mg/m2, e.g., about 20 mg/m2, about 30 mg/m2,
about 40 mg/m2,
about 50 mg/m2, about 60 mg/m2, about 70 mg/m2, about 80 mg/m2, about 90
mg/m2, about 100 mg/m2,
about 110 mg/m2, about 120 mg/m2, about 130 mg/m2, about 140 mg/m2, about 150
mg/m2, about 160
mg/m2, about 170 mg/m2, about 180 mg/m2, about 190 mg/m2, about 200 mg/m2,
about 250 mg/m2, about
300 mg/m2, about 400 mg/m2, about 500 mg/m2, about 600 mg/m2, about 700 mg/m2,
about 800 mg/m2,
about 900 mg/m2, or about 1000 mg/m2). In some instances, the effective amount
of the topoisomerase II
inhibitor (e.g., etoposide) is about 100 mg/m2.
In some instances, the effective amount of the platinum-based chemotherapeutic
agent (e.g.,
carboplatin or cisplatin) is 200 mg-1500 mg (e.g., 300 mg-1200 mg, 400 mg-1100
mg, or 500 mg-1000
mg, e.g., 300 mg-400 mg, 400 mg-500 mg, 500 mg-600 mg, 600 mg-700 mg, 700 mg-
750 mg, 750 mg-
800 mg, 800 mg-900 mg, 900 mg-1000 mg, 1000 mg-1100 mg, or 1100 mg-1200 mg,
e.g., 200 mg, 300
mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg,
1300 mg, 1400
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mg, or 1500 mg). In some instances, the effective amount of the platinum-based
chemotherapeutic agent
(e.g., carboplatin or cisplatin) is 500 mg-1000 mg (e.g., 500 mg, 600 mg, 700
mg, 800 mg, 900 mg, or
1000 mg).
In some instances, the effective amount of the topoisomerase II inhibitor
(e.g., etoposide) is from
10-1000 mg/m2 (e.g., from 20-800 mg/m2, from 30-700 mg/m2, from 40-500 mg/m2,
from 50-300 mg/m2,
from 75-200 mg/m2, or from 80-150 mg/m2, e.g., 20 mg/m2, 30 mg/m2, 40 mg/m2,
50 mg/m2, 60 mg/m2, 70
mg/m2, 80 mg/m2, 90 mg/m2, 100 mg/m2, 110 mg/m2, 120 mg/m2, 130 mg/m2, 140
mg/m2, 150 mg/m2,
160 mg/m2, 170 mg/m2, 180 mg/m2, 190 mg/m2, 200 mg/m2, 250 mg/m2, 300 mg/m2,
400 mg/m2, 500
mg/m2, 600 mg/m2, 700 mg/m2, 800 mg/m2, 900 mg/m2, or 1000 mg/m2). In some
instances, the effective
amount of the topoisomerase II inhibitor (e.g., etoposide) is 100 mg/m2.
In any of the methods and uses of the invention, the anti-TIGIT antagonist
antibody (e.g., an anti-
TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1
axis binding antagonist (e.g.,
anti-PD-L1 antagonist antibody (e.g., atezolizumab)), the platinum-based
chemotherapeutic agent (e.g.,
carboplatin or cisplatin), and the topoisomerase II inhibitor (e.g.,
etoposide)) may be administered in one
or more dosing cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17,18, 19, 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,
43, 44, 45, 46, 47, 48, 49, or 50
or more dosing cycles). In some instances, dosing cycles of the anti-TIGIT
antagonist antibody (e.g., an
anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the
PD-1 axis binding
antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) (with
or without the platinum-based
chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or the
topoisomerase II inhibitor (e.g.,
etoposide)) continue until there is a loss of clinical benefit (e.g.,
confirmed disease progression, drug
resistance, death, or unacceptable toxicity). In some instances, the length of
each dosing cycle is about
18 to 24 days (e.g., 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21
days, 22 days, 23 days, or
24 days). In some instances, the length of each dosing cycle is about 21 days.
In other instances, the
.. length of each dosing cycle is about 14 days. In other instances, the
length of each dosing cycle is about
28 days.
In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) is administered on about Day 1 (e.g., Day
1 3 days) of each dosing
cycle. For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) is administered intravenously at a dose
(e.g., a fixed dose) of about
600 mg on Day 1 of each dosing cycle, e.g., each 21-day cycle (i.e., at a dose
of about 600 mg every
three weeks). In some instances, the anti-TIGIT antagonist antibody (e.g., an
anti-TIGIT antagonist
antibody as disclosed herein, e.g., tiragolumab) is administered intravenously
at a dose (e.g., a fixed
dose) of 600 mg on Day 1 of each dosing cycle, e.g., each 21-day cycle (i.e.,
at a dose of 600 mg every
three weeks). Similarly, in some instances, the PD-1 axis binding antagonist
(e.g., anti-PD-L1 antagonist
antibody (e.g., atezolizumab)) is administered on about Day 1 (e.g., Day 1 3
days) of each dosing cycle.
For example, in some instances, the PD-1 axis binding antagonist (e.g., anti-
PD-L1 antagonist antibody
(e.g., atezolizumab)) is administered intravenously at a dose of about 1200 mg
on Day 1 of each 21-day
cycle (i.e., at a dose of about 1200 mg every three weeks). In other
instances, e.g., the PD-1 axis binding
antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is
administered intravenously at a
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dose of about 1200 mg on Day 1 of each 21-day cycle (i.e., at a dose of about
1200 mg every three
weeks). In some instances, the PD-1 axis binding antagonist (e.g., anti-PD-L1
antagonist antibody (e.g.,
atezolizumab)) is administered intravenously at a dose of 1200 mg on Day 1 of
each 21-day cycle (i.e., at
a dose of 1200 mg every three weeks). In some instances, both the anti-TIGIT
antagonist antibody (e.g.,
an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and
the PD-1 axis binding
antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) are
administered on about Day 1
(e.g., Day 1 3 days) of each dosing cycle. In some instances, the platinum-
based chemotherapeutic
agent is administered on about Day 1 (e.g., Day 1 3 days) of each dosing
cycle. In some instances, the
topoisomerase II inhibitor is on about Day 1 (e.g., Day 1 3 days) of each
dosing cycle. For example, in
some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed
herein, e.g., tiragolumab) is administered intravenously at a dose of about
600 mg on Day 1 of each
21-day cycle (i.e., at a dose of about 600 mg every three weeks), and the PD-1
axis binding antagonist
(e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered
intravenously at a dose of
about 1200 mg on Day 1 of each 21-day cycle (i.e., at a dose of about 1200 mg
every three weeks), the
platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is
administered at a dose sufficient
to achieve AUC = 5 mg/ml/min on Day 1 of each of the four initial dosing
cycles, and the topoisomerase II
inhibitor (e.g., etoposide) is administered at a dose of 100 mg/m2on each of
Days 1,2, and 3 of each of
the four initial dosing cycles. In some instances, the anti-TIGIT antagonist
antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is administered
intravenously at a dose of 600
mg on Day 1 of each 21-day cycle (i.e., at a dose of 600 mg every three
weeks), and the PD-1 axis
binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab))
is administered
intravenously at a dose of1200 mg on Day 1 of each 21-day cycle (i.e., at a
dose of 1200 mg every three
weeks), the platinum-based chemotherapeutic agent (e.g., carboplatin or
cisplatin) is administered at a
dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each of the four
initial dosing cycles, and the
topoisomerase ll inhibitor (e.g., etoposide) is administered at a dose of 100
mg/m20n each of Days 1, 2,
and 3 of each of the four initial dosing cycles.
In some instances, the anti-TIGIT antagonist antibody, PD-1 axis binding
antagonist, platinum-
based chemotherapeutic agent, and topoisomerase II inhibitor are administered
in each of four initial
dosing cycles. In some instances, the anti-TIGIT antagonist antibody is
administered at a dose from
about 30 mg to about 1200 mg on Day 1 of each of the four initial dosing
cycles. In some instances, the
anti-TIGIT antagonist antibody is administered at a dose from about 30 mg to
about 600 mg on Day 1 of
each of the four initial dosing cycles. In some instances, the anti-TIGIT
antagonist antibody is
administered at a dose of about 600 mg on Day 1 of each of the four initial
dosing cycles. In some
instances, the PD-1 axis binding antagonist is administered at a dose from
about 80 mg to about 1600 mg
on Day 1 of each of the four initial dosing cycles (e.g., at a dose of about
1200 mg on Day 1 of each of
the four initial dosing cycles). In some instances, the anti-TIGIT antagonist
antibody is administered at a
dose from 30 mg to 1200 mg on Day 1 of each of the four initial dosing cycles.
In some instances, the
anti-TIGIT antagonist antibody is administered at a dose from 30 mg to 600 mg
on Day 1 of each of the
four initial dosing cycles. In some instances, the anti-TIGIT antagonist
antibody is administered at a dose
of 600 mg on Day 1 of each of the four initial dosing cycles. In some
instances, the PD-1 axis binding
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antagonist is administered at a dose from 80 mg to 1600 mg on Day 1 of each of
the four initial dosing
cycles (e.g., at a dose of 1200 mg on Day 1 of each of the four initial dosing
cycles). In some instances,
the platinum-based chemotherapeutic agent is administered at a dose sufficient
to achieve AUC = 5
mg/ml/min on Day 1 of each of the four initial dosing cycle, and/or the
topoisomerase II inhibitor is
administered at a dose of 100 mg/m2on each of Days 1, 2, and 3 of each of the
four initial dosing cycles.
In some instances, the anti-TIGIT antagonist antibody and the PD-1 axis
binding antagonist are
further administered in one or more additional cycles following the fourth
initial dosing cycle. In some
instances, the anti-TIGIT antagonist antibody is administered at a dose from
about 30 mg to about 1200
mg on Day 1 of each of the one or more additional dosing cycles (e.g., at a
dose from about 30 mg to
about 600 mg on Day 1 of each of the one or more additional dosing cycles). In
some instances, the anti-
TIGIT antagonist antibody is administered at a dose of about 600 mg on Day 1
of each of the one or more
additional dosing cycles. In some instances, the PD-1 axis binding antagonist
is administered at a dose
from about 80 mg to about 2000 mg on Day 1 of each of the one or more
additional dosing cycles (e.g., at
a dose of about 840 mg, 1200 mg, or 1680 mg on Day 1 of each of the one or
more additional dosing
cycles). In some instances, the additional dosing cycles include
administration of the PD-1 axis binding
antagonist (e.g., atezolizumab) at a dose of about 840 mg every two weeks,
about 1200 mg every three
weeks, or about 1680 mg every four weeks. For example, in some instances, each
of the one or more
dosing cycles is about 14 days, and the PD-1 axis binding antagonist (e.g.,
atezolizumab) is administered
at a dose of about 840 mg on Day 1 of each of the one or more additional
dosing cycles. In some
instances, each of the one or more dosing cycles is about 21 days, and the PD-
1 axis binding antagonist
(e.g., atezolizumab) is administered at a dose of about 1200 mg on Day 1 of
each of the one or more
additional dosing cycles. In some instances, each of the one or more dosing
cycles is about 28 days, and
the PD-1 axis binding antagonist (e.g., atezolizumab) is administered at a
dose of about 1 680 mg on Day
1 of each of the one or more additional dosing cycles.
In some instances, the anti-TIGIT antagonist antibody is administered at a
dose from 30 mg to
1200 mg on Day 1 of each of the one or more additional dosing cycles (e.g., at
a dose from 30 mg to 600
mg on Day 1 of each of the one or more additional dosing cycles). In some
instances, the anti-TIGIT
antagonist antibody is administered at a dose of 600 mg on Day 1 of each of
the one or more additional
dosing cycles. In some instances, the PD-1 axis binding antagonist is
administered at a dose from 80 mg
to 2000 mg on Day 1 of each of the one or more additional dosing cycles (e.g.,
at a dose of 840 mg, 1200
mg, or 1680 mg on Day 1 of each of the one or more additional dosing cycles).
In some instances, the
additional dosing cycles include administration of the PD-1 axis binding
antagonist (e.g., atezolizumab) at
a dose of 840 mg every two weeks, 1200 mg every three weeks, or 1680 mg every
four weeks. For
example, in some instances, each of the one or more dosing cycles is 14 days,
and the PD-1 axis binding
antagonist (e.g., atezolizumab) is administered at a dose of 840 mg on Day 1
of each of the one or more
additional dosing cycles. In some instances, each of the one or more dosing
cycles is 21 days, and the
PD-1 axis binding antagonist (e.g., atezolizumab) is administered at a dose of
1200 mg on Day 1 of each
of the one or more additional dosing cycles. In some instances, each of the
one or more dosing cycles is
28 days, and the PD-1 axis binding antagonist (e.g., atezolizumab) is
administered at a dose of 1680 mg
on Day 1 of each of the one or more additional dosing cycles.
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In some instances, a subject or population of subjects having lung cancer
(e.g., SCLC, e.g., ES-
SCLC) is treated by administering to the subject or population of subjects one
or more dosing cycles
(e.g., 21-day dosing cycles) of an anti-TIGIT antagonist antibody (e.g., an
anti-TIGIT antagonist antibody
as disclosed herein, e.g., tiragolumab) at a dose from about 30 mg to about
1200 mg (e.g., between
about 30 mg to about 1100 mg, e.g., between about 60 mg to about 1000 mg,
e.g., between about 100
mg to about 900 mg, e.g., between about 200 mg to about 800 mg, e.g., between
about 300 mg to about
800 mg, e.g., between about 400 mg to about 800 mg, e.g., between about 400 mg
to about 750 mg, e.g.,
between about 450 mg to about 750 mg, e.g., between about 500 mg to about 700
mg, e.g., between
about 550 mg to about 650 mg, e.g., 600 mg 10 mg, e.g., 600 6 mg, e.g.,
600 5 mg, e.g., 600 3
mg, e.g., 600 1 mg, e.g., 600 0.5 mg, e.g., 600 mg) on Day 1 of each
dosing cycle, a PD-1 axis
binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab))
at a dose from about 80 mg
to about 2000 mg (e.g., between about 100 mg to about 1600 mg, e.g., between
about 200 mg to about
1600 mg, e.g., between about 300 mg to about 1600 mg, e.g., between about 400
mg to about 1600 mg,
e.g., between about 500 mg to about 1600 mg, e.g., between about 600 mg to
about 1600 mg, e.g.,
between about 700 mg to about 1600 mg, e.g., between about 800 mg to about
1600 mg, e.g., between
about 900 mg to about 1500 mg, e.g., between about 1000 mg to about 1400 mg,
e.g., between about
1050 mg to about 1350 mg, e.g., between about 1100 mg to about 1300 mg, e.g.,
between about 1150
mg to about 1250 mg, e.g., between about 1175 mg to about 1225 mg, e.g.,
between about 1190 mg to
about 1210 mg, e.g., 1200 mg 5 mg, e.g., 1200 2.5 mg, e.g., 1200 1.0 mg,
e.g., 1200 0.5 mg, e.g.,
1200 mg) on Day 1 of each dosing cycle (e.g., at a dose from about 30 mg to
1200 mg (e.g., between 30
mg to 1100 mg, e.g., between 60 mg to 1000 mg, e.g., between 100 mg to 900 mg,
e.g., between 200 mg
to 800 mg, e.g., between 300 mg to 800 mg, e.g., between 400 mg to 800 mg,
e.g., between 400 mg to
750 mg, e.g., between 450 mg to 750 mg, e.g., between 500 mg to 700 mg, e.g.,
between 550 mg to 650
mg, e.g., 600 mg 10 mg, e.g., 600 6 mg, e.g., 600 5 mg, e.g., 600 3
mg, e.g., 600 1 mg, e.g.,
600 0.5 mg, e.g., 600 mg) on Day 1 of each dosing cycle, a PD-1 axis binding
antagonist (e.g., anti-PD-
L1 antagonist antibody (e.g., atezolizumab)) at a dose from 80 mg to 2000 mg
(e.g., between 100 mg to
1600 mg, e.g., between 200 mg to 1600 mg, e.g., between 300 mg to 1600 mg,
e.g., between 400 mg to
1600 mg, e.g., between 500 mg to 1600 mg, e.g., between 600 mg to 1600 mg,
e.g., between 700 mg to
1600 mg, e.g., between 800 mg to 1600 mg, e.g., between 900 mg to 1500 mg,
e.g., between 1000 mg to
1400 mg, e.g., between 1050 mg to 1350 mg, e.g., between 1100 mg to 1300 mg,
e.g., between 1150 mg
to 1250 mg, e.g., between 1175 mg to 1225 mg, e.g., between 1190 mg to 1210
mg, e.g., 1200 mg 5
mg, e.g., 1200 2.5 mg, e.g., 1200 1.0 mg, e.g., 1200 0.5 mg, e.g., 1200
mg) on Day 1 of each
dosing cycle), a platinum-based chemotherapeutic agent (e.g., carboplatin or
cisplatin) at a dose
sufficient to achieve AUC from 1-50 mg/ml/min (e.g., 2-25 mg/ml/min, 3-15
mg/ml/min, 4-10 mg/ml/min, or
mg/ml/min, e.g., 2 mg/ml/min, 3 mg/ml/min, 4 mg/ml/min, 5 mg/ml/min, 6
mg/ml/min, 7 mg/ml/mm, 8
mg/ml/min, 9 mg/ml/min, 10 mg/ml/min, 11 mg/ml/min, 12 mg/ml/min, 13
mg/ml/min, 14 mg/ml/min, 15
mg/ml/min, 20 mg/ml/min, 25 mg/ml/min, 30 mg/ml/min, 35 mg/ml/min, 40
mg/ml/min, 45 mg/ml/min, 50
mg/ml/min, e.g., 5 mg/ml/min) on Day 1 of each dosing cycle, and a
topoisomerase II inhibitor (e.g.,
etoposide) at a dose of 100 mg/m2 on each of Days 1, 2, and 3 of each dosing
cycle, wherein the
treatment extends PFS and/or OS of the subject or population of subjects as
compared to treatment with
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PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab)), platinum-based
chemotherapeutic agent (e.g., carboplatin or cisplatin), and topoisomerase II
inhibitor (e.g., etoposide)
without the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist
antibody as disclosed herein,
e.g., tiragolumab).
In some instances, a subject or population of subjects having lung cancer
(e.g., SCLC, e.g., ES-
SCLC) is treated by administering to the subject or population of subjects one
or more dosing cycles
(e.g., 21-day dosing cycles) of an anti-TIGIT antagonist antibody (e.g., an
anti-TIGIT antagonist antibody
as disclosed herein, e.g., tiragolumab) at a dose from 30 mg to 1200 mg (e.g.,
between 30 mg to 1100
mg, e.g., between 60 mg to 1000 mg, e.g., between 100 mg to 900 mg, e.g.,
between 200 mg to 800 mg,
e.g., between 300 mg to 800 mg, e.g., between 400 mg to 800 mg, e.g., between
400 mg to 750 mg, e.g.,
between 450 mg to 750 mg, e.g., between 500 mg to 700 mg, e.g., between 550 mg
to 650 mg, e.g., 600
mg 10 mg, e.g., 600 6 mg, e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600
1 mg, e.g., 600 0.5 mg,
e.g., 600 mg) on Day 1 of each dosing cycle, a PD-1 axis binding antagonist
(e.g., anti-PD-L1 antagonist
antibody (e.g., atezolizumab)) at a dose from 80 mg to 2000 mg (e.g., between
100 mg to 1600 mg, e.g.,
between 200 mg to 1600 mg, e.g., between 300 mg to 1600 mg, e.g., between 400
mg to 1600 mg, e.g.,
between 500 mg to 1600 mg, e.g., between 600 mg to 1600 mg, e.g., between 700
mg to 1600 mg, e.g.,
between 800 mg to 1600 mg, e.g., between 900 mg to 1500 mg, e.g., between 1000
mg to 1400 mg, e.g.,
between 1050 mg to 1350 mg, e.g., between 1100 mg to 1300 mg, e.g., between
1150 mg to 1250 mg,
e.g., between 1175 mg to 1225 mg, e.g., between 1190 mg to 1210 mg, e.g., 1200
mg 5 mg, e.g., 1200
2.5 mg, e.g., 1200 1.0 mg, e.g., 1200 0.5 mg, e.g., 1200 mg) on Day 1 of
each dosing cycle, a
platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) at a
dose sufficient to achieve
AUC from 1-50 mg/ml/min (e.g., 2-25 mg/ml/min, 3-15 mg/ml/min, 4-10 mg/ml/min,
or 5 mg/ml/min, e.g., 2
mg/ml/min, 3 mg/ml/min, 4 mg/ml/min, 5 mg/ml/min, 6 mg/ml/min, 7 mg/ml/min, 8
mg/ml/min, 9
mg/ml/min, 10 mg/ml/min, 11 mg/ml/min, 12 mg/ml/min, 13 mg/ml/min, 14
mg/ml/min, 15 mg/ml/min, 20
mg/ml/min, 25 mg/ml/min, 30 mg/ml/min, 35 mg/ml/min, 40 mg/ml/min, 45
mg/ml/min, 50 mg/ml/min, e.g.,
mg/ml/min) on Day 1 of each dosing cycle, and a topoisomerase II inhibitor
(e.g., etoposide) at a dose
of 100 mg/m2 on each of Days 1, 2, and 3 of each dosing cycle, wherein the
treatment extends PFS
and/or OS of the subject or population of subjects as compared to treatment
with PD-1 axis binding
antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)),
platinum-based chemotherapeutic
agent (e.g., carboplatin or cisplatin), and topoisomerase II inhibitor (e.g.,
etoposide) without the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed
herein, e.g., tiragolumab).
In some instances, the treatment extends the OS of the subject or population
of subjects by at
least about 3.3 months (e.g., by 3.3-120 months, by 4-100 months, by 5-80
months, by 6-60 months, by
7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 3.3
months, 3.4 months, 3.5
months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1
months, 4.2 months, 4.3
5 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months,
4.9 months, 5.0 months, 5.5
months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5
months, 9.0 months, 9.5
months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months,
14 months, 15
months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22
months, 23 months, 24
months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31
months, 32 months, 33
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months, 34 months, 35 months, or 36 months) as compared to treatment with the
PD-1 axis binding
antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase
It inhibitor without the
anti-TIG IT antagonist antibody. In some instances, the treatment extends the
OS of the subject or
population of subjects by at least about 5.3 months (e.g., by 5.3-120, by 6-60
months, by 7-48 months, by
8-36 months, or by 10-24 months, e.g., by at least about 5.3 months, 5.5
months, 6.0 months, 6.5
months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5
months, 10 months, 10.5
months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16
months, 17 months,
18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months,
25 months, 26 months,
27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months,
34 months, 35 months,
or 36 months) as compared to treatment with the PD-1 axis binding antagonist,
the platinum-based
chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-
TIG IT antagonist antibody.
In some embodiments, the treatment extends the PFS of the subject or
population of subjects by
at least about 2.4 months (e.g., by 2.4-120 months, by 2.5-100 months, by 3.0-
80 months, by 4.0-60
months, by 5.0-48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12
months, e.g., by at least
about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months,
3.0 months, 3.1 months,
3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8
months, 3.9 months, 4.0
months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6
months, 4.7 months, 4.8
months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0
months, 7.5 months, 8.0
months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months,
11.5 months, 12
months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19
months, 20 months, 21
months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28
months, 29 months, 30
months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months)
as compared to
treatment with the PD-1 axis binding antagonist, the platinum-based
chemotherapeutic agent, and the
topoisomerase II inhibitor without the anti-TIG IT antagonist antibody. In
some embodiments, the
treatment extends the PFS of the subject or population of subjects by at least
about 4 months (e.g., by 4-
120 months, by 5-100 months, by 6-80 months, by 7-60 months, by 8-48 months,
by 9-36 months, or by
10-24 months, e.g., by at least about 4.0 months, 4.1 months, 4.2 months, 4.3
months, 4.4 months, 4.5
months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5
months, 6.0 months, 6.5
months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5
months, 10 months, 10.5
months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16
months, 17 months,
18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months,
25 months, 26 months,
27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months,
34 months, 35 months,
or 36 months) as compared to treatment with the PD-1 axis binding antagonist,
the platinum-based
chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-
TIG IT antagonist antibody.
In some embodiments, the subject or population of subjects receives one or
more additional
dosing cycles (e.g., 21-day dosing cycles) of the anti-TIGIT antagonist
antibody at a dose from about 30
mg to about 1200 mg on Day 1 of each additional dosing cycle and atezolizumab
at a dose from about 80
mg to about 2000 mg on Day 1 of each additional dosing cycle, wherein
carboplatin and etoposide are
omitted from each of the one or more additional dosing cycles.
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In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) is administered to the subject or
population of subjects by intravenous
infusion over about 60 15 minutes (e.g., about 50 minutes, about 51 minutes,
about 52 minutes, about
53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57
minutes, about 58 minutes,
about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about
63 minutes, about 64
minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68
minutes, about 69 minutes, or
about 70 minutes). In some instances, the PD-1 axis binding antagonist (e.g.,
anti-PD-L1 antagonist
antibody (e.g., atezolizumab)) is administered to the subject or population of
subjects by intravenous
infusion over about 60 15 minutes (e.g., about 45 minutes, about 46 minutes,
about 47 minutes, about
48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52
minutes, about 53 minutes,
about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about
58 minutes, about 59
minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63
minutes, about 64 minutes,
about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about
69 minutes, about 70
minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74
minutes, or about 75 minutes).
In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) is administered to the subject or
population of subjects before the PD-
1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab)). In some instances,
for example, following administration of the anti-TIGIT antagonist antibody
and before administration of
the PD-1 axis binding antagonist, the method includes an intervening first
observation period. In some
instances, the method further includes a second observation period following
administration of the PD-1
axis binding antagonist. In some instances, the method includes both a first
observation period following
administration of the anti-TIGIT antagonist antibody and second observation
period following
administration of PD-1 axis binding antagonist. In some instances, the first
and second observation
periods are each between about 30 minutes to about 60 minutes in length. In
instances in which the first
and second observation periods are each about 60 minutes in length, the method
may include recording
the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure,
and temperature) at about 30
10 minutes after administration of the anti-TIGIT antagonist antibody and PD-1
axis binding antagonist
during the first and second observation periods, respectively. In instances in
which the first and second
observation periods are each about 30 minutes in length, the method may
include recording the subject's
vital signs (e.g., pulse rate, respiratory rate, blood pressure, and
temperature) at about 15 10 minutes
after administration of the anti-TIGIT antagonist antibody and PD-1 axis
binding antagonist during the first
and second observation periods, respectively.
In other instances, the PD-1 axis binding antagonist (e.g., anti-PD-L1
antagonist antibody (e.g.,
atezolizumab)) is administered to the subject or population of subjects before
the anti-TIGIT antagonist
.. antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein,
e.g., tiragolumab). In some
instances, for example, following administration of the PD-1 axis binding
antagonist and before
administration of the anti-TIGIT antagonist antibody, the method includes an
intervening first observation
period. In some instances, the method includes a second observation period
following administration of
the anti-TIGIT antagonist antibody. In some instances, the method includes
both a first observation
period following administration of the PD-1 axis binding antagonist and second
observation period
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following administration of the anti-TIGIT antagonist antibody. In some
instances, the first and second
observation periods are each between about 30 minutes to about 60 minutes in
length. In instances in
which the first and second observation periods are each about 60 minutes in
length, the method may
include recording the subject's vital signs (e.g., pulse rate, respiratory
rate, blood pressure, and
temperature) at about 30 10 minutes after administration of the PD-1 axis
binding antagonist and anti-
TIGIT antagonist antibody during the first and second observation periods,
respectively. In instances in
which the first and second observation periods are each about 30 minutes in
length, the method may
include recording the subject's vital signs (e.g., pulse rate, respiratory
rate, blood pressure, and
temperature) at about 15 10 minutes after administration of the PD-1 axis
binding antagonist and anti-
TIGIT antagonist antibody during the first and second observation periods,
respectively.
In other instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist
(e.g., anti-PD-L1 (atezolizumab)
antagonist antibody) are administered to the subject or population of subjects
simultaneously. In some
instances, for example, following administration of the anti-TIGIT antagonist
antibody and the PD-1 axis
binding antagonist (e.g., anti-PD-L1 antagonist antibody) the method includes
an observation period. In
some instances, the observation period is between about 30 minutes to about 60
minutes in length. In
instances in which the observation period is about 60 minutes in length, the
method may include
recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood
pressure, and temperature) at
about 30 10 minutes after administration of the PD-1 axis binding antagonist
(e.g., anti-PD-L1
antagonist antibody) and anti-TIGIT antagonist antibody during the observation
period. In instances in
which the observation period is about 30 minutes in length, the method may
include recording the
subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and
temperature) at about 15 10
minutes after administration of the PD-1 axis binding antagonist (e.g., anti-
PD-L1 antagonist antibody)
and anti-TIGIT antagonist antibody during the observation period.
In any of the methods, uses, or compositions for use described herein, the
anti-TIGIT antagonist
antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab), PD-1 axis
binding antagonist (e.g., anti-PD-L1 antibody (e.g., atezolizumab)), platin
urn-based chemotherapeutic
agent (e.g., carboplatin or cisplatin), and topoisomerase II inhibitor (e.g.,
etoposide)), or a medicament
thereof, may be administered in conjunction with (either separately or
together), one or more additional
anti-cancer therapeutic agent(s) (e.g., an immunomodulatory agent (e.g., an
agent that decreases or
inhibits one or more immune co-inhibitory receptors (e.g., one or more immune
co-inhibitory receptors
selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA),
such as a CTLA-4
antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab
(YERVOYO)), or an agent that
increases or activates one or more immune co-stimulatory receptors (e.g., one
or more immune co-
stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM,
and/or GITR), such as
an OX-40 agonist, e.g., an OX-40 agonist antibody), a chemotherapeutic agent,
a cytotoxic agent, a
growth inhibitory agent, a radiotherapy/radiation therapy, and/or an anti-
hormonal agent, such as those
recited herein above).
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In some instances, the lung cancer is a small cell lung cancer (SCLC), such as
extensive stage
SCLC (ES-SCLC). In some instances, the subject or population of subjects is
treatment-naïve for ES-
SCLC (e.g., chemotherapy-naïve for ES-SCLC).
In some instances, the lung cancer is unselected for PD-L1 expression. In
other instances, the
lung cancer is selected for PD-L1 expression. In some instances, the lung
cancer is selected for PD-L1
expression by an immunohistochemical (INC) assay comprising staining with an
anti-PD-L1 antibody,
such as SP263, 2203, SP142, or 28-8. In some instances, the anti-PD-L1
antibody is SP263 and the
IHC assay is the Ventana SP263 IHC assay; the anti-PD-L1 antibody is 2203 and
the IHC assay is the
pharmDx 2203 IHC assay; the anti-PD-L1 antibody is SP142 and the IHC assay is
the Ventana SP142
IHC assay, or the anti-PD-L1 antibody is 28-8 and the IHC assay is the pharmDx
28-8 IHC assay.
In some instances, in any of the methods, uses, or compositions for use
described herein, a
tumor sample obtained from the individual has a detectable nucleic acid
expression level of PD-L1. In
some instances, the detectable nucleic acid expression level of PD-L1 has been
determined by RNA-seq,
RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY
technique, ISH,
or a combination thereof. In some instances, the sample is selected from the
group consisting of a tissue
sample, a whole blood sample, a serum sample, and a plasma sample. In some
instances, the tissue
sample is a tumor sample. In some instances, the tumor sample comprises tumor-
infiltrating immune
cells, tumor cells, stromal cells, and any combinations thereof.
In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some
embodiments,
.. the SCLC is extensive-stage small cell lung cancer (ES-SCLC), also referred
to as stage 4 (IV) SCLC. In
some embodiments, the SCLC is histologically or cytologically confirmed ES-
SCLC, according to or as
defined by the Veterans Administration Lung Study Group (VALG) staging system
(see, e.g., Micke et at.
Lung Cancer 2002, 37:271-6). In some embodiments, SOLO is classified as ES-
SOLO if the individual is
inoperable and cannot be classified as having limited or limited stage SOLO (L-
SCLC or LS-SCLC). In
.. some embodiments, the ES-SOLO is detectable and/or has spread outside the
originally affected lung. In
some embodiments, the ESSCLC is detectable and/or has spread further into
other (e.g., distant) organs,
such as (but not limited to) the liver, adrenal glands, lymph nodes and/or
brain. In some embodiments,
the ESSCLC is difficult to treat.
In some embodiments, the subject or population of subjects has a poor
prognosis. In some
embodiments, the subject or population of subjects is a treatment-naïve
subject or population of subjects
(e.g., a chemotherapy-naïve subject or population of subjects). In some
embodiments, a treatment-naïve
subject is a subject who has not received prior treatment, e.g., for cancer,
for SOLO, or for ES-SCLC. In
some embodiments, the treatment naïve subject is a subject who has not
received prior treatment for ES-
SOLO. In some embodiments, the treatment-naïve subject is chemotherapy naïve,
e.g., a subject who
has not received prior chemotherapy for the treatment of, e.g., cancer, SCLC,
and/or ES-SOLO. In some
embodiments, the subject or population of subjects has not received treatment
for ES-SCLC. In some
embodiments, the subject or population of subjects has not received prior
systemic treatment for ES-
SOLO. In some embodiments, the subject or population of subjects has received
prior
chemoradiotherapy for limited stage SOLO (LS-SCLC) with curative intent, and
has experienced a
treatment-free cycle of at least six months since the last chemotherapy,
radiotherapy, or
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chemoradiotherapy cycle from the diagnosis of ES-SCLC. In some embodiments,
the subject or
population of subjects has asymptomatic supratentorial or cerebellar central
nervous system (CNS)
metastases. In some embodiments, the subject or population of subjects does
not have metastases to
the midbrain, pans, medulla, or spinal cord. In some embodiments, the subject
or population of subjects
has CNS disease and does not require corticosteroid treatment for CNS disease.
In some embodiments,
the subject or population of subjects has new asymptomatic metastases and has
received radiation
therapy and/or surgery for CNS metastases. In some embodiments, the subject or
population of subjects
has measurable disease, according to/as defined by RECIST v1.1 criteria (see,
e.g., Eisenhauer et al.,
Eur. J. Cancer 2009, 45: 228-247). In some embodiments, the subject or
population of subjects has not
.. received prior treatment with a CD137 agonist or an immune checkpoint
blockade therapy.
In some instances, the treatment results in a CR or a PR. In some instances,
the PFS of the
subject or population of subjects is increased as compared to a reference PFS
time. In some instances,
wherein the reference PFS time is the median PFS time of a population of
subjects who have received a
treatment with (e.g., anti-PD-L1 antibody (e.g., atezolizumab)), platinum-
based chemotherapeutic agent
(e.g., carboplatin or cisplatin), and topoisomerase II inhibitor (e.g.,
etoposide) without the anti-TIGIT
antagonist antibody (e.g., tiragolumab).
In some instances, the methods further comprise an additional therapy. The
additional therapy
may be radiation therapy, surgery (e.g., lumpectomy and a mastectomy),
chemotherapy, gene therapy,
DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow
transplantation, nanotherapy,
monoclonal antibody therapy, or a combination of the foregoing. The additional
therapy may be in the
form of adjuvant or neoadjuvant therapy. In some embodiments, the additional
therapy is the
administration of small molecule enzymatic inhibitor or anti-metastatic agent.
In some embodiments, the
additional therapy is the administration of side-effect limiting agents (e.g.,
agents intended to lessen the
occurrence and/or severity of side effects of treatment, such as anti-nausea
agents, etc.). In some
.. embodiments, the additional therapy is radiation therapy. In some
embodiments, the additional therapy is
surgery. In some embodiments, the additional therapy is a combination of
radiation therapy and surgery.
In some embodiments, the additional therapy is gamma irradiation.
Additional therapeutic antibodies contemplated for use herein include, without
limitation,
alemtuzumab (Campath), bevacizumab (AVASTIN , Genentech); cetuximab (ERBITUX ,
Imclone);
panitumumab (VECTIBIX , Amgen), rituximab (RITUXANO, Genentech/Biogen Idec),
pertuzumab
(OMNITARGO, 2C4, Genentech), trastuzumab (HERCEPTIN , Genentech), tositumomab
(Bexxar,
Corixia), the antibody drug conjugate gemtuzumab ozogamicin (MYLOTARG ,
Wyeth), apolizumab,
aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab
mertansine, cedelizumab,
certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab,
efalizumab, epratuzumab,
erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab
ozogamicin, ipilimumab,
labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab,
natalizumab,
nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, pal ivizumab,
pascolizumab,
pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab,
reslivizumab, reslizumab,
resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab,
tacatuzumab tetraxetan,
.. tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab
celmoleukin,
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tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the anti-
interleukin-12 (ABT-
874/J695, Wyeth Research and Abbott Laboratories).
In some embodiments, the additional therapy is therapy targeting PI3K/AKT/mTOR
pathway,
HSP90 inhibitor, tubulin inhibitor, apoptosis inhibitor, and/or
chemopreventative agent. In some
embodiments, the additional therapy is CTLA-4 (also known as CD152), e.g., a
blocking antibody,
ipilimumab (also known as MDX-010, MDX-101, or Yervoy0), tremelimumab (also
known as ticilimumab
or CP-675,206), an antagonist directed against B7-H3 (also known as CD276),
e.g., a blocking antibody,
MGA271, an antagonist directed against TGF beta, e.g., metelimumab (also known
as CAT-192),
fresolimumab (also known as GC1008), or LY2157299, a treatment comprising
adoptive transfer of a T
cell (e.g., a cytotoxic T cell or CTL) expressing a chimeric antigen receptor
(CAR), a treatment comprising
adoptive transfer of a T cell comprising a dominant-negative TGF beta
receptor, e.g., a dominant-
negative TGF beta type ll receptor, a treatment comprising a HERCREEK/I
protocol (see, e.g.,
ClinicalTrials.gov Identifier NC100889954), an agonist directed against CD137
(also known as TNFRSF9,
4-1BB, or ILA), e.g., an activating antibody, urelumab (also known as BMS-
663513), an agonist directed
against CD40, e.g., an activating antibody, CP-870893, an agonist directed
against 0X40 (also known as
CD134), e.g., an activating antibody, administered in conjunction with a
different anti-0X40 antibody (e.g.,
Agon0X)., an agonist directed against CD27, e.g., an activating antibody, CDX-
1127, indoleamine-2,3-
dioxygenase (IDO), 1-methyl- D-tryptophan (also known as 1-D-MT), an antibody-
drug conjugate (in
some embodiments, comprising mertansine or monomethyl auristatin E (MIVIAE)),
an anti-NaPi2b
antibody-MMAE conjugate (also known as DNIB0600A or RG7599), trastuzumab
emtansine (also known
as TDM1, ado-trastuzumab emtansine, or KADCYLA , Genentech), DMUC5754A, an
antibody-drug
conjugate targeting the endothelin B receptor (EDNBR), e.g., an antibody
directed against EDNBR
conjugated with MMAE, an angiogenesis inhibitor, an antibody directed against
a VEGF, e.g., VEGF-A,
bevacizumab (also known as AVASTIN , Genentech), an antibody directed against
angiopoietin 2 (also
known as Ang2), MEDI3617, an antineoplastic agent, an agent targeting CSF-1R
(also known as M-
CSFR or CD115), anti-CSF-1R (also known as IMCCS4), an interferon, for example
interferon alpha or
interferon gamma, Roferon-A, GM-CSF (also known as recombinant human
granulocyte macrophage
colony stimulating factor, rhu GMCSF, sargramostim, or Leukine0), IL-2 (also
known as aldesleukin or
Proleukine), IL-12, an antibody targeting CD20 (in some embodiments, the
antibody targeting CD20 is
obinutuzumab (also known as GA101 or Gazyva0) or rituximab), an antibody
targeting GITR (in some
embodiments, the antibody targeting GITR is TRX518), in conjunction with a
cancer vaccine (in some
embodiments, the cancer vaccine is a peptide cancer vaccine, which in some
embodiments is a
personalized peptide vaccine; in some embodiments the peptide cancer vaccine
is a multivalent long
peptide, a multi-peptide, a peptide cocktail, a hybrid peptide, or a
peptidepulsed dendritic cell vaccine
(see, e.g., Yamada et al., Cancer Sci, 104:14-21, 2013)), in conjunction with
an adjuvant, a TLR agonist,
e.g., Poly-ICLC (also known as Hiltonole), LPS, MPL, or CpG ODN, tumor
necrosis factor (TNF) alpha,
IL-1, HMGB1, an IL-10 antagonist, an IL-4 antagonist, an IL-13 antagonist, an
HVEM antagonist, an ICOS
agonist, e.g., by administration of ICOS-L, or an agonistic antibody directed
against ICOS, a treatment
targeting CX3CL1, a treatment targeting CXCL10, a treatment targeting CCL5, an
LFA-1 or ICAM1
agonist, a Selectin agonist, a targeted therapy, an inhibitor of B-Rat,
vemurafenib (also known as
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Zelboraf , dabrafenib (also known as Tafinlar8), erlotinib (also known as
Tarceva0), an inhibitor of a
MEK, such as MEK1 (also known as MAP2K1) or MEK2 (also known as MAP2K2).
cobimetinib (also
known as GDC-0973 or XL-518), trametinib (also known as Mekiniste), an
inhibitor of K-Ras, an inhibitor
of c-Met, onartuzumab (also known as MetMAb), an inhibitor of Alk, AF802 (also
known as CH5424802 or
alectinib), an inhibitor of a phosphatidylinositol 3-kinase (PI3K), BKM120,
idelalisib (also known as GS-
1101 or CAL 101), perifosine (also known as KRX-0401), an Akt, MK2206,
GSK690693, GDC-0941, an
inhibitor of mTOR, sirolimus (also known as rapamycin), temsirolimus (also
known as CCI-779 or
Torisele), everolimus (also known as RAD001), ridaforolimus (also known as AP-
23573, MK-8669, or
deforolimus), OSI-027, AZD8055, INK128, a dual PI3K/mTOR inhibitor, XL765, GDC-
0980, BEZ235 (also
known as NVP-BEZ235), BGT226, GSK2126458, PF- 04691502, PF-05212384 (also
known as PKI-587).
The additional therapy may be one or more of the chemotherapeutic agents
described herein.
iii. Methods and uses for treating locally advanced unresectable or metastatic
lung
cancer
Provided herein are methods and uses for treating lung cancer (e.g., non-small
cell lung cancer
(NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including
locally advanced
unresectable NSCLC (e.g., Stage 1118 NSCLC), or recurrent or metastatic NSCLC
(e.g., Stage IV
NSCLC), small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-
SCLC), and
adenocarcinoma of the lung) in a subject or population of subjects comprising
administering to the subject
or population of subjects one or more dosing cycles of an effective amount of
an anti-TIGIT antagonist
antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab), a PD-1 axis
binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as
atezolizumab), and a first and
second chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent
and a non-platinum-
based chemotherapeutic agent).
The present invention includes methods and uses involving administration of an
effective amount
of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody
as disclosed herein, e.g.,
tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist
antibody, such as
atezolizumab), and a chemotherapy combination to a subject or population of
subjects in need thereof. In
some embodiments, the anti-TIGIT antagonist antibody (e.g., anti-TIGIT
antagonist antibody as disclosed
herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-
PD-L1 antagonist antibody,
e.g., atezolizumab) are administered every three weeks (e.g., on Day 1 of each
21-day dosing cycle). In
some aspects, the invention includes methods and uses involving administration
of an effective amount of
an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g.,
tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1
antagonist antibody, such as
atezolizumab) based on body weight (BW) or body surface area (BSA) of a
subject or population of
subjects every three weeks (e.g., on Day 1 of each 21-day dosing cycle).
In some aspects, the invention includes methods and uses involving
administration of an effective
amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist
antibody as disclosed herein,
e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1
antagonist antibody, such as
.. atezolizumab), and a chemotherapy combination to a subject or population of
subjects in need thereof,
wherein the chemotherapy combination includes an effective amount of a
platinum-based
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chemotherapeutic agent and an effective amount of a non-platinum-based
chemotherapeutic agent. In
some instances, the anti-TIGIT antagonist antibody (e.g., anti-TIGIT
antagonist antibody as disclosed
herein, e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-
PD-L1 antagonist antibody,
e.g., atezolizumab) are administered every three weeks (e.g., on Day 1 of each
21-day dosing cycle). In
some instances, the platinum-based chemotherapeutic agent is carboplatin or
cisplatin and the non-
platinum-based chemotherapeutic agent is an antimetabolite (e.g., pemetrexed).
In particular embodiments, the method involves administration of an effective
amount of an anti-
TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab),
a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g.,
atezolizumab), a platinum-
based chemotherapeutic agent (e.g., carboplatin or cisplatin), and an
antimetabolite (e.g., pemetrexed) to
a subject or population of subjects in need thereof, wherein the anti-TIGIT
antagonist antibody (e.g., anti-
TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1
axis binding antagonist
(e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) are administered
every three weeks (e.g., on
Day 1 of each 21-day dosing cycle) and the chemotherapy combination (e.g., the
platinum-based
chemotherapeutic agent (e.g., carboplatin or cisplatin) and the antimetabolite
(e.g., pemetrexed) are
administered at the same frequency (e.g., every three weeks, e.g., on Day 1 of
each 21-day dosing
cycle). In some instances, the dosing continues for four-to-six induction
dosing cycles (e.g., four
induction dosing cycles, five induction dosing cycles, or six induction dosing
cycles). After the induction
dosing cycles, maintenance therapy can be administered in one or more
subsequent (maintenance)
dosing cycles. In certain embodiments, the one or more maintenance dosing
cycles does not include the
platinum-based chemotherapeutic agent.
In some instances, the present invention includes methods and uses involving
administration of
an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g.,
an anti-PD-L1 antagonist
antibody, such as atezolizumab) to a subject or population of subjects in need
thereof every four weeks
(e.g., on Day 1 of each 28-day dosing cycle).
In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) and the PD-1 axis binding
antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab)
results in a CR or a PR. In
some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an
anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the
PD-1 axis binding
antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab)
results in an increase in PFS
or DOR. In some instances, administration of the effective amount of the anti-
TIGIT antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) and the PD-1 axis binding
antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab)
results in an increase in OS.
In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an
anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the
PD-1 axis binding
antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab)
results in an increase in
progression-free survival of the subject or population of subjects, e.g., as
compared to treatment with the
PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as
compared to treatment with
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the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.
In some instances, the
effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist
(e.g., an anti-PD-L1 antagonist
antibody, such as atezolizumab) extends OS of the subject or population of
subjects, e.g., as compared
to treatment with the PD-1 axis binding antagonist without the anti-TIGIT
antagonist antibody or as
compared to treatment with the anti-TIGIT antagonist antibody without the PD-1
axis binding antagonist.
In some instances, administration of the effective amount of an anti-TIGIT
antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab), a PD-1 axis binding
antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab),
and a chemotherapy
combination to a subject or population of subjects in need thereof (e.g., a
combination of a platinum-
based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an
antimetabolite (e.g., pemetrexed))
results in an increase in a median PFS of the subject or population of
subjects as compared to treatment
with pembrolizumab and the chemotherapy combination (e.g., the antimetabolite
(e.g., pemetrexed) and
the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin)).
In some instances, the
treatment extends the PFS of the subject or population of subjects by at least
about 3.5 months or about
4.7 months (e.g., at least about 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3,
4.4, 4.5, 4.6, or 4.7 months, e.g.,
at least about 3.5-3.7 months, 3.7-3.9 months, 3.9-4.1 months, 4.1-4.3 months,
4.3-4.5 months, or 4.5-4.7
months).
In some embodiments, the administration of the effective amount of an anti-
TIGIT antagonist
antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab), a PD-1 axis
binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as
atezolizumab), and a chemotherapy
combination (e.g., a combination of a platinum-based chemotherapeutic agent
(e.g., carboplatin or
cisplatin) and an antimetabolite (e.g., pembrolizumab)) to a subject or
population of subjects having a
lung cancer (e.g., an NSCLC) according to any of the methods described herein
results in a median PFS
of greater than 8.8 months (e.g., at least 8.9 months, at least 9.0 months, at
least 9.2 months, at least 9.5
months, at least 10 months, at least 11 months, at least 12 months, at least
13 months, at least 14
months, at least 15 months, at least 16 months, at least 17 months, at least
18 months, at least 20
months, at least 24 months, at least 30 months, at least 36 months, at least
42 months, at least 48
months, at least 54 months, or more, e.g., about 8.9 months, about 9.0 months,
about 9.2 months, about
9.5 months, about 10 months, about 11 months, about 12 months, about 13
months, about 14 months,
about 15 months, about 16 months, about 17 months, about 18 months, about 20
months, about 24
months, about 30 months, about 36 months, about 42 months, about 48 months,
about 54 months, or
more). In some instances, the treatment results in a median PFS of the
population of subjects of at least
about 8 months (e.g., between 8 months and 36 months, e.g., between 8 months
and 24 months (e.g., 8
months, 9 months, 10 months, 12 months, 13 months, 14 months, 15 months, 16
months, 17 months, 18
months, 19 months, 20 months, 21 months, 22 months, 23 months, or 24 months).
In some instances,
the treatment results in a median PFS of the population of subjects of about
12.5 months to about 14.7
months (e.g., 12.5, 12.7, 12.9, 13.1, 13.3, 13.5, 13.7,13.9, 14.1, 14.3, 14.5,
or 14.7 months, e.g., about
12.5-13 months, 13-13.5 months, 13.5-14 months, or 14-14.7 months. In some
embodiments, the
administration of the effective amount of an anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT antagonist
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antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding
antagonist (e.g., an anti-PD-L1
antagonist antibody, such as atezolizumab), and a chemotherapy combination
(e.g., a combination of a
platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an
antimetabolite (e.g.,
pembrolizumab)) to a subject or population of subjects having a lung cancer
(e.g., an NSCLC) according
to any of the methods described herein results in a median PFS of at least 10
months. In some
embodiments, the administration of the effective amount of an anti-TIGIT
antagonist antibody (e.g., an
anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1
axis binding antagonist
(e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab), and a
chemotherapy combination (e.g.,
a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or
cisplatin) and an
antimetabolite (e.g., pembrolizumab)) to a subject or population of subjects
having a lung cancer (e.g., an
NSCLC) according to any of the methods described herein results in a median
PFS of at least 12 months.
In some instances, administration of the effective amount of an anti-TIGIT
antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab), a PD-1 axis binding
antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab),
and a chemotherapy
combination to a subject or population of subjects having a lung cancer (e.g.,
a combination of a
platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an
antimetabolite (e.g.,
pemetrexed)) results in an increase in a median OS (OS) of the subject or
population of subjects as
compared to treatment with pembrolizumab and the chemotherapy combination
(e.g., the antimetabolite
(e.g., pemetrexed) and the platinum-based chemotherapeutic agent (e.g.,
carboplatin or cisplatin)). In
some instances, the treatment extends the OS of the subject or population of
subjects by at least about 4
months (e.g., between 4 and 12 months (e.g., 4 months, 5 months, 6 months, 7
months, 8 months, 9
months, 10 months, 11 months, or 12 months)). In some instances, the treatment
extends the OS of the
subject or population of subjects by at least about 5.5 months to about 8.0
months (e.g., 5.5., 6.0, 6.5,
7.0, 7.5, or 8.0 months, e.g., 5.5-6.5, 6.5-7.5, or 7.5-8.0 months).
In some embodiments, the administration of the effective amount of an anti-
TIGIT antagonist
antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab), a PD-1 axis
binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as
atezolizumab), and a chemotherapy
combination (e.g., a combination of a platinum-based chemotherapeutic agent
(e.g., carboplatin or
cisplatin) and an antimetabolite (e.g., pembrolizumab)) to a subject or
population of subjects having a
lung cancer (e.g., an NSCLC) according to any of the methods described herein
results in a median OS
of greater than 22 months (e.g., at least 23, at least 24, at least 25, at
least 26, at least 27, at least 28, at
least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at
least 35, at least 36, at least 42, at
least 48, at least 54, at least 60, at least 70, at least 80, at least 90, at
least 100, at least 110, at least
120, at least 130, at least 140, at least 150, at least 160, at least 170, at
least 180, at least 190, or at least
200 months, e.g., about 23, about 24, about 25, about 26, about 27, about 28,
about 29, about 30, about
31, about 32, about, 33, about 34, about 35, about 36, about 40, about 42,
about 48, about 54, about 60,
about 70, about 80, about 90, about 100, about 110, about 120, about 130,
about 140, about 150, about
160, about 170, about 180, about 190, about 200 months). In some embodiments,
the treatment results
in a median OS of the population of subjects of at least about 24 months
(e.g., between 24 months and
42 months (e.g., between 24 months and 36 months (e.g., 24 months, 25 months,
26 months, 27 months,
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28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months,
35 months, or 36
months))). In some embodiments, the treatment results in a median OS of the
population of subjects of
about 27.5 months to about 32.0 months (e.g., 27.5, 28.0, 28.5, 29.0, 29.5,
30.0, 30.5, 31.0, 31.5, or 32.0
months (e.g., 27.5-28.5, 28.5-29.5, 29.5-30.5, 30.5-31.5, or 31.5-32 months).
In some embodiments, the
administration of the effective amount of an anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT antagonist
antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding
antagonist (e.g., an anti-PD-L1
antagonist antibody, such as atezolizumab), and a chemotherapy combination to
a subject or population
of subjects in need thereof (e.g., a combination of a platinum-based
chemotherapeutic agent (e.g.,
carboplatin or cisplatin) and an antimetabolite (e.g., pembrolizumab)) to a
subject or population of
subjects having a lung cancer (e.g., an NSCLC) according to any of the methods
described herein results
in a median OS of at least 24 months. In some embodiments, the administration
of the effective amount
of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody
as disclosed herein, e.g.,
tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist
antibody, such as
atezolizumab), and a chemotherapy combination (e.g., a combination of a
platinum-based
chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite
(e.g., pembrolizumab)) to a
subject or population of subjects having a lung cancer (e.g., an NSCLC)
according to any of the methods
described herein results in a median OS of at least 36 months.
In some instances, administration of the effective amount of an anti-TIGIT
antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab), a PD-1 axis binding
antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab),
and a chemotherapy
combination to a subject or population of subjects in need thereof (e.g., a
combination of a platinum-
based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an
antimetabolite (e.g., pemetrexed))
results in an increase in an overall response rate (ORR) of the subject or
population of subjects as
compared to treatment with pembrolizumab and the chemotherapy combination
(e.g., the antimetabolite
(e.g., pemetrexed) and the platinum-based chemotherapeutic agent (e.g.,
carboplatin or cisplatin)), e.g.,
an increase in ORR of at least 10%, (e.g., at least 15%, at least 20%, at
least 25%, at least 30%, at least
35%, or at least 40%) as compared to treatment with pembrolizumab and the
chemotherapy combination
(e.g., the antimetabolite (e.g., pemetrexed) and the platinum-based
chemotherapeutic agent (e.g.,
carboplatin or cisplatin)).
In some embodiments, the administration of the effective amount of an anti-
TIGIT antagonist
antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab), a PD-1 axis
binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as
atezolizumab), and a chemotherapy
combination (e.g., a combination of a platinum-based chemotherapeutic agent
(e.g., carboplatin or
cisplatin) and an antimetabolite (e.g., pembrolizumab)) to a subject or
population of subjects having a
.. lung cancer (e.g., an NSCLC) according to any of the methods described
herein results in an ORR of
greater than 47.5% (e.g., at least 48%, at least 49%, at least 50%, at least
55%, at least 60%, at least
65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at
least 95%, or 100%, e.g.,
about 48%, about 49%, about 50%, about 55%, about 60%, about 65%, about 70%,
about 75%, about
80%, about 85%, about 90%, about 95%, or about 100%). In some embodiments, the
administration of
.. the effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-
TIGIT antagonist antibody as
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disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an
anti-PD-L1 antagonist
antibody, such as atezolizumab), and a chemotherapy combination (e.g., a
combination of a platinum-
based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an
antimetabolite (e.g.,
pembrolizumab)) to a subject or population of subjects having a lung cancer
(e.g., an NSCLC) according
to any of the methods described herein results in an ORR of at least 50%. In
some embodiments, the
administration of the effective amount of an anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT antagonist
antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding
antagonist (e.g., an anti-PD-L1
antagonist antibody, such as atezolizumab), and a chemotherapy combination
(e.g., a combination of a
platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an
antimetabolite (e.g.,
pembrolizumab)) to a subject or population of subjects having a lung cancer
(e.g., an NSCLC) according
to any of the methods described herein results in an ORR of at least 60%. In
some embodiments, the
administration of the effective amount of an anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT antagonist
antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding
antagonist (e.g., an anti-PD-L1
antagonist antibody, such as atezolizumab), and a chemotherapy combination
(e.g., a combination of a
platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an
antimetabolite (e.g.,
pembrolizumab)) to a subject or population of subjects having a lung cancer
(e.g., an NSCLC) according
to any of the methods described herein results in an ORR of at least 70%.
The present invention includes methods and uses involving administration of an
effective amount
of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody
as disclosed herein, e.g.,
tiragolumab) to a subject or population of subjects in need thereof every four
weeks (e.g., on Day 1 of
each 28-day dosing cycle). In some instances, administration of the effective
amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed
herein, e.g., tiragolumab) results
in a CR or a PR. In some instances, administration of the effective amount of
the anti-TIGIT antagonist
antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) results in an
increase in progression-free survival of the subject or population of subjects
compared to a reference. In
some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an
anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results
in an increase in DOR. In
some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an
anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) extends
OS of the subject or
population of subjects.
The present invention includes methods and uses involving administration of an
effective amount
of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody
as disclosed herein, e.g.,
tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1
antagonist antibody, such as
atezolizumab) to a subject or population of subjects in need thereof every two
weeks (e.g., on Days 1 and
15 of each 28-day dosing cycle). In some instances, administration of the
effective amount of the anti-
TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab)
and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody,
such as atezolizumab)
results in a CR or a PR. In some instances, administration of the effective
amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed
herein, e.g., tiragolumab) and
the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody,
such as atezolizumab) results
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in an increase in progression-free survival of the subject or population of
subjects, e.g., as compared to
treatment with the PD-1 axis binding antagonist without the anti-TIC IT
antagonist antibody or as
compared to treatment with the anti-TIGIT antagonist antibody without the PD-1
axis binding antagonist.
In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody (e.g., an
anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the
PD-1 axis binding
antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab)
extends OS of the subject or
population of subjects, e.g., as compared to treatment with the PD-1 axis
binding antagonist without the
anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT
antagonist antibody
without the PD-1 axis binding antagonist.
In certain instances, the present invention includes methods and uses
involving administration of
an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) to a subject or population of subjects in
need thereof every two weeks
(e.g., on Days 1 and 15 of each 28-day dosing cycle). In some instances,
administration of the effective
amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist
antibody as disclosed herein,
e.g., tiragolumab) results in a CR or a PR. In some instances, administration
of the effective amount of
the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g.,
tiragolumab) results in an increase in progression-free survival of the
subject or population of subjects
compared to a reference. In some instances, administration of the effective
amount of the anti-TIC IT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed
herein, e.g., tiragolumab)
extends OS of the subject or population of subjects.
In some instances, the subject or population of subjects has not received
prior systemic therapy
(e.g., e.g., prior systemic therapy with curative intent, e.g., chemotherapy)
within the month prior to the
administration with the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody (e.g., within
the two months prior, three months prior, four months prior, six months prior,
one year prior, two years
prior, three years prior, four years prior, five years prior, or ten years
prior to the administration with the
PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody). In some
instances, the subject or
population of subjects is chemotherapy naïve.
In some embodiments, the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody
are administered in conjunction with a chemotherapy. For example, a once-every-
two-weeks (Q2W),
once-every-three-weeks (Q3W), or once-every-four-weeks (04W) dosing regimen of
the PD-1 axis
binding antagonist and the anti-TIGIT antagonist antibody can be administered
in conjunction with one or
more chemotherapeutic agents. The one or more chemotherapeutic agents can be
administered at the
same frequency as the frequency of administration of the PD-1 axis binding
antagonist and the anti-TIC IT
antagonist antibody (Q2W, Q3W, or Q4W) or at a different frequency (e.g., 3-
weeks on/1-week off
schedule). For example, in some embodiments, the PD-1 axis binding antagonist
and the anti-TIGIT
antagonist antibody are administered every two weeks and the one or more
chemotherapeutic agents is
administered every week, 3-weeks on/1-week off, every two weeks, every three
weeks, or every four
weeks. Alternatively, the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody are
administered every three weeks and the one or more chemotherapeutic agents is
administered every
week, two weeks, every three weeks, or every four weeks. Alternatively, the PD-
1 axis binding antagonist
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and the anti-TIGIT antagonist antibody are administered every four weeks and
the one or more
chemotherapeutic agents is administered every week, 3-weeks on/1-week off,
every two weeks, every
three weeks, or every four weeks. In certain instances, a chemotherapeutic
agent is administered
multiple times per week (e.g., 2, 3, 4, 5, 6 or 7 times per week (e.g., at
Days 1, 2, and 3 of a dosing
cycle)).
In some embodiments, the dose of a chemotherapeutic agent is reduced after one
or more initial
doses (e.g., after one, two, three, four, or more initial doses). For example,
a subsequent dose of the
chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent (e.g.,
carboplatin or cisplatin)
and/or one or more non-platinum-based chemotherapeutic agents (e.g., an
antimetabolite (e.g.,
pemetrexed or gemcitabine) can be administered at about 95%, 90%, 85%, 80%,
75%, 70%, 65%, 60%,
55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the initial dose.
For example, an initial
dose of cisplatin of about 75 mg/m2 can be reduced for a subsequent dose,
e.g., to 70 mg/m2, 65 mg/m2,
60 mg/m2, 55 mg/m2, 50 mg/m2, or 45 mg/m2; an initial dose of pemetrexed of
about 500 mg/m2 can be
reduced for a subsequent dose, e.g., to 450 mg/m2, 400 mg/m2, 350 mg/m2, 300
mg/m2, 250 mg/m2, or
200 mg/m2; and/or an initial dose of carboplatin of a dose sufficient to
achieve AUC = 5 mg/ml/min can be
reduced for a subsequent dose, e.g., to a dose sufficient to achieve AUC = 4.5
mg/ml/min, 4.0 mg/ml/min,
3.5 mg/ml/min, or 3.0 mg/ml/min.
In some instances, administration of the effective amount of the anti-TIGIT
antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab), the PD-1 axis binding
antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the
platinum-based
chemotherapeutic agent (e.g., carboplatin or cisplatin), and the
antimetabolite (e.g., pemetrexed) results
in a CR or a PR. In some instances, administration of the effective amount of
the anti-TIC IT antagonist
antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab), the PD-1 axis
binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as
atezolizumab), the platinum-based
chemotherapeutic agent (e.g., carboplatin or cisplatin), and the
antimetabolite (e.g., pemetrexed) results
in an increase in progression-free survival of the subject or population of
subjects. In some instances,
administration of the effective amount of the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT antagonist
antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding
antagonist (e.g., anti-PD-L1
antagonist antibody, such as atezolizumab), the platinum-based
chemotherapeutic agent (e.g.,
.. carboplatin or cisplatin), and the antimetabolite (e.g., pemetrexed)
extends OS of the subject or
population of subjects.
In some instances, the subject or population of subjects receiving the anti-
TIGIT antagonist
antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab), the PD-1 axis
binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as
atezolizumab), the platinum-based
chemotherapeutic agent (e.g., carboplatin or cisplatin), and the
antimetabolite (e.g., pemetrexed) is being
treated for a lung cancer, e.g., an NSCLC (e.g., non-squamous NSCLC (e.g.,
locally advanced
unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-squamous
NSCLC))).
Dosing of agents
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Dosing of anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, and
chemotherapeutic
agents is described in Section III(K).
Cancer characterization
In any of the methods, uses, or compositions for use described herein, the
lung cancer may be
an NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced unresectable or
metastatic non-
squamous NSCLC (e.g., Stage IV non-squamous NSCLC))). In some instances, the
subject or
population of subjects has not received prior systemic therapy for the lung
cancer.
In some instances, in any of the methods, uses, or compositions for use
described herein, the
subject has no epidermal growth factor receptor (EGFR) or anaplastic lymphoma
kinase (ALK) genomic
tumor aberrations. In some instances, in any of the methods, uses, or
compositions for use described
herein, the subject does not have an EGFR gene mutation (e.g., a sensitizing
EGFR gene mutation) or
ALKgene rearrangement. In some instances, the subject has an Eastern
Cooperative Oncology Group
(ECOG) Performance Status (PS) of 0 or 1.
Methods for detecting the mutational status EGFR and ALK are well known in the
art, and
include, but are not limited to, sequencing DNA from clinical samples (e.g.,
tumor biopsies or blood
samples (e.g., circulating tumor DNA in blood)) using a next-generation
sequencing method, such as the
targeted gene pulldown and sequencing method described in Frampton et al.
(Nature Biotechnology.
31(11): 1023-1033, 2013), which is incorporated by reference herein in its
entirety. Such a next-
generation sequencing method can be used with any of the methods disclosed
herein to detect various
mutations (e.g., insertions, deletions, base substitutions, focal gene
amplifications, and/or homozygous
gene deletions), while enabling the use of small samples (e.g., from small-
core needle biopsies, fine-
needle aspirations, and/or cell blocks) or fixed samples (e.g., formalin-fixed
and paraffin-embedded
(FFPE) samples). Other methods for the detection of the mutational status of
EGFR and ALK include
fluorescence in situ hybridization (FISH) and immunohistochemical (INC)
methods. Exemplary methods
for the detection of the mutational status of ALK are disclosed in U.S. Patent
No: 9,651,555, which is
herein incorporated by reference in its entirety. In some instances, the
VENTANA anti-ALK(D5F3) IHC
assay is used to determine the mutational status of the ALK gene.
In some instances of any of the methods described herein, the mutation is a
sensitizing EGFR
mutation. Sensitizing EGFR mutations are well known in the art and include
those described in U.S.
Publication No: US 2018/0235968 and in Juan et al. (Therapeutic Advances in
Medical Oncology. 9(3):
201-216, 2017), which are incorporated by reference herein in their
entireties. In some instances, the
sensitizing EGFR mutation is a mutation in any one of exons 18-21 (e.g., a
mutation in exon 18, exon 19,
exon 20, and/or exon 21). In some instances, the sensitizing EGFR mutation is
a deletion of exon 19
(deli 9). In other instances, sensitizing EGFR mutation is a L858R point
mutation in exon 21. In some
instances, the sensitizing EGFR mutation is a G719X point mutation in exon 18,
wherein "X" is most
commonly C, A, or S. In some instances, the sensitizing EGFR mutation is a
G719S point mutation in
exon 18. In some instances, the sensitizing EGFR mutation is a G719A point
mutation in exon 18. In
some instances, the sensitizing EGFR mutation is a S720F point mutation in
exon 18. In some instances,
the sensitizing EGFR mutation is a L861Q point mutation in exon 21. In some
instances, the sensitizing
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EGFR mutation is a L861R point mutation in exon 21. In other instances, the
sensitizing EGFR mutation
is a T790M point mutation. In some instances, the sensitizing EGFR mutation is
an E709X point
mutation, where "X" is most commonly K, A, or H. In some instances, the
sensitizing EGFR mutation is a
S768I point mutation.
In some instances of any of the methods described herein, the mutation is an
ALKgene
rearrangement. ALKgene rearrangements are well known in the art and include
those described in U.S.
Patent No: 9,651,555 and in Du et al. (Thoracic Cancer. 9: 423-430, 2018),
which are incorporated herein
by reference in their entireties. In some instances, the ALKgene rearrangement
results in the creation of
an oncogenic ALK tyrosine kinase that activates downstream signaling pathways
resulting in increased
cell proliferation and survival. In some instances, the ALKgene rearrangement
is an ALK rearrangement
with a gene selected from the group consisting of EML4, KIF5B, KLC1, TFG, TPR,
HIP1, STRN, DCTN1,
SOSTM1, NPM1, BCL11A, BIRC6, RANBP2, AT/C, CLTC, TMP4, and MSN resulting in
the formation of
a fusion oncogene. In some instances, the ALK gene rearrangement is an EML4
rearrangement with
ALK resulting in the formation of the fusion oncogene EML4-ALK.
In some instances, in any of the methods, uses, or compositions for use
described herein, the
subject does not have a pulmonary lymphoepithelioma-like carcinoma subtype of
NSCLC. Methods for
detecting the subtype of NSCLC are well known in the art, and include, but are
not limited to, methods of
determination by histopathological criteria, or by molecular features (e.g., a
subtype characterized by
expression of one or a combination of biomarkers (e.g., particular genes or
proteins encoded by said
genes)). In some instances, the sample is selected from the group consisting
of a tissue sample, a whole
blood sample, a serum sample, and a plasma sample. In some instances, the
tissue sample is a tumor
sample.
In some instances, in any of the methods, uses, or compositions for use
described herein, the subject
does not have an active Epstein-Barr virus (EBV) infection or a known or
suspected chronic active EBV
infection. Indicators of active or chronic active EBV infections for use in
the methods described herein
can include, but are not limited to, EBV IgM, EBV IgG, Epstein-Barr nuclear
antigen (EBNA), and Epstein-
Barr viral particles detected in a sample from the subject (e.g., a blood or
serum sample). Methods for
detecting the presence of one or more indicators of active or chronic active
EBV infection, including EBV
IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr viral
particles in a sample from a
subject are well known in the art, and include, but are not limited to,
methods involving serological
diagnosis (e.g., the detection of EBV DNA (e.g., by PCR analysis of a blood
sample for the detection of
EBV viral particles) or EBV antigens or anti-EBV antibodies (e.g., detection
of EBNA, EBV IgM, or EBV
IgG using heterophilic antibodies). In some instances, the sample is selected
from the group consisting
of a whole blood sample, a serum sample, and a plasma sample. In some
instances, the subject is
negative for EBV IgM and/or negative by EBV PCR. In some instances, the
subject is negative for EBV
IgM and/or negative by EBV PCR and is positive for EBV IgG and/or positive for
Epstein-Barr nuclear
antigen (EBNA). In other instances, the subject is negative for EBV IgG and/or
negative for EBNA.
In some instances, the subject has a PD-L1 selected tumor (e.g., a tumor PD-L1
expression with
a minimum PD-L1-positive tumor cell fraction or TPS 30% (e.g., 50%) as
determined by an IHC with
the 5P263 or 22C3 antibody or a proportion of tumor area occupied by PD-L1
expressing tumor-
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infiltrating immune cells (ICs) is greater than or equal to 1% in the tumor
sample as determined by an IHC
with the SP142 antibody). In some instances, the PD-L1 selected tumor is a
tumor that has been
determined to have a PD-L1-positive tumor cell fraction or PD-L1 TPS of
greater than, or equal to, 30%
(e.g., greater than, or equal to, 50%) by an immunohistochemical (IHC) assay.
In some instances, the
PD-L1 selected tumor is a tumor that has been determined to have a proportion
of tumor area occupied
by PD-L1 expressing immune cells (lCs) greater than or equal to 1% by an
immunohistochemical (IHC)
assay. In some instances, the IHC assay uses the anti-PD-L1 antibody SP263,
22C3, SP142, or 28-8. In
some instances, the IHC assay uses anti-PD-L1 antibody SP263. In some
instances, the INC assay uses
anti-PD-L1 antibody SP142. In some instances, the IHC assay uses anti-PD-L1
antibody 22C3. In some
instances, the tumor sample has been determined to have a TPS of greater than,
or equal to, 50%. In
some instances, the PD-L1-positive tumor cell fraction is greater than, or
equal to, 50% (e.g., as
determined by positive staining with the anti-PD-L1 antibody SP263 (e.g.,
using the Ventana assay), as
determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using
the pharmDx assay), or as
determined by positive staining with the anti-PD-L1 antibody 28-8). In some
embodiments, the PD-L1-
positive tumor cell fraction is greater than, or equal to, 30%, as determined
by positive staining with the
anti-PD-L1 antibody SP142. In some instances, the ICs has been determined to
be greater than, or equal
to, 1% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In
some instances, the ICs
has been determined to be greater than, or equal to, 5% (e.g., as determined
using the Ventana (SP142)
PD-L1 IHC assay). In some instances, the ICs has been determined to be greater
than, or equal to, 10%
(e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some
instances, the ICs has been
determined to be greater than, or equal to, 1 ./0 and less than 50% (e.g., as
determined using the Ventana
(SP142) PD-L1 IHC assay). In some instances, the ICs has been determined to be
greater than, or equal
to, 1 ./0 and less than 30% (e.g., as determined using the Ventana (SP142) PD-
L1 IHC assay).
In some instances, in any of the methods, uses, or compositions for use
described herein, a
tumor sample obtained from the individual has a detectable protein expression
level of PD-L1. In some
instances, the detectable protein expression level of PD-L1 has been
determined by an IHC assay. In
some instances, the IHC assay uses anti-PD-L1 antibody SP142. In some
instances, the tumor sample
has been determined to have a detectable expression level of PD-L1 in greater
than, or equal to, 1 A, of
the tumor cells in the tumor sample. In some instances, the tumor sample has
been determined to have
a detectable expression level of PD-L1 in greater than, or equal to, 1% and
less than 5% of the tumor
cells in the tumor sample. In some instances, the tumor sample has been
determined to have a
detectable expression level of PD-L1 in greater than, or equal to, 5% and less
than 50% of the tumor cells
in the tumor sample. In some instances, the tumor sample has been determined
to have a detectable
expression level of PD-L1 in greater than, or equal to, 50% of the tumor cells
in the tumor sample. In
some instances, the tumor sample has been determined to have a detectable
expression level of PD-L1
in tumor-infiltrating immune cells that comprise greater than, or equal to, 1%
of the tumor sample. In
some instances, the tumor sample has been determined to have a detectable
expression level of PD-L1
in tumor-infiltrating immune cells that comprise greater than, or equal to, 1
./0 and less than 5% of the
tumor sample. In some instances, the tumor sample has been determined to have
a detectable
expression level of PD-L1 in tumor-infiltrating immune cells that comprise
greater than, or equal to, 5%
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and less than 10% of the tumor sample. In some instances, the tumor sample has
been determined to
have a detectable expression level of PD-L1 in tumor-infiltrating immune cells
that comprise greater than,
or equal to, 10% of the tumor sample.
In some instances, the subject has a lung cancer (e.g., NSCLC (e.g., non-
squamous NSCLC
(e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g.,
Stage IV non-squamous
NSCLC)))) that has not been evaluated from PD-L1 expression. For example, in
some instances, the
subject having a lung cancer has not been determined to have a PD-L1-positive
tumor cell fraction
greater than, or equal to, 50% (e.g., the subject has not been determined to
have a PD-L1-positive tumor
cell fraction greater than, or equal to, 45%, 40%, 35%, or 30%). For example,
in some instances, the
subject has not been determined to have a TPS of greater than, or equal to,
50% PD-L1-positive (e.g.,
the subject has not been determined to have a TPS of greater than, or equal
to, 45% PD-L1-positive,
40% PD-L1-positive, 35% PD-L1-positive, or 30% PD-L1-positive), e.g., as
assessed using any of the
IHC methods described herein or known in the art.
In some instances, the subject having a lung cancer (e.g., NSCLC (e.g., non-
squamous NSCLC
(e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g.,
Stage IV non-squamous
NSCLC)))) has been determined to have a PD-L1-positive tumor cell fraction of
less than 50% (e.g., from
1% to 50%, from 1% to 49%, from 5% to 45%, from 10% to 40%, from 15% to 35%,
or from 20% to 30%,
e.g., from 1% to 5%, from 5% to 10%, from 10% to 15%, from 15% to 20%, from
20% to 25%, from 25%
to 30%, from 30% to 35%, from 35% to 40%, from 40% to 45%, or from 45% to 49%,
e.g., less than 49%,
less than 45%, less than 40%, less than 35%, less than 30%, less than 25%,
less than 20%, less than
15%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%,
less than 5%, less than
4%, less than 3%, less than 2%, less than 1%, or about 0%). For example, in
certain instances, the
subject having a lung cancer has been determined to have a PD-L1-positive
tumor cell fraction from 1-
49% (e.g., from 1% to 5%, from 5% to 10%, from 10% to 15%, from 15% to 20%,
from 20% to 25%, from
25% to 30%, from 30% to 35%, from 35% to 40%, from 40% to 45%, or from 45% to
49%). In other
instances, the subject having a lung cancer has been determined to have a PD-
L1-positive tumor cell
fraction of less than 1% (e.g., about 0%, or an undetectable PD-L1
expression).
For example, in some instances, the subject having a lung cancer (e.g., NSCLC
(e.g., non-
squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous
NSCLC (e.g., Stage
IV non-squamous NSCLC)))) has been determined to have a TPS of less than 50%
PD-L1-positive (e.g.,
from 1% to 50%, from 1% to 49%, from 5% to 45%, from 10% to 40%, from 15% to
35%, or from 20% to
30% PD-L1-positive, e.g., from 1% to 5%, from 5% to 10%, from 10% to 15%, from
15% to 20%, from
20% to 25%, from 25% to 30%, from 30% to 35%, from 35% to 40%, from 40% to
45%, or from 45% to
49% PD-L1-positive, e.g., less than 49%, less than 45%, less than 40%, less
than 35%, less than 30%,
less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less
than 8%, less than 7%,
less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less
than 1%, or about 0% PD-L1-
positive). For example, in certain instances, the subject having a lung cancer
has been determined to
have a TPS from 1-49% PD-L1-positive (e.g., from 1% to 5%, from 5% to 10%,
from 10% to 15%, from
15% to 20%, from 20% to 25%, from 25% to 30%, from 30% to 35%, from 35% to
40%, from 40% to
45%, or from 45% to 49% PD-L1-positive). In other instances, the subject
having a lung cancer has been
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determined to have a TPS of less than 1% PD-L1-positive (e.g., about 0%, or an
undetectable PD-L1
expression).
In particular embodiments, the subject has an NSCLC (e.g., non-squamous NSCLC
(e.g., locally
advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-
squamous NSCLC)))
that has not been evaluated from PD-L1 expression. For example, in some
instances, the subject having
an NSCLC has not been determined to have a PD-L1-positive tumor cell fraction
greater than, or equal to,
50% (e.g., the subject has not been determined to have a PD-L1-positive tumor
cell fraction greater than,
or equal to, 45%, 40%, 35%, or 30%). For example, in some instances, the
subject has not been
determined to have a TPS of greater than, or equal to, 50% PD-L1-positive
(e.g., the subject has not
been determined to have a TPS of greater than, or equal to, 45% PD-L1-
positive, 40% PD-L1-positive,
35% PD-L1-positive, or 30% PD-L1-positive), e.g., as assessed using any of the
IHC methods described
herein or known in the art.
In some instances, the subject having an NSCLC (e.g., non-squamous NSCLC
(e.g., locally
advanced unresectable or metastatic non-squamous NSCLC (e.g., Stage IV non-
squamous NSCLC)))
has been determined to have a PD-L1-positive tumor cell fraction of less than
50% (e.g., from 1% to 50%,
from 1% to 49%, from 5% to 45%, from 10% to 40%, from 15% to 35%, or from 20%
to 30%, e.g., from
1 /0 to 5%, from 5% to 10%, from 10% to 15%, from 15% to 20%, from 20% to 25%,
from 25% to 30%,
from 30% to 35%, from 35% to 40%, from 40% to 45%, or from 45% to 49%, e.g.,
less than 49%, less
than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less
than 20%, less than 15%,
less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less
than 5%, less than 4%, less
than 3%, less than 2%, less than 1%, or about 0%). For example, in certain
instances, the subject having
an NSCLC has been determined to have a PD-L1-positive tumor cell fraction from
1-49% (e.g., from 1%
to 5%, from 5% to 10%, from 10% to 15%, from 15% to 20%, from 20% to 25%, from
25% to 30%, from
30% to 35%, from 35% to 40%, from 40% to 45%, or from 45% to 49%). In other
instances, the subject
having an NSCLC has been determined to have a PD-L1-positive tumor cell
fraction of less than 1% (e.g.,
about 0%, or an undetectable PD-L1 expression).
For example, in some instances, the subject having an NSCLC (e.g., non-
squamous NSCLC
(e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g.,
Stage IV non-squamous
NSCLC))) has been determined to have a TPS of less than 50% PD-L1-positive
(e.g., from 1 /0 to 50%,
from 1% to 49%, from 5% to 45%, from 10% to 40%, from 15% to 35%, or from 20%
to 30% PD-L1-
positive, e.g., from 1% to 5%, from 5% to 10%, from 10% to 15%, from 15% to
20%, from 20% to 25%,
from 25% to 30%, from 30% to 35%, from 35% to 40%, from 40% to 45%, or from
45% to 49% PD-L1-
positive, e.g., less than 49%, less than 45%, less than 40%, less than 35%,
less than 30%, less than
25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%,
less than 7%, less than
.. 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%,
or about 0% PD-L1-positive).
For example, in certain instances, the subject having an NSCLC has been
determined to have a TPS
from 1-49% PD-L1-positive (e.g., from 1% to 5%, from 5% to 10 /e, from 10% to
15%, from 15% to 20%,
from 20% to 25%, from 25% to 30%, from 30% to 35%, from 35% to 40%, from 40%
to 45%, or from 45%
to 49% PD-L1-positive). In other instances, the subject having an NSCLC has
been determined to have a
TPS of less than 1% PD-L1-positive (e.g., about 0%, or an undetectable PD-L1
expression).
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In some instances, a tumor sample obtained from the individual has a
detectable nucleic acid
expression level of PD-L1. In some instances, the detectable nucleic acid
expression level of PD-L1 has
been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR,
microarray analysis,
SAGE, MassARRAY technique, ISH, or a combination thereof. In some instances,
the sample is selected
from the group consisting of a tissue sample, a whole blood sample, a serum
sample, and a plasma
sample. In some instances, the tissue sample is a tumor sample. In some
instances, the tumor sample
comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any
combinations thereof.
In some instances, a tumor sample obtained from a subject having a lung cancer
(e.g., NSCLC
(e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic
non-squamous NSCLC
(e.g., Stage IV non-squamous NSCLC)))) has a low or undetectable nucleic acid
expression level of PD-
L1. In some instances, the nucleic acid expression level of PD-L1 has been
determined by RNA-seq, RT-
qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY
technique, ISH, or a
combination thereof. In some instances, the sample is selected from the group
consisting of a tissue
sample, a whole blood sample, a serum sample, and a plasma sample. In some
instances, the tissue
sample is a tumor sample. In some instances, the tumor sample comprises tumor-
infiltrating immune
cells, tumor cells, stromal cells, and any combinations thereof.
In some instances of any of the methods described herein, the subject having a
lung cancer (e.g.,
NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced unresectable or
metastatic non-squamous
NSCLC (e.g., Stage IV non-squamous NSCLC)))) has received no prior systemic
treatment for the lung
cancer (e.g., no prior systemic treatment with curative intent). In particular
embodiments, the subject has
a locally advanced lung cancer and has received no prior systemic treatment
for the locally advanced
lung cancer. In some instances, the subject has an NSCLC (e.g., a non-squamous
NSCLC, e.g., a locally
advanced unresectable or metastatic non-squamous NSCLC) and has received no
prior systemic
treatment for the NSCLC (e.g., a non-squamous NSCLC, e.g., a locally advanced
unresectable or
metastatic non-squamous NSCLC). Prior systemic treatments include prior neo-
adjuvant, adjuvant
chemotherapy, radiotherapy, and chemoradiotherapy with curative intent for non-
metastatic disease.
In other instances, the subject having a lung cancer (e.g., NSCLC (e.g., non-
squamous NSCLC
(e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g.,
Stage IV non-squamous
NSCLC)))) has received prior systemic treatment for the lung cancer and has
experienced a treatment-
free interval of at least 12 months before treatment according to any of the
methods of the present
invention.
iv. Methods and uses for treating resectable lung cancer
Provided herein are methods and uses for treating lung cancer (e.g., early
stage lung cancer
(e.g., resectable lung cancer (e.g., NSCLC (e.g., squamous or non-squamous
NSCLC)))) in a subject
comprising administering to the subject one or more dosing cycles of an
effective amount of an anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed
herein, e.g., tiragolumab) and a
PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as
atezolizumab, or an anti-
PD-1 antagonist antibody, such as pembrolizumab). In some instances, at least
one dosing cycle is
administered as a neoadjuvant treatment. In some instances, the treatment is a
neoadjuvant treatment.
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In some instances, at least one dosing cycle is administered as an adjuvant
treatment. In some
instances, the treatment is an adjuvant treatment. In some instances, the
treatment comprises a
neoadjuvant treatment and an adjuvant treatment. In some instances, the lung
cancer is a resectable
lung cancer. In some instances, the lung cancer is an early stage lung cancer
(e.g., stage II, IIIA, or IIIB
lung cancer). In some instances, the lung cancer is an NSCLC (e.g., a squamous
or non-squamous
NSCLC). In some instances, the lung cancer is PD-L1 positive (e.g., PD-L1
high). In some instances,
the lung cancer has no epidermal growth factor receptor (EGFR) or anaplastic
lymphoma kinase (ALK)
genomic tumor aberrations. In some embodiments, the subject has not been
previously treated for lung
cancer (e.g., a prior surgery, a prior immunotherapy, a prior chemotherapy, or
a prior radiotherapy). In
some instances, the subject is eligible to receive a platinum-based
chemotherapy regimen. In some
instances, the subject is eligible for an RO resection with curative intent.
The subject is preferably a
human.
The present invention includes methods and uses for treating a subject having
a resectable lung
cancer (e.g., a resectable NSCLC (e.g., a resectable squamous or non-squamous
NSCLC)), the method
comprising administering to the subject one or more dosing cycles of an anti-
TIGIT antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) at a dose (e.g., a fixed
dose) of between about 30 mg to about 1200 mg every three weeks (e.g., on Day
1 of each 21-day
dosing cycle) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1
antagonist antibody, such as
atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g.,
pembrolizumab) at a dose (e.g., a fixed
dose) of between about 80 mg to about 1600 mg every three weeks (e.g., on Day
1 of each 21-day
dosing cycle). In some aspects, the method comprises administering to the
subject one or more dosing
cycles of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist
antibody as disclosed herein,
e.g., tiragolumab) at a dose (e.g., a fixed dose) of between 30 mg to 1200 mg
every three weeks (e.g., on
Day 1 of each 21-day dosing cycle) and a PD-1 axis binding antagonist (e.g.,
an anti-PD-L1 antagonist
antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as
e.g., pembrolizumab) at a
dose (e.g., a fixed dose) of between 80 mg to 1600 mg every three weeks (e.g.,
on Day 1 of each 21-day
dosing cycle).
The present invention includes methods and uses involving administration of an
effective amount
of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody
as disclosed herein, e.g.,
tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1
antagonist antibody, such as
atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g.,
pembrolizumab) to a subject in need
thereof every three weeks (e.g., on Day 1 of each 21-day dosing cycle). In
some instances, at least one
of the dosing cycles comprises administering to the subject the anti-TIGIT
antagonist antibody at a dose
(e.g., a fixed dose) of between about 30 mg to about 1200 mg every three weeks
(e.g., a dose of 600 mg
every three weeks) and the PD-1 axis binding antagonist at a dose (e.g., a
fixed dose) of between about
80 mg to about 1 600 mg every three weeks (e.g., a dose of about 1200 mg every
three weeks) as a
neoadjuvant treatment. In some instances, at least one of the dosing cycles
comprises administering to
the subject the anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose)
of between about 30 mg to
about 1200 mg every three weeks (e.g., a dose of 600 mg every three weeks) and
the PD-1 axis binding
antagonist at a dose (e.g., a fixed dose) of between about 80 mg to about 1600
mg every three weeks
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(e.g., a dose of about 1200 mg every three weeks) as an adjuvant treatment. In
some instances, at least
one of the dosing cycles comprises administering to the subject the anti-TIGIT
antagonist antibody at a
dose (e.g., a fixed dose) of between 30 mg to 1200 mg every three weeks (e.g.,
a dose of 600 mg every
three weeks) and the PD-1 axis binding antagonist at a dose (e.g., a fixed
dose) of between 80 mg to
1600 mg every three weeks (e.g., a dose of 1200 mg every three weeks) as a
neoadjuvant treatment. In
some instances, at least one of the dosing cycles comprises administering to
the subject the anti-TIGIT
antagonist antibody at a dose (e.g., a fixed dose) of between 30 mg to 1200 mg
every three weeks (e.g.,
a dose of 600 mg every three weeks) and the PD-1 axis binding antagonist at a
dose (e.g., a fixed dose)
of between 80 mg to 1600 mg every three weeks (e.g., a dose of 1200 mg every
three weeks) as an
adjuvant treatment.
In some instances, the subject receiving the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis
binding antagonist (e.g.,
anti-PD-L1 antagonist antibody, such as atezolizumab) is being treated for a
lung cancer (e.g., an early
stage lung cancer (e.g., a resectable lung cancer (e.g., an NSCLC (e.g., a
squamous or non-squamous
.. NSCLC)))).
The PD-1 axis binding antagonist anti-TIGIT antagonist antibody may be
administered in any
suitable manner known in the art. For example, the PD-1 axis binding
antagonist and anti-TIGIT
antagonist antibody may be administered sequentially (on different days) or
concurrently (on the same
day or during the same treatment cycle). In some instances, the anti-TIGIT
antagonist antibody and/or
the PD-1 axis binding antagonist are administered on about Day 1 (e.g., Day -
3, Day -2, Day -1, Day 1,
Day 2, or Day 3) of a dosing cycle. In some instances, the PD-1 axis binding
antagonist and anti-TIGIT
antagonist antibody may be administered on the same day. In some instances,
the PD-1 axis binding
antagonist is administered before the anti-TIGIT antagonist antibody. In some
instances, the PD-1 axis
binding antagonist is administered after the anti-TIGIT antagonist antibody.
In some instances, the PD-1
axis binding antagonist is administered simultaneously with the anti-TIGIT
antagonist antibody. In some
instances, the PD-1 axis binding antagonist may be administered prior to an
anti-TIGIT antagonist
antibody that is administered on the same day. In some instances, the PD-1
axis binding antagonist may
be administered after to an anti-TIGIT antagonist antibody that is
administered on the same day. In yet
other instances, the PD-1 axis binding antagonist is administered at the same
time as the anti-TIGIT
antagonist antibody. In some instances, the PD-1 axis binding antagonist is in
a separate composition as
the anti-TIGIT antagonist antibody. In some instances, the PD-1 axis binding
antagonist is in the same
composition as the anti-TIGIT antagonist antibody. In some instances, the PD-1
axis binding antagonist
is administered through a separate intravenous line from any other therapeutic
agent administered to the
patient on the same day. The PD-1 axis binding antagonist and anti-TIGIT
antagonist antibody may be
administered by the same route of administration or by different routes of
administration. In some
instances, the PD-1 axis binding antagonist is administered intravenously,
intramuscularly,
subcutaneously, topically, orally, transdermally, intraperitoneally,
intraorbitally, by implantation, by
inhalation, intrathecally, intraventricularly, or intranasally. In some
instances, the PD-1 axis binding
antagonist is administered intravenously. In some instances, the anti-TIGIT
antagonist antibody is
administered intravenously, intramuscularly, subcutaneously, topically,
orally, transdermally,
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intraperitoneally, intraorbitally, by implantation, by inhalation,
intrathecally, intraventricularly, or
intranasally. In some instances, the anti-TIGIT antagonist antibody is
administered intravenously. In
some instances, there is a first observation period following administration
of the PD-1 axis binding
antagonist. In some instances, there is a second observation period following
administration of the PD-1
axis binding antagonist. In some instances, there is a first observation
period following administration of
the anti-TIGIT antagonist antibody. In some instances, there is a second
observation period following
administration of the anti-TIGIT antagonist antibody. In some instances, the
observation period is
between about 30 minutes to about 60 minutes in length. In some instances, the
anti-TIGIT antagonist
antibody and/or PD-1 axis binding antagonist are administered intravenously or
subcutaneously. In some
instances, the intravenous infusion is over 30 10 minutes and/or over 60
15 minutes. In one example,
atezolizumab may be administered intravenously over 60 minutes; if the first
infusion is tolerated, all
subsequent infusions may be delivered over 30 minutes. In some examples, the
PD-1 axis binding
antagonist is not administered as an intravenous push or bolus. In one
example, tiragolumab may be
administered intravenously over 60 minutes; if the first infusion is
tolerated, all subsequent infusions may
be delivered over 30 minutes. In some examples, the anti-TIGIT antagonist
antibody is not administered
as an intravenous push or bolus.
In any of the preceding examples, each dosing cycle may have any suitable
length, e.g., about 7
days (about 5, 6, 7, 8, or 9 days), about 14 days (e.g., about 12, 13, 14, 15,
or 16 days), about 21 days
(e.g., about 18, 19, 20, 21, 22, 23, or 24 days), about 28 days (about 25, 26,
27, 28, 29, 30, or 31 days),
or longer. In some instances, each dosing cycle is about 21 days.
In some instances, a PD-L1 expression level of a sample (e.g., a tumor sample,
a blood sample
(e.g., a plasma sample), or a lymph sample) obtained from the subject has been
determined. In some
instances, the sample has been determined to have a detectable expression
level of PD-L1 (e.g., a
detectable protein and/or nucleic acid expression level of PD-L1). In some
instances, the detectable
expression level of PD-L1 is a detectable protein expression level of PD-L1.
In some instances, the
detectable expression level of PD-L1 is a PD-L1-positive tumor cell fraction
(e.g., a PD-L1-positive tumor
cell fraction of greater than or equal to 50%). In some instances, the
detectable protein expression level
of PD-L1 has been determined by an immunohistochemical (INC) assay comprising
staining with an anti-
PD-L1 antibody suitable for staining (e.g., anti-PD-L1 antibody SP263). In
some instances, the IHC
assay is a Ventana SP263 IHC assay. In some instances, the detectable
expression level of PD-L1 is a
detectable nucleic acid expression level of PD-L1. In some instances, the
mutational status of epidermal
growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) is
determined. In some instances,
the method further comprises obtaining a sample from the subject. In some
instances, the method further
comprises determining the expression level of PD-L1.
In some instances, the first dosing cycle is initiated prior to a surgery
(e.g., a segmentectomy, a
lobectomy, a bilobectomy, or a pneumonectomy). In some instances, one or more
dosing cycles are
completed prior to a surgery. In some instances, at least 1, 2, 3, or 4 dosing
cycles (e.g., 1, 2, 3, 4, 5, 6,
7, 8, or more dosing cycles) are completed prior to a surgery. In some
instances, 4 dosing cycles are
completed prior to a surgery. In some instances, one or more dosing cycles
(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more dosing cycles) are
initiated after a surgery. In some
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instances, 16 dosing cycles are completed after a surgery. In some instances,
the treatment includes a
surgery. In some instances, the surgery is a segmentectomy, a lobectomy, a
bilobectomy, or a
pneumonectomy. In some instances, the treatment includes a radiotherapy (e.g.,
a post-operative
radiotherapy).
In some instances, the treating results in an increase in major pathological
response (MPR) rate
as compared to a reference MPR rate. In some instances, the treating results
in a pathological complete
response (pCR) and/or an increase in pCR rate as compared to a reference pCR
rate. In some
instances, the treating results in an increase in event-free survival (EFS) as
compared to a reference EFS
time. In some instances, the treating results in an increase in OS as compared
to a reference OS time.
In some instances, the reference MPR rate, reference pCR rate, and/or
reference EFS time are an MPR
rate, a pCR rate, and/or an EFS time of a population of subjects who have
received a treatment
comprising: (a) a PD-1 axis binding antagonist without an anti-TIGIT
antagonist antibody; and/or (b)
cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab. In some
instances, administration of
the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-
TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist
(e.g., an anti-PD-L1 antagonist
antibody, such as atezolizumab) results in an increase in MPR rate. In some
instances, administration of
the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-
TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist
(e.g., an anti-PD-L1 antagonist
antibody, such as atezolizumab) results in a pCR. In some instances,
administration of the effective
amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist
antibody as disclosed herein,
e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1
antagonist antibody, such as
atezolizumab) results in an increase in EFS. In some instances, administration
of the effective amount of
the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein, e.g.,
tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1
antagonist antibody, such as
atezolizumab) results in an increase in OS.
In some instances, the treatment further comprises one or more
chemotherapeutic agents (e.g., a
platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or
one or more non-platinum-
based chemotherapeutic agents (e.g., an antimetabolite (e.g., pemetrexed or
gemcitabine) and/or a
taxane (e.g., paclitaxel, e.g., nab-paclitaxel)). In some instances, the
neoadjuvant and/or adjuvant
treatment further comprises one or more chemotherapeutic agents (e.g., a
platinum-based
chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-
platinum-based
chemotherapeutic agents (e.g., an antimetabolite (e.g., pemetrexed or
gemcitabine) and/or a taxane (e.g.,
paclitaxel, e.g., nab-paclitaxel)). In some instances, the one or more
chemotherapeutic agents are one or
more platinum-based chemotherapeutic agents and/or one or more non-platinum-
based
chemotherapeutic agents. In some instances, the platinum-based
chemotherapeutic agent is carboplatin
or cisplatin. In some instances, the non-platinum-based chemotherapeutic
agents are an antimetabolite
(e.g., pemetrexed or gemcitabine) and/or a taxane (e.g., paclitaxel, e.g., nab-
paclitaxel). In some
instances, the one or more chemotherapeutic agents are a platinum-based
chemotherapeutic agent (e.g.,
carboplatin or cisplatin) and a non-platinum-based chemotherapeutic agent
(e.g., an antimetabolite (e.g.,
pemetrexed or gemcitabine) and/or a taxane (e.g., paclitaxel, e.g., nab-
paclitaxel)). In some instances, at
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least one or more chemotherapeutic agents are: (a) carboplatin and pemetrexed;
(b) carboplatin and
paclitaxel; (c) cisplatin and pemetrexed; (d) carboplatin and gemcitabine; or
(e) cisplatin and gemcitabine.
In some instances, the one or more chemotherapeutic agents used in a treatment
for non-squamous
NSCLC are (a) carboplatin and pemetrexed, (b) carboplatin and paclitaxel, or
(c) cisplatin and
pemetrexed. In some instances, the one or more chemotherapeutic agents used in
a treatment for
squamous NSCLC are (a) carboplatin and gemcitabine, (b) carboplatin and
paclitaxel, or (c) cisplatin and
gemcitabine. In some instances, the treatment further comprises administering
one or more
chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g.,
carboplatin or cisplatin)
and/or one or more non-platinum-based chemotherapeutic agents (e.g., an
antimetabolite (e.g.,
pemetrexed or gemcitabine) and/or a taxane (e.g., paclitaxel, e.g., nab-
paclitaxel)). In some instances,
the one or more chemotherapeutic agents are administered every three weeks. In
some instances, the
one or more chemotherapeutic agents are administered on about Day 1 (e.g., Day
-3, Day -2, Day -1,
Day 1, Day 2, or Day 3) of one or more dosing cycles. In some instances, the
one or more
chemotherapeutic agents are administered on about Day 1 (e.g., Day -3, Day -2,
Day -1, Day 1, Day 2, or
Day 3) and on about Day 8 (e.g., Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, or
Day 11) of one or more
dosing cycles. In some instances, the dosing cycles are, e.g., about 7 days
(about 5, 6, 7, 8, or 9 days),
about 14 days (e.g., about 12, 13, 14, 15, or 16 days), about 21 days (e.g.,
about 18, 19, 20, 21, 22, 23,
or 24 days), about 28 days (about 25, 26, 27, 28, 29, 30, or 31 days), or
longer. In some instances, each
dosing cycle is about 21 days. In some instances, the one or more
chemotherapeutic agents are
administered intravenously, intramuscularly, subcutaneously, topically,
orally, transdermally,
intraperitoneally, intraorbitally, by implantation, by inhalation,
intrathecally, intraventricularly, or
intranasally. In some instances, the one or more chemotherapeutic agents are
administered after the
PD-1 axis binding antagonist (e.g., atezolizumab) and/or anti-TIGIT antagonist
antibody (e.g., an anti-
TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab). In some
instances, the non-platinum-
based chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed or
gemcitabine) and/or a taxane
(e.g., paclitaxel, e.g., nab-paclitaxel)) is administered before the platinum-
based chemotherapeutic agent
(e.g., carboplatin or cisplatin).
The present invention includes methods and uses for treating a subject having
a resectable lung
cancer (e.g., an early stage resectable lung cancer (e.g., a resectable NSCLC
(e.g., a resectable
squamous or non-squamous NSCLC))), the method comprising administering to the
subject one or more
dosing cycles of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed
herein, e.g., tiragolumab) at a dose (e.g., a fixed dose) of between about 30
mg to about 600 mg every
three weeks, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist
antibody, such as
atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g.,
pembrolizumab) at a dose (e.g., a fixed
dose) of between about 80 mg to about 1600 mg every three weeks, a platinum-
based chemotherapeutic
agent (e.g., cisplatin or carboplatin), and a non-platinum-based
chemotherapeutic agent (e.g., an
antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane (e.g., paclitaxel
or nab-paclitaxel)). In some
aspects, the method comprising administering to the subject one or more dosing
cycles of an anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed
herein, e.g., tiragolumab) at a
dose (e.g., a fixed dose) of between 30 mg to 600 mg every three weeks, a PD-1
axis binding antagonist
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(e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-
1 antagonist antibody,
such as e.g., pembrolizumab) at a dose (e.g., a fixed dose) of between 80 mg
to 1600 mg every three
weeks, a platinum-based chemotherapeutic agent (e.g., cisplatin or
carboplatin), and a non-platinum-
based chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed or
gemcitabine) or a taxane
.. (e.g., paclitaxel or nab-paclitaxel)).
The present invention includes methods and uses for treating a subject having
a lung cancer
(e.g., an early stage lung cancer (e.g., a resectable lung cancer (e.g., an
NSCLC (e.g., a squamous or
non-squamous NSCLC)))), the method comprising administering to the subject one
or more dosing cycles
of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody
as disclosed herein, e.g.,
tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist
antibody, such as
atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g.,
pembrolizumab), a platinum-based
chemotherapeutic agent (e.g., cisplatin or carboplatin), and a non-platinum-
based chemotherapeutic
agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane
(e.g., paclitaxel or nab-
paclitaxel)), wherein at least one of the dosing cycles comprises
administering to the subject the anti-
TIGIT antagonist antibody at a dose (e.g., a fixed dose) of between about 30
mg to about 600 mg every
three weeks, the PD-1 axis binding antagonist at a dose (e.g., a fixed dose)
of between about 80 mg to
about 1600 mg every three weeks, a platinum-based chemotherapeutic agent
(e.g., cisplatin or
carboplatin), and a non-platinum-based chemotherapeutic agent (e.g., an
antimetabolite (e.g.,
pemetrexed or gemcitabine) or a taxane (e.g., paclitaxel or nab-paclitaxel))
as a neoadjuvant treatment.
In some aspects, at least one of the dosing cycles comprises administering to
the subject the anti-TIGIT
antagonist antibody at a dose (e.g., a fixed dose) of between 30 mg to 600 mg
every three weeks, the
PD-1 axis binding antagonist at a dose (e.g., a fixed dose) of between 80 mg
to 1600 mg every three
weeks, a platinum-based chemotherapeutic agent (e.g., cisplatin or
carboplatin), and a non-platinum-
based chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed or
gemcitabine) or a taxane
(e.g., paclitaxel or nab-paclitaxel)) as a neoadjuvant treatment.
The present invention includes methods and uses for treating a subject having
a resectable lung
cancer (e.g., an early stage resectable lung cancer (e.g., a resectable NSCLC
(e.g., a resectable
squamous or non-squamous NSCLC))), the method comprising administering to the
subject one or more
dosing cycles of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed
herein, e.g., tiragolumab) at a dose (e.g., a fixed dose) of between about 30
mg to about 600 mg every
three weeks, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist
antibody, such as
atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g.,
pembrolizumab) at a dose (e.g., a fixed
dose) of between about 80 mg to about 1600 mg every three weeks, and: (a) (i)
a platinum-based
chemotherapeutic agent (e.g., cisplatin or carboplatin) at a dose targeted to
achieve an AUC of 5
mg/mUmin or an AUC of 6 mg/mUmin every three weeks; or (ii) a platinum-based
chemotherapeutic
agent (e.g., cisplatin or carboplatin) at a dose of about 75 mg/m2 every three
weeks; and (b) (i) an
antimetabolite at a dose of about 500 mg/m2 every three weeks or about 1000
mg/m2 or about 1250
mg/m2 on Days 1 and 8 of each dosing cycle; or (ii) a taxane at a dose of
about 100 mg/m2, about 175
mg/m2, or about 200 mg/m2 every three weeks. In some aspects, the method
comprises administering to
the subject one or more dosing cycles of an anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT antagonist
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antibody as disclosed herein, e.g., tiragolumab) at a dose (e.g., a fixed
dose) of between 30 mg to 600
mg every three weeks, a PD-1 axis binding antagonist (e.g., an anti-PD-L1
antagonist antibody, such as
atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g.,
pembrolizumab) at a dose (e.g., a fixed
dose) of between 80 mg to 1600 mg every three weeks, and: (a) (i) a platinum-
based chemotherapeutic
agent (e.g., cisplatin or carboplatin) at a dose targeted to achieve an AUC of
5 mg/mUmin or an AUC of 6
mg/mUmin every three weeks; or (ii) a platinum-based chemotherapeutic agent
(e.g., cisplatin or
carboplatin) at a dose of 75 mg/m2 every three weeks; and (b) (i) an
antimetabolite at a dose of 500
mg/m2 every three weeks or 1000 mg/m2 or 1250 mg/m2 on Days 1 and 8 of each
dosing cycle; or (ii) a
taxane at a dose of 100 mg/m2, 175 mg/m2, or 200 mg/m2 every three weeks.
The present invention includes methods and uses for treating a subject having
a lung cancer
(e.g., an early stage lung cancer (e.g., a resectable lung cancer (e.g., an
NSCLC (e.g., a squamous or
non-squamous NSCLC)))), the method comprising administering to the subject one
or more dosing cycles
of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody
as disclosed herein, e.g.,
tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist
antibody, such as
atezolizumab, or an anti-PD-1 antagonist antibody, such as e.g.,
pembrolizumab), a platinum-based
chemotherapeutic agent (e.g., cisplatin or carboplatin), and a non-platinum-
based chemotherapeutic
agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane
(e.g., paclitaxel or nab-
paclitaxel)), wherein at least one of the dosing cycles comprises
administering to the subject: (a) the anti-
TIGIT antagonist antibody at a dose (e.g., a fixed dose) of between about 30
mg to about 600 mg every
three weeks; (b) the PD-1 axis binding antagonist at a dose (e.g., a fixed
dose) of between about 80 mg
to about 1600 mg every three weeks; (c) the platinum-based chemotherapeutic
agent: (i) at a dose
targeted to achieve an AUC of 5 mg/mUmin or an AUC of 6 mg/mUmin every three
weeks; or (ii) at a
dose of about 75 mg/m2 every three weeks; and (d) the non-platinum-based
chemotherapeutic agent,
wherein the non-platinum-based chemotherapeutic agent is: (i) an
antimetabolite at a dose of about 500
mg/m2 every three weeks or about 1000 mg/m2 or about 1250 mg/m2 on Days 1 and
8 of each dosing
cycle; or (ii) a taxane at a dose of about 100 mg/m2, about 175 mg/m2, or
about 200 mg/m2 every three
weeks; wherein the treatment is a neoadjuvant treatment. In some aspects, at
least one of the dosing
cycles comprises administering to the subject: (a) the anti-TIGIT antagonist
antibody at a dose (e.g., a
fixed dose) of between 30 mg to 600 mg every three weeks; (b) the PD-1 axis
binding antagonist at a
dose (e.g., a fixed dose) of between 80 mg to 1600 mg every three weeks; (c)
the platinum-based
chemotherapeutic agent: (i) at a dose targeted to achieve an AUC of 5 mg/mUmin
or an AUC of 6
mg/mUmin every three weeks; or (ii) at a dose of 75 mg/m2 every three weeks;
and (d) the non-platinum-
based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic
agent is: (i) an
antimetabolite at a dose of 500 mg/m2 every three weeks or 1000 mg/m2 or 1250
mg/m2 on Days 1 and 8
.. of each dosing cycle; or (ii) a taxane at a dose of 100 mg/m2, 175 mg/m2,
or 200 mg/m2 every three
weeks; wherein the treatment is a neoadjuvant treatment.
The present invention includes methods and uses for treating a subject having
a lung cancer
(e.g., an early stage lung cancer (e.g., a resectable lung cancer (e.g., an
NSCLC (e.g., a squamous or
non-squamous NSCLC)))), the method comprising administering to the subject one
or more dosing cycles
of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist,
wherein: (a) at least one of the
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dosing cycles comprises administering to the subject the anti-TIGIT antagonist
antibody at a dose (e.g., a
fixed dose) of between about 30 mg to about 1200 mg every three weeks and the
PD-1 axis binding
antagonist at a dose (e.g., a fixed dose) of between about 80 mg to about 1600
mg every three weeks as
a neoadjuvant treatment; and (b) at least one of the dosing cycles comprises
administering to the subject
.. the anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of
between about 30 mg to about 1200
mg every three weeks and the PD-1 axis binding antagonist at a dose (e.g., a
fixed dose) of between
about 80 mg to about 1600 mg every three weeks as an adjuvant treatment. In
some aspects, the
method comprises administering to the subject one or more dosing cycles of an
anti-TIGIT antagonist
antibody and a PD-1 axis binding antagonist, wherein: (a) at least one of the
dosing cycles comprises
.. administering to the subject the anti-TIGIT antagonist antibody at a dose
(e.g., a fixed dose) of between
30 mg to 1200 mg every three weeks and the PD-1 axis binding antagonist at a
dose (e.g., a fixed dose)
of between 80 mg to 1600 mg every three weeks as a neoadjuvant treatment; and
(b) at least one of the
dosing cycles comprises administering to the subject the anti-TIGIT antagonist
antibody at a dose (e.g., a
fixed dose) of between 30 mg to 1200 mg every three weeks and the PD-1 axis
binding antagonist at a
dose (e.g., a fixed dose) of between 80 mg to 1600 mg every three weeks as an
adjuvant treatment.
The present invention includes methods and uses for treating a subject having
a lung cancer
(e.g., an early stage lung cancer (e.g., a resectable lung cancer (e.g., an
NSCLC (e.g., a squamous or
non-squamous NSCLC)))), the method comprising administering to the subject one
or more dosing cycles
of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist,
wherein: (I) at least one of the
dosing cycles is a neoadjuvant treatment and comprises administering to the
subject: (a) the anti-TIGIT
antagonist antibody at a dose (e.g., a fixed dose) of between about 30 mg to
about 1200 mg every three
weeks; (b) the PD-1 axis binding antagonist at a dose (e.g., a fixed dose) of
between about 80 mg to
about 1600 mg every three weeks as a neoadjuvant treatment; (c) a platinum-
based chemotherapeutic
agent: (i) at a dose targeted to achieve an AUC of 5 mg/mUmin or an AUC of 6
mg/mUmin every three
weeks; or (ii) at a dose of about 75 mg/m2 every three weeks; and (d) a non-
platinum-based
chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent
is: (i) an
antimetabolite at a dose of about 500 mg/m2 every three weeks or about 1000
mg/m2 or about 1250
mg/m2 on Days 1 and 8 of each dosing cycle; or (ii) a taxane at a dose of
about 100 mg/m2, about 175
mg/m2, or about 200 mg/m2 every three weeks; and (II) at least one of the
dosing cycles comprises
administering to the subject the anti-TIGIT antagonist antibody at a dose
(e.g., a fixed dose) of between
about 30 mg to about 1200 mg every three weeks and the PD-1 axis binding
antagonist at a dose (e.g., a
fixed dose) of between about 80 mg to about 1 600 mg every three weeks as an
adjuvant treatment. In
some aspects, the method comprises administering to the subject: (a) the anti-
TIGIT antagonist antibody
at a dose (e.g., a fixed dose) of between 30 mg to 1200 mg every three weeks;
(b) the PD-1 axis binding
.. antagonist at a dose (e.g., a fixed dose) of between 80 mg to 1600 mg every
three weeks as a
neoadjuvant treatment; (c) a platinum-based chemotherapeutic agent: (i) at a
dose targeted to achieve an
AUC of 5 mg/mUmin or an AUC of 6 mg/milmin every three weeks; or (ii) at a
dose of 75 mg/m2 every
three weeks; and (d) a non-platinum-based chemotherapeutic agent, wherein the
non-platinum-based
chemotherapeutic agent is: (i) an antimetabolite at a dose of 500 mg/m2 every
three weeks or 1000
.. mg/m2 or 1250 mg/m2 on Days 1 and 8 of each dosing cycle; or (ii) a taxane
at a dose of 100 mg/m2, 175
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mg/m2, or 200 mg/m2 every three weeks; and (II) at least one of the dosing
cycles comprises
administering to the subject the anti-TIGIT antagonist antibody at a dose
(e.g., a fixed dose) of between
30 mg to 1200 mg every three weeks and the PD-1 axis binding antagonist at a
dose (e.g., a fixed dose)
of between 80 mg to 1600 mg every three weeks as an adjuvant treatment.
In some instances, the treatment may further comprise an additional therapy.
Any suitable
additional therapy known in the art or described herein may be used. The
additional therapy may be
radiation therapy (e.g., a post-operative radiotherapy), surgery, gene
therapy, DNA therapy, viral therapy,
RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy,
monoclonal antibody therapy,
gamma irradiation, or a combination of the foregoing.
In some instances, the additional therapy is the administration of side-effect
limiting agents (e.g.,
agents intended to lessen the occurrence and/or severity of side effects of
treatment, such as anti-nausea
agents, a corticosteroid (e.g., prednisone or an equivalent, e.g., at a dose
of 1-2 mg/kg/day), hormone
replacement medicine(s), and the like).
Also provided herein are methods for treating lung cancer in a subject
comprising administering
to the subject a treatment regimen comprising an effective amount of a PD-1
axis binding antagonist
(e.g., atezolizumab) and/or anti-TIGIT antagonist antibody (e.g., an anti-
TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab) in combination with one or more
chemotherapeutic agents (e.g., a
platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or
one or more non-platinum-
based chemotherapeutic agents (e.g., an antimetabolite (e.g., pemetrexed or
gemcitabine) and/or a
taxane (e.g., paclitaxel, e.g., nab-paclitaxel))) and/or cancer therapy (e.g.,
a surgery and/or a
radiotherapy). For example, a PD-1 axis binding antagonist may be administered
in combination with an
additional chemotherapy or chemotherapeutic agent (see definition above); a
targeted therapy or targeted
therapeutic agent; an immunotherapy or immunotherapeutic agent, for example, a
monoclonal antibody;
one or more cytotoxic agents (see definition above); or combinations thereof.
Dosing of agents
Dosing of anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, and
chemotherapeutic
agents is described in Section III(K).
Cancer characterization and selection
In some instances, in any of the methods, uses, or compositions for use
described herein, the
lung cancer (e.g., early-stage lung cancer (e.g., resectable lung cancer
(e.g., NSCLC (e.g., squamous or
non-squamous NSCLC)))) is resectable (e.g., eligible for RO resection with
curative intent). In some
instances, the lung cancer is an NSCLC. In some instances, the NSCLC is a
squamous or non-
squamous NSCLC. In some instances, the lung cancer is PD-L1 positive. In some
instances, the lung
cancer is PD-L1 high. In some instances, the lung cancer has no epidermal
growth factor receptor
(EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. In some
instances, the lung
cancer is a stage II, IIIA, or IIIB lung cancer.
In some instances, in any of the methods, uses, or compositions for use
described herein, the
subject is eligible for platinum-based chemotherapy. In some instances, the
subject has an Eastern
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Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1. In some
instances, the subject
has not received a prior therapy (e.g., an immunotherapy, a chemotherapy, or a
radiotherapy) for lung
cancer.
In some instances, in any of the methods, uses, or compositions for use
described herein, the
presence or level of circulating tumor DNA (ctDNA) may be assessed. In some
instances, ctDNA is
assessed in a sample (e.g., a blood sample (e.g., a plasma sample)) from the
subject. In some
instances, ctDNA is assessed in a sample from the subject prior to day 1 of
the first dosing cycle (e.g., the
first dosing cycle of an anti-TIGIT antagonist antibody and a PD-1 axis
binding antagonist). In some
instances, ctDNA is assessed in a sample from the subject prior to surgery. In
some instances, ctDNA is
assessed in a sample from the subject after surgery.
In some instances, in any of the methods, uses, or compositions for use
described herein, the
presence or level of immune cells (e.g., T cells) may be assessed. In some
instances, the presence or
level of immune cells is assessed in a sample (e.g., a blood sample, a tumor
tissue sample, or a lymph
node sample) from the subject. In some instances, the presence or level of
immune cells is assessed in
a sample from the subject prior to surgery. In some instances, the presence or
level of immune cells is
assessed in a sample from the subject after surgery.
Assessment of PD-L1 Expression
The expression of PD-L1 may be assessed as described in Section 1I1(L).
Assessment of EGFR and ALK aberrations
Methods for detecting the mutational status EGFR and ALK are described in
Section III(N) herein.
Responses to Treatment
In some embodiments of any of the methods described herein, a subject's
response to the
therapy can be characterized by one or more measures. In some embodiments, the
treatment results in
an increase in major pathological response (MPR) rate. In some embodiments,
the treatment results in a
pCR. In some embodiments, the treatment results in an increase in event-free
survival (EFS). In some
embodiments, the treatment results in an improvement in patient-reported
outcomes. In some
embodiments, the treatment results in an improvement in patient-reported
physical functioning, role
functioning, or GHS/QoL, as measured by the EORTC-QLQ-C30. In some
embodiments, the treatment
results in an improvement in patient-reported lung cancer symptoms for cough,
dyspnea, and chest pain,
as measured through the use of the EORTC-QLQ-LC13.
In some instances, the treatment results in an increase in MPR rate of the
subject, e.g., as
compared to treatment with the PD-1 axis binding antagonist without the anti-
TIGIT antagonist antibody
or as compared to treatment with the anti-TIGIT antagonist antibody without
the PD-1 axis binding
antagonist. In some instances, the treatment results in an increase in MPR
rate of the subject, e.g., as
compared to treatment with the PD-1 axis binding antagonist and the anti-TIGIT
antagonist antibody
without chemotherapy (e.g., a platinum-based doublet chemotherapy (e.g., a
platinum-based
chemotherapeutic agent (e.g., carboplatin or cisplatin) and a non-platinum-
based chemotherapeutic agent
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(e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane (e.g.,
paclitaxel or nab-
paclitaxel)))).
In some instances, the treatment results in an increase in pCR of the subject,
e.g., as compared
to treatment with the PD-1 axis binding antagonist without the anti-TIGIT
antagonist antibody or as
compared to treatment with the anti-TIGIT antagonist antibody without the PD-1
axis binding antagonist.
In some instances, the treatment results in an increase in pCR of the subject,
e.g., as compared to
treatment with the PD-1 axis binding antagonist and the anti-TIGIT antagonist
antibody without
chemotherapy (e.g., a platinum-based doublet chemotherapy (e.g., a platinum-
based chemotherapeutic
agent (e.g., carboplatin or cisplatin) and a non-platinum-based
chemotherapeutic agent (e.g., an
antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane (e.g., paclitaxel
or nab-paclitaxel)))).
In some instances, the treatment extends OS of the subject, e.g., as compared
to treatment with
the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or
as compared to treatment
with the anti-TIGIT antagonist antibody without the PD-1 axis binding
antagonist. In some instances, the
treatment extends OS of the subject, e.g., as compared to treatment with the
PD-1 axis binding
antagonist and the anti-TIGIT antagonist antibody without chemotherapy (e.g.,
a platinum-based doublet
chemotherapy (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin
or cisplatin) and a non-
platinum-based chemotherapeutic agent (e.g., an antimetabolite (e.g.,
pemetrexed or gemcitabine) or a
taxane (e.g., paclitaxel or nab-paclitaxel)))).
In some instances, the treatment extends EFS of the subject, e.g., as compared
to treatment
with the PD-1 axis binding antagonist without the anti-TIGIT antagonist
antibody or as compared to
treatment with the anti-TIGIT antagonist antibody without the PD-1 axis
binding antagonist. In some
instances, the treatment extends EFS of the subject, e.g., as compared to
treatment with the PD-1 axis
binding antagonist and the anti-TIGIT antagonist antibody without chemotherapy
(e.g., a platinum-based
doublet chemotherapy (e.g., a platinum-based chemotherapeutic agent (e.g.,
carboplatin or cisplatin) and
a non-platinum-based chemotherapeutic agent (e.g., an antimetabolite (e.g.,
pemetrexed or gemcitabine)
or a taxane (e.g., paclitaxel or nab-paclitaxel)))).
In some embodiments, a treatment described increases the MPR rate by at least
1% (e.g., by
5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,
85%, 90%,
95%, or 100%).
In some embodiments, a treatment described herein extends the pCR of the
subject by at least
about 2 months (e.g., by 2-120 months, by 2.5-100 months, by 3.0-80 months, by
4.0-60 months, by 5.0-
48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12 months, e.g., by at
least about 2.4 months,
2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1
months, 3.2 months, 3.3
months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9
months, 4.0 months, 4.1
.. months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7
months, 4.8 months, 4.9
months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5
months, 8.0 months, 8.5
months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5
months, 12 months, 13
months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20
months, 21 months, 22
months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29
months, 30 months, 31
months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some
embodiments, the
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treatment extends the pCR of the subject by at least about 4 months (e.g., by
4-120 months, by 5-100
months, by 6-80 months, by 7-60 months, by 8-48 months, by 9-36 months, or by
10-24 months, e.g., by
at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5
months, 4.6 months, 4.7
months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5
months, 7.0 months, 7.5
months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5
months, 11 months, 11.5
months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18
months, 19 months, 20
months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27
months, 28 months, 29
months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or
36 months).
In some embodiments, a treatment described herein extends the EFS of the
subject by at least
about 2 months (e.g., by 2-120 months, by 2.5-100 months, by 3.0-80 months, by
4.0-60 months, by 5.0-
48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12 months, e.g., by at
least about 2.4 months,
2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1
months, 3.2 months, 3.3
months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9
months, 4.0 months, 4.1
months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7
months, 4.8 months, 4.9
months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5
months, 8.0 months, 8.5
months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5
months, 12 months, 13
months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20
months, 21 months, 22
months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29
months, 30 months, 31
months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some
embodiments, the
.. treatment extends the EFS of the subject by at least about 4 months (e.g.,
by 4-120 months, by 5-100
months, by 6-80 months, by 7-60 months, by 8-48 months, by 9-36 months, or by
10-24 months, e.g., by
at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5
months, 4.6 months, 4.7
months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5
months, 7.0 months, 7.5
months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5
months, 11 months, 11.5
months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18
months, 19 months, 20
months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27
months, 28 months, 29
months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or
36 months).
In some embodiments, OS is measured as the period of time from the start of
treatment to death.
In some instances, the treatment extends the OS of the subject by at least
about 2 months (e.g., by 2-120
months, by 3-110 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-
48 months, by 8-36
months, or by 10-24 months, e.g., by at least about 2 months, 2.1 months, 2.2
months, 2.3 months, 2.4
months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0
months, 3.1 months, 3.2
months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8
months, 3.9 months, 4.0
months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6
months, 4.7 months, 4.8
months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0
months, 7.5 months, 8.0
months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months,
11.5 months, 12
months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19
months, 20 months, 21
months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28
months, 29 months, 30
months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
In some instances,
.. the treatment extends the OS of the subject by at least about 3.3 months
(e.g., by 3.3-120 months, by 4-
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100 months, by 5-80 months, by 6-60 months, by 7-48 months, by 8-36 months, or
by 10-24 months, e.g.,
by at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months,
3.8 months, 3.9 months,
4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6
months, 4.7 months, 4.8
months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0
months, 7.5 months, 8.0
months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months,
11.5 months, 12
months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19
months, 20 months, 21
months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28
months, 29 months, 30
months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).
In some instances,
the treatment extends the OS of the subject by at least about 5.3 months
(e.g., by 5.3-120, by 6-60
months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least
about 5.3 months, 5.5
months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5
months, 9.0 months, 9.5
months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months,
14 months, 15
months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22
months, 23 months, 24
months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31
months, 32 months, 33
months, 34 months, 35 months, or 36 months).
C. Therapeutic and diagnostic methods and uses relating to cervical cancer
Cervical cancer
Cervical cancer is the fourth most frequently diagnosed cancer and the fourth
leading cause of
cancer-related death. More than 500,000 women are diagnosed with cervical
cancer annually worldwide,
resulting in more than 300,000 deaths. Almost 90% of cervical cancer deaths
occur in developing
countries. In the United States, there are 13,000 new cases of invasive
cervical cancer and
approximately 4000 cancer-related deaths each year.
Treatment for early and locally advanced cervical cancer consists of surgery
and definitive
chemoradiotherapy, respectively, and can be quite effective in eliciting a
remission. However, if cancer
recurs or fails to resolve with primary treatment, prognosis is quite poor
with 5-year survival rates of
approximately 15%, which is comparable to that of patients with de novo
metastatic disease. With few
exceptions, the standard of care for recurrent, persistent, or de novo
metastatic disease is chemotherapy
plus bevacizumab based on the Gynecology Oncology Group 240 trial, which
showed that bevacizumab
added to chemotherapy improved median OS compared with chemotherapy alone (17
vs. 13.3 months,
respectively).
Currently, no globally-accepted standard of care exists after recurrence or
progression on
chemotherapy plus bevacizumab. As such, treatment options for these patients
largely comprise various
cytotoxic chemotherapy agents, administered as either a single agent or in
combination. However, given
the historically low response rates of approximately 10%-15%, increasing focus
has been given to
whether cytotoxic chemotherapies represent an acceptable standard of care over
best supportive care
given the impact and burden such agents can impart on patient quality of life.
Historically low efficacy rates of existing therapies, coupled with the
engagement of the immune
response owing to HPV infection of the cervical epithelial cells, makes
cervical cancer a particularly
attractive opportunity for novel immunotherapy-based approaches.
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Thus, there is an unmet need in the field for the development of efficacious
immunotherapies and
methods of dosing the same for the treatment of cancers (e.g., cervical
cancer, e.g., Stage IVB,
metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic
and/or recurrent PD-L1-positive
cervical carcinoma).
Methods and uses for treating cervical cancer
Provided herein are methods and uses for treating cancer with a detectable
expression level of
PD-L1 (e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or
persistent cervical cancer, e.g., a
metastatic and/or recurrent PD-L1-positive cervical carcinoma) in a subject or
population of subjects
comprising administering to the subject or population of subjects one or more
dosing cycles of an
effective amount of an anti-TIGIT antagonist antibody and a PD-1 axis binding
antagonist (e.g., an anti-
PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist
antibody (e.g., MDX-1106
(nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))).
Dosing Regimens and Administration
The therapeutic methods and uses of the invention described herein include, in
one aspect,
administering to a subject or population of subjects having a cancer with a
detectable expression level of
PD-L1 (e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or
persistent cervical cancer, e.g., a
metastatic and/or recurrent PD-L1-positive cervical carcinoma) one or more
dosing cycles of an effective
amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist
antibody as disclosed herein,
e.g., tiragolumab) and an effective amount of a PD-1 axis binding antagonist
(e.g., an anti-PD-L1
antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody
(e.g., MDX-1106
(nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))),
thereby treating the
subject or population of subjects.
In some instances, the effective amount of the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a
fixed dose) of between about
mg to about 1200 mg (e.g., between about 30 mg to about 1100 mg, e.g., between
about 60 mg to
about 1000 mg, e.g., between about 100 mg to about 900 mg, e.g., between about
200 mg to about 800
mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to
about 800 mg, e.g.,
30 between about 400 mg to about 750 mg, e.g., between about 450 mg to
about 750 mg, e.g., between
about 500 mg to about 700 mg, e.g., between about 550 mg to about 650 mg,
e.g., 600 mg 10 mg, e.g.,
600 6 mg, e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600 1 mg, e.g., 600
0.5 mg, e.g., 600 mg) every
three weeks. In some instances, the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-
TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose
(e.g., a fixed dose) of between
about 30 mg to about 600 mg (e.g., between about 50 mg to between 600 mg,
e.g., between about 60 mg
to about 600 mg, e.g., between about 100 mg to about 600 mg, e.g., between
about 200 mg to about 600
mg, e.g., between about 200 mg to about 550 mg, e.g., between about 250 mg to
about 500 mg, e.g.,
between about 300 mg to about 450 mg, e.g., between about 350 mg to about 400
mg, e.g., about 375
mg) every three weeks. In some instances, the effective amount of the anti-
TIGIT antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) is a dose (e.g., a fixed
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dose) of about 600 mg every three weeks. In some instances, the effective
amount of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed
herein, e.g., tiragolumab) is a
dose (e.g., a fixed dose) of between 30 mg to 1200 mg (e.g., between 30 mg to
1100 mg, e.g., between
60 mg to 1000 mg, e.g., between 100 mg to 900 mg, e.g., between 200 mg to 800
mg, e.g., between 300
mg to 800 mg, e.g., between 400 mg to 800 mg, e.g., between 400 mg to 750 mg,
e.g., between 450 mg
to 750 mg, e.g., between 500 mg to 700 mg, e.g., between 550 mg to 650 mg,
e.g., 600 mg 10 mg, e.g.,
600 6 mg, e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600 1 mg, e.g., 600
0.5 mg, e.g., 600 mg) every
three weeks. In some instances, the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-
TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose
(e.g., a fixed dose) of between
30 mg to 600 mg (e.g., between 50 mg to between 600 mg, e.g., between 60 mg to
600 mg, e.g.,
between 100 mg to 600 mg, e.g., between 200 mg to 600 mg, e.g., between 200 mg
to 550 mg, e.g.,
between 250 mg to 500 mg, e.g., between 300 mg to 450 mg, e.g., between 350 mg
to 400 mg, e.g., 375
mg) every three weeks. In some instances, the effective amount of the anti-
TIGIT antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) is a dose (e.g., a fixed
dose) of 600 mg every three weeks. In some instances, effective amount of the
anti-TIGIT antagonist
antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) is a dose (e.g., a
fixed dose) of 600 mg every three weeks. In some instances, the dose of the
anti-TIGIT antagonist
antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) administered in a
combination therapy (e.g., a combination treatment with a PD-1 axis binding
antagonist (e.g., an anti-PD-
L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist
antibody (e.g., MDX-1106
(nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab)))
may be reduced as
compared to a standard dose of the anti-TIGIT antagonist antibody administered
as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of
between about 80 mg to about
2000 mg (e.g., between about 80 mg to about 1950 mg, e.g., between about 80 mg
to about 1900 mg,
e.g., between about 80 mg to about 1800 mg, e.g., between about 100 mg to
about 1700 mg, e.g.,
between about 200 mg to about 1600 mg, e.g., between about 300 mg to about
1400 mg, e.g., between
about 400 mg to about 1300 mg, e.g., between about 500 mg to about 1200 mg,
e.g., between about 600
mg to about 1100 mg, e.g., between about 700 mg to about 1000 mg, e.g.,
between about 740 mg to
about 940 mg, e.g., between about 790 mg to about 890 mg, e.g., between about
815 mg to about 865
mg, e.g., between about 830 mg to about 850 mg, e.g., 840 mg 5 mg, e.g., 840
2.5 mg, e.g., 840
1.0 mg, e.g., 840 0.5 mg, e.g., 840 mg) every two weeks. In some instances,
the effective amount of
the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab)) is a dose of
between about 80 mg to about 2000 mg (e.g., between about 100 mg to about 2000
mg, e.g., between
about 200 mg to about 1900 mg, e.g., between about 300 mg to about 1700 mg,
e.g., between about 400
mg to about 1600 mg, e.g., between about 500 mg to about 1600 mg, e.g.,
between about 600 mg to
about 1600 mg, e.g., between about 700 mg to about 1600 mg, e.g., between
about 800 mg to about
1600 mg, e.g., between about 900 mg to about 1500 mg, e.g., between about 1000
mg to about 1400 mg,
e.g., between about 1050 mg to about 1350 mg, e.g., between about 1100 mg to
about 1300 mg, e.g.,
between about 1150 mg to about 1250 mg, e.g., between about 1175 mg to about
1225 mg, e.g.,
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between about 1190 mg to about 1210 mg, e.g., 1200 mg 5 mg, e.g., 1200 2.5
mg, e.g., 1200 1.0
mg, e.g., 1200 0.5 mg, e.g., 1200 mg) every three weeks. In some instances,
the effective amount of
the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab)) is a dose of
between about 80 mg to about 2000 mg (e.g., between about 100 mg to about 2000
mg, e.g., between
about 200 mg to about 2000 mg, e.g., between about 300 mg to about 2000 mg,
e.g., between about 400
mg to about 2000 mg, e.g., between about 500 mg to about 2000 mg, e.g.,
between about 600 mg to
about 1900 mg, e.g., between about 700 mg to about 1800 mg, e.g., between
about 800 mg to about
1800 mg, e.g., between about 900 mg to about 1800 mg, e.g., between about 1000
mg to about 1800 mg,
e.g., between about 1100 mg to about 1800 mg, e.g., between about 1200 mg to
about 1800 mg, e.g.,
between about 1300 mg to about 1800 mg, e.g., between about 1400 mg to about
1800 mg, e.g.,
between about 1500 mg to about 1800 mg, e.g., between about 1580 mg to about
1780 mg, e.g.,
between about 1630 mg to about 1730 mg, e.g., between about 1655 mg to about
1705 mg, e.g.,
between about 1670 mg to about 1690 mg, e.g., 1680 mg 5 mg, e.g., 1680 2.5
mg, e.g., 1680 1.0
mg, e.g., 1680 0.5 mg, e.g., 1680 mg) every four weeks. In some instances,
the effective amount of the
PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab)) is a dose of
about 840 mg every two weeks. In some instances, the effective amount of the
PD-1 axis binding
antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a
dose of 840 mg every two
weeks. In some instances, the effective amount of the PD-1 axis binding
antagonist (e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab)) is a dose of about 1200 mg every
three weeks. In some
instances, the effective amount of the PD-1 axis binding antagonist (e.g.,
anti-PD-L1 antagonist antibody
(e.g., atezolizumab)) is a dose (e.g., a fixed dose) of between 80 mg to 2000
mg (e.g., between 80 mg to
1950 mg, e.g., between 80 mg to 1900 mg, e.g., between 80 mg to 1800 mg, e.g.,
between 100 mg to
1700 mg, e.g., between 200 mg to 1600 mg, e.g., between 300 mg to 1400 mg,
e.g., between 400 mg to
1300 mg, e.g., between 500 mg to 1200 mg, e.g., between 600 mg to 1100 mg,
e.g., between 700 mg to
1000 mg, e.g., between 740 mg to 940 mg, e.g., between 790 mg to 890 mg, e.g.,
between 815 mg to
865 mg, e.g., between 830 mg to 850 mg, e.g., 840 mg 5 mg, e.g., 840 2.5
mg, e.g., 840 1.0 mg,
e.g., 840 0.5 mg, e.g., 840 mg) every two weeks. In some instances, the
effective amount of the PD-1
axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab)) is a dose of between
80 mg to 2000 mg (e.g., between 100 mg to 2000 mg, e.g., between 200 mg to
1900 mg, e.g., between
300 mg to 1700 mg, e.g., between 400 mg to 1600 mg, e.g., between 500 mg to
1600 mg, e.g., between
600 mg to 1600 mg, e.g., between 700 mg to 1600 mg, e.g., between 800 mg to
1600 mg, e.g., between
900 mg to 1500 mg, e.g., between 1000 mg to 1400 mg, e.g., between 1050 mg to
1350 mg, e.g.,
between 1100 mg to 1300 mg, e.g., between 1150 mg to 1250 mg, e.g., between
1175 mg to 1225 mg,
e.g., between 1190 mg to 1210 mg, e.g., 1200 mg 5 mg, e.g., 1200 2.5 mg,
e.g., 1200 1.0 mg, e.g.,
1200 0.5 mg, e.g., 1200 mg) every three weeks. In some instances, the
effective amount of the PD-1
axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab)) is a dose of between
80 mg to 2000 mg (e.g., between 100 mg to 2000 mg, e.g., between 200 mg to
2000 mg, e.g., between
300 mg to 2000 mg, e.g., between 400 mg to 2000 mg, e.g., between 500 mg to
2000 mg, e.g., between
600 mg to 1900 mg, e.g., between 700 mg to 1800 mg, e.g., between 800 mg to
1800 mg, e.g., between
900 mg to 1800 mg, e.g., between 1000 mg to 1800 mg, e.g., between 1100 mg to
1800 mg, e.g.,
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between 1200 mg to 1800 mg, e.g., between 1300 mg to 1800 mg, e.g., between
1400 mg to 1800 mg,
e.g., between 1500 mg to 1800 mg, e.g., between 1580 mg to 1780 mg, e.g.,
between 1630 mg to 1730
mg, e.g., between 1655 mg to 1705 mg, e.g., between 1670 mg to 1690 mg, e.g.,
1680 mg 5 mg, e.g.,
1680 2.5 mg, e.g., 1680 1.0 mg, e.g., 1680 0.5 mg, e.g., 1680 mg) every
four weeks. In some
instances, the effective amount of the PD-1 axis binding antagonist (e.g.,
anti-PD-L1 antagonist antibody
(e.g., atezolizumab)) is a dose of 840 mg every two weeks. In some instances,
the effective amount of
the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab)) is a dose of
840 mg every two weeks. In some instances, the effective amount of the PD-1
axis binding antagonist
(e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of 1200
mg every three weeks. In
some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-L1 antagonist
antibody (e.g., atezolizumab)) is a dose of 1200 mg every three weeks. In some
instances, the effective
amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist
antibody (e.g., atezolizumab)) is
a dose of about 1680 mg every four weeks. In some instances, the effective
amount of the PD-1 axis
binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab))
is a dose of 1680 mg every
four weeks. In some instances, the dose of the PD-1 axis binding antagonist
(e.g., anti-PD-L1 antagonist
antibody (e.g., atezolizumab)) administered in a combination therapy (e.g., a
combination treatment with
an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody
disclosed herein, e.g.,
tiragolumab) may be reduced as compared to a standard dose of the anti-PD-L1
antagonist antibody
administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01
mg/kg to about 50 mg/kg of the
subject's body weight (e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g.,
between about 0.1 mg/kg
to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g.,
between about 2.5 mg/kg to
about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between
about 10 mg/kg to about
20 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., about 15 2
mg/kg, about 15 1
mg/kg, about 15 0.5 mg/kg, about 15 0.2 mg/kg, or about 15 0.1 mg/kg,
e.g., about 15 mg/kg) every
three weeks. In some instances, the effective amount of the PD-1 axis binding
antagonist (e.g., anti-PD-
L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01
mg/kg to about 15 mg/kg of
the subject's body weight (e.g., between about 0.1 mg/kg to about 15 mg/kg,
e.g., between about 0.5
mg/kg to about 15 mg/kg, e.g., between about 1 mg/kg to about 15 mg/kg, e.g.,
between about 2.5 mg/kg
to about 15 mg/kg, e.g., between about 5 mg/kg to about 15 mg/kg, e.g.,
between about 7.5 mg/kg to
about 15 mg/kg, e.g., between about 10 mg/kg to about 15 mg/kg, e.g., between
about 12.5 mg/kg to
about 15 mg/kg, e.g., between about 14 mg/kg to about 15 mg/kg, e.g., about 15
1 mg/kg, e.g., about
15 0.5 mg/kg, e.g., about 15 0.2 mg/kg, e.g., about 15 0.1 mg/kg, e.g.,
about 15 mg/kg) every three
.. weeks. In some instances, the effective amount of anti-PD-L1 antagonist
antibody (e.g., atezolizumab) is
a dose of about 15 mg/kg administered every three weeks. In some instances,
the effective amount of
the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab)) is a dose of
between 0.01 mg/kg to 50 mg/kg of the subject's body weight (e.g., between
0.01 mg/kg to 45 mg/kg,
e.g., between 0.1 mg/kg to 40 mg/kg, e.g., between 1 mg/kg to 35 mg/kg, e.g.,
between 2.5 mg/kg to 30
mg/kg, e.g., between 5 mg/kg to 25 mg/kg, e.g., between 10 mg/kg to 20 mg/kg,
e.g., between 12.5
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mg/kg to 15 mg/kg, e.g., 15 2 mg/kg, 15 1 mg/kg, 15 0.5 mg/kg, 15 0.2
mg/kg, or 15 0.1 mg/kg,
e.g., 15 mg/kg) every three weeks. In some instances, the effective amount of
the PD-1 axis binding
antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a
dose of between 0.01 mg/kg to
15 mg/kg of the subject's body weight (e.g., between 0.1 mg/kg to 15 mg/kg,
e.g., between 0.5 mg/kg to
15 mg/kg, e.g., between 1 mg/kg to 15 mg/kg, e.g., between 2.5 mg/kg to 15
mg/kg, e.g., between 5
mg/kg to 15 mg/kg, e.g., between 7.5 mg/kg to 15 mg/kg, e.g., between 10 mg/kg
to 15 mg/kg, e.g.,
between 12.5 mg/kg to 15 mg/kg, e.g., between 14 mg/kg to 15 mg/kg, e.g., 15
1 mg/kg, e.g., 15 0.5
mg/kg, e.g., 15 0.2 mg/kg, e.g., 15 0.1 mg/kg, e.g., 15 mg/kg) every three
weeks. In some instances,
the effective amount of anti-PD-L1 antagonist antibody (e.g., atezolizumab) is
a dose of 15 mg/kg
administered every three weeks. In some instances, the dose of the PD-1 axis
binding antagonist (e.g.,
anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered in a
combination therapy (e.g., a
combination treatment with an anti-TIGIT antagonist antibody, such as an anti-
TIGIT antagonist antibody
disclosed herein, e.g., tiragolumab) may be reduced as compared to a standard
dose of the PD-1 axis
binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)
or anti-PD-1 antagonist
antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously
known as
lambrolizumab))) administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-1
antagonist antibody (e.g., pembrolizumab)) is a dose (e.g., a fixed dose) of
between about 20 mg to about
1000 mg (e.g., between about 40 mg to about 900 mg, e.g., between about 60 mg
to about 800 mg, e.g.,
between about 80 mg to about 700 mg, e.g., between about 80 mg to about 600
mg, e.g., between about
100 mg to about 500 mg, e.g., between about 120 mg to about 400 mg, e.g.,
between about 140 mg to
about 300 mg, e.g., between about 160 mg to about 350 mg, e.g., between about
180 mg to about 300
mg, e.g., between about 180 mg to about 250 mg, e.g., between about 180 mg to
about 220 mg, e.g.,
between about 190 mg to about 210 mg, e.g., 200 mg 5 mg, e.g., 200 2.5 mg,
e.g., 200 1.0 mg,
e.g., 200 0.5 mg, e.g., 200 mg) every three weeks. In some instances, the
effective amount of the PD-1
axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g.,
pembrolizumab)) is a dose (e.g., a fixed
dose) of between 20 mg to 1000 mg (e.g., between 40 mg to 900 mg, e.g.,
between 60 mg to 800 mg,
e.g., between 80 mg to 700 mg, e.g., between 80 mg to 600 mg, e.g., between
100 mg to 500 mg, e.g.,
between 120 mg to 400 mg, e.g., between 140 mg to 300 mg, e.g., between 160 mg
to 350 mg, e.g.,
between 180 mg to 300 mg, e.g., between 180 mg to 250 mg, e.g., between 180 mg
to 220 mg, e.g.,
between 190 mg to 210 mg, e.g., 200 mg 5 mg, e.g., 200 2.5 mg, e.g., 200
1.0 mg, e.g., 200 0.5
mg, e.g., 200 mg) every three weeks. In some instances, the effective amount
of the PD-1 axis binding
antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is a
dose (e.g., a fixed dose) of
200 mg every three weeks. In some instances, the dose of the PD-1 axis binding
antagonist (e.g., anti-
PD-1 antagonist antibody (e.g., pembrolizumab)) administered in a combination
therapy (e.g., a
combination treatment with an anti-TIGIT antagonist antibody, such as an anti-
TIGIT antagonist antibody
disclosed herein, e.g., tiragolumab) may be reduced as compared to a standard
dose of the anti-PD-L1
antagonist antibody administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-1
antagonist antibody (e.g., nivolumab)) is a dose (e.g., a fixed dose) of
between about 20 mg to about
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1000 mg (e.g., between about 40 mg to about 900 mg, e.g., between about 60 mg
to about 800 mg, e.g.,
between about 80 mg to about 700 mg, e.g., between about 80 mg to about 600
mg, e.g., between about
100 mg to about 500 mg, e.g., between about 120 mg to about 400 mg, e.g.,
between about 140 mg to
about 300 mg, e.g., between about 160 mg to about 350 mg, e.g., between about
180 mg to about 300
mg, e.g., between about 200 mg to about 280 mg, e.g., between about 220 mg to
about 260 mg, e.g.,
between about 230 mg to about 250 mg, e.g., 240 mg 5 mg, e.g., 240 2.5 mg,
e.g., 240 1.0 mg,
e.g., 240 0.5 mg, e.g., 240 mg) every two weeks. In some instances, the
effective amount of the PD-1
axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g.,
nivolumab)) is a dose of 240 mg every
two weeks. In some instances, the effective amount of the PD-1 axis binding
antagonist (e.g., anti-PD-1
antagonist antibody (e.g., nivolumab)) is a dose of between about 100 mg to
about 1000 mg (e.g.,
between about 200 mg to about 900 mg, e.g., between about 300 mg to about 800
mg, e.g., between
about 400 mg to about 700 mg, e.g., between about 400 mg to about 600 mg,
e.g., between about 400
mg to about 550 mg, e.g., between about 420 mg to about 540 mg, e.g., between
about 440 mg to about
520 mg, e.g., between about 460 mg to about 500 mg, e.g., between about 470 mg
to about 490 mg, e.g.,
480 mg 5 mg, e.g., 480 2.5 mg, e.g., 480 1.0 mg, e.g., 480 0.5 mg,
e.g., 480 mg) every four
weeks. In some instances, the effective amount of the PD-1 axis binding
antagonist (e.g., anti-PD-1
antagonist antibody (e.g., nivolumab)) is a dose (e.g., a fixed dose) of
between 20 mg to 1000 mg (e.g.,
between 40 mg to 900 mg, e.g., between 60 mg to 800 mg, e.g., between 80 mg to
700 mg, e.g.,
between 80 mg to 600 mg, e.g., between 100 mg to 500 mg, e.g., between 120 mg
to 400 mg, e.g.,
between 140 mg to 300 mg, e.g., between 160 mg to 350 mg, e.g., between 180 mg
to 300 mg, e.g.,
between 200 mg to 280 mg, e.g., between 220 mg to 260 mg, e.g., between 230 mg
to 250 mg, e.g., 240
mg 5 mg, e.g., 240 2.5 mg, e.g., 240 1.0 mg, e.g., 240 0.5 mg, e.g.,
240 mg) every two weeks. In
some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-1 antagonist
antibody (e.g., nivolumab)) is a dose of 240 mg every two weeks. In some
instances, the effective
amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist
antibody (e.g., nivolumab)) is a
dose of between 100 mg to 1000 mg (e.g., between 200 mg to 900 mg, e.g.,
between 300 mg to 800 mg,
e.g., between 400 mg to 700 mg, e.g., between 400 mg to 600 mg, e.g., between
400 mg to 550 mg, e.g.,
between 420 mg to 540 mg, e.g., between 440 mg to 520 mg, e.g., between 460 mg
to 500 mg, e.g.,
between 470 mg to 490 mg, e.g., 480 mg 5 mg, e.g., 480 2.5 mg, e.g., 480
1.0 mg, e.g., 480 0.5
mg, e.g., 480 mg) every four weeks. In some instances, the effective amount of
the PD-1 axis binding
antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose
of 480 mg every four weeks.
In some instances, the dose of the PD-1 axis binding antagonist (e.g., anti-PD-
1 antagonist antibody
(e.g., nivolumab)) administered in a combination therapy (e.g., a combination
treatment with an anti-TIGIT
antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed
herein, e.g., tiragolumab) may
be reduced as compared to a standard dose of the anti-PD-L1 antagonist
antibody administered as a
monotherapy.
In any of the methods and uses of the invention, the anti-TIGIT antagonist
antibody (e.g., an anti-
TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1
axis binding antagonist
(e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1
antagonist antibody (e.g., MDX-
1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as
lambrolizumab))) may be
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administered in one or more dosing cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18,
19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,
38, 39, 40, 41, 42, 43, 44, 45, 46,
47, 48, 49, or 50 or more dosing cycles). In some instances, the dosing cycles
of the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed
herein, e.g., tiragolumab) and
the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab) or anti-PD-1
antagonist antibody (e.g., 1VIDX-1106 (nivolumab) or MK-3475 (pembrolizumab,
previously known as
lambrolizumab))) continue until there is a loss of clinical benefit (e.g.,
confirmed disease progression,
drug resistance, death, or unacceptable toxicity). In some instances, the
length of each dosing cycle is
about 14 to 28 days (e.g., 14 days, 15 days, 16 days, 17 days, 18 days, 19
days, 20 days, 21 days, 22
days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days). In some
instances, the length of each
dosing cycle is about 21 days. In some instances, the length of each dosing
cycle is about 14 days. In
some instances, the length of each dosing cycle is about 28 days. In some
instances, the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed
herein, e.g., tiragolumab) is
administered on about Day 1 (e.g., Day 1 3 days) of each dosing cycle. For
example, the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed
herein, e.g., tiragolumab) is
administered intravenously at a dose (e.g., a fixed dose) of about 600 mg on
Day 1 of each 21-day cycle
(i.e., at a dose of about 600 mg every three weeks). In some instances, the
anti-TIGIT antagonist
antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) is administered
intravenously at a dose (e.g., a fixed dose) of 600 mg on Day 1 of each 21-day
cycle (i.e., at a dose of
.. 600 mg every three weeks). Similarly, in some instances, the PD-1 axis
binding antagonist (e.g., an anti-
PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist
antibody (e.g., MDX-1106
(nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) is
administered on about
Day 1 (e.g., Day 1 3 days) of each dosing cycle. For example, the PD-1 axis
binding antagonist (e.g.,
anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered
intravenously at a dose of about
1200 mg on Day 1 of each 21-day cycle (i.e., at a dose of about 1200 mg every
three weeks). For
example, the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody
(e.g., pembrolizumab)) is
administered intravenously at a dose of about 200 mg on Day 1 of each 21-day
cycle (i.e., at a dose of
about 200 mg every three weeks). For example, the PD-1 axis binding antagonist
(e.g., anti-PD-1
antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose
of about 240 mg on Day 1
of each 14-day cycle (i.e., at a dose of about 240 mg every two weeks). For
example, the PD-1 axis
binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is
administered intravenously at
a dose of about 480 mg on Day 1 of each 28-day cycle (i.e., at a dose of about
480 mg every four
weeks). In some instances, the PD-1 axis binding antagonist (e.g., anti-PD-L1
antagonist antibody (e.g.,
atezolizumab)) is administered intravenously at a dose of about 1200 mg on Day
1 of each 21-day cycle
(i.e., at a dose of about 1200 mg every three weeks). For example, the PD-1
axis binding antagonist
(e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is administered
intravenously at a dose of
about 200 mg on Day 1 of each 21-day cycle (i.e., at a dose of about 200 mg
every three weeks). For
example, the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody
(e.g., nivolumab)) is
administered intravenously at a dose of about 240 mg on Day 1 of each 14-day
cycle (i.e., at a dose of
about 240 mg every two weeks). For example, the PD-1 axis binding antagonist
(e.g., anti-PD-1
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antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose
of about 480 mg on Day 1
of each 28-day cycle (i.e., at a dose of about 480 mg every four weeks).
In some instances, both the anti-TIGIT antagonist antibody (e.g., an anti-
TIGIT antagonist
antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding
antagonist (e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody
(e.g., MDX-1106 (nivolumab) or
MK-3475 (pembrolizumab, previously known as lambrolizumab))) are administered
on about Day 1 (e.g.,
Day 1 3 days) of each dosing cycle. For example, the anti-TIGIT antagonist
antibody (e.g., an anti-
TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is
administered intravenously at a dose
(e.g., a fixed dose) of about 600 mg on Day 1 of each 21-day cycle (i.e., at a
dose of about 600 mg every
three weeks), and the PD-1 axis binding antagonist (e.g., anti-PD-L1
antagonist antibody (e.g.,
atezolizumab)) is administered intravenously at a dose (e.g., a fixed dose) of
about 1200 mg on Day 1 of
each 21-day cycle (i.e., at a dose of about 1200 mg every three weeks). For
example, the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed
herein, e.g., tiragolumab) is
administered intravenously at a dose of about 600 mg on Day 1 of each 21-day
cycle (i.e., at a dose of
about 600 mg every three weeks), and the PD-1 axis binding antagonist (e.g.,
anti-PD-L1 antagonist
antibody (e.g., pembrolizumab)) is administered intravenously at a dose of
about 200 mg on Day 1 of
each 21-day cycle (i.e., at a dose of about 200 mg every three weeks). In some
examples, the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed
herein, e.g., tiragolumab) is
administered intravenously at a dose (e.g., a fixed dose) of 600 mg on Day 1
of each 21-day cycle (i.e., at
a dose of 600 mg every three weeks), and the PD-1 axis binding antagonist
(e.g., anti-PD-L1 antagonist
antibody (e.g., atezolizumab)) is administered intravenously at a dose (e.g.,
a fixed dose) of 1200 mg on
Day 1 of each 21-day cycle (i.e., at a dose of 1200 mg every three weeks). For
example, the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed
herein, e.g., tiragolumab) is
administered intravenously at a dose of 600 mg on Day 1 of each 21-day cycle
(i.e., at a dose of 600 mg
every three weeks), and the PD-1 axis binding antagonist (e.g., anti-PD-L1
antagonist antibody (e.g.,
pembrolizumab)) is administered intravenously at a dose of 200 mg on Day 1 of
each 21-day cycle (i.e.,
at a dose of 200 mg every three weeks).
In some instances, both the anti-TIGIT antagonist antibody (e.g., an anti-
TIGIT antagonist
antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis binding
antagonist (e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody
(e.g., MDX-1106 (nivolumab) or
MK-3475 (pembrolizumab, previously known as lambrolizumab))) are administered
on about Day 1 (e.g.,
Day 1 3 days) of the first dosing cycle. For example, the anti-TIGIT
antagonist antibody (e.g., an anti-
TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is
administered intravenously at a dose
(e.g., a fixed dose) of about 600 mg on Day 1 of each 21-day cycle (i.e., at a
dose of about 600 mg every
three weeks), and the PD-1 axis binding antagonist (e.g., anti-PD-L1
antagonist antibody (e.g.,
nivolumab)) is administered intravenously at a dose (e.g., a fixed dose) of
about 240 mg on Day 1 of each
14-day cycle (i.e., at a dose of about 240 mg every two weeks). For example,
the anti-TIGIT antagonist
antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) is administered
intravenously at a dose of about 600 mg on Day 1 of each 21-day cycle (i.e.,
at a dose of about 600 mg
every three weeks), and the PD-1 axis binding antagonist (e.g., anti-PD-L1
antagonist antibody (e.g.,
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nivolumab)) is administered intravenously at a dose of about 480 mg on Day 1
of each 28-day cycle (i.e.,
at a dose of about 480 mg every four weeks). In some examples, the anti-TIGIT
antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) is administered
intravenously at a dose (e.g., a fixed dose) of 600 mg on Day 1 of each 21-day
cycle (i.e., at a dose of
600 mg every three weeks), and the PD-1 axis binding antagonist (e.g., anti-PD-
L1 antagonist antibody
(e.g., nivolumab)) is administered intravenously at a dose (e.g., a fixed
dose) of 240 mg on Day 1 of each
14-day cycle (i.e., at a dose of 240 mg every two weeks). For example, the
anti-TIGIT antagonist
antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) is administered
intravenously at a dose of 600 mg on Day 1 of each 21-day cycle (i.e., at a
dose of 600 mg every three
.. weeks), and the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist
antibody (e.g., nivolumab)) is
administered intravenously at a dose of 480 mg on Day 1 of each 28-day cycle
(i.e., at a dose of 480 mg
every four weeks).
In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) is administered to the subject or
population of subjects by intravenous
infusion over about 60 15 minutes (e.g., about 50 minutes, about 51 minutes,
about 52 minutes, about
53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57
minutes, about 58 minutes,
about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about
63 minutes, about 64
minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68
minutes, about 69 minutes, or
about 70 minutes). In some instances, the PD-1 axis binding antagonist (e.g.,
anti-PD-L1 antagonist
antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106
(nivolumab) or MK-3475
(pembrolizumab, previously known as lambrolizumab))) is administered to the
subject or population of
subjects by intravenous infusion over about 60 15 minutes (e.g., about 45
minutes, about 46 minutes,
about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about
51 minutes, about 52
minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56
minutes, about 57 minutes,
about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about
62 minutes, about 63
minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67
minutes, about 68 minutes,
about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about
73 minutes, about 74
minutes, or about 75 minutes).
In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) is administered to the subject or
population of subjects by intravenous
infusion over about 30 10 minutes (e.g., about 20 minutes, about 21 minutes,
about 22 minutes, about
23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27
minutes, about 28 minutes,
about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about
33 minutes, about 34
minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38
minutes, about 39 minutes, or
about 40 minutes). In some instances, the PD-1 axis binding antagonist (e.g.,
anti-PD-L1 antagonist
antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106
(nivolumab) or MK-3475
(pembrolizumab, previously known as lambrolizumab))) is administered to the
subject or population of
subjects by intravenous infusion over about 30 10 minutes (e.g., about 20
minutes, about 21 minutes,
about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about
26 minutes, about 27
minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31
minutes, about 32 minutes,
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about 33 minutes, about 34 minutes, about 35 minutes, about 36 minutes, about
37 minutes, about 38
minutes, about 39 minutes, or about 40 minutes).
In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) is administered to the subject or
population of subjects before the PD-
1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab) or anti-PD-1
antagonist antibody (e.g., 1VIDX-1106 (nivolumab) or MK-3475 (pembrolizumab,
previously known as
lambrolizumab))). In some instances, for example, following administration of
the anti-TIGIT antagonist
antibody and before administration of the PD-1 axis binding antagonist (e.g.,
anti-PD-L1 antagonist
antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106
(nivolumab) or MK-3475
(pembrolizumab, previously known as lambrolizumab))), the method includes an
intervening first
observation period. In some instances, the method further includes a second
observation period
following administration of the PD-1 axis binding antagonist (e.g., anti-PD-L1
antagonist antibody (e.g.,
atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or
MK-3475
(pembrolizumab, previously known as lambrolizumab))). In some instances, the
method includes both a
first observation period following administration of the anti-TIGIT antagonist
antibody and second
observation period following administration of the PD-1 axis binding
antagonist (e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody
(e.g., MDX-1106 (nivolumab) or
MK-3475 (pembrolizumab, previously known as lambrolizumab))). In some
instances, the first and
second observation periods are each between about 30 minutes to about 60
minutes in length. In
instances in which the first and second observation periods are each about 60
minutes in length, the
method may include recording the subject or population of subjects' vital
signs (e.g., pulse rate,
respiratory rate, blood pressure, and temperature) at about 30 10 minutes
after administration of the
anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g., anti-PD-
L1 antagonist antibody
(e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106
(nivolumab) or MK-3475
(pembrolizumab, previously known as lambrolizumab))) during the first and
second observation periods,
respectively. In instances in which the first and second observation periods
are each about 30 minutes in
length, the method may include recording the subject or population of
subjects' vital signs (e.g., pulse
rate, respiratory rate, blood pressure, and temperature) at about 15 10
minutes after administration of
the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g.,
anti-PD-L1 antagonist antibody
(e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106
(nivolumab) or MK-3475
(pembrolizumab, previously known as lambrolizumab))) during the first and
second observation periods,
respectively.
In other instances, the PD-1 axis binding antagonist (e.g., anti-PD-L1
antagonist antibody (e.g.,
atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or
MK-3475
(pembrolizumab, previously known as lambrolizumab))) is administered to the
subject or population of
subjects before the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed
herein, e.g., tiragolumab). In some instances, for example, following
administration of a PD-1 axis
binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g.,
atezolizumab) or an anti-PD-1
antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab,
previously known as
lambrolizumab))) and before administration of the anti-TIGIT antagonist
antibody, the method includes an
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intervening first observation period. In some instances, the method includes a
second observation period
following administration of the anti-TIGIT antagonist antibody. In some
instances, the method includes
both a first observation period following administration of the PD-1 axis
binding antagonist (e.g., anti-PD-
L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody
(e.g., MDX-1106
.. (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab)))
and second observation
period following administration of the anti-TIGIT antagonist antibody. In some
instances, the first and
second observation periods are each between about 30 minutes to about 60
minutes in length. In
instances in which the first and second observation periods are each about 60
minutes in length, the
method may include recording the subject or population of subjects' vital
signs (e.g., pulse rate,
.. respiratory rate, blood pressure, and temperature) at about 30 10 minutes
after administration of the
PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab) or anti-PD-1
antagonist antibody (e.g., 1V1DX-1106 (nivolumab) or MK-3475 (pembrolizumab,
previously known as
lambrolizumab))) and anti-TIGIT antagonist antibody during the first and
second observation periods,
respectively. In instances in which the first and second observation periods
are each about 30 minutes in
.. length, the method may include recording the subject or population of
subjects' vital signs (e.g., pulse
rate, respiratory rate, blood pressure, and temperature) at about 15 10
minutes after administration of
the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab) or anti-PD-1
antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab,
previously known as
lambrolizumab))) and anti-TIGIT antagonist antibody during the first and
second observation periods,
respectively.
In other instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist
(e.g., anti-PD-L1 antagonist
antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106
(nivolumab) or MK-3475
(pembrolizumab, previously known as lambrolizumab))) are administered to the
subject or population of
subjects simultaneously. In some instances, for example, following
administration of the anti-TIGIT
antagonist antibody and the PD-1 axis binding antagonist (e.g., anti-PD-L1
antagonist antibody (e.g.,
atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or
MK-3475
(pembrolizumab, previously known as lambrolizumab))) the method includes an
observation period. In
some instances, the observation period is between about 30 minutes to about 60
minutes in length. In
.. instances in which the observation period is about 60 minutes in length,
the method may include
recording the subject or population of subjects' vital signs (e.g., pulse
rate, respiratory rate, blood
pressure, and temperature) at about 30 10 minutes after administration of
the PD-1 axis binding
antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-
PD-1 antagonist antibody
(e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as
lambrolizumab))) and
.. anti-TIGIT antagonist antibody during the observation period. In instances
in which the observation
period is about 30 minutes in length, the method may include recording the
subject or population of
subjects' vital signs (e.g., pulse rate, respiratory rate, blood pressure, and
temperature) at about 15 10
minutes after administration of the PD-1 axis binding antagonist (e.g., anti-
PD-L1 antagonist antibody
(e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106
(nivolumab) or MK-3475
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(pembrolizumab, previously known as lambrolizumab))) and anti-TIGIT antagonist
antibody during the
observation period.
In another aspect, the invention provides a method of treating a subject or
population of subjects
having a Stage IVB, metastatic, recurrent, or persistent cervical cancer by
administering to the subject or
population of subjects one or more dosing cycles of an anti-TIGIT antagonist
antibody at a dose (e.g., a
fixed dose) of 600 mg every three weeks and atezolizumab at a dose (e.g., a
fixed dose) of 1200 mg
every three weeks, wherein the anti-TIGIT antagonist antibody has a VH domain
having the amino acid
sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence
of SEQ ID NO: 19,
as described in further detail below. In some instances, the anti-TIGIT
antagonist antibody has a VH
domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having
the amino acid
sequence of SEQ ID NO: 19. In some instances, the anti-TIGIT antagonist
antibody has a VH domain
having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the
amino acid sequence of
SEQ ID NO: 19.
In another aspect, the invention provides a method of treating a subject or
population of subjects
having a Stage IVB, metastatic, recurrent, or persistent cervical cancer by
administering to the subject or
population of subjects one or more dosing cycles of tiragolumab at a dose
(e.g., a fixed dose) of 600 mg
every three weeks and atezolizumab at a dose (e.g., a fixed dose) of 1200 mg
every three weeks.
In another aspect, the invention provides a method of treating a subject or
population of subjects
having a Stage IVB, metastatic, recurrent, or persistent cervical cancer by
administering to the subject or
population of subjects one or more dosing cycles of tiragolumab at a dose
(e.g., a fixed dose) of 600 mg
every three weeks and pembrolizumab at a dose (e.g., a fixed dose) of 200 mg
every three weeks.
In another aspect, the invention provides a method of treating a subject or
population of subjects
having a Stage IVB, metastatic, recurrent, or persistent cervical cancer by
administering to the subject or
population of subjects one or more dosing cycles of tiragolumab at a dose
(e.g., a fixed dose) of 600 mg
every three weeks and nivolumab at a dose (e.g., a fixed dose) of 240 mg every
two weeks.
In another aspect, the invention provides a method of treating a subject or
population of subjects
having a Stage IVB, metastatic, recurrent, or persistent cervical cancer by
administering to the subject or
population of subjects one or more dosing cycles of tiragolumab at a dose
(e.g., a fixed dose) of 600 mg
every three weeks and nivolumab at a dose (e.g., a fixed dose) of 480 mg every
four weeks.
In another aspect, the invention provides an anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and an PD-1 axis
binding antagonist (e.g., an
anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist
antibody (e.g., MDX-1106
(nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab)))
for use in a method of
treating a subject or population of subjects having a cancer with a detectable
expression level of PD-L1
(e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or persistent
cervical cancer, e.g., a
metastatic and/or recurrent PD-L1-positive cervical carcinoma), wherein the
method comprises
administering to the subject or population of subjects one or more dosing
cycles of an effective amount of
an anti-TIGIT antagonist antibody and an effective amount of a PD-1 axis
binding antagonist (e.g., an
anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist
antibody (e.g., MDX-1106
(nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))).
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In some instances, the effective amount of the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a
fixed dose) of between about
30 mg to about 1200 mg (e.g., between about 30 mg to about 1100 mg, e.g.,
between about 60 mg to
about 1000 mg, e.g., between about 100 mg to about 900 mg, e.g., between about
200 mg to about 800
.. mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg
to about 800 mg, e.g.,
between about 400 mg to about 750 mg, e.g., between about 450 mg to about 750
mg, e.g., between
about 500 mg to about 700 mg, e.g., between about 550 mg to about 650 mg,
e.g., 600 mg 10 mg, e.g.,
600 6 mg, e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600 1 mg, e.g., 600
0.5 mg, e.g., 600 mg) every
three weeks. In some instances, the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-
TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose of
between about 30 mg to
about 600 mg (e.g., between about 50 mg to between 600 mg, e.g., between about
60 mg to about 600
mg, e.g., between about 100 mg to about 600 mg, e.g., between about 200 mg to
about 600 mg, e.g.,
between about 200 mg to about 550 mg, e.g., between about 250 mg to about 500
mg, e.g., between
about 300 mg to about 450 mg, e.g., between about 350 mg to about 400 mg,
e.g., about 375 mg) every
three weeks. In some instances, the effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-
TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose
(e.g., a fixed dose) of between
30 mg to 1200 mg (e.g., between 30 mg to 1100 mg, e.g., between 60 mg to 1000
mg, e.g., between 100
mg to 900 mg, e.g., between 200 mg to 800 mg, e.g., between 300 mg to 800 mg,
e.g., between 400 mg
to 800 mg, e.g., between 400 mg to 750 mg, e.g., between 450 mg to 750 mg,
e.g., between 500 mg to
.. 700 mg, e.g., between 550 mg to 650 mg, e.g., 600 mg 10 mg, e.g., 600 6
mg, e.g., 600 5 mg, e.g.,
600 3 mg, e.g., 600 1 mg, e.g., 600 0.5 mg, e.g., 600 mg) every three
weeks. In some instances,
the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-
TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab) is a dose of between 30 mg to 600 mg
(e.g., between 50 mg to
between 600 mg, e.g., between 60 mg to 600 mg, e.g., between 100 mg to 600 mg,
e.g., between 200
.. mg to 600 mg, e.g., between 200 mg to 550 mg, e.g., between 250 mg to 500
mg, e.g., between 300 mg
to 450 mg, e.g., between 350 mg to 400 mg, e.g., 375 mg) every three weeks. In
some instances, the
effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) is a dose of about 600 mg every three
weeks. In some instances,
effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) is a dose of 600 mg every three weeks. In
some instances, the dose
of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody
as disclosed herein, e.g.,
tiragolumab) is to be administered in a combination therapy (e.g., a
combination treatment with a PD-1
axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g.,
atezolizumab) or an anti-PD-1
antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab,
previously known as
lambrolizumab))) may be reduced as compared to a standard dose of the anti-
TIGIT antagonist antibody
is to be administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of
between about 80 mg to about
2000 mg (e.g., between about 80 mg to about 1950 mg, e.g., between about 80 mg
to about 1900 mg,
e.g., between about 80 mg to about 1800 mg, e.g., between about 100 mg to
about 1700 mg, e.g.,
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between about 200 mg to about 1600 mg, e.g., between about 300 mg to about
1400 mg, e.g., between
about 400 mg to about 1300 mg, e.g., between about 500 mg to about 1200 mg,
e.g., between about 600
mg to about 1100 mg, e.g., between about 700 mg to about 1000 mg, e.g.,
between about 740 mg to
about 940 mg, e.g., between about 790 mg to about 890 mg, e.g., between about
815 mg to about 865
mg, e.g., between about 830 mg to about 850 mg, e.g., 840 mg 5 mg, e.g., 840
2.5 mg, e.g., 840
1.0 mg, e.g., 840 0.5 mg, e.g., 840 mg) every two weeks. In some instances,
the effective amount of
the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab)) is a dose of
between about 80 mg to about 2000 mg (e.g., between about 100 mg to about 2000
mg, e.g., between
about 200 mg to about 1900 mg, e.g., between about 300 mg to about 1700 mg,
e.g., between about 400
mg to about 1600 mg, e.g., between about 500 mg to about 1600 mg, e.g.,
between about 600 mg to
about 1600 mg, e.g., between about 700 mg to about 1600 mg, e.g., between
about 800 mg to about
1600 mg, e.g., between about 900 mg to about 1500 mg, e.g., between about 1000
mg to about 1400 mg,
e.g., between about 1050 mg to about 1350 mg, e.g., between about 1100 mg to
about 1300 mg, e.g.,
between about 1150 mg to about 1250 mg, e.g., between about 1175 mg to about
1225 mg, e.g.,
between about 1190 mg to about 1210 mg, e.g., 1200 mg 5 mg, e.g., 1200 2.5
mg, e.g., 1200 1.0
mg, e.g., 1200 0.5 mg, e.g., 1200 mg) every three weeks. In some instances,
the effective amount of
the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab)) is a dose of
between about 80 mg to about 2000 mg (e.g., between about 100 mg to about 2000
mg, e.g., between
about 200 mg to about 2000 mg, e.g., between about 300 mg to about 2000 mg,
e.g., between about 400
mg to about 2000 mg, e.g., between about 500 mg to about 2000 mg, e.g.,
between about 600 mg to
about 1900 mg, e.g., between about 700 mg to about 1800 mg, e.g., between
about 800 mg to about
1800 mg, e.g., between about 900 mg to about 1800 mg, e.g., between about 1000
mg to about 1800 mg,
e.g., between about 1100 mg to about 1800 mg, e.g., between about 1200 mg to
about 1800 mg, e.g.,
between about 1300 mg to about 1800 mg, e.g., between about 1400 mg to about
1800 mg, e.g.,
between about 1500 mg to about 1800 mg, e.g., between about 1580 mg to about
1780 mg, e.g.,
between about 1630 mg to about 1730 mg, e.g., between about 1655 mg to about
1705 mg, e.g.,
between about 1670 mg to about 1690 mg, e.g., 1680 mg 5 mg, e.g., 1680 2.5
mg, e.g., 1680 1.0
mg, e.g., 1680 0.5 mg, e.g., 1680 mg) every four weeks. In some instances,
the effective amount of the
PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab)) is a dose (e.g., a
fixed dose) of between 80 mg to 2000 mg (e.g., between 80 mg to 1950 mg, e.g.,
between 80 mg to 1900
mg, e.g., between 80 mg to 1800 mg, e.g., between 100 mg to 1700 mg, e.g.,
between 200 mg to 1600
mg, e.g., between 300 mg to 1400 mg, e.g., between 400 mg to 1300 mg, e.g.,
between 500 mg to 1200
mg, e.g., between 600 mg to 1100 mg, e.g., between 700 mg to 1000 mg, e.g.,
between 740 mg to 940
mg, e.g., between 790 mg to 890 mg, e.g., between 815 mg to 865 mg, e.g.,
between 830 mg to 850 mg,
e.g., 840 mg 5 mg, e.g., 840 2.5 mg, e.g., 840 1.0 mg, e.g., 840 0.5
mg, e.g., 840 mg) every two
weeks. In some instances, the effective amount of the PD-1 axis binding
antagonist (e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab)) is a dose of between 80 mg to 2000
mg (e.g., between 100 mg
to 2000 mg, e.g., between 200 mg to 1900 mg, e.g., between 300 mg to 1700 mg,
e.g., between 400 mg
to 1600 mg, e.g., between 500 mg to 1600 mg, e.g., between 600 mg to 1600 mg,
e.g., between 700 mg
to 1600 mg, e.g., between 800 mg to 1600 mg, e.g., between 900 mg to 1500 mg,
e.g., between 1000 mg
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to 1400 mg, e.g., between 1050 mg to 1350 mg, e.g., between 1100 mg to 1300
mg, e.g., between 1150
mg to 1250 mg, e.g., between 1175 mg to 1225 mg, e.g., between 1190 mg to 1210
mg, e.g., 1200 mg
mg, e.g., 1200 2.5 mg, e.g., 1200 1.0 mg, e.g., 1200 0.5 mg, e.g., 1200
mg) every three weeks.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-L1 antagonist
5 antibody (e.g., atezolizumab)) is a dose of between 80 mg to 2000 mg
(e.g., between 100 mg to 2000 mg,
e.g., between 200 mg to 2000 mg, e.g., between 300 mg to 2000 mg, e.g.,
between 400 mg to 2000 mg,
e.g., between 500 mg to 2000 mg, e.g., between 600 mg to 1900 mg, e.g.,
between 700 mg to 1800 mg,
e.g., between 800 mg to 1800 mg, e.g., between 900 mg to 1800 mg, e.g.,
between 1000 mg to 1800 mg,
e.g., between 1100 mg to 1800 mg, e.g., between 1200 mg to 1800 mg, e.g.,
between 1300 mg to 1800
mg, e.g., between 1400 mg to 1800 mg, e.g., between 1500 mg to 1800 mg, e.g.,
between 1580 mg to
1780 mg, e.g., between 1630 mg to 1730 mg, e.g., between 1655 mg to 1705 mg,
e.g., between 1670 mg
to 1690 mg, e.g., 1680 mg 5 mg, e.g., 1680 2.5 mg, e.g., 1680 1.0 mg,
e.g., 1680 0.5 mg, e.g.,
1680 mg) every four weeks. In some instances, the effective amount of the PD-1
axis binding antagonist
(e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of about
840 mg every two weeks.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-L1 antagonist
antibody (e.g., atezolizumab)) is a dose of 840 mg every two weeks. In some
instances, the effective
amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist
antibody (e.g., atezolizumab)) is
a dose of about 1200 mg every three weeks. In some instances, the effective
amount of the PD-1 axis
binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab))
is a dose of 1200 mg every
three weeks. In some instances, the effective amount of the PD-1 axis binding
antagonist (e.g., anti-PD-
L1 antagonist antibody (e.g., atezolizumab)) is a dose of about 1680 mg every
four weeks. In some
instances, the effective amount of the PD-1 axis binding antagonist (e.g.,
anti-PD-L1 antagonist antibody
(e.g., atezolizumab)) is a dose of 1680 mg every four weeks. In some
instances, the dose of the PD-1
axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab)) to be administered in a
combination therapy (e.g., a combination treatment with an anti-TIGIT
antagonist antibody, such as an
anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be
reduced as compared to a
standard dose of the anti-PD-L1 antagonist antibody to be administered as a
monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-1
antagonist antibody (e.g., pembrolizumab)) is a dose (e.g., a fixed dose) of
between about 20 mg to about
1000 mg (e.g., between about 40 mg to about 900 mg, e.g., between about 60 mg
to about 800 mg, e.g.,
between about 80 mg to about 700 mg, e.g., between about 80 mg to about 600
mg, e.g., between about
100 mg to about 500 mg, e.g., between about 120 mg to about 400 mg, e.g.,
between about 140 mg to
about 300 mg, e.g., between about 160 mg to about 350 mg, e.g., between about
180 mg to about 300
mg, e.g., between about 180 mg to about 250 mg, e.g., between about 180 mg to
about 220 mg, e.g.,
between about 190 mg to about 210 mg, e.g., 200 mg 5 mg, e.g., 200 2.5 mg,
e.g., 200 1.0 mg,
e.g., 200 0.5 mg, e.g., 200 mg) every three weeks. In some instances, the
effective amount of the PD-1
axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g.,
pembrolizumab)) is a dose (e.g., a fixed
dose) of between 20 mg to 1000 mg (e.g., between 40 mg to 900 mg, e.g.,
between 60 mg to 800 mg,
e.g., between 80 mg to 700 mg, e.g., between 80 mg to 600 mg, e.g., between
100 mg to 500 mg, e.g.,
between 120 mg to 400 mg, e.g., between 140 mg to 300 mg, e.g., between 160 mg
to 350 mg, e.g.,
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between 180 mg to 300 mg, e.g., between 180 mg to 250 mg, e.g., between 180 mg
to 220 mg, e.g.,
between 190 mg to 210 mg, e.g., 200 mg 5 mg, e.g., 200 2.5 mg, e.g., 200
1.0 mg, e.g., 200 0.5
mg, e.g., 200 mg) every three weeks. In some instances, the effective amount
of the PD-1 axis binding
antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is a
dose of about 200 mg every
three weeks. In some instances, the effective amount of the PD-1 axis binding
antagonist (e.g., anti-PD-1
antagonist antibody (e.g., pembrolizumab)) is a dose of 200 mg every three
weeks. In some instances,
the dose of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist
antibody (e.g., pembrolizumab))
administered in a combination therapy (e.g., a combination treatment with an
anti-TIGIT antagonist
antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g.,
tiragolumab) may be reduced
as compared to a standard dose of the anti-PD-L1 antagonist antibody
administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-1
antagonist antibody (e.g., nivolumab)) is a dose (e.g., a fixed dose) of
between about 20 mg to about
1000 mg (e.g., between about 40 mg to about 900 mg, e.g., between about 60 mg
to about 800 mg, e.g.,
between about 80 mg to about 700 mg, e.g., between about 80 mg to about 600
mg, e.g., between about
100 mg to about 500 mg, e.g., between about 120 mg to about 400 mg, e.g.,
between about 140 mg to
about 300 mg, e.g., between about 160 mg to about 350 mg, e.g., between about
180 mg to about 300
mg, e.g., between about 200 mg to about 280 mg, e.g., between about 220 mg to
about 260 mg, e.g.,
between about 230 mg to about 250 mg, e.g., 240 mg 5 mg, e.g., 240 2.5 mg,
e.g., 240 1.0 mg,
e.g., 240 0.5 mg, e.g., 240 mg) every two weeks. In some instances, the
effective amount of the PD-1
.. axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g.,
nivolumab)) is a dose of about 240 mg
every two weeks. In some instances, the effective amount of the PD-1 axis
binding antagonist (e.g., anti-
PD-1 antagonist antibody (e.g., nivolumab)) is a dose of 240 mg every two
weeks. In some instances,
the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1
antagonist antibody (e.g.,
nivolumab)) is a dose of between about 100 mg to about 1000 mg (e.g., between
about 200 mg to about
900 mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg
to about 700 mg, e.g.,
between about 400 mg to about 600 mg, e.g., between about 400 mg to about 550
mg, e.g., between
about 420 mg to about 540 mg, e.g., between about 440 mg to about 520 mg,
e.g., between about 460
mg to about 500 mg, e.g., between about 470 mg to about 490 mg, e.g., 480 mg
5 mg, e.g., 480 2.5
mg, e.g., 480 1.0 mg, e.g., 480 0.5 mg, e.g., 480 mg) every four weeks. In
some instances, the
effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-1
antagonist antibody (e.g.,
nivolumab)) is a dose (e.g., a fixed dose) of between 20 mg to 1000 mg (e.g.,
between 40 mg to 900 mg,
e.g., between 60 mg to 800 mg, e.g., between 80 mg to 700 mg, e.g., between 80
mg to 600 mg, e.g.,
between 100 mg to 500 mg, e.g., between 120 mg to 400 mg, e.g., between 140 mg
to 300 mg, e.g.,
between 160 mg to 350 mg, e.g., between 180 mg to 300 mg, e.g., between 200 mg
to 280 mg, e.g.,
between 220 mg to 260 mg, e.g., between 230 mg to 250 mg, e.g., 240 mg 5 mg,
e.g., 240 2.5 mg,
e.g., 240 1.0 mg, e.g., 240 0.5 mg, e.g., 240 mg) every two weeks. In some
instances, the effective
amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist
antibody (e.g., nivolumab)) is a
dose of 240 mg every two weeks. In some instances, the effective amount of the
PD-1 axis binding
antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose
of 240 mg every two weeks.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-1 antagonist
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antibody (e.g., nivolumab)) is a dose of between 100 mg to 1000 mg (e.g.,
between 200 mg to 900 mg,
e.g., between 300 mg to 800 mg, e.g., between 400 mg to 700 mg, e.g., between
400 mg to 600 mg, e.g.,
between 400 mg to 550 mg, e.g., between 420 mg to 540 mg, e.g., between 440 mg
to 520 mg, e.g.,
between 460 mg to 500 mg, e.g., between 470 mg to 490 mg, e.g., 480 mg 5 mg,
e.g., 480 2.5 mg,
e.g., 480 1.0 mg, e.g., 480 0.5 mg, e.g., 480 mg) every four weeks. In
some instances, the effective
amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist
antibody (e.g., nivolumab)) is a
dose of about 480 mg every four weeks. In some instances, the effective amount
of the PD-1 axis
binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is
a dose of 480 mg every four
weeks. In some instances, the dose of the PD-1 axis binding antagonist (e.g.,
anti-PD-1 antagonist
antibody (e.g., nivolumab)) administered in a combination therapy (e.g., a
combination treatment with an
anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody
disclosed herein, e.g.,
tiragolumab) may be reduced as compared to a standard dose of the anti-PD-L1
antagonist antibody
administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01
mg/kg to about 50 mg/kg of the
subject's body weight (e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g.,
between about 0.1 mg/kg
to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g.,
between about 2.5 mg/kg to
about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between
about 10 mg/kg to about
mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., about 15 2
mg/kg, about 15 1
20 mg/kg, about 15 0.5 mg/kg, about 15 0.2 mg/kg, or about 15 0.1
mg/kg, e.g., about 15 mg/kg) every
three weeks. In some instances, the effective amount of the PD-1 axis binding
antagonist (e.g., anti-PD-
L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01
mg/kg to about 15 mg/kg of
the subject's body weight (e.g., between about 0.1 mg/kg to about 15 mg/kg,
e.g., between about 0.5
mg/kg to about 15 mg/kg, e.g., between about 1 mg/kg to about 15 mg/kg, e.g.,
between about 2.5 mg/kg
to about 15 mg/kg, e.g., between about 5 mg/kg to about 15 mg/kg, e.g.,
between about 7.5 mg/kg to
about 15 mg/kg, e.g., between about 10 mg/kg to about 15 mg/kg, e.g., between
about 12.5 mg/kg to
about 15 mg/kg, e.g., between about 14 mg/kg to about 15 mg/kg, e.g., about 15
1 mg/kg, e.g., about
15 0.5 mg/kg, e.g., about 15 0.2 mg/kg, e.g., about 15 0.1 mg/kg, e.g.,
about 15 mg/kg) every three
weeks. In some instances, effective amount of anti-PD-L1 antagonist antibody
(e.g., atezolizumab) is a
dose of about 15 mg/kg to be administered every three weeks. In some
instances, the effective amount
of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody
(e.g., atezolizumab)) is a dose
of between 0.01 mg/kg to 50 mg/kg of the subject's body weight (e.g., between
0.01 mg/kg to 45 mg/kg,
e.g., between 0.1 mg/kg to 40 mg/kg, e.g., between 1 mg/kg to 35 mg/kg, e.g.,
between 2.5 mg/kg to 30
mg/kg, e.g., between 5 mg/kg to 25 mg/kg, e.g., between 10 mg/kg to 20 mg/kg,
e.g., between 12.5
mg/kg to 15 mg/kg, e.g., 15 2 mg/kg, 15 1 mg/kg, 15 0.5 mg/kg, 15 0.2
mg/kg, or 15 0.1 mg/kg,
e.g., 15 mg/kg) every three weeks. In some instances, the effective amount of
the PD-1 axis binding
antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a
dose of between 0.01 mg/kg to
15 mg/kg of the subject's body weight (e.g., between 0.1 mg/kg to 15 mg/kg,
e.g., between 0.5 mg/kg to
15 mg/kg, e.g., between 1 mg/kg to 15 mg/kg, e.g., between 2.5 mg/kg to 15
mg/kg, e.g., between 5
mg/kg to 15 mg/kg, e.g., between 7.5 mg/kg to 15 mg/kg, e.g., between 10 mg/kg
to 15 mg/kg, e.g.,
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between 12.5 mg/kg to 15 mg/kg, e.g., between 14 mg/kg to 15 mg/kg, e.g., 15
1 mg/kg, e.g., 15 0.5
mg/kg, e.g., 15 0.2 mg/kg, e.g., 15 0.1 mg/kg, e.g., 15 mg/kg) every three
weeks. In some instances,
effective amount of anti-PD-L1 antagonist antibody (e.g., atezolizumab) is a
dose of 15 mg/kg to be
administered every three weeks. In some instances, the dose of the PD-1 axis
binding antagonist (e.g.,
an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1
antagonist antibody (e.g., MDX-
1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as
lambrolizumab))) is administered in
a combination therapy (e.g., a combination treatment with an anti-TIGIT
antagonist antibody, such as an
anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be
reduced as compared to a
standard dose of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist
antibody (e.g.,
.. atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab)
or MK-3475
(pembrolizumab, previously known as lambrolizumab))) administered as a
monotherapy.
The anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as
disclosed herein,
e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1
antagonist antibody (e.g.,
atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab)
or MK-3475
(pembrolizumab, previously known as lambrolizumab))) may be administered in
one or more dosing
cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,
19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,
47, 48, 49, or 50 or more dosing
cycles). In some instances, the dosing cycles of the anti-TIGIT antagonist
antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis
binding antagonist (e.g., an
anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist
antibody (e.g., MDX-1106
(nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab)))
continue until there is a
loss of clinical benefit (e.g., confirmed disease progression, drug
resistance, death, or unacceptable
toxicity). In some instances, the length of each dosing cycle is about 14 to
28 days (e.g., 14 days,15
days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days,
24 days, 25 days, 26
days, 27 days, or 28 days). In some instances, the length of each dosing cycle
is about 21 days. In
some instances, the length of each dosing cycle is about 14 days. In some
instances, the length of each
dosing cycle is about 28 days. In some instances, the anti-TIGIT antagonist
antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is to be
administered on about Day 1 (e.g.,
Day 1 3 days) of each dosing cycle. For example, the anti-TIGIT antagonist
antibody (e.g., an anti-
TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is to be
administered intravenously at a
dose (e.g., a fixed dose) of about 600 mg on Day 1 of each 21-day cycle (i.e.,
at a dose of about 600 mg
every three weeks). Similarly, in some instances, the PD-1 axis binding
antagonist (e.g., an anti-PD-L1
antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody
(e.g., MDX-1106
(nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) is
to be administered on
about Day 1 (e.g., Day 1 3 days) of each dosing cycle. For example, the PD-1
axis binding antagonist
(e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is to be
administered intravenously at a dose
(e.g., a fixed dose) of about 1200 mg on Day 1 of each 21-day cycle (i.e., at
a dose of about 1200 mg
every three weeks). For example, the PD-1 axis binding antagonist (e.g., anti-
PD-1 antagonist antibody
(e.g., pembrolizumab)) is to be administered intravenously at a dose of about
200 mg on Day 1 of each
21-day cycle (i.e., at a dose of about 200 mg every three weeks). For example,
the PD-1 axis binding
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antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is to be
administered intravenously at a
dose of about 240 mg on Day 1 of each 14-day cycle (i.e., at a dose of about
240 mg every two weeks).
For example, the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist
antibody (e.g., nivolumab)) is to
be administered intravenously at a dose of about 480 mg on Day 1 of each 28-
day cycle (i.e., at a dose of
about 480 mg every four weeks). In some instances, both the anti-TIGIT
antagonist antibody (e.g., an
anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the
PD-1 axis binding
antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an
anti-PD-1 antagonist
antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously
known as
lambrolizumab))) are to be administered on about Day 1 (e.g., Day 1 3 days)
of each dosing cycle. In
some instances, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist
(e.g., an anti-PD-L1 antagonist
antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-
1106 (nivolumab) or MK-
3475 (pembrolizumab, previously known as lambrolizumab))) are to be
administered on about Day 1
(e.g., Day 1 3 days) of the first dosing cycle. For example, the anti-TIGIT
antagonist antibody (e.g., an
anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is to
be administered intravenously
at a dose of about 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of
about 600 mg every three
weeks), and thePD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist
antibody (e.g., nivolumab)) is
administered intravenously at a dose of about 240 mg on Day 1 of each 14-day
cycle (i.e., at a dose of
about 240 mg every two weeks). For example, the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is to be
administered intravenously at a dose
of about 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of about 600 mg
every three weeks), and
the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
nivolumab)) is administered
intravenously at a dose of about 480 mg on Day 1 of each 28-day cycle (i.e.,
at a dose of about 480 mg
every four weeks). In some examples, the PD-1 axis binding antagonist (e.g.,
anti-PD-L1 antagonist
antibody (e.g., atezolizumab)) is to be administered intravenously at a dose
(e.g., a fixed dose) of 1200
mg on Day 1 of each 21-day cycle (i.e., at a dose of 1200 mg every three
weeks). For example, the PD-1
axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g.,
pembrolizumab)) is to be administered
intravenously at a dose of 200 mg on Day 1 of each 21-day cycle (i.e., at a
dose of 200 mg every three
weeks). For example, the PD-1 axis binding antagonist (e.g., anti-PD-1
antagonist antibody (e.g.,
nivolumab)) is to be administered intravenously at a dose of 240 mg on Day 1
of each 14-day cycle (i.e.,
at a dose of 240 mg every two weeks). For example, the PD-1 axis binding
antagonist (e.g., anti-PD-1
antagonist antibody (e.g., nivolumab)) is to be administered intravenously at
a dose of 480 mg on Day 1
of each 28-day cycle (i.e., at a dose of 480 mg every four weeks). In some
instances, both the anti-TIGIT
antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed
herein, e.g., tiragolumab) and
the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody
(e.g., atezolizumab) or an anti-
PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475
(pembrolizumab, previously known
as lambrolizumab))) are to be administered on Day 1 (e.g., Day 1 3 days) of
each dosing cycle. In
some instances, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist
(e.g., an anti-PD-L1 antagonist
antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-
1106 (nivolumab) or MK-
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3475 (pembrolizumab, previously known as lambrolizumab))) are to be
administered on Day 1 (e.g., Day
1 3 days) of the first dosing cycle. For example, the anti-TIGIT antagonist
antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is to be
administered intravenously at a dose
of 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of 600 mg every three
weeks), and thePD-1 axis
binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., nivolumab)) is
administered intravenously
at a dose of 240 mg on Day 1 of each 14-day cycle (i.e., at a dose of 240 mg
every two weeks). For
example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist
antibody as disclosed herein,
e.g., tiragolumab) is to be administered intravenously at a dose of 600 mg on
Day 1 of each 21-day cycle
(i.e., at a dose of 600 mg every three weeks), and the PD-1 axis binding
antagonist (e.g., anti-PD-L1
antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose
of 480 mg on Day 1 of
each 28-day cycle (i.e., at a dose of 480 mg every four weeks).
In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) is to be administered to the subject or
population of subjects by
intravenous infusion over about 60 15 minutes (e.g., about 50 minutes, about
51 minutes, about 52
minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56
minutes, about 57 minutes,
about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about
62 minutes, about 63
minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67
minutes, about 68 minutes,
about 69 minutes, or about 70 minutes). In some instances, the PD-1 axis
binding antagonist (e.g., an
anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist
antibody (e.g., MDX-1106
(nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) is
to be administered to
the subject or population of subjects by intravenous infusion over about 60
15 minutes (e.g., about 45
minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49
minutes, about 50 minutes,
about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about
55 minutes, about 56
minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60
minutes, about 61 minutes,
about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about
66 minutes, about 67
minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71
minutes, about 72 minutes,
about 73 minutes, about 74 minutes, or about 75 minutes).
In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) is to be administered to the subject or
population of subjects by
intravenous infusion over about 30 10 minutes (e.g., about 20 minutes, about
21 minutes, about 22
minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26
minutes, about 27 minutes,
about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about
32 minutes, about 33
minutes, about 34 minutes, about 35 minutes, about 36 minutes, about 37
minutes, about 38 minutes,
about 39 minutes, or about 40 minutes). In some instances, the PD-1 axis
binding antagonist (e.g., an
anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist
antibody (e.g., MDX-1106
(nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) is
to be administered to
the subject or population of subjects by intravenous infusion over about 30
10 minutes (e.g., about 20
minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24
minutes, about 25 minutes,
about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about
30 minutes, about 31
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minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35
minutes, about 36 minutes,
about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes).
In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) is to be administered to the subject or
population of subjects before
the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody
(e.g., atezolizumab) or an anti-
PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475
(pembrolizumab, previously known
as lambrolizumab))). In some instances, for example, following administration
of the anti-TIGIT
antagonist antibody and before administration of the PD-1 axis binding
antagonist (e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody
(e.g., MDX-1106 (nivolumab) or
MK-3475 (pembrolizumab, previously known as lambrolizumab))), the method
includes an intervening
first observation period. In some instances, the method further includes a
second observation period
following administration of the PD-1 axis binding antagonist (e.g., anti-PD-L1
antagonist antibody (e.g.,
atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or
MK-3475
(pembrolizumab, previously known as lambrolizumab))). In some instances, the
method includes both a
first observation period following administration of the anti-TIGIT antagonist
antibody and second
observation period following administration of the PD-1 axis binding
antagonist (e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody
(e.g., MDX-1106 (nivolumab) or
MK-3475 (pembrolizumab, previously known as lambrolizumab))). In some
instances, the first and
second observation periods are each between about 30 minutes to about 60
minutes in length. In
instances in which the first and second observation periods are each about 60
minutes in length, the
method may include recording the subject or population of subjects' vital
signs (e.g., pulse rate,
respiratory rate, blood pressure, and temperature) at about 30 10 minutes
after administration of the
anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g., anti-PD-
L1 antagonist antibody
(e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106
(nivolumab) or MK-3475
(pembrolizumab, previously known as lambrolizumab))) during the first and
second observation periods,
respectively. In instances in which the first and second observation periods
are each about 30 minutes in
length, the method may include recording the subject or population of
subjects' vital signs (e.g., pulse
rate, respiratory rate, blood pressure, and temperature) at about 15 10
minutes after administration of
the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist (e.g.,
anti-PD-L1 antagonist antibody
(e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106
(nivolumab) or MK-3475
(pembrolizumab, previously known as lambrolizumab))) during the first and
second observation periods,
respectively.
In other instances, the PD-1 axis binding antagonist (e.g., an anti-PD-L1
antagonist antibody
(e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106
(nivolumab) or MK-3475
(pembrolizumab, previously known as lambrolizumab))) is to be administered to
the subject or population
of subjects before the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as disclosed
herein, e.g., tiragolumab). In some instances, for example, following
administration of the PD-1 axis
binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)
or anti-PD-1 antagonist
antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously
known as
lambrolizumab))) and before administration of the anti-TIGIT antagonist
antibody, the method includes an
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intervening first observation period. In some instances, the method includes a
second observation period
following administration of the anti-TIGIT antagonist antibody. In some
instances, the method includes
both a first observation period following administration of the PD-1 axis
binding antagonist (e.g., anti-PD-
L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody
(e.g., MDX-1106
(nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab)))
and second observation
period following administration of the anti-TIGIT antagonist antibody. In some
instances, the first and
second observation periods are each between about 30 minutes to about 60
minutes in length. In
instances in which the first and second observation periods are each about 60
minutes in length, the
method may include recording the subject or population of subjects' vital
signs (e.g., pulse rate,
respiratory rate, blood pressure, and temperature) at about 30 10 minutes
after administration of the
PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab) or anti-PD-1
antagonist antibody (e.g., 1V1DX-1106 (nivolumab) or MK-3475 (pembrolizumab,
previously known as
lambrolizumab))) and anti-TIGIT antagonist antibody during the first and
second observation periods,
respectively. In instances in which the first and second observation periods
are each about 30 minutes in
length, the method may include recording the subject or population of
subjects' vital signs (e.g., pulse
rate, respiratory rate, blood pressure, and temperature) at about 15 10
minutes after administration of
the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab) or anti-PD-1
antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab,
previously known as
lambrolizumab))) and anti-TIGIT antagonist antibody during the first and
second observation periods,
respectively.
In other instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT
antagonist antibody as
disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist
(e.g., anti-PD-L1 antagonist
antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106
(nivolumab) or MK-3475
(pembrolizumab, previously known as lambrolizumab))) is to be administered to
the subject or population
of subjects simultaneously. In some instances, for example, following
administration of the anti-TIGIT
antagonist antibody and the PD-1 axis binding antagonist (e.g., anti-PD-L1
antagonist antibody (e.g.,
atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or
MK-3475
(pembrolizumab, previously known as lambrolizumab))) the method includes an
observation period. In
some instances, the observation period is between about 30 minutes to about 60
minutes in length. In
instances in which the observation period is about 60 minutes in length, the
method may include
recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood
pressure, and temperature) at
about 30 10 minutes after administration of the PD-1 axis binding antagonist
(e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody
(e.g., MDX-1106 (nivolumab) or
MK-3475 (pembrolizumab, previously known as lambrolizumab))) and anti-TIGIT
antagonist antibody
during the observation period. In instances in which the observation period is
about 30 minutes in length,
the method may include recording the subject's vital signs (e.g., pulse rate,
respiratory rate, blood
pressure, and temperature) at about 15 10 minutes after administration of
the PD-1 axis binding
antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-
PD-1 antagonist antibody
(e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as
lambrolizumab))) and
anti-TIGIT antagonist antibody during the observation period.
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In another aspect, the invention provides an anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis binding
antagonist (e.g., anti-PD-
L1 antagonist antibody (e.g., atezolizumab)) for use in a method of treating a
subject or population of
subjects having a cancer with a detectable expression level of PD-L1 (e.g.,
cervical cancer, e.g., Stage
IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic
and/or recurrent PD-L1-positive
cervical carcinoma), wherein the method comprises administering to the subject
or population of subjects
one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose
(e.g., a fixed dose) of 600 mg
every three weeks and atezolizumab at a dose (e.g., a fixed dose) of 1200 mg
every three weeks,
wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising
the amino acid sequence
of SEQ ID NO: 17 or 18; and a VL domain comprising the amino acid sequence of
SEQ ID NO: 19, as
described in further detail below. In some instances, the anti-TIGIT
antagonist antibody has a VH domain
having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the
amino acid sequence of
SEQ ID NO: 19. In some instances, the anti-TIGIT antagonist antibody has a VH
domain having the
amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid
sequence of SEQ ID
NO: 19.
In another aspect, the invention provides an anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis binding
antagonist (e.g., anti-PD-1
antagonist antibody (e.g., pembrolizumab)) for use in a method of treating a
subject or population of
subjects having a cancer with a detectable expression level of PD-L1 (e.g.,
cervical cancer, e.g., Stage
IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic
and/or recurrent PD-L1-positive
cervical carcinoma), wherein the method comprises administering to the subject
or population of subjects
one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose
(e.g., a fixed dose) of 600 mg
every three weeks and pembrolizumab at a dose (e.g., a fixed dose) of 200 mg
every three weeks,
wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising
the amino acid sequence
of SEQ ID NO: 17 or 18; and a VL domain comprising the amino acid sequence of
SEQ ID NO: 19, as
described in further detail below. In some instances, the anti-TIGIT
antagonist antibody has a VH domain
having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the
amino acid sequence of
SEQ ID NO: 19. In some instances, the anti-TIGIT antagonist antibody has a VH
domain having the
amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid
sequence of SEQ ID
NO: 19.
In another aspect, the invention provides an anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis binding
antagonist (e.g., anti-PD-1
antagonist antibody (e.g., nivolumab)) for use in a method of treating a
subject or population of subjects
having a cancer with a detectable expression level of PD-L1 (e.g., cervical
cancer, e.g., Stage IVB,
metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic
and/or recurrent PD-L1-positive
cervical carcinoma), wherein the method comprises administering to the subject
or population of subjects
one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose
(e.g., a fixed dose) of 600 mg
every three weeks and nivolumab at a dose (e.g., a fixed dose) of 240 mg every
two weeks, wherein the
anti-TIGIT antagonist antibody comprises: a VH domain comprising the amino
acid sequence of SEQ ID
NO: 17 or 18; and a VL domain comprising the amino acid sequence of SEQ ID NO:
19, as described in
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further detail below. In some instances, the anti-TIGIT antagonist antibody
has a VH domain having the
amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid
sequence of SEQ ID
NO: 19. In some instances, the anti-TIGIT antagonist antibody has a VH domain
having the amino acid
sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of
SEQ ID NO: 19.
In another aspect, the invention provides an anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis binding
antagonist (e.g., anti-PD-1
antagonist antibody (e.g., nivolumab)) for use in a method of treating a
subject or population of subjects
having a cancer with a detectable expression level of PD-L1 (e.g., cervical
cancer, e.g., Stage IVB,
metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic
and/or recurrent PD-L1-positive
cervical carcinoma), wherein the method comprises administering to the subject
or population of subjects
one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose
(e.g., a fixed dose) of 600 mg
every three weeks and nivolumab at a dose (e.g., a fixed dose) of 480 mg every
four weeks, wherein the
anti-TIGIT antagonist antibody comprises: a VH domain comprising the amino
acid sequence of SEQ ID
NO: 17 or 18; and a VL domain comprising the amino acid sequence of SEQ ID NO:
19, as described in
.. further detail below. In some instances, the anti-TIGIT antagonist antibody
has a VH domain having the
amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid
sequence of SEQ ID
NO: 19. In some instances, the anti-TIGIT antagonist antibody has a VH domain
having the amino acid
sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of
SEQ ID NO: 19.
In another aspect, the invention provides an anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis binding
antagonist (e.g., anti-PD-
L1 antagonist antibody (e.g., atezolizumab)) for use in a method of treating a
subject or population of
subjects having a cancer with a detectable expression level of PD-L1 (e.g.,
cervical cancer, e.g., Stage
IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic
and/or recurrent PD-L1-positive
cervical carcinoma), wherein the method comprises administering to the subject
or population of subjects
one or more dosing cycles of tiragolumab at a dose (e.g., a fixed dose) of 600
mg every three weeks and
atezolizumab at a dose (e.g., a fixed dose) of 1200 mg every three weeks.
In another aspect, the invention provides an anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis binding
antagonist (e.g., anti-PD-1
antagonist antibody (e.g., MK-3475 (pembrolizumab, previously known as
lambrolizumab)) for use in a
.. method of treating a subject or population of subjects having a cancer with
a detectable expression level
of PD-L1 (e.g., cervical cancer, e.g., Stage IVB, metastatic, recurrent, or
persistent cervical cancer, e.g., a
metastatic and/or recurrent PD-L1-positive cervical carcinoma), wherein the
method comprises
administering to the subject or population of subjects one or more dosing
cycles of tiragolumab at a dose
(e.g., a fixed dose) of 600 mg every three weeks and pembrolizumab at a dose
(e.g., a fixed dose) of 200
mg every three weeks.
In another aspect, the invention provides an anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis binding
antagonist (e.g., anti-PD-1
antagonist antibody (e.g., IVIDX-1106 (nivolumab)) for use in a method of
treating a subject or population
of subjects having a cancer with a detectable expression level of PD-L1 (e.g.,
cervical cancer, e.g., Stage
.. IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a
metastatic and/or recurrent PD-L1-positive
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cervical carcinoma), wherein the method comprises administering to the subject
or population of subjects
one or more dosing cycles of tiragolumab at a dose (e.g., a fixed dose) of 600
mg every three weeks and
nivolumab at a dose (e.g., a fixed dose) of 240 mg every two weeks.
In another aspect, the invention provides an anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis binding
antagonist (e.g., anti-PD-1
antagonist antibody (e.g., 1VIDX-1106 (nivolumab)) for use in a method of
treating a subject or population
of subjects having a cancer with a detectable expression level of PD-L1 (e.g.,
cervical cancer, e.g., Stage
IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic
and/or recurrent PD-L1-positive
cervical carcinoma), wherein the method comprises administering to the subject
or population of subjects
one or more dosing cycles of tiragolumab at a dose (e.g., a fixed dose) of 600
mg every three weeks and
nivolumab at a dose (e.g., a fixed dose) of 480 mg every four weeks.
In another aspect, the invention provides uses of an anti-TIGIT antagonist
antibody (e.g., an anti-
TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and PD-1 axis
binding antagonist (e.g.,
anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist
antibody (e.g., MDX-1106
(nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) in
the manufacture or
preparation of a medicament for use in a method of treating a subject or
population of subjects having a
cancer with a detectable expression level of PD-L1 (e.g., cervical cancer,
e.g., Stage IVB, metastatic,
recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent
PD-L1-positive cervical
carcinoma), wherein the method comprises administering to the subject or
population of subjects one or
more dosing cycles of the medicament, and wherein the medicament is formulated
for administration of
an effective amount of the anti-TIGIT antagonist antibody and an effective
amount of the PD-1 axis
binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)
or anti-PD-1 antagonist
antibody (e.g., 1VIDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously
known as
lambrolizumab))).
In another aspect, the invention provides uses of an anti-TIGIT antagonist
antibody in the
manufacture of a medicament for use in a method of treating a subject or
population of subjects having a
cancer with a detectable expression level of PD-L1 (e.g., cervical cancer,
e.g., Stage IVB, metastatic,
recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent
PD-L1-positive cervical
carcinoma), wherein the method comprises administering to the subject or
population of subjects one or
more dosing cycles of the medicament and a PD-1 axis binding antagonist (e.g.,
an anti-PD-L1 antagonist
antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-
1106 (nivolumab) or MK-
3475 (pembrolizumab, previously known as lambrolizumab))), and wherein the
medicament is formulated
for administration of an effective amount of the anti-TIGIT antagonist
antibody and an effective amount of
the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab) or anti-PD-1
antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab,
previously known as
lambrolizumab))).
In another aspect, the invention provides uses of a PD-1 axis binding
antagonist (e.g., an anti-
PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist
antibody (e.g., MDX-1106
(nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) in
the manufacture of a
medicament for use in a method of treating a subject or population of subjects
having a cancer with a
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detectable expression level of PD-L1 (e.g., cervical cancer, e.g., Stage IVB,
metastatic, recurrent, or
persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1-positive
cervical carcinoma), wherein
the method comprises administering to the subject or population of subjects
one or more dosing cycles of
the medicament and an anti-TIGIT antagonist antibody, and wherein the
medicament is formulated for
administration an effective amount of the PD-1 axis binding antagonist (e.g.,
anti-PD-L1 antagonist
antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106
(nivolumab) or MK-3475
(pembrolizumab, previously known as lambrolizumab))) and an effective amount
of the anti-TIGIT
antagonist antibody is to be administered.
In some instances, the effective amount of the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose (e.g., a
fixed dose) of between about
30 mg to about 1200 mg (e.g., between about 30 mg to about 1100 mg, e.g.,
between about 60 mg to
about 1000 mg, e.g., between about 100 mg to about 900 mg, e.g., between about
200 mg to about 800
mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to
about 800 mg, e.g.,
between about 400 mg to about 750 mg, e.g., between about 450 mg to about 750
mg, e.g., between
about 500 mg to about 700 mg, e.g., between about 550 mg to about 650 mg,
e.g., 600 mg 10 mg, e.g.,
600 6 mg, e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600 1 mg, e.g., 600
0.5 mg, e.g., 600 mg) every
three weeks. In some instances, an effective amount of the anti-TIGIT
antagonist antibody (e.g., an anti-
TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose of
between about 30 mg to
about 600 mg (e.g., between about 50 mg to between 600 mg, e.g., between about
60 mg to about 600
mg, e.g., between about 100 mg to about 600 mg, e.g., between about 200 mg to
about 600 mg, e.g.,
between about 200 mg to about 550 mg, e.g., between about 250 mg to about 500
mg, e.g., between
about 300 mg to about 450 mg, e.g., between about 350 mg to about 400 mg,
e.g., about 375 mg) (e.g.,
between 30 mg to 1200 mg (e.g., between 30 mg to 1100 mg, e.g., between 60 mg
to 1000 mg, e.g.,
between 100 mg to 900 mg, e.g., between 200 mg to 800 mg, e.g., between 300 mg
to 800 mg, e.g.,
between 400 mg to 800 mg, e.g., between 400 mg to 750 mg, e.g., between 450 mg
to 750 mg, e.g.,
between 500 mg to 700 mg, e.g., between 550 mg to 650 mg, e.g., 600 mg 10
mg, e.g., 600 6 mg,
e.g., 600 5 mg, e.g., 600 3 mg, e.g., 600 1 mg, e.g., 600 0.5 mg,
e.g., 600 mg) every three weeks.
In some instances, an effective amount of the anti-TIGIT antagonist antibody
(e.g., an anti-TIGIT
antagonist antibody as disclosed herein, e.g., tiragolumab) is a dose of
between 30 mg to 600 mg (e.g.,
.. between 50 mg to between 600 mg, e.g., between 60 mg to 600 mg, e.g.,
between 100 mg to 600 mg,
e.g., between 200 mg to 600 mg, e.g., between 200 mg to 550 mg, e.g., between
250 mg to 500 mg, e.g.,
between 300 mg to 450 mg, e.g., between 350 mg to 400 mg, e.g., 375 mg)) every
three weeks. In some
instances, the effective amount of the anti-TIGIT antagonist antibody (e.g.,
an anti-TIGIT antagonist
antibody as disclosed herein, e.g., tiragolumab) is a dose of about 600 mg
every three weeks. In some
instances, effective amount of the anti-TIGIT antagonist antibody (e.g., an
anti-TIGIT antagonist antibody
as disclosed herein, e.g., tiragolumab) is a dose of 600 mg every three weeks.
In some instances, the
dose of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist
antibody as disclosed herein,
e.g., tiragolumab) is to be administered in a combination therapy (e.g., a
combination treatment with a
PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g.,
atezolizumab) or an anti-PD-
1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab,
previously known as
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lambrolizumab)))) may be reduced as compared to a standard dose of the anti-
TIGIT antagonist antibody
is to be administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab)) is a dose (e.g., a fixed dose) of
between about 80 mg to about
2000 mg (e.g., between about 80 mg to about 1950 mg, e.g., between about 80 mg
to about 1900 mg,
e.g., between about 80 mg to about 1800 mg, e.g., between about 100 mg to
about 1700 mg, e.g.,
between about 200 mg to about 1600 mg, e.g., between about 300 mg to about
1400 mg, e.g., between
about 400 mg to about 1300 mg, e.g., between about 500 mg to about 1200 mg,
e.g., between about 600
mg to about 1100 mg, e.g., between about 700 mg to about 1000 mg, e.g.,
between about 740 mg to
about 940 mg, e.g., between about 790 mg to about 890 mg, e.g., between about
815 mg to about 865
mg, e.g., between about 830 mg to about 850 mg, e.g., 840 mg 5 mg, e.g., 840
2.5 mg, e.g., 840
1.0 mg, e.g., 840 0.5 mg, e.g., 840 mg) (e.g., between 80 mg to 2000 mg
(e.g., between 80 mg to 1950
mg, e.g., between 80 mg to 1900 mg, e.g., between 80 mg to 1800 mg, e.g.,
between 100 mg to 1700
mg, e.g., between 200 mg to 1600 mg, e.g., between 300 mg to 1400 mg, e.g.,
between 400 mg to 1300
mg, e.g., between 500 mg to 1200 mg, e.g., between 600 mg to 1100 mg, e.g.,
between 700 mg to 1000
mg, e.g., between 740 mg to 940 mg, e.g., between 790 mg to 890 mg, e.g.,
between 815 mg to 865 mg,
e.g., between 830 mg to 850 mg, e.g., 840 mg 5 mg, e.g., 840 2.5 mg, e.g.,
840 1.0 mg, e.g., 840
0.5 mg, e.g., 840 mg)) every two weeks. In some instances, the effective
amount of the PD-1 axis
binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab))
is a dose of between about
80 mg to about 2000 mg (e.g., between about 100 mg to about 2000 mg, e.g.,
between about 200 mg to
about 1900 mg, e.g., between about 300 mg to about 1700 mg, e.g., between
about 400 mg to about
1600 mg, e.g., between about 500 mg to about 1600 mg, e.g., between about 600
mg to about 1600 mg,
e.g., between about 700 mg to about 1600 mg, e.g., between about 800 mg to
about 1600 mg, e.g.,
between about 900 mg to about 1500 mg, e.g., between about 1000 mg to about
1400 mg, e.g., between
about 1050 mg to about 1350 mg, e.g., between about 1100 mg to about 1300 mg,
e.g., between about
1150 mg to about 1250 mg, e.g., between about 1175 mg to about 1225 mg (e.g.,
between 100 mg to
2000 mg, e.g., between 200 mg to 1900 mg, e.g., between 300 mg to 1700 mg,
e.g., between 400 mg to
1600 mg, e.g., between 500 mg to 1600 mg, e.g., between 600 mg to 1600 mg,
e.g., between 700 mg to
1600 mg, e.g., between 800 mg to 1600 mg, e.g., between 900 mg to 1500 mg,
e.g., between 1000 mg to
1400 mg, e.g., between 1050 mg to 1350 mg, e.g., between 1100 mg to 1300 mg,
e.g., between 1150 mg
to 1250 mg, e.g., between 1175 mg to 1225 mg), e.g., between about 1190 mg to
about 1210 mg (e.g.,
between 1190 mg to 1210 mg), e.g., 1200 mg 5 mg, e.g., 1200 2.5 mg, e.g.,
1200 1.0 mg, e.g.,
1200 0.5 mg, e.g., 1200 mg) every three weeks. In some instances, the
effective amount of the PD-1
axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab)) is a dose of between
about 80 mg to about 2000 mg (e.g., between about 100 mg to about 2000 mg,
e.g., between about 200
mg to about 2000 mg, e.g., between about 300 mg to about 2000 mg, e.g.,
between about 400 mg to
about 2000 mg, e.g., between about 500 mg to about 2000 mg, e.g., between
about 600 mg to about
1900 mg, e.g., between about 700 mg to about 1800 mg, e.g., between about 800
mg to about 1800 mg,
e.g., between about 900 mg to about 1800 mg, e.g., between about 1000 mg to
about 1800 mg, e.g.,
between about 1100 mg to about 1800 mg, e.g., between about 1200 mg to about
1800 mg, e.g.,
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between about 1300 mg to about 1800 mg, e.g., between about 1400 mg to about
1800 mg, e.g.,
between about 1500 mg to about 1800 mg, e.g., between about 1580 mg to about
1780 mg, e.g.,
between about 1630 mg to about 1730 mg, e.g., between about 1655 mg to about
1705 mg, e.g.,
between about 1670 mg to about 1690 mg (e.g., between 100 mg to 2000 mg, e.g.,
between 200 mg to
2000 mg, e.g., between 300 mg to 2000 mg, e.g., between 400 mg to 2000 mg,
e.g., between 500 mg to
2000 mg, e.g., between 600 mg to 1900 mg, e.g., between 700 mg to 1800 mg,
e.g., between 800 mg to
1800 mg, e.g., between 900 mg to 1800 mg, e.g., between 1000 mg to 1800 mg,
e.g., between 1100 mg
to 1800 mg, e.g., between 1200 mg to 1800 mg, e.g., between 1300 mg to 1800
mg, e.g., between 1400
mg to 1800 mg, e.g., between 1500 mg to 1800 mg, e.g., between 1580 mg to 1780
mg, e.g., between
1630 mg to 1730 mg, e.g., between 1655 mg to 1705 mg, e.g., between 1670 mg to
1690 mg), e.g., 1680
mg 5 mg, e.g., 1680 2.5 mg, e.g., 1680 1.0 mg, e.g., 1680 0.5 mg,
e.g., 1680 mg) every four
weeks. In some instances, the effective amount of the PD-1 axis binding
antagonist (e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab)) is a dose of about 840 mg every two
weeks. In some instances,
the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1
antagonist antibody (e.g.,
atezolizumab)) is a dose of 840 mg every two weeks. In some instances, the
effective amount of the PD-
1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g.,
atezolizumab)) is a dose of about
1200 mg every three weeks. In some instances, the effective amount of the PD-1
axis binding antagonist
(e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of 1200
mg every three weeks. In
some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-L1 antagonist
antibody (e.g., atezolizumab)) is a dose of about 1 680 mg every four weeks.
In some instances, the
effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1
antagonist antibody (e.g.,
atezolizumab)) is a dose of 1680 mg every four weeks. In some instances, the
dose of the PD-1 axis
binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g.,
atezolizumab) or an anti-PD-1
antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab,
previously known as
lambrolizumab))) to be administered in a combination therapy (e.g., a
combination treatment with an anti-
TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed
herein, e.g., tiragolumab)
may be reduced as compared to a standard dose of the anti-PD-L1 antagonist
antibody to be
administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-1
.. antagonist antibody (e.g., pembrolizumab)) is a dose (e.g., a fixed dose)
of between about 20 mg to about
1000 mg (e.g., between about 40 mg to about 900 mg, e.g., between about 60 mg
to about 800 mg, e.g.,
between about 80 mg to about 700 mg, e.g., between about 80 mg to about 600
mg, e.g., between about
100 mg to about 500 mg, e.g., between about 120 mg to about 400 mg, e.g.,
between about 140 mg to
about 300 mg, e.g., between about 160 mg to about 350 mg, e.g., between about
180 mg to about 300
.. mg, e.g., between about 180 mg to about 250 mg, e.g., between about 180 mg
to about 220 mg, e.g.,
between about 190 mg to about 210 mg (e.g., between 40 mg to 900 mg, e.g.,
between 60 mg to 800 mg,
e.g., between 80 mg to 700 mg, e.g., between 80 mg to 600 mg, e.g., between
100 mg to 500 mg, e.g.,
between 120 mg to 400 mg, e.g., between 140 mg to 300 mg, e.g., between 160 mg
to 350 mg, e.g.,
between 180 mg to 300 mg, e.g., between 180 mg to 250 mg, e.g., between 180 mg
to 220 mg, e.g.,
between 190 mg to 210 mg), e.g., 200 mg 5 mg, e.g., 200 2.5 mg, e.g., 200
1.0 mg, e.g., 200 0.5
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mg, e.g., 200 mg) every three weeks. In some instances, the effective amount
of the PD-1 axis binding
antagonist (e.g., anti-PD-1 antagonist antibody (e.g., pembrolizumab)) is a
dose of about 200 mg every
three weeks. In some instances, the effective amount of the PD-1 axis binding
antagonist (e.g., anti-PD-1
antagonist antibody (e.g., pembrolizumab)) is a dose of 200 mg every three
weeks. In some instances,
the dose of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist
antibody (e.g., pembrolizumab))
administered in a combination therapy (e.g., a combination treatment with an
anti-TIGIT antagonist
antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g.,
tiragolumab) may be reduced
as compared to a standard dose of the anti-PD-L1 antagonist antibody
administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-1
antagonist antibody (e.g., nivolumab)) is a dose (e.g., a fixed dose) of
between about 20 mg to about
1000 mg (e.g., 20 mg to 1000 mg) (e.g., between about 40 mg to about 900 mg,
e.g., between about 60
mg to about 800 mg, e.g., between about 80 mg to about 700 mg, e.g., between
about 80 mg to about
600 mg, e.g., between about 100 mg to about 500 mg, e.g., between about 120 mg
to about 400 mg, e.g.,
between about 140 mg to about 300 mg, e.g., between about 160 mg to about 350
mg, e.g., between
about 180 mg to about 300 mg, e.g., between about 200 mg to about 280 mg,
e.g., between about 220
mg to about 260 mg, e.g., between about 230 mg to about 250 mg (e.g., between
40 mg to 900 mg, e.g.,
between 60 mg to 800 mg, e.g., between 80 mg to 700 mg, e.g., between 80 mg to
600 mg, e.g.,
between 100 mg to 500 mg, e.g., between 120 mg to 400 mg, e.g., between 140 mg
to 300 mg, e.g.,
between 160 mg to 350 mg, e.g., between 180 mg to 300 mg, e.g., between 200 mg
to 280 mg, e.g.,
between 220 mg to 260 mg, e.g., between 230 mg to 250 mg), e.g., 240 mg 5
mg, e.g., 240 2.5 mg,
e.g., 240 1.0 mg, e.g., 240 0.5 mg, e.g., 240 mg) every two weeks. In some
instances, the effective
amount of the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist
antibody (e.g., nivolumab)) is a
dose of about 240 mg every two weeks. In some instances, the effective amount
of the PD-1 axis binding
antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is a dose
of 240 mg every two weeks.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-1 antagonist
antibody (e.g., nivolumab)) is a dose of between about 100 mg to about 1000 mg
(e.g., between 100 mg
to 1000 mg) (e.g., between about 200 mg to about 900 mg, e.g., between about
300 mg to about 800 mg,
e.g., between about 400 mg to about 700 mg, e.g., between about 400 mg to
about 600 mg, e.g.,
between about 400 mg to about 550 mg, e.g., between about 420 mg to about 540
mg, e.g., between
about 440 mg to about 520 mg, e.g., between about 460 mg to about 500 mg,
e.g., between about 470
mg to about 490 mg (e.g., between 200 mg to 900 mg, e.g., between 300 mg to
800 mg, e.g., between
400 mg to 700 mg, e.g., between 400 mg to 600 mg, e.g., between 400 mg to 550
mg, e.g., between 420
mg to 540 mg, e.g., between 440 mg to 520 mg, e.g., between 460 mg to 500 mg,
e.g., between 470 mg
to 490 mg), e.g., 480 mg 5 mg, e.g., 480 2.5 mg, e.g., 480 1.0 mg, e.g.,
480 0.5 mg, e.g., 480 mg)
every four weeks. In some instances, the effective amount of the PD-1 axis
binding antagonist (e.g., anti-
PD-1 antagonist antibody (e.g., nivolumab)) is a dose of about 480 mg every
four weeks. In some
instances, the effective amount of the PD-1 axis binding antagonist (e.g.,
anti-PD-1 antagonist antibody
(e.g., nivolumab)) is a dose of 480 mg every four weeks. In some instances,
the dose of the PD-1 axis
binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab))
administered in a combination
therapy (e.g., a combination treatment with an anti-TIGIT antagonist antibody,
such as an anti-TIGIT
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antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced as
compared to a standard dose
of the anti-PD-L1 antagonist antibody administered as a monotherapy.
In some instances, the effective amount of the PD-1 axis binding antagonist
(e.g., anti-PD-L1
antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01
mg/kg to about 50 mg/kg of the
subject's body weight (e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g.,
between about 0.1 mg/kg
to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g.,
between about 2.5 mg/kg to
about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between
about 10 mg/kg to about
20 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., about 15 2
mg/kg, about 15 1
mg/kg, about 15 0.5 mg/kg, about 15 0.2 mg/kg, or about 15 0.1 mg/kg,
e.g., about 15 mg/kg) every
three weeks. In some instances, the effective amount of the PD-1 axis binding
antagonist (e.g., anti-PD-
L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01
mg/kg to about 15 mg/kg of
the subject's body weight (e.g., between about 0.1 mg/kg to about 15 mg/kg,
e.g., between about 0.5
mg/kg to about 15 mg/kg, e.g., between about 1 mg/kg to about 15 mg/kg, e.g.,
between about 2.5 mg/kg
to about 15 mg/kg, e.g., between about 5 mg/kg to about 15 mg/kg, e.g.,
between about 7.5 mg/kg to
about 15 mg/kg, e.g., between about 10 mg/kg to about 15 mg/kg, e.g., between
about 12.5 mg/kg to
about 15 mg/kg, e.g., between about 14 mg/kg to about 15 mg/kg, e.g., about 15
1 mg/kg, e.g., about
15 0.5 mg/kg, e.g., about 15 0.2 mg/kg, e.g., about 15 0.1 mg/kg, e.g.,
about 15 mg/kg) every three
weeks. In some instances, the effective amount of anti-PD-L1 antagonist
antibody (e.g., atezolizumab) is
a dose of about 15 mg/kg to be administered every three weeks. In some
instances, the dose of the PD-
1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g.,
atezolizumab) or an anti-PD-1
antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab,
previously known as
lambrolizumab))) administered in a combination therapy (e.g., a combination
treatment with an anti-TIGIT
antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed
herein, e.g., tiragolumab) may
be reduced as compared to a standard dose of the anti-PD-L1 antagonist
antibody administered as a
monotherapy.
In any of the uses of the invention, the medicament comprising the anti-TIGIT
antagonist antibody
(e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g.,
tiragolumab) and the PD-1 axis binding
antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an
anti-PD-1 antagonist
antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously
known as
lambrolizumab))) may be administered in one or more dosing cycles (e.g., 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,
31, 32, 33, 34, 35, 36, 37, 38, 39,
40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 or more dosing cycles). In some
instances, the dosing cycles
of the medicament comprising anti-TIGIT antagonist antibody (e.g., an anti-
TIGIT antagonist antibody as
disclosed herein, e.g., tiragolumab) and the PD-1 axis binding antagonist
(e.g., an anti-PD-L1 antagonist
antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-
1106 (nivolumab) or MK-
3475 (pembrolizumab, previously known as lambrolizumab))) continue until there
is a loss of clinical
benefit (e.g., confirmed disease progression, drug resistance, death, or
unacceptable toxicity). In some
instances, the length of each dosing cycle is about 14 to 28 days (e.g., 14
days,15 days, 16 days, 17
days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days,
26 days, 27 days, or 28
days). In some instances, the length of each dosing cycle is about 21 days. In
some instances, the
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