IL294800A - Methods for treatment of cancer with an anti-tigit antagonist antibody - Google Patents
Methods for treatment of cancer with an anti-tigit antagonist antibodyInfo
- Publication number
- IL294800A IL294800A IL294800A IL29480022A IL294800A IL 294800 A IL294800 A IL 294800A IL 294800 A IL294800 A IL 294800A IL 29480022 A IL29480022 A IL 29480022A IL 294800 A IL294800 A IL 294800A
- Authority
- IL
- Israel
- Prior art keywords
- subject
- dose
- weeks
- subjects
- population
- Prior art date
Links
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Classifications
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- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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Claims (503)
1. 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.
2. 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.
3. 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.
4. The method of claim 2 or 3, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.
5. The method of any one of claims 1 -4, wherein the anti-TIGIT antagonist antibody is an IgG class antibody, in particular an lgG1 subclass antibody.
6. The method of any one of claims 1 -5, wherein the anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs):(a) an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);(b) an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2);(c) an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3);(d) an HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);(e) an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and (f) an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).
7. The method of any one of claims 1 -6, wherein the anti-TIGIT antagonist antibody further comprises the following light chain variable region framework regions (FRs):(a) an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); 806 WO 2021/154761 PCT/US2021/015143 (b) an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);(c) an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and(d) an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10), andthe following heavy chain variable region FRs:(a) an FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), wherein X1 is E or Q;(b) an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12);(c) an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and(d) an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).
8. The method of any one of claims 1 -7, wherein the anti-TIGIT antagonist antibody comprises:(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or(c) 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.
9. The method of any one of claims 1 -8, wherein the anti-TIGIT antagonist antibody is tiragolumab.
10. The method of any one of claims 1 -9, wherein the PD-1 axis binding antagonist is a PD-Lbinding antagonist or a PD-1 binding antagonist.
11. The method of any one of claims 1 -10, wherein the PD-1 axis binding antagonist is an anti-PD-Lantagonist antibody or an anti-PD-1 antagonist antibody.
12. The method of any one of claim 1-11, wherein the PD-1 axis binding antagonist is an anti-PD-Lantagonist antibody.
13. The method of claim 12, wherein the anti-PD-L1 antagonist antibody atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, envafolimab, TQB2450, ZKAB001, LP-002, CX-072, IMG- 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, or HS-636.
14. The method of any one of claim 1-13, wherein the PD-1 axis binding antagonist is atezolizumab. 807 WO 2021/154761 PCT/US2021/015143
15. The method of any one of claim 1-11, wherein the PD-1 axis binding antagonist is an anti-PD-antagonist antibody.
16. The method of claim 15, wherein the anti-PD-1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, cemiplimab, BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, Bl 754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, or hAb21.
17. The method of any one of claims 2-16, wherein the method comprises administering to the subject an effective amount of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.
18. The method of claim 1 or 17, wherein the non-platinum-based chemotherapeutic agent is a topoisomerase II inhibitor.
19. The method of claim 18, wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, an ellipticine, aurintricarboxylic acid, or HU-331, in particular etoposide.
20. The method of claim 18 or 19, wherein the topoisomerase II inhibitor is administered at a dose of 100 mg/m2.
21. The method of any one of claims 17-20, wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin, in particular carboplatin.
22. The method of any one of claims 17-21, wherein the platinum-based chemotherapeutic agent is administered at a dose sufficient to achieve AUG = 5 mg/ml/min on the day of administration.
23. The method of any one of claims 1 -22, wherein the method comprises a dosing regimen comprising an induction phase and a maintenance phase.
24. The method of claim 23, wherein the induction phase comprises four initial dosing cycles and wherein the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and non-platinum-based chemotherapeutic agent are administered in each of four initial dosing cycles.
25. The method of claim 23 or 24, wherein the maintenance phase does not comprise administration of the platinum-based chemotherapeutic agent and/or non-platinum based chemotherapeutic agent. 808 WO 2021/154761 PCT/US2021/015143
26. The method of any one of claims 1-25, wherein the treatment extends progression-free survival (PFS) of the subject as compared to treatment without the anti-TIGIT antagonist antibody.
27. The method of any one of claims 1-26, wherein the treatment extends overall survival of the subject as compared to treatment without the anti-TIGIT antagonist antibody.
28. The method of any one of claims 1 -27, wherein the cancer is lung cancer.
29. The method of claim 28, wherein the lung cancer is a small cell lung cancer (SCLC), in particular extensive stage SCLC (ES-SCLC).
30. The method of claim 28, wherein the lung cancer is a non-small cell lung cancer (NSCLC), in particular locally advanced unresectable NSCLC (Stage IIIB NSCLC).
31. The method of claim 28, wherein the lung cancer is locally advanced unresectable or metastatic non-squamous NSCLC.
32. The method of claim 28, wherein the lung cancer is resectable lung cancer.
33. The method of any one of claims 1-27, wherein the cancer is cervical cancer.
34. The method of any one of claims 1-27, wherein the cancer is an early triple-negative breastcancer (eTNBC).
35. The method of any one of claims 1-27, wherein the cancer is a head and neck cancer.
36. The method of any one of claims 1 -27, wherein the cancer is a liver cancer, in particularhepatocellular carcinoma (HCC).
37. The method of any one of claims 1 -27, wherein the cancer is a bladder cancer.
38. The method of claim 37, wherein the cancer is a urothelial carcinoma (UC), in particular a metastatic urothelial carcinoma (mUC).
39. The method of any one of claims 1-27, wherein the cancer is a pancreatic cancer, in particular a pancreatic ductal adenocarcinoma (PDAC).
40. The method of any one of claims 1-27, wherein the cancer is an esophageal cancer, in particular an advanced or metastatic esophageal cancer. 809 WO 2021/154761 PCT/US2021/015143
41. 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 method of any one of claims 1- 40.
42. The kit of claim 41, wherein the kit further comprises one or more chemotherapeutic agents.
43. 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 any one of claims 1-40.
44. 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 method of any one of claims 1 -40.
45. The use of claim 44, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations.
46. The use of claim 44, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single formulation.
47. 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.
48. 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.
49. The method of claim 47 or 48, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.
50. The method of claim 49, wherein the method comprises administering to the subject a platinum- based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.
51. 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 810 WO 2021/154761 PCT/US2021/015143 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.
52. The method of claim 50 or 51, wherein the method comprises an induction phase and a maintenance phase.
53. The method of claim 52, wherein the induction phase and maintenance phase each comprise one or more dosing cycles.
54. The method of claim 52 or 53, wherein the maintenance phase does not comprise administration of the platinum-based chemotherapeutic agent.
55. The method of any one of claims 52-54, wherein the maintenance phase does not comprise administration of the non-platinum-based chemotherapeutic agent.
56. The method of claim 55, wherein 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.
57. 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.
58. 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 tiragolumab and pembrolizumab, wherein the pembrolizumab is administered at a dose of between about 300 mg to about 500 mg every six weeks.
59. 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.
60. 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 811 WO 2021/154761 PCT/US2021/015143 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.
61. The method of claim 49, wherein the one or more chemotherapeutic agents are gemcitabine and nab-paclitaxel.
62. 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.
63. 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.
64. 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.
65. The method of any one of claims 53-56, 63, and 64, wherein the induction phase comprises four to six dosing cycles.
66. The method of any one of claims 50-56 and 63-65, wherein 812 WO 2021/154761 PCT/US2021/015143 (a) the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum- based chemotherapeutic agent is pemetrexed;(b) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is paclitaxel; or(c) the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is etoposide.
67. The method of any one of claims 47-66, wherein the cancer is a solid tumor.
68. The method of any one of claims 47-67, wherein the cancer is locally advanced or metastatic.
69. The method of any one of claims 47-68, wherein the cancer is a lung cancer, a pancreatic cancer,a cervical cancer, a breast cancer, a head and neck cancer, a liver cancer, a bladder cancer, anesophageal cancer, a gastric cancer, a colorectal cancer, a kidney cancer, a renal cancer, a melanoma, or an ovarian cancer.
70. The method of claim 69, wherein the cancer is a lung cancer.
71. The method of claim 70, wherein the lung cancer is an NSCLC, in particular a locally advanced unresectable NSCLC.
72. The method of claim 71, wherein the NSCLC is a Stage 11 IB NSCLC.
73. The method of any one of claims 70-72, wherein the lung cancer is a recurrent or metastatic NSCLC.
74. The method of claim 73, wherein the NSCLC is a Stage IV NSCLC.
75. The method of claim 74, wherein the subject has not been previously treated for Stage IVNSCLC.
76. The method of claim 70, wherein the lung cancer is a small cell lung cancer (SCLC).
77. A method of treating a subject or population of subjects having a lung cancer, the methodcomprising 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-axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody. 813 WO 2021/154761 PCT/US2021/015143
78. 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.
79. The method of claim 77 or 78, wherein the treatment extends overall survival (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.
80. The method of any one of claims 77-79, wherein the treatment extends the PFS of the subject or population of subjects by at least about 2.4 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.
81. The method of claim 80, wherein the treatment extends the PFS of the subject or population of subjects by at least about 3 months to about 4 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.
82. 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 OS 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.
83. 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.
84. The method of any one of claims 79-83, wherein the treatment extends the OS of the subject or population of subjects by at least about 3.3 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. 814 WO 2021/154761 PCT/US2021/015143
85. The method of any one of claims 79-83, wherein the treatment extends the OS of the subject or population of subjects by at least about 3 months to about 5.3 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.
86. The method of any one of claims 77-85, wherein 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.
87. The method of any one of claims 77-86, wherein the anti-TIGIT antagonist antibody and the PD-axis binding antagonist are further administered in one or more additional cycles following the fourth initial dosing cycle.
88. The method of claim 87, wherein the platinum-based chemotherapeutic agent and the topoisomerase II inhibitor are omitted from each of the one or more additional dosing cycles.
89. The method of any one of claims 77-88, wherein the platinum-based chemotherapeutic agent is carboplatin and the topoisomerase II inhibitor is etoposide.
90. The method of any one of claims 77-89, wherein the lung cancer is a small cell lung cancer (SCLC).
91. The method of claim 90, wherein the SCLC is extensive stage SCLC (ES-SCLC).
92. The method of claim 91, wherein the subject or subjects are treatment-naive for ES-SCLC.
93. The method of any one of claims 77-92, wherein the subject or subjects do not have a presence or history of brain metastases.
94. The method of any one of claims 77-93, wherein the lung cancer is unselected for PD-Lexpression.
95. The method of any one of claims 77-93, wherein the lung cancer is selected for PD-Lexpression.
96. The method of claim 95, wherein the lung cancer is selected for PD-L1 expression by a detectable expression level of PD-L1.
97. The method of any one of claims 77-96, wherein the lung cancer is metastatic. 815 WO 2021/154761 PCT/US2021/015143
98. The method of claim 97, wherein the lung cancer has metastasized to the brain, liver, lymph nodes, and/or adrenal gland.
99. The method of claim 97 or 98, wherein the lung cancer has not metastasized to the brain.
100. The method of any one of claims 77-99, wherein the treatment results in a complete response (CR) or a partial response (PR).
101. 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 AUG = 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.
102. 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 AUG = 5 mg/ml/min on Day 1 of each initial dosing cycle, and etoposide at a dose of 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.
103. 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. 816 WO 2021/154761 PCT/US2021/015143
104. The method of claim 103, wherein the lung cancer has not been evaluated for PD-Lexpression.
105. The method of claim 103 or 104, wherein the subject or subjects have not been determined to have a PD-L1-positive tumor cell fraction of greater than, or equal to, 50%.
106. The method of claim 105, wherein the subject or subjects have been determined to have a PD- L1-positive tumor cell fraction of less than 50%.
107. The method of claim 105 or 106, wherein the PD-L1 -positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is SP263 or 22C3.
108. The method of any one of claims 103-107, wherein the subject or subjects do not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (,ALK) genomic tumor aberration.
109. The method of any one of claims 103-108, wherein the subject or subjects have received no prior systemic therapy for the lung cancer.
110. The method of any one of claims 103-109, wherein the lung cancer is a locally advanced lung cancer.
111. The method of any one of claims 103-110, wherein the lung cancer is an NSCLC, in particular a locally advanced unresectable or metastatic non-squamous NSCLC.
112. The method of claim 111, wherein the non-squamous NSCLC is a Stage IV non-squamous NSCLC.
113. The method of any one of claims 103-112, wherein the dosing regimen comprises an induction phase comprising four dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the non-platinum-based chemotherapeutic agent are administered on Day 1 of each dosing cycle of the induction phase.
114. The method of claim 113, wherein the dosing regimen comprises a maintenance phase following the induction phase, wherein the maintenance phase comprises one or more dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, and the non-platinum-based chemotherapeutic agent are administered on Day 1 of each dosing cycle of the maintenance phase.
115. The method of claim 114, wherein the one or more dosing cycles of the maintenance phase do not comprise administration of the platinum-based chemotherapeutic agent. 817 WO 2021/154761 PCT/US2021/015143
116. The method of any one of claims 103-115, wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed.
117. 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 AUG = 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.
118. 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 AUG = 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.
119. The method of any one of claims 103-118, wherein the treatment extends the PFS of the subject or population of subjects by at least about 3.5 months or about 4.7 months.
120. The method of any one of claims 103-118, wherein the treatment results in a median PFS of the population of subjects of about 12.5 months to about 14.7 months.
121. The method of any one of claims 103-118, wherein the treatment extends the OS of the subject or population of subjects by at least about 5.5 months or about 8.0 months.
122. The method of anyone of claims 103-118, wherein the treatment results in a median OS of the population of subjects of about 27.5 months to about 32.0 months.
123. 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 818 WO 2021/154761 PCT/US2021/015143 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.
124. 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 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.
125. The method of claim 124, 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 about 700 mg every three weeks and the PD-1 axis binding antagonist at a dose of between about 900 mg to about 15every three weeks as an adjuvant treatment.
126. The method of claim 124 or 125, wherein the lung cancer is a resectable lung cancer.
127. The method of any one of claims 123-126, wherein the lung cancer is an early stage lung cancer.
128. The method of any one of claims 123-127, wherein the lung cancer is a stage II, IHA, or 11 IB lung cancer.
129. The method of any one of claims 123-128, wherein the subject is eligible for an R0 resection with curative intent.
130. The method of any one of claims 123-129, wherein the subject has not received a prior therapy for lung cancer.
131. The method of claim 130, wherein the prior therapy is an immunotherapy, a chemotherapy, or a radiotherapy.
132. The method of any one of claims 123-131, wherein the subject is eligible to receive a platinum- based chemotherapy regimen.
133. The method of any one of claims 123-132, wherein the first dosing cycle is initiated prior to a surgery.
134. The method of claim 133, wherein at least 1,2, 3, or 4 dosing cycles are completed prior to the surgery. 819 WO 2021/154761 PCT/US2021/015143
135. The method of claim 133 or 134, wherein 4 dosing cycles are completed prior to the surgery.
136. The method of any one of claims 123-135, wherein at least one dosing cycle is initiated after a surgery.
137. The method of claim 136, wherein 16 dosing cycles are completed after the surgery.
138. The method of any one of claims 133-137, wherein the surgery is a segmentectomy, a lobectomy, a bilobectomy, or a pneumonectomy.
139. The method of any one of claims 123-138, wherein the method further comprises a radiotherapy.
140. The method of claim 139, wherein the radiotherapy is a post-operative radiotherapy.
141. The method of any one of claims 123-140, wherein the method further comprises administering one or more chemotherapeutic agents.
142. The method of claim 141, wherein the one or more chemotherapeutic agents are administered after a surgery.
143. The method of claim 142, wherein the one or more chemotherapeutic agents are administered in dosing cycles after the surgery.
144. The method of anyone of claims 141-143, wherein the one or more chemotherapeutic agents are a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.
145. The method of claim 144, wherein:(a) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is pemetrexed;(b) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is gemcitabine;(c) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is paclitaxel;(d) the platinum-based chemotherapeutic agent is cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed; or(e) the platinum-based chemotherapeutic agent is cisplatin and the non-platinum-based chemotherapeutic agent is gemcitabine. 820 WO 2021/154761 PCT/US2021/015143
146. The method of anyone of claims 123-145, wherein the treating results in an increase in major pathological response (MPR) rate as compared to a reference MPR rate.
147. The method of claim 146, wherein the reference MPR rate is an MPR rate of 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.
148. The method of anyone of claims 123-147, wherein the treating results in a pathological complete response (pCR) and/or an increase in pCR rate as compared to a reference pCR rate.
149. The method of claim 148, wherein the reference pCR rate is a pCR rate of 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.
150. The method of anyone of claims 123-149, wherein the treating results in an increase in event- free survival (EPS) as compared to a reference EPS time.
151. The method of claim 150, wherein the reference EPS time is an EPS 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.
152. 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 mg/mL/min 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.
153. 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: 821 WO 2021/154761 PCT/US2021/015143 (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 AUG of 5 mg/mL/min 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/mL/min every three weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every three weeks;or(ill) 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.
154. The method of any one of claims 123-153, wherein a detectable protein expression level of RD- L1 determined by an IHC assay comprising staining with anti-PD-L1 antibody SP263 has been determined.
155. The method of claim 154, wherein the detectable protein expression level of PD-L1 is a PD-L1- positive tumor cell fraction greater than, or equal to, 50%.
156. The method of any one of claims 70, 103-110, and 123-155, wherein the lung cancer is an NSCLC.
157. The method of claim 156, wherein the NSCLC is a squamous NSCLC.
158. The method of claim 156, wherein the NSCLC is a non-squamous NSCLC.
159. The method of claim 69, wherein the cancer is a cervical cancer.
160. 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 5mg 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. 822 WO 2021/154761 PCT/US2021/015143
161. 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 IHC 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 5mg 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.
162. The method of claim 160 or 161, wherein the cervical cancer is a squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma.
163. The method of anyone of claims 160-162, wherein the cervical cancer is Stage IVB, metastatic, recurrent, or persistent.
164. The method of any one of claims 160-163, wherein the cervical cancer is a metastatic and/or recurrent PD-L1-positive cervical carcinoma.
165. The method of any one of claims 160-164, wherein the subject or subjects have received at least one line of prior therapy.
166. The method of any one of claims 160-165, wherein the subject or subjects have received two lines of prior therapy.
167. The method of any one of claims 160-166, wherein the subject or subjects have not received more than two lines of prior therapy.
168. The method of any one of claims 160-164, wherein the subject or subjects have not received prior therapy.
169. The method of any one of claims 165-168, wherein the prior therapy is chemotherapy, surgery, and/or radiotherapy.
170. The method of any one of claims 160 and 162-169, wherein the treating results in a clinical response.
171. The method of claim 170, wherein the clinical response is an increase in an objective response rate (ORR) of the population of subjects as compared to a reference ORR. 823 WO 2021/154761 PCT/US2021/015143
172. The method of claim 171, wherein the reference ORR is the median ORR of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.
173. The method of claim 170, wherein the reference ORR is at least about 14.6% to about 26%.
174. The method of claim 170, wherein the clinical response is a CR or a PR.
175. The method of any one of claims 170-174, wherein the clinical response is an increase in the progression-free survival (PFS) of the subject as compared to a reference PFS time, an increase in the duration of response (DOR) of the subject as compared to a reference DOR time, or an increase in the overall survival (OS) of the subject as compared to a reference OS time.
176. The method of claim 175, wherein:(a) the reference PFS time is the median PFS time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;(b) the reference DOR time is the median DOR time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; or(c) the reference OS time is the median OS time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.
177. 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.
178. The method of any one of claims 160-177, wherein the subject is identified as one who is likely to benefit from the treatment based on PD-L1 expression on tumor cells having been detected.
179. The method of any one of claims 160-178, wherein PD-L1 expression level is detected using anti-PD-L1 antibody SP263.
180. The method of anyone of claims 160-179, wherein the detectable expression level of PD-L1 is a tumor-associated immune-cell (TIC) of greater than or equal to 5% in a sample from the subject.
181. The method of any one of claims 160-178, wherein PD-L1 expression level is detected using anti-PD-L1 antibody 22C3.
182. The method of anyone of claims 160-179, wherein the detectable expression level of PD-L1 is a combined positive score (CPS) of greater than or equal to 1 in a sample from the subject. 824 WO 2021/154761 PCT/US2021/015143
183. The method of claim 69, wherein the cancer is a breast cancer.
184. 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.
185. The method of claim 183 or 184, wherein the breast cancer is a triple-negative breast cancer (TNBC).
186. The method of claim 185, wherein the TNBC is an unresectable locally advanced or metastatic TNBC.
187. The method of any one of claims 183-186, wherein the subject or subjects have not received prior systemic therapy for metastatic breast cancer.
188. The method of any one of claims 183-187, wherein the treatment results in an ORR of the population of subjects of at least about 53% to at least about 67.5%.
189. The method of any one of claims 183-188, wherein the treatment results in a median OS of the population of subjects of about 25.0 months.
190. 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.
191. The method of claim 190, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.
192. The method of claim 191, wherein the one or more chemotherapeutic agents are a platinum- based chemotherapeutic agent, a taxane, a topoisomerase II inhibitor, or an alkylating agent.
193. The method of claim 190, wherein the method further comprises administering (a) one or more dosing cycles of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, and a taxane or a taxane and a platinum-based chemotherapeutic agent; and (b) one or more dosing cycles of the anti- TIGIT antagonist antibody, the PD-1 axis binding antagonist, a topoisomerase II inhibitor, an alkylating 825 WO 2021/154761 PCT/US2021/015143 agent, and granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF).
194. The method of claim 192 or 193, wherein the alkylating agent is cyclophosphamide.
195. The method of claim 194, wherein the cyclophosphamide is administered at a dose of about 6mg/m2.
196. The method of any one of claims 190-192, 194, and 195, wherein the method comprises further administering to the subject a G-CSF, or GM-CSF.
197. The method of claim 193 or 196, wherein the G-CSF is pegfilgrastim or filgrastim.
198. The method of claim 197, wherein the G-CSF is pegfilgrastim.
199. The method of claim 198, wherein the pegfilgrastim is administered at a dose of about 6 mg.
200. The method of any one of claims 191,192, and 194-199, wherein the method comprises further administering to the subject one or more subsequent doses of the one or more chemotherapeutic agents and/or G-CSF or GM-CSF.
201. The method of any one of claims 191,192, and 194-200, wherein the one or more chemotherapeutic agents and/or G-CSF or GM-CSF are each administered once per week, once every two weeks, or once every three weeks.
202. The method of any one of claims 192-201, wherein the platinum-based chemotherapeutic agent is administered every three weeks, the taxane is administered every week, the topoisomerase II inhibitor is administered every two weeks, the alkylating agent is administered every two weeks, and the G-CSF or GM-CSF is administered every two weeks.
203. The method of any one of claims 192-202, wherein the taxane or the taxane and the platinum- based chemotherapeutic agent are administered for the first 12 weeks of the dosing regimen.
204. The method of any one of claims 192-203, wherein the topoisomerase II inhibitor, the alkylating agent, and the G-CSF or GM-CSF are administered during weeks 13-19 of the dosing regimen.
205. The method of any one of claims 190-204, wherein the total length of the dosing regimen is weeks.
206. The method of any one of claims 190-205, wherein the method is a neoadjuvant treatment. 826 WO 2021/154761 PCT/US2021/015143
207. The method of any one of claims 190-206, wherein the dosing regimen is followed by surgery.
208. The method of claim 207, wherein the surgery is performed between two and six weeks after the last dose of the dosing regimen.
209. The method of claim 207 or 208, wherein the surgery comprises a mastectomy.
210. The method of any one of claims 207-209, wherein the surgery comprises an axillary lymph node surgery.
211. The method of any one of claims 192-210, wherein the topoisomerase II inhibitor is doxorubicin.
212. The method of anyone of claims 192-210, wherein the taxane is nab-paclitaxel, the platinum- based chemotherapeutic agent is carboplatin, and the topoisomerase II inhibitor is doxorubicin.
213. The method of claim 211 or 212, wherein doxorubicin is administered at a dose of about mg/m2.
214. 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 AUG of 5 mg/mL/min 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. 827 WO 2021/154761 PCT/US2021/015143
215. The method of any one of claims 184-214, wherein a detectable protein expression level of RD- L1 in a tumor sample from the subject is determined by an IHC assay comprising staining with anti-PD-Lantibody SP142 has been determined.
216. The method of claim 215, wherein a proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (ICs) in the tumor sample is greater than or equal to 1%.
217. The method of any one of claims 190-216, wherein the eTNBC is a T2-4d TNBC at presentation.
218. The method of any one of claims 190-217, wherein the eTNBC is a cT2-cT4, cN0-cN3, and cMO TNBC at presentation.
219. The method of any one of claims 190-218, wherein the subject has not been previously treated for eTNBC.
220. The method of any one of claims 190-219, wherein the treatment results in a pathological complete response (pCR).
221. The method of any one of claims 190-220, wherein the treatment results in an increase in overall survival (OS) or event-free survival (EPS).
222. The method of claim 69, wherein the cancer is a head and neck cancer.
223. The method of claim 222, wherein the head and neck cancer is a squamous cell carcinoma of the head and neck (SCCHN).
224. 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 1500 mg every three weeks.
225. 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 828 WO 2021/154761 PCT/US2021/015143 between about 500 mg to about 700 mg every three weeks based on PD-L1 expression having been detected.
226. 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.
227. The method of any one of claims 224-226, wherein a tumor sample obtained from the subject or subjects have been determined to have a detectable expression level of PD-L1.
228. The method of any one of claims 223-227, wherein the SSCHN is human papillomavirus (HPV)- positive.
229. The method of any one of claims 223-228, wherein the SSCHN is HPV-negative.
230. The method of claim 228 or 229, wherein HPV status is determined by pt 6 IHC, in situ hybridization, or by PCR.
231. The method of any one of claims 223-230, wherein the SCCHN is a recurrent and/or metastatic SCCHN.
232. The method of any one of claims 222-231, wherein the subject or subjects have not received prior therapy.
233. The method of claim 232, wherein the prior therapy is a prior systemic therapy for recurrent and/or metastatic disease.
234. The method of any one of claims 222-224 and 226-233, wherein the treating results in a CR or PR.
235. The method of any one of claims 222-224 and 226-233, wherein the treating results in an increase in the objective response rate (ORR) of the population of subjects as compared to a reference ORR.
236. The method of claim 235, wherein the reference ORR is the median ORR of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.
237. The method of claim 235 or 236, wherein the reference ORR is at least about 19% to about 36%. 829 WO 2021/154761 PCT/US2021/015143
238. The method of any one of claims 222-224 and 226-237, wherein the treating results in an increase in the progression-free survival (PFS) of the subject or population of subjects as compared to a reference PFS time, an increase in the duration of response (DOR) of the subject or population of subjects as compared to a reference DOR time, or an increase in the overall survival (OS) of the subject or population of subjects as compared to a reference OS time.
239. The method of claim 238, wherein:(a) the reference PFS time is the median PFS time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;(b) the reference DOR time is the median DOR time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; or(c) the reference OS time is the median OS time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.
240. The method of claim 238, wherein the reference DOR time is at least about 6.7 months to about 23.4 months.
241. The method of claim 238, wherein the reference OS time is at least about 11.6 months to about 14.9 months.
242. The method of any one of claims 224-241, wherein the detectable expression level of PD-L1 is a detectable protein expression level of PD-L1 determined by an immunohistochemical (IHC) assay comprising staining with anti-PD-L1 antibody SP263.
243. The method of claim 242, wherein the detectable protein expression level of PD-L1 is a tumor- associated immune-cell (TIC) of:(a) greater than or equal to 5%;(b) greater than or equal to 5% and less than 20%; or(c) greater than or equal to 20% in the tumor sample.
244. The method of any one of claims 224-243, wherein the subject or population of subjects are identified as one who is likely to benefit from the treatment based on PD-L1 expression on tumor cells having been detected.
245. The method of claim 69, wherein the cancer is a liver cancer.
246. The method of claim 245, wherein the liver cancer is a hepatocellular carcinoma (HCC). 830 WO 2021/154761 PCT/US2021/015143
247. A method of treating a subject or population of subjects having a hepatocellular carcinoma (HCC), 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.
248. The method of claim 247, wherein the method further comprises administering to the subject or population of subjects a VEGF antagonist.
249. A method of treating a subject or population of subjects having an HCC, 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.
250. The method of claim 248 and 249, wherein the VEGF antagonist is administered at a dose of about 5 mg/kg to about 25 mg/kg every three weeks.
251. The method of any one of claims 247-250, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 500 mg to about 700 mg every three weeks.
252. The method of any one of claims 247-251, wherein the PD-1 axis binding antagonist is administered at a dose of about 900 mg to about 1500 mg every three weeks.
253. The method of claim 248 or 249, wherein the VEGF antagonist is administered at a dose of about 1 mg/kg to about 20 mg/kg every two weeks.
254. The method of claim 253, wherein the VEGF antagonist is administered at a dose of about mg/kg to about 10 mg/kg every two weeks.
255. The method of claim 254, wherein the VEGF antagonist is administered at a dose of about mg/kg, about 7.5 mg/kg, or about 10 mg/kg every two weeks.
256. The method of any one of claims 247-249 and 253-255, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 300 mg to about 800 mg every two weeks.
257. The method of any one of claims 247-249 and 253-256, wherein the PD-1 axis binding antagonist is administered at a dose of about 200 mg to about 1200 mg every two weeks.
258. The method of claim 247-249, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 700 mg to about 1000 mg every four weeks. 831 WO 2021/154761 PCT/US2021/015143
259. The method of any one of claims 247-249 and 258, wherein the PD-1 axis binding antagonist is administered at a dose of about 1400 mg to about 2000 mg every four weeks.
260. The method of any one of claims 247-259, wherein the HCC is a locally advanced or metastatic HCC.
261. The method of any one of claims 247-260, wherein the HCC is an unresectable HCC.
262. The method of any one of claims 247-261, wherein the subject or subjects have been determined to have adequate liver function.
263. The method of claim 262, wherein the adequate liver function is characterized as Child-Pugh class A.
264. The method of any one of claims 247-263, wherein an HCC tumor sample obtained from the subject or subjects has been determined to have a detectable expression level of PD-L1.
265. The method of any one of claims 247-264, wherein the method comprises administering to the subject or population of subjects at least four dosing cycles.
266. The method of claim 261, wherein the method comprises administering to the subject or population of subjects at least 16 dosing cycles.
267. 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.
268. The method of any one of claims 249-267, wherein the subject or subjects have received no prior systemic treatment for HCC.
269. The method of any one of claims 247-268, wherein the treatment results in a median PFS of the population of subjects of at least about 5.6 months to at least about 6.83 months.
270. The method of claim 69, wherein the cancer is a bladder cancer.
271. The method of claim 270, wherein the bladder cancer is a muscle-invasive bladder cancer (MIBC). 832 WO 2021/154761 PCT/US2021/015143
272. 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.
273. 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.
274. The method of claim 272 or 273, wherein the subject or subjects have a creatinine clearance of <60 mL/min.
275. The method of any one of claims 272-274, wherein the subject or subjects have a greater than or equal to grade 2 hearing loss.
276. The method of any one of claims 272-275, wherein the subject or subjects have a greater than or equal to grade 2 neuropathy.
277. The method of any one of claims 272-276, wherein the subject or subjects have refused treatment with a platinum-based chemotherapeutic agent.
278. The method of any one of claims 272 or 274-277, wherein the platinum-based chemotherapeutic agent is cisplatin.
279. The method of any one of claims 272-278, wherein the MIBC is surgically operable.
280. The method of claim 279, wherein the method further comprises a surgery.
281. The method of claim 280, wherein at least one dosing cycle is initiated prior to the surgery.
282. The method of claim 280, wherein at least 1,2, or 3 dosing cycles are completed prior to the surgery.
283. The method of any one of claims 280-282, wherein at least one dosing cycle is initiated between 4-6 weeks after the surgery.
284. The method of claim 283, wherein 1-17 dosing cycles are completed after the surgery. 833 WO 2021/154761 PCT/US2021/015143
285. The method of any one of claims 280-284, wherein the surgery is a cystectomy and/or lymph node dissection.
286. The method of any one of claims 272-285, wherein the treating results in a pathological complete response (pCR).
287. The method of any one of claims 272-286, wherein the treating results in an increase in the recurrence-free survival (RFS) of the subject or subjects as compared to a reference RFS time, an increase in the event-free survival (EFS) of the subject or subjects as compared to a reference EFS time, or an increase in the overall survival (OS) of the subject or subjects as compared to a reference OS time.
288. The method of claim 287, wherein:(a) the reference RFS time is the median RFS time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody;(b) the reference EFS time is the median EFS time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; or(c) the reference OS time is the median OS time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.
289. The method of any one of claims 272-288, wherein the treating results in a pathological downstaging.
290. 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.
291. 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 treatment is a perioperative treatment.
292. The method of any one of claims 272-291, wherein the treatment results in an ORR of the population of subjects of at least about 13.4% to at least about 15%.
293. The method of any one of claims 272-292, wherein the treatment results in a median OS of the population of subjects of about 7.9 months to about 8.6 months. 834 WO 2021/154761 PCT/US2021/015143
294. The method of any one of claims 272-293, wherein a detectable protein expression level of RD- L1 determined by an IHC assay comprising staining with anti-PD-L1 antibody SP142 has been determined.
295. The method of claim 294, wherein the detectable protein expression level of PD-L1 is a PD-L1- positive tumor cell fraction with a proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (ICs) greater than or equal to 5%.
296. The method of claim 270, wherein the bladder cancer is a urothelial carcinoma (UC).
297. The method of claim 296, wherein the UC is a metastatic urothelial carcinoma (mUC).
298. 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.
299. The method of claim 298, wherein the subject or subjects have not received a prior cancer immunotherapy.
300. The method of claim 298 or 299, wherein the treatment is a second-line treatment.
301. The method of any one of claims 298-300, wherein the mUC has progressed during or following a platinum-containing therapy.
302. The method of any one of claims 298-301, wherein the method further comprises administering to the subject or population of subjects a second dosing regimen after the subject or population of subjects have experienced disease progression or unacceptable toxicity.
303. The method of claim 302, wherein the second dosing regimen comprises one or more dosing cycles of a PD-1 axis binding antagonist and an antibody-drug conjugate (ADC).
304. The method of claim 303, wherein the ADC is (a) enfortumab vedotin or (b) sacituzumab govitecan.
305. The method of claim 304, wherein (a) enfortumab vedotin is administered at a dose of 1.mg/kg every week for 2-weeks on/1 week off or (b) sacituzumab govitecan is administered at a dose of mg/kg every week for 2-weeks on/1 week off. 835 WO 2021/154761 PCT/US2021/015143
306. 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.
307. 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.
308. The method of any one of claims 298-307, wherein the treatment results in an ORR of the population of subjects of at least about 13.4% to at least about 31%.
309. The method of any one of claims 298-308, wherein the treatment results in a median OS of the population of subjects of about 7.9 months to about 16.3 months.
310. The method of claim 69, wherein the cancer is a pancreatic cancer.
311. 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/m2 on Days 1,8, and 15 of each 28-day dosing cycle.
312. The method of claim 310 or 311, wherein the pancreatic cancer is a pancreatic ductal adenocarcinoma (PDAC).
313. The method of claim 312, wherein the PDAC is a metastatic PDAC.
314. The method of any one of claims 310-313, wherein the subject or subjects have not received prior systemic therapy for metastatic PDAC. 836 WO 2021/154761 PCT/US2021/015143
315. The method of any one of claims 310-314, wherein the treatment results in an ORR of the population of subjects of at least about 41.7% to about 46.7%.
316. The method of any one of claims 310-315, wherein the treatment results in an increase in ORR of at least about 20% compared to a treatment comprising gemcitabine and nab-paclitaxel without an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist.
317. The method of any one of claims 310-316, wherein the treatment results in a median PFS of the population of subjects of at least about 5.5 months to about 7 months.
318. The method of any one of claims 310-317, wherein the treatment results in a median OS of the population of subjects of at least about 8.5 months to about 10.6 months.
319. The method of claim 69, wherein the cancer is an esophageal cancer.
320. 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.
321. 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 5mg 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.
322. The method of claim 320, wherein the subject or subjects have been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.
323. The method of claim 321 or 322, wherein the subject or subjects have experienced disease progression or unacceptable toxicity during the previous treatment.
324. The method of claim 320, wherein the 21 -day dosing cycles further comprise a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.
325. The method of claim 324, wherein the platinum-based chemotherapeutic agent is omitted from the dosing regimen after six doses. 837 WO 2021/154761 PCT/US2021/015143
326. The method of any one of claims 321 -325, wherein the platinum-based chemotherapeutic agent is cisplatin.
327. The method of claim 326, wherein cisplatin is administered at a dose of about 80 mg/m2 on Day of each dosing cycle.
328. The method of any one of claims 321 -327, wherein the non-platinum-based chemotherapeutic agent is an antimetabolite.
329. The method of claim 328, wherein the antimetabolite is 5-fluorouracil.
330. The method of claim 329, wherein 5-fluorouracil is administered at a dose of 800 mg/m2 /hours on Days 1 -5 of each 21 -day cycle.
331. The method of any one of claims 321 -330, wherein the esophageal cancer is an advanced or metastatic esophageal cancer.
332. The method of claim 320 or 331, wherein the subject or subjects have had no prior treatment for metastatic esophageal cancer.
333. 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 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 /hours on Days 1 -5 of each 21 -day cycle, wherein cisplatin is omitted from the dosing regimen after six doses.
334. 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 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 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. 838 WO 2021/154761 PCT/US2021/015143
335. The method of any one of claims 321 -334, wherein the treatment results in an ORR of the population of subjects of at least about 14%.
336. The method of any one of claims 47-335, wherein the anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs):an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2);an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3);an HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); andan HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).
337. The method of claim 336, wherein the anti-TIGIT antagonist antibody further comprises the following light chain variable region framework regions (FRs):an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); andan FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).
338. The method of claim 336, wherein the anti-TIGIT antagonist antibody further comprises the following heavy chain variable region FRs:an FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), wherein X1 is E or Q;an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12);an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); andan FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).
339. The method of claim 338, wherein X1 is E.
340. The method of claim 338, wherein X1 is Q.
341. The method of any one of claims 336-340, wherein the anti-TIGIT antagonist antibody comprises:(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18; 839 WO 2021/154761 PCT/US2021/015143 (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or(c) a VH domain as in (a) and a VL domain as in (b).
342. The method of any one of claims 336-341, wherein the anti-TIGIT antagonist antibody comprises:(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and(b) a VL domain comprising the amino acid sequence of SEQ ID NO: 19.
343. The method of any one of claims 336-339, 341, and 342, wherein the anti-TIGIT antagonist antibody comprises:(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 17; and(b) a VL domain comprising the amino acid sequence of SEQ ID NO: 19.
344. The method of any one of claims 336-339 and 341 -343, wherein the anti-TIGIT antagonist antibody comprises:(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 33; and(b) a light chain comprising the amino acid sequence of SEQ ID NO: 34.
345. The method of any one of claims 336-344, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody.
346. The method of any one of claims 336-345, wherein the anti-TIGIT antagonist antibody is a human antibody.
347. The method of any one of claims 336-346, wherein the anti-TIGIT antagonist antibody is a full- length antibody.
348. The method of any one of claims 336-347, wherein the anti-TIGIT antagonist antibody has intact Fc-mediated effector function.
349. The method of any one of claims 336-339 and 341 -348, wherein the anti-TIGIT antagonist antibody is tiragolumab.
350. The method of any one of claims 336-346, wherein the anti-TIGIT antagonist antibody is an antibody fragment that binds TIGIT selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, single chain variable fragment (scFv), and (Fab’)2 fragments.
351. The method of any one of claims 336-349, wherein the anti-TIGIT antagonist antibody is an IgG class antibody. 840 WO 2021/154761 PCT/US2021/015143
352. The method of claim 351, wherein the IgG class antibody is an IgG 1 subclass antibody.
353. The method of any one of claims 336-352, wherein the PD-1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist.
354. The method of claim 353, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist.
355. The method of claim 354, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners.
356. The method of claim 355, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1, B7-1, or both PD-1 and B7-1.
357. The method of any one of claims 354-356, wherein the PD-L1 binding antagonist is an anti-PD- L1 antagonist antibody.
358. The method of claim 357, wherein the anti-PD-L1 antagonist antibody is atezolizumab, MDX- 1105, durvalumab, avelumab, SHR-1316, CS1001, envafolimab, TQB2450, 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, or HS-636.
359. The method of claim 358, wherein the anti-PD-L1 antagonist antibody is atezolizumab.
360. The method of claim 357, wherein the anti-PD-L1 antagonist antibody comprises the following HVRs:an HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20);an HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 21);an HVR-H3 sequence comprising the amino acid sequence of RHWPGGFDY (SEQ ID NO: 22);an HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23);an HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); andan HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO: 25).
361. The method of claim 360, wherein the anti-PD-L1 antagonist antibody comprises:(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26; 841 WO 2021/154761 PCT/US2021/015143 (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27; or(c) a VH domain as in (a) and a VL domain as in (b).
362. The method of claim 361, wherein the anti-PD-L1 antagonist antibody comprises:(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 26; and(b) a VL domain comprising the amino acid sequence of SEQ ID NO: 27.
363. The method of claim 362, wherein the anti-PD-L1 antagonist antibody comprises:(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 28; and(b) a light chain comprising the amino acid sequence of SEQ ID NO: 29.
364. The method of any one of claims 360-363, wherein the anti-PD-L1 antagonist antibody is a monoclonal antibody.
365. The method of any one of claims 360-364, wherein the anti-PD-L1 antagonist antibody is a humanized antibody.
366. The method of claim 364 or 365, wherein the anti-PD-L1 antagonist antibody is a full-length antibody.
367. The method of any one of claims 360-365, wherein the anti-PD-L1 antagonist antibody is an antibody fragment that binds PD-L1 selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, scFv, and (Fab’)2 fragments.
368. The method of any one of claims 360-366, wherein the anti-PD-L1 antagonist antibody is an IgG class antibody.
369. The method of claim 368, wherein the IgG class antibody is an lgG1 subclass antibody.
370. The method of claim 353, wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist.
371. The method of claim 370, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners.
372. The method of claim 371, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1, PD-L2, or both PD-L1 and PD-L2. 842 WO 2021/154761 PCT/US2021/015143
373. The method of any one of claims 370-372, wherein the PD-1 binding antagonist is an anti-PD-antagonist antibody.
374. The method of claim 373, wherein the anti-PD-1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, cemiplimab, BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, Bl 754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, or hAb21.
375. The method of any one of claims 370-372, wherein the PD-1 binding antagonist is an Fc fusion protein.
376. The method of claim 375, wherein the Fc fusion protein is AMP-224.
377. The method of any one of claims 77-101, 103-116, 119-122, and 247-249, wherein the method comprises administering to the subject or population of subjects the anti-TIGIT antagonist antibody at a dose of between about 500 mg to about 700 mg every three weeks.
378. The method of any one of claims 57, 59, 60, 62-64, 101,123-151, 160, 161,224, 225, 247-255, 272-289, 298-305, 320-332, and 377, wherein the method comprises administering to the subject the anti-TIGIT antagonist antibody at a dose of about 600 mg every three weeks.
379. The method of any one of claims 77, 78, 82, and 83, wherein the method comprises administering to the subject or population of subjects the anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every four weeks.
380. The method of any one of claims 47, 56, 64, 258, and 379, wherein the method comprises administering to the subject the anti-TIGIT antagonist antibody at a dose of about 840 mg every four weeks.
381. The method of any one of claims 77, 78, 82, 83, and 256, wherein the method comprises administering to the subject or population of subjects the anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks.
382. The method of any one of claims 48, 190-213, 215-221,256, and 381, wherein the method comprises administering to the subject the anti-TIGIT antagonist antibody at a dose of about 420 mg every two weeks. 843 WO 2021/154761 PCT/US2021/015143
383. The method of any one of claims 47-382, wherein the dose of the anti-TIGIT antagonist antibody is a fixed dose.
384. The method of any one of claims 77-100, 103-116, 119-122, and 243-245, wherein the method comprises administering to the subject or population of subjects the PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg every three weeks.
385. The method of any one of claims 59, 60, 62-64, 123-151, 160, 161,224, 225, 247-258, 272- 289,298-305, 320-332, and 384, wherein the method comprises administering to the subject the PD-axis binding antagonist at a dose of about 1200 mg every three weeks.
386. The method of any one of claims 77, 78, 82, and 83, wherein the method comprises administering to the subject or population of subjects the PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every four weeks.
387. The method of any one of claims 47, 56, 64, 259, and 386, wherein the method comprises administering to the subject the PD-1 axis binding antagonist at a dose of about 1680 mg every four weeks.
388. The method of claim 77, 78, 82, 83, and 257, wherein the method comprises administering to the subject or population of subjects the PD-1 axis binding antagonist at a dose of between about 600 mg to about 1200 mg every two weeks.
389. The method of any one of claims 48, 190-213, 215-221,257, and 388, wherein the method comprises administering to the subject the PD-1 axis binding antagonist at a dose of about 840 mg every two weeks.
390. The method of any one of claims 47-389, wherein the dose of the PD-1 axis binding antagonist is a fixed dose.
391. The method of claim 58, wherein the method comprises administering to the subject pembrolizumab at a fixed dose of about 400 mg every six weeks.
392. The method of any one of claims 51,57, 59, 60, 62, 77, 78, 82, 83, 103, and 161, wherein the length of each of the one or more dosing cycles is 21 days.
393. The method of any one of claims 47, 56, 64, 77, 184-189, and 253-259, wherein the length of each of the one or more dosing cycles is 28 days. 844 WO 2021/154761 PCT/US2021/015143
394. The method of any one of claims 47-393, wherein the method comprises administering to the subject or population of subjects the anti-TIGIT antagonist antibody on about Day 1 of each of the one or more dosing cycles.
395. The method of any one of claims 47-394, wherein the method comprises administering to the subject or population of subjects the PD-1 axis binding antagonist on about Day 1 of each of the one or more dosing cycles.
396. The method of claim 256, wherein the method comprises administering to the subject the anti- TIGIT antagonist antibody on about Day 15 of each of the one or more dosing cycles.
397. The method of claim 257, wherein the method comprises administering to the subject the PD-axis binding antagonist on about Day 15 of each of the one or more dosing cycles.
398. The method of any one of claims 47-397, wherein the method comprises administering to the subject or population of subjects the PD-1 axis binding antagonist before the anti-TIGIT antagonist antibody.
399. The method of claim 398, wherein the method comprises a first observation period following administration of the PD-1 axis binding antagonist.
400. The method of claim 399, wherein the first observation period is between about 30 minutes to about 60 minutes in length.
401. The method of claim 399 or 400, wherein the method comprises a second observation period following administration of the anti-TIGIT antagonist antibody.
402. The method of claim 401, wherein the second observation period is between about 30 minutes to about 60 minutes in length.
403. The method of any one of claims 47-397, wherein the method comprises administering to the subject or population of subjects the PD-1 axis binding antagonist simultaneously with the anti-TIGIT antagonist antibody.
404. The method of any one of claims 47-403, wherein the method comprises administering to the subject or population of subjects the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist intravenously. 845 WO 2021/154761 PCT/US2021/015143
405. The method of claim 404, wherein the method comprises administering to the subject or population of subjects the PD-1 axis binding antagonist by intravenous infusion over 30 ± 10 minutes and/or over 60 ± 10 minutes.
406. The method of claim 404 or 405, wherein the method comprises administering to the subject or population of subjects the anti-TIGIT antagonist antibody by intravenous infusion over 30 ± 10 minutes and/or over 60 ± 10 minutes.
407. The method of any one of claims 47-103 and 105-406, wherein a PD-L1 expression level of a tumor sample obtained from the subject or subjects have been determined.
408. The method of claim 407, wherein the tumor sample obtained from the subject or subjects have been determined to have a detectable expression level of PD-L1.
409. The method of claim 408, wherein the detectable expression level of PD-L1 is a detectable protein expression level of PD-L1.
410. The method of claim 409, wherein the detectable protein expression level of PD-L1 has been determined by an immunohistochemical (IHC) assay comprising staining with an anti-PD-L1 antibody suitable for staining.
411. The method of claim 410, wherein the anti-PD-L1 antibody suitable for staining is the anti-PD-Lantibody SP263, SP142, 2203, or 28-8.
412. The method of claim 410 or 411, wherein the detectable protein expression level of PD-L1 is determined using a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, a Ventana SP142 IHC assay, or a pharmDx 28-8 IHC assay.
413. The method of any one any one of claims 47-102, 159, 181 -223, and 245-335, wherein a detectable protein expression level of PD-L1 determined by an IHC assay comprising staining with anti- PD-L1 antibody SP263 has been determined.
414. The method of any one any one of claims 47-189, 222-269, and 296-335, wherein a detectable protein expression level of PD-L1 determined by an IHC assay comprising staining with anti-PD-Lantibody SP142 has been determined.
415. The method of any one any one of claims 47-189 and 222-335, wherein a detectable protein expression level of PD-L1 determined by an IHC assay comprising staining with anti-PD-L1 antibody 22C3 has been determined. 846 WO 2021/154761 PCT/US2021/015143
416. The method of any one any one of claims 47-103 and 105-335, wherein a detectable protein expression level of PD-L1 determined by an IHC assay comprising staining with anti-PD-L1 antibody 28-has been determined.
417. The method of claim 413, wherein the detectable protein expression level of PD-L1 is a tumor- associated immune-cell (TIC) of greater than or equal to 5% in the tumor sample.
418. The method of claim 413, wherein the detectable protein expression level of PD-L1 is a TIC of greater than or equal to 5% and less than 20% in the tumor sample.
419. The method of claim 413, wherein the detectable protein expression level of PD-L1 is a TIC of greater than or equal to 10% in the tumor sample.
420. The method of claim 413, wherein the detectable protein expression level of PD-L1 is a TIC of greater than or equal to 20% in the tumor sample.
421. The method of claim 413, wherein the detectable protein expression level of PD-L1 is a TIC of greater than or equal to 10% and less than 50% in the tumor sample.
422. The method of claim 413, wherein the detectable protein expression level of PD-L1 is a TIC of greater than or equal to 50% in the tumor sample.
423. The method of any one of claims 413, 415, and 416, wherein the detectable protein expression level of PD-L1 is a PD-L1-positive tumor cell fraction of greater than or equal to 1%.
424. The method of any one of claims 413, 415, and 416, wherein the detectable protein expression level of PD-L1 is a PD-L1-positive tumor cell fraction of greater than or equal to 30%.
425. The method of any one of claims 413, 415, and 416, wherein the detectable protein expression level of PD-L1 is a PD-L1-positive tumor cell fraction of greater than or equal to 1% and less than 50% in the tumor sample.
426. The method of any one of claims 413, 415, and 416, wherein the detectable protein expression level of PD-L1 is a PD-L1-positive tumor cell fraction of greater than or equal to 50%.
427. The method of claim 414, wherein the PD-L1-positive tumor cell fraction is a proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (ICs).
428. The method of claim 414, wherein the proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating ICs is greater than or equal to 1%. 847 WO 2021/154761 PCT/US2021/015143
429. The method of claim 414, wherein the proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating ICs is greater than or equal to 5%.
430. The method of claim 415, wherein the detectable protein expression level of PD-L1 is a combined positive score (CPS) of greater than or equal to 1.
431. The method of claim 415, wherein the detectable protein expression level of PD-L1 is a CPS of greater than or equal to 10.
432. The method of claim 415, wherein the detectable protein expression level of PD-L1 is a CPS of greater than or equal to 20.
433. The method of any one of claims 427-429, wherein the IHC assay is a Ventana SP142 IHC assay.
434. The method of claim 408, wherein the detectable expression level of PD-L1 is a detectable nucleic acid expression level of PD-L1.
435. The method of claim 434, wherein 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.
436. The method of any one of claims 47-335, wherein the treating results in an increase in overall survival (OS) of the subject as compared to a reference OS time and/or progression-free survival (PFS) of the subject as compared to a reference PFS time.
437. The method of claim 436, wherein:(a) the reference OS time is the median OS time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or a treatment comprising an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist; and/or(b) the reference PFS time is the median PFS time of a population of subjects who have received a treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or a treatment comprising an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist.
438. The method of any one of claims 49, 141, and 190, wherein the one or more chemotherapeutic agents are one or more platinum-based chemotherapeutic agents and/or one or more non-platinum- based chemotherapeutic agents. 848 WO 2021/154761 PCT/US2021/015143
439. The method of claim 438, wherein the platinum-based chemotherapeutic agents is carboplatin or cisplatin.
440. The method of claim 66, 89, 116, 145, 212, and 439, wherein the carboplatin is administered at a dose sufficient to achieve an AUG = 5 mg/ml/min or an AUG = 6 mg/ml/min.
441. The method of claim 66, 116, 145, 147, 149, 151,278, and 326, wherein the cisplatin is administered at a dose of about 75 mg/m2 or 80 mg/m2.
442. The method of any one of claims 438-441, wherein the one or more non-platinum-based chemotherapeutic agents are an antimetabolite, a taxane, or a topoisomerase II inhibitor.
443. The method of claim 59 or 442, wherein the antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil.
444. The method of any one of claims 66, 116,145, and 443, wherein the pemetrexed is administered at a dose of about 500 mg/m2.
445. The method of claim any one of claims 60, 61, 145, 316, and 443, wherein the gemcitabine is administered at a dose of about 1000 mg/m2 or about 1250 mg/m2.
446. The method of claim 59 or 443, wherein the antimetabolite is capecitabine.
447. The method of claim 443 or 446, wherein the capecitabine is administered at a dose of about 1250 mg/m2.
448. The method of any one of claims 193, 202, 203, and 442-447, wherein the taxane is paclitaxel or nab-paclitaxel.
449. The method of any one of claims 66, 145, and 448, wherein the paclitaxel is administered at a dose of about 175 mg/m2 or about 200 mg/m2.
450. The method of any one of claims 60, 61,212,316, and 448, wherein the nab-paclitaxel is administered at a dose of about 100 mg/m2.
451. The method of any one of claims 77, 78, 82, 83, 192, 193, and 442-450, wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, an ellipticine, aurintricarboxylic acid, or HU-331. 849 WO 2021/154761 PCT/US2021/015143
452. The method of any one of claims 66, 89, and 451, wherein the etoposide is administered at a dose of about 100 mg/m2.
453. The method of any one of claims 438-452, wherein the one or more chemotherapeutic agents are each administered once per week, once every two weeks, once every three weeks, twice every three weeks, once every four weeks, twice every four weeks, or three times every four weeks.
454. The method of any one of claims 438-453, wherein the one or more chemotherapeutic agents are administered on Day 1 of one or more dosing cycles.
455. The method of any one of claims 443-454, wherein the gemcitabine is administered three times every four weeks.
456. The method of any one of claims 443-455, wherein the gemcitabine is administered on Days 1, 8, and/or 15 of one or more dosing cycles.
457. The method of any one of claims 443-456, wherein the capecitabine is administered daily for two weeks.
458. The method of any one of claims 443-457, wherein the capecitabine is administered on Days 1 - of one or more dosing cycles.
459. The method of any one of claims 448-458, wherein the nab-paclitaxel is administered three times every four weeks.
460. The method of any one of claims 448-459, wherein the nab-paclitaxel is administered on Days 1, 8, and 15 of one or more dosing cycles.
461. The method of any one of claims 451 -460, wherein the etoposide is administered on Days 1 -every three weeks.
462. The method of any one of claims 451 -461, wherein the etoposide is administered on Days 1 -3 of one or more dosing cycles.
463. The method of any one of claims 438-462, wherein the one or more chemotherapeutic agents are administered before the PD-1 axis binding antagonist and/or the anti-TIGIT antagonist antibody.
464. The method of any one of claims 438-463, wherein the one or more chemotherapeutic agents are administered after the PD-1 axis binding antagonist and/or the anti-TIGIT antagonist antibody. 850 WO 2021/154761 PCT/US2021/015143
465. The method of any one of claims 438-464, wherein the one or more chemotherapeutic agents are administered intravenously or orally.
466. The method of any one of claims 62, 248, and 249, wherein the VEGF antagonist is administered at a dose of about 5 mg/kg to about 25 mg/kg every three weeks.
467. The method of claim 250 or 466, wherein the VEGF antagonist is administered at a dose of about 10 mg/kg to about 20 mg/kg every three weeks.
468. The method of claim 467, wherein the VEGF antagonist is administered at a dose of about mg/kg every three weeks.
469. The method of any one of claims 62, 248-250, 253-255, and 466-468, wherein the VEGF antagonist is an anti-VEGF antibody.
470. The method of claim 469, wherein the anti-VEGF antibody is bevacizumab.
471. The method of any one of claims 62, 248-250, and 253-255, wherein the anti-TIGIT antagonist antibody is tiragolumab, the PD-1 axis binding antagonist is atezolizumab, and the VEGF antagonist is bevacizumab.
472. The method of any one of claims 62, 248-250, 253-255, and 466-471, wherein the method comprises administering to the subject the VEGF antagonist on Day 1 of one or more dosing cycles.
473. The method of any one of claims 253-255, wherein the method comprises administering to the subject the VEGF antagonist on Day 15 of one or more dosing cycles.
474. The method of any one of claims 62, 248-250, 253-255, and 466-471, wherein the VEGF antagonist is administered intravenously.
475. The method of claim 474, wherein the VEGF antagonist is administered to the subject by intravenous infusion over 90 ± 15 minutes.
476. The method of any one of claims 62, 248-250, 253-255, and 466-475, wherein the method comprises administering to the subject the PD-1 axis binding antagonist before the VEGF antagonist and the VEGF antagonist before the anti-TIGIT antagonist antibody.
477. The method of claim 476, wherein the method comprises a first observation period following administration of the PD-1 axis binding antagonist, a second observation period following administration 851 WO 2021/154761 PCT/US2021/015143 of the VEGF antagonist, and a third observation period following administration of the anti-TIGIT antagonist antibody.
478. The method of claim 477, wherein the first observation period, the second observation period, and the third observation period are each between about 30 minutes to about 120 minutes in length.
479. The method of any one of claims 102, 117, 118, 152, 153, 177, 184, 214, 226, 267, 290, 291, 306, 307, 311,333, and 334, wherein tiragolumab and atezolizumab are combined in an IV bag prior to administration.
480. The method of any one of claims 47-479, wherein the subject is a human.
481. 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 method of any one of claims 47-160, 162-224, and 226-480.
482. 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 method of any one of claims 47-160, 162-224, and 226-480.
483. The kit of claim 482, wherein the kit further comprises an anti-TIGIT antagonist antibody.
484. The kit of any one of claims 481 -483, wherein the anti-TIGIT antagonist antibody is tiragolumab.
485. The kit of any one of claims 481 -484, wherein the PD-1 axis binding antagonist is atezolizumab.
486. 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 method of any one of claims 47- 160, 162-224, and 226-480.
487. The kit of claim 486, wherein the kit further comprises a PD-1 axis binding antagonist.
488. The kit of claim 486 or 487, wherein the PD-1 axis binding antagonist is atezolizumab.
489. The kit of any one of claims 486-488, wherein the anti-TIGIT antagonist antibody is tiragolumab.
490. The kit of any one of claims 486-489, wherein the kit further comprises one or more chemotherapeutic agents. 852 WO 2021/154761 PCT/US2021/015143
491. The kit of claim 490, wherein the one or more chemotherapeutic agents are one or more platinum-based chemotherapeutic agents and/or one or more non-platinum-based chemotherapeutic agents.
492. The kit of claim 491, wherein the one or more platinum-based chemotherapeutic agents are carboplatin or cisplatin.
493. The kit of claim 491 or 492, wherein the one or more non-platinum-based chemotherapeutic agent are an antimetabolite, a taxane, or a topoisomerase II inhibitor.
494. The kit of claim 493, wherein the antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5- fluorouracil.
495. The kit of claim 493 or 494, wherein the taxane is paclitaxel or nab-paclitaxel.
496. The kit of any one of claims 493-495, wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, an ellipticine, aurintricarboxylic acid, or HU-331.
497. The kit of any one of claims 481 -496, wherein the kit further comprises a VEGF antagonist.
498. The kit of claim 497, wherein the VEGF antagonist is an anti-VEGF antibody.
499. The kit of claim 498, wherein the anti-VEGF antibody is bevacizumab.
500. 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 any one of claims 47-160, 162-224, and 226-480.
501. 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 method of any one of claims 47-160, 162-224, and 226-480.
502. The use of claim 501, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations.
503. The use of claim 501, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single formulation. 853
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Family Cites Families (38)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
| US6548640B1 (en) | 1986-03-27 | 2003-04-15 | Btg International Limited | Altered antibodies |
| DE3920358A1 (en) | 1989-06-22 | 1991-01-17 | Behringwerke Ag | BISPECIFIC AND OLIGO-SPECIFIC, MONO- AND OLIGOVALENT ANTI-BODY CONSTRUCTS, THEIR PRODUCTION AND USE |
| US6075181A (en) | 1990-01-12 | 2000-06-13 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
| US6150584A (en) | 1990-01-12 | 2000-11-21 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
| CA2122732C (en) | 1991-11-25 | 2008-04-08 | Marc D. Whitlow | Multivalent antigen-binding proteins |
| GB9300059D0 (en) | 1992-01-20 | 1993-03-03 | Zeneca Ltd | Quinazoline derivatives |
| GB9314893D0 (en) | 1993-07-19 | 1993-09-01 | Zeneca Ltd | Quinazoline derivatives |
| IL112248A0 (en) | 1994-01-25 | 1995-03-30 | Warner Lambert Co | Tricyclic heteroaromatic compounds and pharmaceutical compositions containing them |
| IL112249A (en) | 1994-01-25 | 2001-11-25 | Warner Lambert Co | Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds |
| US5679683A (en) | 1994-01-25 | 1997-10-21 | Warner-Lambert Company | Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family |
| HU216142B (en) | 1994-07-21 | 1999-04-28 | Akzo Nobel N.V. | Cyclic ketone peroxide formulations and their use for modification of (co)polymers |
| US5804396A (en) | 1994-10-12 | 1998-09-08 | Sugen, Inc. | Assay for agents active in proliferative disorders |
| EP2163546B1 (en) | 1995-03-30 | 2016-06-01 | Pfizer Products Inc. | Quinazoline derivatives |
| US5641870A (en) | 1995-04-20 | 1997-06-24 | Genentech, Inc. | Low pH hydrophobic interaction chromatography for antibody purification |
| GB9508565D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quiazoline derivative |
| GB9508538D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
| US5747498A (en) | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
| BR9609617B1 (en) | 1995-07-06 | 2010-07-27 | 7h-pyrrol [2,3-d] pyrimidine derivatives, and pharmaceutical composition. | |
| US5760041A (en) | 1996-02-05 | 1998-06-02 | American Cyanamid Company | 4-aminoquinazoline EGFR Inhibitors |
| GB9603095D0 (en) | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline derivatives |
| BR9708640B1 (en) | 1996-04-12 | 2013-06-11 | irreversible tyrosine kinase inhibitors and pharmaceutical composition comprising them. | |
| AU3766897A (en) | 1996-07-13 | 1998-02-09 | Glaxo Group Limited | Fused heterocyclic compounds as protein tyrosine kinase inhibitors |
| ID18494A (en) | 1996-10-02 | 1998-04-16 | Novartis Ag | PIRAZOLA DISTRIBUTION IN THE SEQUENCE AND THE PROCESS OF MAKING IT |
| US6002008A (en) | 1997-04-03 | 1999-12-14 | American Cyanamid Company | Substituted 3-cyano quinolines |
| UA73073C2 (en) | 1997-04-03 | 2005-06-15 | Уайт Холдінгз Корпорейшн | Substituted 3-cyan chinolines |
| DE69815340T2 (en) | 1997-05-06 | 2004-05-06 | Wyeth Holdings Corp. | USE OF CHINAZOLIN COMPOUNDS FOR TREATING POLYCYSTIC KIDNEY DISEASE |
| ZA986732B (en) | 1997-07-29 | 1999-02-02 | Warner Lambert Co | Irreversible inhibitiors of tyrosine kinases |
| ZA986729B (en) | 1997-07-29 | 1999-02-02 | Warner Lambert Co | Irreversible inhibitors of tyrosine kinases |
| TW436485B (en) | 1997-08-01 | 2001-05-28 | American Cyanamid Co | Substituted quinazoline derivatives |
| CN1278176A (en) | 1997-11-06 | 2000-12-27 | 美国氰胺公司 | Use of quinazoline derivatives as tyrosine kinase inhibitors for treating colonic polyps |
| BR9813365A (en) | 1997-12-05 | 2004-06-15 | Scripps Research Inst | Method for Production and Humanization of a Mouse Monoclonal Antibody |
| PL347717A1 (en) | 1998-11-19 | 2002-04-22 | Warner Lambert Co | N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, an irreversible inhibitor of tyrosine kinases |
| ES2564127T5 (en) | 2004-06-04 | 2020-03-26 | Genentech Inc | EGFR mutations |
| EP2898329B1 (en) | 2012-09-24 | 2017-05-17 | Ventana Medical Systems, Inc. | Method of identifying treatment responsive non-small cell lung cancer using anaplastic lymphoma kinase (alk) as a marker |
| JP7048319B2 (en) | 2015-05-12 | 2022-04-05 | ジェネンテック， インコーポレイテッド | Treatment and diagnosis methods for cancer |
| JP7144935B2 (en) | 2015-05-29 | 2022-09-30 | ジェネンテック， インコーポレイテッド | Therapeutic and diagnostic methods for cancer |
| US20200399376A1 (en) * | 2018-02-26 | 2020-12-24 | Genentech, Inc. | Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies |
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