Methods for treatment of pancreatic cancer with Anti-PD-l1 ab, Anti-tigit ab, gemcitabine and NAB-placlitaxel

Abstract

The present invention relates to the treatment of PD-L1 -positive pancreatic cancer, e.g., PD-L1-positive pancreatic ductal adenocarcinoma (PDAC), e.g., PD-L1 -positive metastatic PDAC. More specifically, the invention pertains to the treatment of patients having a PD-L1 -positive pancreatic cancer by administering an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody, e.g., by administering an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody in combination with one or more chemotherapeutic agents.

Description

[0001] METHODS FOR TREATMENT OF PANCREATIC CANCER WITH ANTI-PD-L1 AB, ANTI-TIGIT AB, GEMCITABINE AND NAB- PLACLITAXEL

[0002] SEQUENCE LISTING

[0003] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on January 30, 2025, is named 50474-348WO2_Sequence_Listing_1_30_25, and is 39,297 bytes in size.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to the treatment of PD-L1 -positive pancreatic cancer, e.g., PD-L1 - positive pancreatic ductal adenocarcinoma (PDAC), e.g., PD-L1 -positive metastatic PDAC. More specifically, the invention pertains to the treatment of patients having a PD-L1 -positive pancreatic cancer by administering an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody, e.g., by administering an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody in combination with one or more chemotherapeutic agents.

[0006] BACKGROUND OF THE INVENTION

[0007] Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid tumor of the pancreatic ductal epithelium. It is the third-leading cause of cancer-related mortality in the United States as well as in the European Union, with increasing world-wide mortality rates that align with the projection of being the second leading cause of cancer death in the United States by 2030.

[0008] Presently, surgical resection offers the only means of cure. However, only 15-20% of patients have resectable disease, while 80-85% of patients present with advanced disease at initial diagnosis that is not amenable to curative resection. Patients who have locally advanced and unresectable disease comprise approximately one third of new PDAC diagnoses and are typically treated with chemoradiation and / or systemic chemotherapy resulting in a median overall survival (OS) of up to 2 years. The majority of PDAC patients present with metastatic disease at initial diagnosis, receive chemotherapy, and have a poor prognosis, with a median OS of 8.5-11 .1 months and a 5-year OS of 2%. Therefore, there is a high unmet need for improved systemic treatments.

[0009] SUMMARY OF THE INVENTION

[0010] In one aspect, the invention provides a method of treating a subject having a pancreatic cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody, wherein a tumor sample from the subject has been determined to be PD-L1 -positive; and wherein: (a) 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); and an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6); and (b) 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); and an HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO: 25).

[0011] In some aspects, the pancreatic cancer is a pancreatic ductal adenocarcinoma (PDAC). In some aspects, the PDAC is a metastatic PDAC.

[0012] In some aspects, the subject has not received prior systemic therapy for pancreatic cancer.

[0013] In some aspects, the anti-TIG IT 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; and (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.

[0014] In some aspects, the anti-TIG IT 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; and (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.

[0015] In some aspects, the anti-TIG IT 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. In some aspects, the anti-TIG IT 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.

[0016] In some aspects, the anti-TIG IT 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.

[0017] In some aspects, the anti-TIG IT antagonist antibody is tiragolumab.

[0018] In some aspects, the method comprises administering the anti-TIGIT antagonist antibody to the subject at a dose of about 840 mg every four weeks. For example, in some aspects, the method comprises administering tiragolumab to the subject intravenously at a dose of about 840 mg (e.g., at a dose of 840 mg) every four weeks.

[0019] In some aspects, the method comprises administering the anti-TIGIT antagonist antibody to the subject subcutaneously.

[0020] In some aspects, the method comprises administering the anti-TIGIT antagonist antibody to the subject subcutaneously at a dose of about 880 mg (e.g., at a dose of 880 mg) every two weeks, every three weeks, or every four weeks. For example, in some aspects, the method comprises administering tiragolumab to the subject subcutaneously at a dose of about 880 mg (e.g., at a dose of 880 mg) every two weeks, comprises administering tiragolumab to the subject subcutaneously at a dose of about 880 mg (e.g., at a dose of 880 mg) every three weeks, or comprises administering tiragolumab to the subject subcutaneously at a dose of about 880 mg (e.g., at a dose of 880 mg) every four weeks. In some aspects, the method comprises administering the anti-TIGIT antagonist antibody to the subject subcutaneously at a dose of about 1000 mg (e.g., at a dose of 1000 mg) every two weeks, every three weeks, or every four weeks. For example, in some aspects, the method comprises administering tiragolumab to the subject subcutaneously at a dose of about 1000 mg (e.g., at a dose of 1000 mg) every two weeks, comprises administering tiragolumab to the subject subcutaneously at a dose of about 1000 mg (e.g., at a dose of 1000 mg) every three weeks, or comprises administering tiragolumab to the subject subcutaneously at a dose of about 1000 mg (e.g., at a dose of 1000 mg) every four weeks.

[0021] In some aspects, 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; and (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.

[0022] In some aspects, 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.

[0023] In some aspects, 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.

[0024] In some aspects, the anti-PD-L1 antagonist antibody is atezolizumab.

[0025] In some aspects, the method comprises administering the anti-PD-L1 antagonist antibody to the subject at a dose of about 1680 mg every four weeks.

[0026] In some aspects, the method comprises administering the anti-PD-L1 antagonist antibody to the subject subcutaneously.

[0027] In some aspects, the method comprises administering the anti-PD-L1 antagonist antibody to the subject subcutaneously at a dose of about 1875 mg (e.g., at a dose of 1875 mg) every two weeks, every three weeks, or every four weeks. For example, in some aspects, the method comprises administering atezolizumab to the subject subcutaneously at a dose of about 1875 mg (e.g., at a dose of 1875 mg) every two weeks, comprises administering atezolizumab to the subject subcutaneously at a dose of about 1875 mg (e.g., at a dose of 1875 mg) every three weeks, or comprises administering atezolizumab to the subject subcutaneously at a dose of about 1875 mg (e.g., at a dose of 1875 mg) every four weeks.

[0028] In some aspects, the method comprises administering the anti-PD-L1 antagonist antibody to the subject subcutaneously at a dose of about 2000 mg (e.g., at a dose of 2000 mg) every two weeks, every three weeks, or every four weeks. For example, in some aspects, the method comprises administering atezolizumab to the subject subcutaneously at a dose of about 2000 mg (e.g., at a dose of 2000 mg) every two weeks, comprises administering atezolizumab to the subject subcutaneously at a dose of about 2000 mg (e.g., at a dose of 2000 mg) every three weeks, or comprises administering atezolizumab to the subject subcutaneously at a dose of about 2000 mg (e.g., at a dose of 2000 mg) every four weeks.

[0029] In some aspects, the method comprises co-administering the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody (e.g., intravenously or subcutaneously co-administering the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody). In some aspects, the co-administered anti- TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody (e.g., tiragolumab and atezolizumab) are co-formulated. In other aspects, the co-administered anti-TIGIT antagonist antibody and the anti-PD- L1 antagonist antibody (e.g., tiragolumab and atezolizumab) formulated separately and are mixed by the physician administering the drugs (e.g., are combined in an IV bag prior to administration).

[0030] In other aspects, the method comprises administering the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody separately (e.g., comprises separately administering the antibody and the anti-PD-L1 antagonist antibody intravenously or subcutaneously).

[0031] In some aspects, the length of each of the one or more dosing cycles is 28 days. In some aspects, the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are administered on about Day 1 of each dosing cycle.

[0032] In some aspects, the method comprises further administering to the subject one or more chemotherapeutic agents. In some aspects, the method comprises administering to the subject a taxane and an antimetabolite.

[0033] In some aspects, the taxane is nab-paclitaxel. In some aspects, the length of each of the one or more dosing cycles is 28 days, and nab-paclitaxel is administered three times over the course of each 28- day dosing cycle. In some aspects, nab-paclitaxel is administered on Days 1 , 8, and 15 of each 28-day dosing cycle. In some aspects, nab-paclitaxel is administered at a dose of about 125 mg / m2.

[0034] In some aspects, the antimetabolite is gemcitabine. In some aspects, the length of each of the one or more dosing cycles is 28 days, and gemcitabine is administered three times over the course of each 28-day dosing cycle. In some aspects, gemcitabine is administered on Days 1 , 8, and 15 of each 28-day dosing cycle. In some aspects, gemcitabine is administered at a dose of about 1000 mg / m2.

[0035] In some aspects, on Day 1 of each 28-day dosing cycle, the method comprises (i) administering the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody before administering nab- paclitaxel and (ii) administering nab-paclitaxel before administering gemcitabine.

[0036] In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody, the anti-PD-L1 antagonist antibody, the taxane, and / or the antimetabolite intravenously.

[0037] In another aspect, the invention provides a method of treating a subject having a pancreatic cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of atezolizumab, tiragolumab, nab-paclitaxel, and gemcitabine, wherein a tumor sample from the subject has been determined to have a PD-L1 tumor area positive (TAP) score of equal to or greater than 1 % using the VENTANA PD-L1 (SP263) CDx Assay, and wherein the pancreatic cancer is a metastatic pancreatic ductal adenocarcinoma (PDAC).

[0038] In some aspects, the method comprises administering tiragolumab to the subject at a dose of about 840 mg every four weeks; administering atezolizumab to the subject at a dose of about 1680 mg every four weeks; administering nab-paclitaxel to the subject at a dose of about 125 mg / m2; and administering gemcitabine to the subject at a dose of about 1000 mg / m2.

[0039] In some aspects, the method comprises co-administering atezolizumab and tiragolumab.

[0040] In some aspects, the length of each of the one or more dosing cycles is 28 days, and tiragolumab is administered on about Day 1 of each dosing cycle; atezolizumab is administered on about Day 1 of each dosing cycle; nab-paclitaxel is administered on Days 1 , 8, and 15 of each 28-day dosing cycle; and gemcitabine is administered on Days 1 , 8, and 15 of each 28-day dosing cycle.

[0041] In another aspect, the invention provides an anti-TIGIT antagonist antibody and / or an anti-PD-L1 antagonist antibody for use in a method of treating a subject having a pancreatic cancer, wherein the method comprises administering to the subject a dosing regimen comprising one or more dosing cycles of the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody, wherein a tumor sample from the subject has been determined to be PD-L1 -positive; and wherein (a) 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); and an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6); and (b) 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); and an HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO: 25).

[0042] In some aspects, the pancreatic cancer is a pancreatic ductal adenocarcinoma (PDAC). In some aspects, the PDAC is a metastatic PDAC.

[0043] In some aspects, the subject has not received prior systemic therapy for pancreatic cancer.

[0044] In some aspects, 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; and (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.

[0045] In some aspects, 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; and (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.

[0046] In some aspects, 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.

[0047] In some aspects, 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.

[0048] In some aspects, 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.

[0049] In some aspects, the anti-TIGIT antagonist antibody is tiragolumab.

[0050] In some aspects, the anti-TIGIT antagonist antibody is to be administered to the subject at a dose of about 840 mg every four weeks.

[0051] In some aspects, the anti-TIGIT antagonist antibody is to be administered to the subject subcutaneously. In some aspects, the anti-TIG IT antagonist antibody is to be administered to the subject subcutaneously at a dose of about 880 mg (e.g., at a dose of 880 mg) every two weeks, every three weeks, or every four weeks. For example, in some aspects, tiragolumab is to be administered to the subject subcutaneously at a dose of about 880 mg (e.g., at a dose of 880 mg) every two weeks, tiragolumab is to be administered to the subject subcutaneously at a dose of about 880 mg (e.g., at a dose of 880 mg) every three weeks, or tiragolumab is to be administered to the subject subcutaneously at a dose of about 880 mg (e.g., at a dose of 880 mg) every four weeks.

[0052] In some aspects, the anti-TIG IT antagonist antibody is to be administered to the subject subcutaneously at a dose of about 1000 mg (e.g., at a dose of 1000 mg) every two weeks, every three weeks, or every four weeks. For example, in some aspects, tiragolumab is to be administered to the subject subcutaneously at a dose of about 1000 mg (e.g., at a dose of 1000 mg) every two weeks, tiragolumab is to be administered to the subject subcutaneously at a dose of about 1000 mg (e.g., at a dose of 1000 mg) every three weeks, or tiragolumab is to be administered to the subject subcutaneously at a dose of about 1000 mg (e.g., at a dose of 1000 mg) every four weeks.

[0053] In some aspects, 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; and (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.

[0054] In some aspects, 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.

[0055] In some aspects, 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.

[0056] In some aspects, the anti-PD-L1 antagonist antibody is atezolizumab.

[0057] In some aspects, the anti-PD-L1 antagonist antibody is to be administered to the subject at a dose of about 1680 mg every four weeks

[0058] In some aspects, the anti-PD-L1 antagonist antibody is to be administered to the subject subcutaneously.

[0059] In some aspects, the anti-PD-L1 antagonist antibody is to be administered to the subject subcutaneously at a dose of about 1875 mg (e.g., at a dose of 1875 mg) every two weeks, every three weeks, or every four weeks. For example, in some aspects, atezolizumab is to be administered to the subject subcutaneously at a dose of about 1875 mg (e.g., at a dose of 1875 mg) every two weeks, atezolizumab is to be administered to the subject subcutaneously at a dose of about 1875 mg (e.g., at a dose of 1875 mg) every three weeks, or atezolizumab is to be administered to the subject subcutaneously at a dose of about 1875 mg (e.g., at a dose of 1875 mg) every four weeks.

[0060] In some aspects, the anti-PD-L1 antagonist antibody is to be administered to the subject subcutaneously at a dose of about 2000 mg (e.g., at a dose of 2000 mg) every two weeks, every three weeks, or every four weeks. For example, in some aspects, atezolizumab is to be administered to the subject subcutaneously at a dose of about 2000 mg (e.g., at a dose of 2000 mg) every two weeks, atezolizumab is to be administered to the subject subcutaneously at a dose of about 2000 mg (e.g., at a dose of 2000 mg) every three weeks, or atezolizumab is to be administered to the subject subcutaneously at a dose of about 2000 mg (e.g., at a dose of 2000 mg) every four weeks.

[0061] In some aspects, the anti-TIG IT antagonist antibody and the anti-PD-L1 antagonist antibody are to be co-administered (e.g., are to be intravenously or subcutaneously co-administered). In some aspects, the co-administered anti-TIG IT antagonist antibody and the anti-PD-L1 antagonist antibody (e.g., tiragolumab and atezolizumab) are co-formulated. In other aspects, the co-administered anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody (e.g., tiragolumab and atezolizumab) formulated separately and are mixed by the physician administering the drugs (e.g., are combined in an IV bag prior to administration).

[0062] In other aspects, the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are to be administered separately (e.g., are to be separately administered intravenously or subcutaneously).

[0063] In some aspects, the length of each of the one or more dosing cycles is 28 days. In some aspects, the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are to be administered on about Day 1 of each dosing cycle.

[0064] In some aspects, the method comprises further administering to the subject one or more chemotherapeutic agents. In some aspects, a taxane and an antimetabolite are to be administered to the subject.

[0065] In some aspects, the taxane is nab-paclitaxel. In some aspects, the length of each of the one or more dosing cycles is 28 days, and nab-paclitaxel is to be administered three times over the course of each 28-day dosing cycle. In some aspects, nab-paclitaxel is to be administered on Days 1 , 8, and 15 of each 28-day dosing cycle. In some aspects, nab-paclitaxel is to be administered at a dose of about 125 mg / m2.

[0066] In some aspects, the antimetabolite is gemcitabine. In some aspects, the length of each of the one or more dosing cycles is 28 days, and gemcitabine is to be administered three times over the course of each 28-day dosing cycle. In some aspects, gemcitabine is to be administered on Days 1 , 8, and 15 of each 28-day dosing cycle. In some aspects, gemcitabine is to be administered at a dose of about 1000 mg / m2.

[0067] In some aspects, on Day 1 of each 28-day dosing cycle, (i) the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are to be administered before nab-paclitaxel and (ii) nab-paclitaxel is to be administered before gemcitabine.

[0068] In some aspects, the anti-TIGIT antagonist antibody, the anti-PD-L1 antagonist antibody, the taxane, and / or the antimetabolite are to be administered to the subject intravenously.

[0069] In another aspect, the invention provides atezolizumab and / or tiragolumab for use in a method of treating a subject having a pancreatic cancer, wherein the method comprises administering to the subject a dosing regimen comprising one or more dosing cycles of atezolizumab, tiragolumab, nab-paclitaxel, and gemcitabine, wherein a tumor sample from the subject has been determined to have a PD-L1 tumor area positive (TAP) score of equal to or greater than 1 % using the VENTANA PD-L1 (SP263) CDx Assay, and wherein the pancreatic cancer is a metastatic pancreatic ductal adenocarcinoma (PDAC).

[0070] In some aspects, tiragolumab is to be administered to the subject at a dose of about 840 mg every four weeks; atezolizumab is to be administered to the subject at a dose of about 1680 mg every four weeks; nab-paclitaxel is to be administered to the subject at a dose of about 125 mg / m2; and gemcitabine is to be administered to the subject at a dose of about 1000 mg / m2.

[0071] In some aspects, atezolizumab and tiragolumab are to be co-administered.

[0072] In some aspects, the length of each of the one or more dosing cycles is 28 days, and tiragolumab is to be administered on about Day 1 of each dosing cycle; atezolizumab is to be administered on about Day 1 of each dosing cycle; nab-paclitaxel is to be administered on Days 1 , 8, and 15 of each 28-day dosing cycle; and gemcitabine is to be administered on Days 1 , 8, and 15 of each 28-day dosing cycle.

[0073] In some aspects, the tumor sample from the subject has been determined to be PD-L1 -positive by an immunohistochemical (IHC) assay comprising staining with an anti-PD-L1 antibody suitable for staining. In some aspects, the anti-PD-L1 antibody suitable for staining is the anti-PD-L1 antibody SP263, SP142, 22C3, or 28-8. In some aspects, the 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.

[0074] In some aspects, the anti-PD-L1 antibody suitable for staining is the anti-PD-L1 antibody SP263, and the protein expression level of PD-L1 has been determined using the VENTANA PD-L1 (SP263) CDx Assay. In some aspects, the tumor sample obtained from the subject has been determined to have a PD- L1 tumor area positive (TAP) score of equal to or greater than 1 %.

[0075] In some aspects, the tumor sample from the subject has been determined to be PD-L1 -positive by an assay that detects a nucleic acid expression level of PD-L1 . In some aspects, the nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT- qPCR, microarray analysis, SAGE, MassARRAY technique, ISH, or a combination thereof.

[0076] In some aspects, the treating results in an increase in progression-free survival (PFS) as compared to a reference PFS. In some aspects, the reference PFS is the mean or median PFS of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIG IT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

[0077] In some aspects, the treating results in an increase in overall survival (OS) as compared to a reference OS. In some aspects, the reference OS is the mean or median OS of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIGIT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

[0078] In some aspects, the treating results in an increase in OS rate at 12 months as compared to a reference 12-month OS rate. In some aspects, the reference 12-month OS rate is the 12-month OS rate of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIGIT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

[0079] In some aspects, the treating results in an increase in OS rate at 24 months as compared to a reference 24-month OS rate. In some aspects, the reference 24-month OS rate is the 24-month OS rate of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIG IT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

[0080] In some aspects, the treating results in an increase in objective response rate (ORR) as compared to a reference ORR. In some aspects, the reference ORR is the mean or median ORR of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIG IT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

[0081] In some aspects, the treating results in an increase in duration of response (DOR) as compared to a reference DOR. In some aspects, the reference DOR is the mean or median DOR of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIG IT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

[0082] In some aspects, the treating results in an increase in disease control rate (DCR) as compared to a reference DCR. In some aspects, the reference DCR is the DCR of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIG IT antagonist antibody and does not comprise administration of an anti-PD- L1 antagonist antibody.

[0083] In some aspects, the subject is a human.

[0084] BRIEF DESCRIPTION OF THE DRAWINGS

[0085] FIG. 1 A is a schematic diagram showing the overall design of the GO45216 study. PDAC = pancreatic ductal adenocarcinoma; ECOG = Eastern Cooperative Oncology Group; PD-L1 = programmed death ligand 1 ; PS = performance status; TAP = tumor area positive score; R = randomization; nab- paclitaxel = nanoparticle albumin-bound paclitaxel.

[0086] FIG. 1 B is a schematic diagram showing the design of the GO45216 study. IV = intravenous; ROW = rest of world.

[0087] FIG. 2 is a schematic diagram showing possible outcomes of a gating decision made by an independent Data Monitoring Committee (iDMC) following the enrollment of approximately 100 patients in the Phase 1 b part of the GO45216 study. HR = hazard ratio; OS = overall survival; PFS = progression- free survival. DETAILED DESCRIPTION OF THE INVENTION

[0088] I. Definitions

[0089] It is to be understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of” aspects and embodiments. As used herein, the singular form “a,” “an,” and “the” includes plural references unless indicated otherwise.

[0090] The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) aspects that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.”

[0091] The term “comparator” or “comparator arm” as used herein refers to a reference (e.g., a reference population of patients) used as a basis of comparison for a treatment or treatment arm in a study, e.g., a clinical trial. For example, a comparator arm may be a control arm in a clinical trial. The comparator arm may include a population of patients who have received a control treatment, such as one or more previously approved treatments or marketed products.

[0092] The term “TIGIT” or “T-cell immunoreceptor with Ig and ITIM domains” as used herein refers to any native TIGIT from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. TIGIT is also known in the art as DKFZp667A205, FLJ39873, V-set and immunoglobulin domain-containing protein 9, V-set and transmembrane domain-containing protein 3, VSIG9, VSTM3, and WUCAM. The term encompasses “full-length,” unprocessed TIGIT (e.g., full-length human TIGIT having the amino acid sequence of SEQ ID NO: 30), as well as any form of TIGIT that results from processing in the cell (e.g., processed human TIGIT without a signal sequence, having the amino acid sequence of SEQ ID NO: 31 ). The term also encompasses naturally occurring variants of TIGIT, e.g., splice variants or allelic variants. The amino acid sequence of an exemplary human TIGIT may be found under UniProt Accession Number Q495A1 .

[0093] As used herein, “tiragolumab” is a fully human lgG1 / kappa MAb that binds TIGIT and comprises the heavy chain sequence of SEQ ID NO: 33 and the light chain sequence of SEQ ID NO: 34. Tiragolumab comprises two N-linked glycosylation sites (N306) in the Fc domain. Tiragolumab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 117, Vol. 31 , No. 2, published June 9, 2017 (see page 343). Tiragolumab (Genentech) is also known as MTIG7192A, RG6058, or RO7092284. Tiragolumab is described in PCT Pub. Nos. WQ2003072305A8, WQ2004024068A3, WQ2004024072A3, WQ2009126688A2, WQ2015009856A2, WQ2016011264A1 , WQ2016109546A2, WQ2017053748A2, and WQ2019165434A1 ; US Pub. Nos. 2017 / 0044256, 2017 / 0037127, 2017 / 0145093, 2017 / 260594, 2017 / 0088613, 2018 / 0186875, 2019 / 0119376; and US Pat. Nos. US9873740B2, US10626174B2, US10611836B2, US9499596B2, US8431350B2, US10047158B2, and US10017572B2.

[0094] The term “anti-TIG IT antagonist antibody” refers to an antibody or an antigen-binding fragment or variant thereof that is capable of binding TIGIT with sufficient affinity such that it substantially or completely inhibits the biological activity of TIGIT. For example, an anti-TIG IT antagonist antibody may block signaling through PVR, PVRL2, and / or PVRL3 so as to restore a functional response by T-cells (e.g., proliferation, cytokine production, target cell killing) from a dysfunctional state to antigen stimulation. For example, an anti-TIGIT antagonist antibody may block signaling through PVR without impacting PVR- CD226 interaction. It will be understood by one of ordinary skill in the art that in some instances, an anti- TIGIT antagonist antibody may antagonize one TIGIT activity without affecting another TIGIT activity. For example, an anti-TIGIT antagonist antibody for use in certain of the methods or uses described herein is an anti-TIGIT antagonist antibody that antagonizes TIGIT activity in response to one of PVR interaction, PVRL3 interaction, or PVRL2 interaction, e.g., without affecting or minimally affecting any of the other TIGIT interactions. In one aspect, the extent of binding of an anti-TIGIT antagonist antibody to an unrelated, non-TIGIT protein is less than about 10% of the binding of the antibody to TIGIT as measured, e.g., by a radioimmunoassay (RIA). In certain aspects, an anti-TIGIT antagonist antibody that binds to TIGIT has a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10-8M or less, e.g., from 10-8M to 10-13M, e.g., from 10-9M to 10-13M). In certain aspects, an anti-TIGIT antagonist antibody binds to an epitope of TIGIT that is conserved among TIGIT from different species or an epitope on TIGIT that allows for cross-species reactivity. In some aspects, the anti-TIGIT binding antibody has intact Fc-mediated effector function (e.g., tiragolumab, vibostolimab, etigilimab, EOS084448, or TJ-T6). In some aspects, the anti-TIGIT binding antibody has enhanced Fc- mediated effector function (e.g., SGN-TGT). In other aspects, the anti-TIGIT binding antibody lacks Fc- mediated effector function (e.g., domvanalimab, BMS-986207, ASP8374, or COM902). In some aspects, the anti-TIGIT binding antibody is an lgG1 class antibody (e.g., tiragolumab, vibostolimab, domvanalimab, BMS-986207, etigilimab, BGB-A1217, SGN-TGT, EOS084448 (EOS-448), TJ-T6, or AB308). In other aspects, the anti-TIGIT binding antibody is an lgG4 class antibody (e.g., ASP8374 or COM902). In one aspect, the anti-TIGIT antagonist antibody is tiragolumab.

[0095] The terms “programmed death ligand 1 ” and “PD-L1” refer herein to native sequence human PD- L1 polypeptide. Native sequence PD-L1 polypeptides are provided under Uniprot Accesion No. Q9NZQ7. For example, the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accesion No. Q9NZQ7-1 (isoform 1 ) (SEQ ID NO: 32). In another example, the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accesion No. Q9NZQ7-2 (isoform 2). In yet another example, the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accesion No. Q9NZQ7-3 (isoform 3). PD-L1 is also referred to in the art as “programmed cell death 1 ligand 1 ,” “PDCD1 LG1 ,” “CD274,” “B7-H,” and “PDL1 .”

[0096] For the purposes herein, “atezolizumab” is an Fc-engineered, humanized, non-glycosylated lgG1 kappa immunoglobulin that binds PD-L1 and comprises the heavy chain sequence of SEQ ID NO: 28 and the light chain sequence of SEQ ID NO: 29. Atezolizumab comprises a single amino acid substitution (asparagine to alanine) at position 297 on the heavy chain (N297A) using EU numbering of Fc region amino acid residues, which results in a non-glycosylated antibody that has minimal binding to Fc receptors. Atezolizumab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 112, Vol. 28, No. 4, published January 16, 2015 (see page 485).

[0097] The term “PD-1 axis binding antagonist” refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with either one or more of its binding partners, so as to remove T-cell dysfunction resulting from signaling on the PD-1 signaling axis, with a result being to restore or enhance T-cell function (e.g., proliferation, cytokine production, and / or target cell killing). As used herein, a PD-1 axis binding antagonist includes a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist. In some instances, the PD-1 axis binding antagonist includes a PD-L1 binding antagonist or a PD-1 binding antagonist. In a preferred aspect, the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

[0098] The term “PD-L1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1 and / or B7-1 . In some instances, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1 and / or B7-1 . In some instances, the PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and / or B7-1 . In one instance, a PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD- L1 so as to render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some instances, the PD-L1 binding antagonist binds to PD-L1 . In some instances, a PD- L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001 , envafolimab, 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, and HS-636. In some aspects, the anti-PD-L1 antibody is atezolizumab, MDX-1105, MEDI4736 (durvalumab), or MSB0010718C (avelumab). In one specific aspect, the PD-L1 binding antagonist is MDX-1105. In another specific aspect, the PD-L1 binding antagonist is MEDI4736 (durvalumab). In another specific aspect, the PD-L1 binding antagonist is MSB0010718C (avelumab). In other aspects, the PD-L1 binding antagonist may be a small molecule, e.g., GS-4224, INCB086550, MAX-10181 , INCB090244, CA-170, or ABSK041 , which in some instances may be administered orally. Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003, and JS-003. In a preferred aspect, the PD-L1 binding antagonist is atezolizumab.

[0099] The term “PD-1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and / or PD-L2. PD-1 (programmed death 1 ) is also referred to in the art as “programmed cell death 1 ,” “PDCD1 ,” “CD279,” and “SLEB2.” An exemplary human PD-1 is shown in UniProtKB / Swiss-Prot Accession No. Q15116. In some instances, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In a specific aspect, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In one instance, a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T- cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some instances, the PD-1 binding antagonist binds to PD-1 . In some instances, the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 antagonist antibody). Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (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, and hAb21 . In a specific aspect, a PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific aspect, a PD-1 binding antagonist is MK-3475 (pembrolizumab). In another specific aspect, a PD-1 binding antagonist is a PD-L2 Fc fusion protein, e.g., AMP-224. In another specific aspect, a PD-1 binding antagonist is MED1 -0680. In another specific aspect, a PD-1 binding antagonist is PDR001 (spartalizumab). In another specific aspect, a PD-1 binding antagonist is REGN2810 (cemiplimab). In another specific aspect, a PD-1 binding antagonist is BGB-108. In another specific aspect, a PD-1 binding antagonist is prolgolimab. In another specific aspect, a PD-1 binding antagonist is camrelizumab. In another specific aspect, a PD-1 binding antagonist is sintilimab. In another specific aspect, a PD-1 binding antagonist is tislelizumab. In another specific aspect, a PD-1 binding antagonist is toripalimab. Other additonal exemplary PD-1 binding antagonists include BION-004, CB201 , AUNP-012, ADG104, and LBL-006.

[0100] The term “PD-L2 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 . PD-L2 (programmed death ligand 2) is also referred to in the art as “programmed cell death 1 ligand 2,” “PDCD1 LG2,” “CD273,” “B7-DC,” “Btdc,” and “PDL2.” An exemplary human PD-L2 is shown in UniProtKB / Swiss-Prot Accession No. Q9BQ51 . In some instances, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In a specific aspect, the PD-L2 binding antagonist inhibits binding of PD-L2 to PD-1 . Exemplary PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 . In one aspect, a PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L2 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some aspects, the PD-L2 binding antagonist binds to POUT In some aspects, a PD-L2 binding antagonist is an immunoadhesin. In other aspects, a PD-L2 binding antagonist is an anti-PD-L2 antagonist antibody.

[0101] As used herein, the term “chemotherapeutic agent” refers to a compound useful in the treatment of cancer, such as pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC). Examples of chemotherapeutic agents include EGFR inhibitors (including small molecule inhibitors (e.g., erlotinib (TARCEVA®, Genentech / OSI Pharm.); PD 183805 (Cl 1033, 2-propenamide, N-[4-[(3-chloro-4- fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3’-Chloro-4’-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3- chloro-4-fluoro-phenyl)-N2-(1 -methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1 -phenylethyl)amino]-1 H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4- hydroxyphenyl)-4-[(1 -phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3- bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3- cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271 ; Pfizer); and dual EGFR / HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3 fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4- quinazolinamine)); a tyrosine kinase inhibitor (e.g., an EGFR inhibitor; a small molecule HER2 tyrosine kinase inhibitor such as TAK165 (Takeda); CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; PKI-166 (Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 (ISIS Pharmaceuticals) which inhibit Raf-1 signaling; non-H ER-targeted tyrosine kinase inhibitors such as imatinib mesylate (GLEEVEC®, Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787 / ZK222584, Novartis / Schering AG); MAPK extracellular regulated kinase I inhibitor CI- 1040 (Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805 (Warner- Lamber); antisense molecules (e.g., those that bind to HER-encoding nucleic acid); quinoxalines (U.S. Patent No. 5,804,396); tryphostins (U.S. Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis / Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS 3521 ; Isis / Lilly); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); INC-1 C1 1 (Imclone); and rapamycin (sirolimus, RAPAMUNE®)); proteasome inhibitors such as bortezomib (VELCADE®, Millennium Pharm.); disulfiram; epigallocatechin gallate; salinosporamide A; carfilzomib; 17-AAG (geldanamycin); radicicol; lactate dehydrogenase A (LDH-A); fulvestrant (FASLODEX®, AstraZeneca); letrozole (FEMARA®, Novartis), finasunate (VATALANIB®, Novartis); oxaliplatin (ELOXATIN®, Sanofi); 5-FU (5-fluorouracil); leucovorin; lonafamib (SCH 66336); sorafenib (NEXAVAR®, Bayer Labs); AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1 -TM1 ); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin y1 and calicheamicin w1 ); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, detorubicin, 6-diazo-5-oxo-L- norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2- ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2”-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; etoposide (VP-16); ifosfamide; mitoxantrone; novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the above.

[0102] Chemotherapeutic agents also include (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine (a 1 ,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; (ix) growth inhibitory agents including vincas (e.g., vincristine and vinblastine), NAVELBINE® (vinorelbine), taxanes (e.g., paclitaxel, nab-paclitaxel, and docetaxel), topoisomerase II inhibitors (e.g., doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin), and DNA alkylating agents (e.g., tamoxigen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C); and (x) pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the above.

[0103] The term “cytotoxic agent” as used herein refers to any agent that is detrimental to cells (e.g., causes cell death, inhibits proliferation, or otherwise hinders a cellular function). Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212and radioactive isotopes of Lu); chemotherapeutic agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof. Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism. In one instance, the cytotoxic agent is a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin). In one instance, the cytotoxic agent is an antagonist of EGFR, e.g., N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (e.g., erlotinib). In one instance the cytotoxic agent is a RAF inhibitor, e.g., a BRAF and / or CRAF inhibitor. In one instance the RAF inhibitor is vemurafenib. In one instance, the cytotoxic agent is a PI3K inhibitor.

[0104] The term “cancer” refers to a disease caused by an uncontrolled division of abnormal cells in a part of the body. In one instance, the cancer is a pancreatic cancer, e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC.

[0105] The term “tumor” refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” “cell proliferative disorder,” “proliferative disorder,” and “tumor” are not mutually exclusive as referred to herein. A “tumor cell” as used herein, refers to any tumor cell present in a tumor or a sample thereof. Tumor cells may be distinguished from other cells that may be present in a tumor sample, for example, stromal cells and tumor-infiltrating immune cells, using methods known in the art and / or described herein.

[0106] As used herein, “treating” comprises effective cancer treatment with an effective amount of a therapeutic agent (e.g., a PD-1 axis binding antagonist (e.g., atezolizumab), an anti-TIGIT antagonist antibody (e.g., tiragolumab), or a chemotherapeutic agent or combination of therapeutic agents (e.g., a PD-1 axis binding antagonist (e.g., atezolizumab) and an anti-TIGIT antagonist antibody (e.g., tiragolumab) or a PD-1 axis binding antagonist (e.g., atezolizumab), an anti-TIGIT antagonist antibody (e.g., tiragolumab), and one or more chemotherapeutic agents (e.g., a taxane and an antimetabolite, e.g., nab-paclitaxel and gemcitabine)). Treating herein includes, inter alia, adjuvant therapy, neoadjuvant therapy, non-metastatic cancer therapy (e.g., locally advanced cancer therapy), and metastatic cancer therapy. The treatment may be first-line treatment (e.g., the patient may be previously untreated or not have received prior systemic therapy), or second-line or later treatment.

[0107] Herein, an “effective amount” refers to the amount of a therapeutic agent (e.g., a PD-1 axis binding antagonist (e.g., atezolizumab) or a combination of therapeutic agents (e.g., a PD-1 axis antagonist and one or more additional therapeutic agents, e.g., an anti-TIGIT antagonist antibody (e.g., tiragolumab) and / or one or more chemotherapeutic agents (e.g., a taxane and an antimetabolite, e.g., nab-paclitaxel and gemcitabine), that achieves a therapeutic result. In some examples, the effective amount of a therapeutic agent or a combination of therapeutic agents is the amount of the agent or of the combination of agents that achieves a clinical endpoint of improved progression-free survival (PFS), improved overall survival (OS), improved OS rate at 12 months or 24 months, improved duration of response (DOR), and / or improved disease control rate (DCR). Improvement (e.g., in terms of PFS, OS, OS rate, DOR, or DCR) may be relative to a suitable reference treatment, for example, treatment that does not include the PD-1 axis binding antagonist and / or treatment that does not include the anti-TIGIT antagonist antibody and / or the one or more chemotherapeutic agents.

[0108] As used herein, “survival” refers to the patient remaining alive, and includes overall survival as well as progression-free survival.

[0109] As used herein, “progression-free survival” (PFS) refers to the length of time during and after treatment during which the disease being treated (e.g., cancer) does not get worse (e.g., a patient having the disease does not experience disease progression). Progression-free survival may include the amount of time patients have experienced a CR or a PR, as well as the amount of time patients have experienced stable disease.

[0110] As used herein, “complete response” or “CR” refers to disappearance of all target lesions.

[0111] As used herein, “partial response” or “PR” refers to at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD, in the absence of a complete response.

[0112] As used herein, “complete response” and “CR” refers to disappearance of all target lesions.

[0113] As used herein, “partial response” and “PR” refers to at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD prior to treatment.

[0114] As used here, “progressive disease” and “PD” refers to at least a 20% increase in the SLD of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In some embodiments, to be defined as PD, the sum of diameters must also demonstrate an absolute increase of > 5 mm.

[0115] As used herein, “stable disease” and “SD” refer to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

[0116] As used herein, “overall survival” and “OS” refer to the length of time from either the date of diagnosis or the start of treatment for a disease (e.g., cancer) that the patient is still alive. For example, OS may be defined as the time from first study treatment to death from any cause.

[0117] As used herein, “objective response rate” (ORR) refers to the proportion of patients with a confirmed objective response (i.e. , CR or PR on two consecutive occasions > 4 weeks apart). As used herein, “duration of response” (DOR) is defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first.

[0118] As used herein, “disease control rate” (DCR) is defined as the proportion of participants with stable disease (SD) for > 12 weeks or a complete response (CR) or partial response (PR), e.g., as determined according to RECIST v1 .1 .

[0119] As used herein, “subject” or “individual” is meant a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline. In some embodiments, the subject is a human. Patients are also subjects herein.

[0120] As used herein, the term “PD-L1 -positive” refers to, for example, a tumor sample that expresses any detectable level of PD-L1 protein. In some aspects, a PD-L1 -positive tumor sample is a tumor sample that has been determined to have a PD-L1 TAP score of at least 1 % as determined using an IHC assay comprising staining with the anti-PD-L1 antibody SP263, e.g., as determined using the VENTANA PD-L1 (SP263) CDx Assay.

[0121] As used herein, a “PD-L1 -positive tumor cell fraction” is the percentage of viable tumor cells showing partial or complete membrane staining (exclusive of cytoplasmic staining) at any intensity relative to all viable tumor cells present in a sample, following staining of the sample in the context of an immunohistochemical (IHC) assay, e.g., an IHC assay staining for PD-L1 using the antibody SP142, SP263, 22C3, or 28-8. Accordingly, a PD-L1 -positive tumor cell fraction may be calculated using the PD- L1 IHC SP142 (Ventana) assay, for example, by the formula PD-L1 -positive tumor cell fraction = (number of PD-L1 -positive tumor cel ls) / (total number of PD-L1 -positive and PD-L1 negative tumor cells), wherein PD-L1 cytoplasmic staining of tumor cells and all non-tumor cells (e.g., tumor-infiltrating immune cells, normal cells, necrotic cells, and debris) are excluded from evaluation and scoring. It will be appreciated that any given diagnostic PD-L1 antibody may correspond with a particular IHC assay protocol and / or scoring terminology that can be used to derive a PD-L1 -positive tumor cell fraction. For example, a PD- L1 -positive tumor cell fraction can be derived from a tumor cell sample stained with SP263, 22C3, SP142, or 28-8 using OPTIVIEW® detection on Benchmark ULTRA, EnVision Flex on AutostainerLink 48, OPTIVIEW® detection and amplification on Benchmark ULTRA, or EnVision Flex on AutostainerLink 48, respectively.

[0122] As used herein, the “Ventana SP142 IHC assay” is conducted according to the Ventana PD-L1 (SP142) Assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.

[0123] As used herein, the “Ventana SP263 IHC assay” is conducted according to the Ventana PD-L1 (SP263) Assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.

[0124] As used herein, the “pharmDx 22C3 IHC assay” is conducted according to the PD-L1 IHC 22C3 pharmDx package insert (Carpinteria, CA: Dako, Agilent Pathology Solutions), which is incorporated herein by reference in its entirety.

[0125] As used herein, the “pharmDx 28-8 IHC assay” is conducted according to the PD-L1 IHC 28-8 pharmDx package insert (Carpinteria, CA: Dako, Agilent Pathology Solutions), which is incorporated herein by reference in its entirety. The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and / or warnings concerning the use of such therapeutic products.

[0126] As used herein, “in combination with” refers to administration of one treatment modality in addition to another treatment modality, for example, a treatment regimen that includes administration of a PD-1 axis binding antagonist (e.g., atezolizumab) and an anti-TIG IT antagonist antibody (e.g., tiragolumab) or a PD-1 axis binding antagonist (e.g., atezolizumab), an anti-TIG IT antagonist antibody (e.g., tiragolumab), and one or more chemotherapeutic agents (e.g., a taxane and an antimetabolite, e.g., nab-paclitaxel and gemcitabine). As such, “in combination with” refers to administration of one treatment modality before, during, or after administration of the other treatment modality to the patient.

[0127] The term “antibody” herein specifically covers monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired biological activity. In one instance, the antibody is a full-length monoclonal antibody.

[0128] The term IgG “isotype” or “subclass” as used herein is meant any of the subclasses of immunoglobulins defined by the chemical and antigenic characteristics of their constant regions.

[0129] Depending on the amino acid sequences of the constant domains of their heavy chains, antibodies (immunoglobulins) can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG 1 , lgG2, lgG3, lgG4, lgA1 , and lgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, y, e, y, and p, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known and described generally in, for example, Abbas et al. Cellular and Mol. Immunology, 4th ed. (W.B. Saunders, Co., 2000). An antibody may be part of a larger fusion molecule, formed by covalent or non- covalent association of the antibody with one or more other proteins or peptides.

[0130] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody in its substantially intact form, not antibody fragments as defined below. The terms refer to an antibody comprising an Fc region.

[0131] The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one aspect, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C- terminus of the heavy chain. Therefore, an antibody produced by a host cell by expression of a specific nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain, or it may include a cleaved variant of the full-length heavy chain. This may be the case where the final two C- terminal amino acids of the heavy chain are glycine (G446) and lysine (K447). Therefore, the C-terminal lysine (Lys447), or the C-terminal glycine (Gly446) and lysine (Lys447), of the Fc region may or may not be present. Amino acid sequences of heavy chains including an Fc region are denoted herein without the C-terminal lysine (Lys447) if not indicated otherwise. In one aspect, a heavy chain including an Fc region as specified herein, comprised in an antibody disclosed herein, comprises an additional C-terminal glycine-lysine dipeptide (G446 and K447). In one aspect, a heavy chain including an Fc region as specified herein, comprised in an antibody disclosed herein, comprises an additional C-terminal glycine residue (G446). In one aspect, a heavy chain including an Fc region as specified herein, comprised in an antibody disclosed herein, comprises an additional C-terminal lysine residue (K447). In one embodiment, the Fc region contains a single amino acid substitution N297A of the heavy chain. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 .

[0132] The Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1 -107 of the light chain and residues 1 -1 13 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991 )). The “EU numbering system” or “EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). The “EU index as in Kabat” refers to the residue numbering of the human IgG 1 EU antibody.

[0133] The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci.

[0134] The term “hypervariable region” or “HVR” as used herein refers to each of the regions of an antibody variable domain which are hypervariable in sequence and which determine antigen binding specificity, for example “complementarity determining regions” (“CDRs”).

[0135] Generally, antibodies comprise six CDRs: three in the VH (CDR-H1 , CDR-H2, CDR-H3), and three in the VL (CDR-L1 , CDR-L2, CDR-L3). Exemplary CDRs herein include:

[0136] (a) hypervariable loops occurring at amino acid residues 26-32 (L1 ), 50-52 (L2), 91 -96 (L3), 26-32 (H1 ), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901 -917 (1987));

[0137] (b) CDRs occurring at amino acid residues 24-34 (L1 ), 50-56 (L2), 89-97 (L3), 31 -35b (H1 ), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991 )); and

[0138] (c) antigen contacts occurring at amino acid residues 27c-36 (L1 ), 46-55 (L2), 89-96 (L3), 30-35b (H1 ), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262: 732-745 (1996)). Unless otherwise indicated, the CDRs are determined according to Kabat et al., supra. One of skill in the art will understand that the CDR designations can also be determined according to Chothia, supra, McCallum, supra, or any other scientifically accepted nomenclature system.

[0139] “Framework” or “FR” refers to variable domain residues other than complementary determining regions (CDRs). The FR of a variable domain generally consists of four FR domains: FR1 , FR2, FR3, and FR4. Accordingly, the CDR and FR sequences generally appear in the following sequence in VH (or VL): FR1 -CDR-H1 (CDR-L1 )-FR2- CDR-H2(CDR-L2)-FR3- CDR-H3(CDR-L3)-FR4.

[0140] The term “variable domain residue numbering as in Kabat” or “amino acid position numbering as in Kabat,” and variations thereof, refers to the numbering system used for heavy chain variable domains or light chain variable domains of the compilation of antibodies in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or HVR of the variable domain. For example, a heavy chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g., residues 82a, 82b, and 82c, etc., according to Kabat) after heavy chain FR residue 82. The Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence.

[0141] “Antibody fragments” comprise a portion of an intact antibody, preferably comprising the antigen-binding region thereof. In some instances, the antibody fragment described herein is an antigenbinding fragment. Examples of antibody fragments include Fab, Fab’, F(ab’)2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFvs); and multispecific antibodies formed from antibody fragments.

[0142] The term “effector functions” refers to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell- mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), cytokine secretion, immune complex-mediated antigen uptake by antigen presenting cells, down regulation of cell surface receptors (e.g., B cell receptor), and B cell activation.

[0143] “Percent (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0144] In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows:

[0145] 100 times the fraction X / Y where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program’s alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0146] II. THERAPEUTIC AND METHODS AND USES

[0147] A. Therapeutic methods and uses comprising a PD-1 axis binding antagonist and an anti- TIGIT antagonist antibody

[0148] Provided herein are methods of treating a subject (e.g., a human subject) having a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC) comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIG IT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab), wherein a tumor sample from the subject has been determined to be PD- L1 -positive. In some aspects, the method comprises further administering to the subject one or more chemotherapeutic agents (e.g., a taxane and an antimetabolite, e.g., nab-paclitaxel and gemcitabine).

[0149] Accordingly, in another aspect, provided herein is a method of treating a subject (e.g., a human subject) having a pancreatic cancer (e.g., PDAC, e.g., a metastatic PDAC) comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIG IT antagonist antibody (e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab), a taxane (e.g., nab-paclitaxel), and an antimetabolite (e.g., gemcitabine), wherein a tumor sample from the subject has been determined to be PD-L1 -positive.

[0150] In another aspect, provided herein is a method of treating a subject having a pancreatic cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of atezolizumab, tiragolumab, nab-paclitaxel, and gemcitabine, wherein a tumor sample from the subject has been determined to have a PD-L1 tumor area positive (TAP) score of equal to or greater than 1 % using the VENTANA PD-L1 (SP263) CDx Assay, and wherein the pancreatic cancer is a metastatic PDAC

[0151] Also provided herein are a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) and / or an anti-TIG IT antagonist antibody (e.g., tiragolumab) for use in any of the methods provided herein. For example, in one aspect, the invention provides a PD-1 axis binding antagonist (e.g., atezolizumab) and / or an anti-TIGIT antagonist antibody (e.g., tiragolumab) for use in a method of treating a subject having a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC), wherein the method comprises administering to the subject a dosing regimen comprising one or more dosing cycles of the anti-TIGIT antagonist antibody (e.g., tiragolumab) and the anti-PD-L1 antagonist antibody (e.g., atezolizumab), wherein a tumor sample from the subject has been determined to be PD-L1 -positive. In some aspects, the PD-1 axis binding antagonist and / or anti-TIGIT antagonist antibody are to be administered in combination with one or more chemotherapeutic agents (e.g., a taxane and an antimetabolite, e.g., nab-paclitaxel and gemcitabine).

[0152] Further provided herein are uses of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab) and / or an anti-TIGIT antagonist antibody (e.g., tiragolumab) in the manufacture of a medicament for treating a patient according to any of the methods provided herein.

[0153] Cancer type and previous treatment

[0154] In some aspects, the pancreatic cancer is a pancreatic ductal adenocarcinoma (PDAC). In some aspects, the pancreatic cancer (e.g., PDAC) is metastatic, e.g., the pancreatic cancer is a metastatic pancreatic cancer or is a metastatic PDAC.

[0155] In some aspects, the subject has not received prior systemic therapy for pancreatic cancer (e.g., PDAC), e.g., is chemotherapy-naive and / or is treatment-naive. For example, in some aspects, the subject has received no prior neoadjuvant or adjuvant systemic treatment for the pancreatic cancer (e.g., PDAC). The subject may have had a prior surgery (e.g., a surgical resection of the pancreatic cancer) and / or have been treated with radiation.

[0156] Dosing and administration order

[0157] PD- 1 axis binding antagonist

[0158] In some aspects, in each of the one or more dosing cycles, the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, e.g., atezolizumab) is administered every four weeks (e.g., is administered in 28-day dosing cycles, e.g., is administered on Day 1 of each of one or more 28-day dosing cycles). Exemplary PD-1 axis binding antagonists that may be used in the present methods, and dosing regimens for the same, are provided in Section V, below.

[0159] In some aspects, the PD-1 axis binding antagonist is atezolizumab, and the atezolizumab is administered at a fixed dose of about 1680 mg (e.g., a fixed dose of 1680 mg) every four weeks. In some aspects, the length of each of the one or more dosing cycles is 28 days, and the atezolizumab is administered on about Day 1 of each 28-day dosing cycle.

[0160] In some aspects, the PD-1 axis binding antagonist (e.g., atezolizumab) is administered intravenously. In other aspects, the PD-1 axis binding antagonist (e.g., atezolizumab) is administered subcutaneously. Anti-TIGIT antagonist antibody

[0161] In some aspects, in each of the one or more dosing cycles, the anti-TIGIT antagonist antibody (e.g., tiragolumab) is administered every four weeks (e.g., is administered in 28-day dosing cycles, e.g., is administered on Day 1 of each of one or more 28-day dosing cycles). Exemplary anti-TIGIT antagonist antibodies that may be used in the present methods, and dosing regimens for the same, are provided in Section IV, below.

[0162] In some aspects, the anti-TIGIT antagonist antibody is tiragolumab, and the tiragolumab is administered at a fixed dose of about 840 mg (e.g., a dose of 840 mg) every four weeks. In some aspects, the length of each of the one or more dosing cycles is 28 days, and the tiragolumab is administered on about Day 1 of each 28-day dosing cycle.

[0163] In some aspects, the anti-TIGIT antagonist antibody (e.g., tiragolumab) is administered intravenously. In other aspects, the anti-TIGIT antagonist antibody (e.g., tiragolumab) is administered subcutaneously.

[0164] Chemotherapeutic agents

[0165] One or more chemotherapeutic agents may be administered in each of the one or more dosing cycles. Exemplary chemotherapeutic agents and dosing regimens therefor are provided in Section VI, below.

[0166] In some aspects, a taxane (e.g., nab-paclitaxel) and / or an antimetabolite (e.g., pemetrexed) are administered in each of the one or more dosing cycles.

[0167] For example, in some aspects, nab-paclitaxel is administered (e.g., intravenously administered) in each of the one or more dosing cycles, wherein the length of each of the one or more dosing cycles is 28 days, and wherein nab-paclitaxel is administered three times over the course of each 28-day dosing cycle (e.g., on Days 1 , 8, and 15 of each 28-day dosing cycle). In some aspects, nab-paclitaxel is administered at a dose of about 125 mg / m2(e.g., at a dose of 125 mg / m2). Further exemplary dosing regimens for nab-paclitaxel that may be used in the present methods are provided in Section VI, below.

[0168] In some aspects, gemcitabine is administered (e.g., intravenously administered) in each of the one or more dosing cycles, wherein the length of each of the one or more dosing cycles is 28 days, and wherein gemcitabine is administered three times over the course of each 28-day dosing cycle (e.g., on Days 1 , 8, and 15 of each 28-day dosing cycle). In some aspects, gemcitabine is administered at a dose of about 1000 mg / m2(e.g., at a dose of 1000 mg / m2). Further exemplary dosing regimens for gemcitabine that may be used in the present methods are provided in Section VI, below. Atezolizumab, tiragolumab, nab-paclitaxel, and gemcitabine

[0169] Accordingly, in some aspects, provided herein are methods of treating a subject (e.g., a human subject) having a pancreatic cancer (e.g., a PDAC, e.g., a metastatic PDAC) comprising administering to the subject one or more 28-day dosing cycles of atezolizumab, tiragolumab, nab-paclitaxel, and gemcitabine, wherein a tumor sample from the subject has been determined to be PD-L1 -positive, and wherein (i) atezolizumab is administered intravenously at a fixed dose of 1680 mg on Day 1 of each 28- day cycle; (ii) tiragolumab is administered intravenously at a fixed dose of 840 mg on Day 1 of each 28- day cycle; (iii) nab-paclitaxel is administered at a dose of about 125 mg / m2on Days 1 , 8, and 15 of each 28-day dosing cycle, and (iv) gemcitabine is administered at a dose of about 1000 mg / m2on Days 1 , 8, and 15 of each 28-day dosing cycle.

[0170] Administration order

[0171] In some aspects in which the method comprises administration of an anti-TIG IT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab), the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are coadministered (e.g., as described below). Alternatively, in some aspects, the method comprises administering the anti-TIGIT antagonist antibody before the PD-1 axis binding antagonist or comprises administering the PD-1 axis binding antagonist before the anti-TIGIT antagonist antibody.

[0172] In some aspects in which the method comprises administration of an anti-TIGIT antagonist antibody (e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab), and one or more chemotherapeutic agents, the anti-TIGIT antagonist antibody and the PD- 1 axis binding antagonist are co-administered (e.g., as described below) before the one or more chemotherapeutic agents. Alternatively, in some aspects, the method comprises (i) administering the one or more chemotherapeutic agents before co-administering the anti-TIGIT antagonist antibody and the PD- 1 axis binding antagonist or (ii) separately administering the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist second, and the one or more chemotherapeutic agents.

[0173] In some aspects in which the method comprises administration of an anti-TIGIT antagonist antibody (e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab), a taxane (e.g., nab-paclitaxel), and an antimetabolite (e.g., gemcitabine), the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are co-administered (e.g., as described below) first, the taxane is administered second, and the antimetabolite is administered third (e.g., tiragolumab and atezolizumab are administered first, nab-paclitaxel is administered second, and gemcitabine is administered third.

[0174] Alternatively, in some aspects, (i) the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are co-administered first, the antimetabolite is administered second, and the taxane is administered third; (ii) the taxane is administered first, the antimetabolite is administered second, and the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are co-administered third; (iii) the antimetabolite is administered first, the taxane is administered second, and the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are co-administered third; (iv) the taxane is administered first, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are co-administered second, and the antimetabolite is administered third; or (v) the antimetabolite is administered first, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are co-administered second, and the taxane is administered third.

[0175] Co-administration of the PD- 1 axis binding antagonist and the anti-TIGIT antagonist antibody

[0176] In some aspects, the anti-TIGIT antagonist antibody (e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., atezolizumab) are co-administered. For example, in some aspects, tiragolumab and atezolizumab are co-administered intravenously. In some aspects, the co-infused tiragolumab and atezolizumab are mixed prior to infusion (e.g., are formulated separately and are mixed by the physician administering the drugs), e.g., are combined in an IV bag prior to administration. In other aspects, the coinfused tiragolumab and atezolizumab are formulated together (i.e., are not mixed by the physician administering the drugs) and are administered as an IV-administered fixed dose combination (FDC). In some aspects, the IV-administered co-infusion of tiragolumab and atezolizumab (e.g., FDC) comprises atezolizumab at a dose of 1680 mg and tiragolumab at a dose of 840 mg. In other aspects, the IV- administered co-infusion of tiragolumab and atezolizumab (e.g., FDC) comprises atezolizumab at a dose of 1200 mg and tiragolumab at a dose of 600 mg.

[0177] In some aspects, the anti-TIGIT antagonist antibody (e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., atezolizumab) are combined in an IV bag and are co-administered intravenously every four weeks (Q4W), wherein the co-infusion comprises the anti-TIGIT antagonist antibody (e.g., tiragolumab) at a dose of about 840 mg (e.g., a dose of 840 mg) and the PD-1 axis binding antagonist (e.g., atezolizumab) at a dose of about 1680 mg (e.g., a dose of 1680 mg).

[0178] In some aspects, the anti-TIGIT antagonist antibody (e.g., tiragolumab) and the PD-1 axis binding antagonist (e.g., atezolizumab) are co-infused simultaneously. In some aspects, the co-infused tiragolumab and atezolizumab are mixed prior to infusion (e.g., are formulated separately and are mixed by the physician administering the drugs). In other aspects, the co-infused tiragolumab and atezolizumab are formulated together (i.e., are not mixed by the physician administering the drugs) and are administered as an SC-administered FDC. In some aspects, a SC-administered co-infusion of tiragolumab and atezolizumab (e.g., FDC) comprises atezolizumab at a dose of 1875 mg or 2000 mg and tiragolumab at a dose of 880 mg. In other aspects, the SC-administered co-infusion of tiragolumab and atezolizumab (e.g., FDC) comprises atezolizumab at a dose of 1875 mg or 2000 mg and tiragolumab at a dose of 1000 mg.

[0179] In some aspects, the method comprises both IV and SC administration of tiragolumab and / or atezolizumab, e.g., comprises one or more IV-administered doses and one or more SC-administered doses of tiragolumab and / or atezolizumab. For example, in some aspects, the method comprises administering at least one dose of tiragolumab and atezolizumab as an IV-administered FDC and comprises administering at least one dose of tiragolumab and atezolizumab as an SC-administered FDC.

[0180] Exemplary IV and SC FDC doses and formulations of tiragolumab and atezolizumab are provided in WO 2023 / 122665 A1 and in U.S. Provisional Patent Application Nos. 63 / 493,691 (filed March 31 , 2023) and 63 / 494,983 (filed April 7, 2023) (both titled “Methods of Treating Tumors with Anti-TIGIT Antibodies”), each of which is incorporated herein by reference in its entirety. Benefit from treatment

[0181] Increased duration of PFS

[0182] In some aspects, treating a subject according to any one of the methods provided herein results in an increase in progression-free survival (PFS) as compared to a reference PFS. In some aspects, the reference PFS is a PFS in a population of subjects (e.g., is the mean or median PFS of a population of subjects) who have received a control treatment.

[0183] In some embodiments, PFS is measured as the period of time from the start of treatment to the first occurrence of disease progression. In some instances, the treatment extends the PFS of the subject by at least about 2 months as compared to a reference PFS (e.g., by 2-120 months, by 3-1 10 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 1 1 months, 1 1 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some instances, the treatment extends the

[0184] PFS of the subject by at least about 3.3 months (e.g., by 3.3-120 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 1 1 months, 1 1 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some instances, the treatment extends the PFS of the subject by at least about 5.3 months (e.g., by 5.3-120, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 1 1 months, 1 1 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

[0185] In some aspects, the reference PFS is a PFS (e.g., a mean or median duration of PFS) in a population of subjects having a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC) (e.g., a PD-L1 -positive pancreatic cancer) who have been treated according to a method comprising administering to each subject one or more dosing cycles of a taxane and an antimetabolite (e.g., administering one or more dosing cycles of nab-paclitaxel and gemcitabine), wherein the treatment (i) does not comprise administration of an anti-TIGIT antagonist antibody, (ii) does not comprise administration of an anti-PD-L1 antagonist antibody, or (iii) does not comprise administration of an anti-TIGIT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody (e.g., comprises administration of only the taxane and the antimetabolite).

[0186] Increased duration of OS

[0187] In some aspects, treating a subject according to any one of the methods provided herein results in an increase in overall survival (OS) as compared to a reference OS. In some aspects, the reference OS is an OS in a population of subjects (e.g., is the mean or median OS of a population of subjects) who have received a control treatment.

[0188] In some embodiments, OS is measured as the period of time from the start of treatment to death. In some instances, the treatment extends the OS of the subject by at least about 2 months as compared to a reference OS (e.g., by 2-120 months, by 3-1 10 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 1 1 months, 1 1 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some instances, the treatment extends the OS of the subject by at least about 3.3 months (e.g., by 3.3-120 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 1 1 months, 1 1 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some instances, the treatment extends the OS of the subject by at least about 5.3 months (e.g., by 5.3-120, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 1 1 months, 1 1 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some aspects, the reference OS is an OS (e.g., a mean or median duration of OS) in a population of subjects having a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC) (e.g., a PD-L1 -positive pancreatic cancer) who have been treated according to a method comprising administering to each subject one or more dosing cycles of a taxane and an antimetabolite (e.g., administering one or more dosing cycles of nab-paclitaxel and gemcitabine), wherein the treatment (i) does not comprise administration of an anti-TIGIT antagonist antibody, (ii) does not comprise administration of an anti-PD-L1 antagonist antibody, or (iii) does not comprise administration of an anti-TIGIT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody (e.g., comprises administration of only the taxane and the antimetabolite).

[0189] Increased 12- mo nth or 24- month OS rate

[0190] In some aspects, treating a population of subjects according to any one of the methods provided herein results in an increase in the OS rate in the population of subjects at a selected time point (e.g., 12 months or 24 months after randomization in a clinical trial and / or initiation of treatment) as compared to a reference OS rate. OS rate may be defined, e.g., as the proportion of subjects in a population of subjects treated according to the method who are alive at the selected time point. In some aspects, the reference OS rate is an OS rate in a population of subjects (e.g., is the mean or median OS rate of a population of subjects) who have received a control treatment.

[0191] In some embodiments, the treatment results in an OS rate (e.g., 12-month or 24-month OS rate) of the population of subjects of at least about 20% (e.g., about 20% to about 100% (e.g., about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%)).

[0192] In some embodiments, a treatment described herein increases the OS rate (e.g., 12-month or 24- month OS rate) of a population of subjects treated according to the method compared to a reference OS rate by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 85%, 100%, or more than 100%, e.g., increases the OS rate by 5%-10%, 10%- 20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90%-100% relative to a reference OS rate.

[0193] In some aspects, the reference OS rate is an OS rate in a population of subjects having a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC) (e.g., a PD- L1 -positive pancreatic cancer) who have been treated according to a method comprising administering to each subject one or more dosing cycles of a taxane and an antimetabolite (e.g., administering one or more dosing cycles of nab-paclitaxel and gemcitabine), wherein the treatment (i) does not comprise administration of an anti-TIGIT antagonist antibody, (ii) does not comprise administration of an anti-PD-L1 antagonist antibody, or (iii) does not comprise administration of an anti-TIGIT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody (e.g., comprises administration of only the taxane and the antimetabolite). Increased ORR

[0194] In some aspects, treating a population of subjects according to any one of the methods provided herein results in an increase in objective response rate (ORR) in the population of subjects as compared to a reference ORR. In some aspects, the reference ORR is an ORR in a population of subjects (e.g., is the mean or median ORR of a population of subjects) who have received a control treatment.

[0195] In some embodiments, the treatment results in an ORR of the population of subjects of at least about 50% (e.g., about 50% to about 100% (e.g., about 51 %, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61 %, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%)).

[0196] In some embodiments, a treatment described herein increases the ORR of a population of subjects treated according to the method compared to a reference ORR by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 85%, 100%, or more than 100%, e.g., increases the ORR by 5%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%- 60%, 60%-70%, 70%-80%, 80%-90%, or 90%-100% relative to a reference ORR.

[0197] In some aspects, the reference ORR is an ORR in a population of subjects having a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC) (e.g., a PD-L1 -positive pancreatic cancer) who have been treated according to a method comprising administering to each subject one or more dosing cycles of a taxane and an antimetabolite (e.g., administering one or more dosing cycles of nab-paclitaxel and gemcitabine), wherein the treatment (i) does not comprise administration of an anti-TIGIT antagonist antibody, (ii) does not comprise administration of an anti-PD-L1 antagonist antibody, or (iii) does not comprise administration of an anti-TIGIT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody (e.g., comprises administration of only the taxane and the antimetabolite).

[0198] Increased DOR

[0199] In some aspects, treating a subject according to any one of the methods provided herein results in an increase in duration of response (DOR) as compared to a reference DOR. In some aspects, the reference DOR is a DOR in a population of subjects (e.g., is the mean or median DOR of a population of subjects) who have received a control treatment.

[0200] In some embodiments, a treatment described herein extends the DOR of the subject compared to a reference DOR by at least about 2 months (e.g., by 2-120 months, by 2.5-100 months, by 3.0-80 months, by 4.0-60 months, by 5.0-48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12 months, e.g., by at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 1 1 months, 1 1 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment extends the DOR of the subject by at least about 4 months (e.g., by 4-120 months, by 5-100 months, by 6-80 months, by 7-60 months, by 8-48 months, by 9- 36 months, or by 10-24 months, e.g., by at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 1 1 months, 1 1 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment extends the DOR of the subject by at least about 2 months (e.g., by 2-120 months, by 3-100 months, by 4-80 months, by 6-60 months, by 8-48 months, by 9-36 months, or by 10-24 months, e.g., by at least about 2.0 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 1 1 months, 1 1 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

[0201] In some aspects, the reference DOR is a DOR in a population of subjects having a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC) (e.g., a PD-L1 -positive pancreatic cancer) who have been treated according to a method comprising administering to each subject one or more dosing cycles of a taxane and an antimetabolite (e.g., administering one or more dosing cycles of nab-paclitaxel and gemcitabine), wherein the treatment (i) does not comprise administration of an anti-TIG IT antagonist antibody, (ii) does not comprise administration of an anti-PD-L1 antagonist antibody, or (iii) does not comprise administration of an anti-TIGIT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody (e.g., comprises administration of only the taxane and the antimetabolite).

[0202] Increased DC Fl

[0203] In some aspects, treating a population of subjects according to any one of the methods provided herein results in an increase in the disease control rate (DOR) of the population of subjects as compared to a reference DOR. DOR may be defined, e.g., as the proportion of subjects in a population of subjects treated according to the method who achieve stable disease for > 12 weeks, a complete response, or a partial response. In some aspects, the reference DOR is a DOR in a population of subjects (e.g., is the mean or median DOR of a population of subjects) who have received a control treatment. In some embodiments, the treatment results in an DCR of the population of subjects of at least about 20% (e.g., about 20% to about 100% (e.g., about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%)).

[0204] In some embodiments, a treatment described herein increases the DCR of a population of subjects treated according to the method compared to a reference DCR by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 85%, 100%, or more than 100%, e.g., increases the DCR by 5%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%- 60%, 60%-70%, 70%-80%, 80%-90%, or 90%-100% relative to a reference DCR.

[0205] In some aspects, the reference DCR is a DCR in a population of subjects having a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC) (e.g., a PD-L1 -positive pancreatic cancer) who have been treated according to a method comprising administering to each subject one or more dosing cycles of a taxane and an antimetabolite (e.g., administering one or more dosing cycles of nab-paclitaxel and gemcitabine), wherein the treatment (i) does not comprise administration of an anti-TIG IT antagonist antibody, (ii) does not comprise administration of an anti-PD-L1 antagonist antibody, or (iii) does not comprise administration of an anti-TIGIT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody (e.g., comprises administration of only the taxane and the antimetabolite).

[0206] III. PD-L1 POSITIVITY

[0207] The presence and / or expression level of PD-L1 may be assessed in a patient identified, selected, stratified, and / or treated according to any of the methods and compositions for use described herein. The methods, uses, and compositions for use may include determining the expression level of PD-L1 in a biological sample (e.g., a tumor sample) obtained from the patient.

[0208] In some aspects, the expression level of PD-L1 in the tumor sample has been determined prior to initiation of treatment. In other aspects, the expression level of PD-L1 in the tumor sample is determined after initiation of treatment.

[0209] PD-L1 expression may be determined using any suitable approach.

[0210] In some examples, assessment of the presence and / or expression level of PD-L1 , and / or patient selection, may involve the use of two distinct affinity histochemical (AHC) assays (e.g., IHC assays) for PD-L1 protein: (a) an immune-directed PD-L1 assay; and (b) an immune-agnostic PD-L1 assay.

[0211] As described herein, an immune-directed PD-L1 assay is any AHC assay specific for human PD- L1 protein that has been designed to highlight immune cell expression of PD-L1 , for example, by preferentially staining PD-L1 -expressing immune cells versus PD-L1 -expressing tumor cells. The highlighting of the immune cells may be a result of (a) inherent antibody specificity for immune-expressed PD-L1 versus expression by other cell types; (b) careful selection of staining conditions, such as antigen retrieval process, antibody diluent selection, buffer selection, detection system, labeling time and temperature, etc.; or (c) a combination of (a) and (b). An example of a commercially available immune- directed PD-L1 assay is the VENTANA PD-L1 (SP142) Assay (“SP142 Assay”). The SP142 Assay is an affinity histochemical assay that uses: (a) a PD-L1 rabbit monoclonal antibody (clone SP142, see US 10,689,445); (b) an automated IHC / ISH staining platform (BENCHMARK IHC / ISH staining platform (Roche)); and (c) a tyramide-amplified 3,3'-diaminobenzedine (DAB)-based detection system (OPTIVIEW DAB IHC detection kit with OPTIVIEW Amplification kit (Roche)).

[0212] In an embodiment, the immune-directed PD-L1 assay is an AHC assay (e.g., an IHC assay) that has, for the given scoring algorithm and cutoff, at least 80% overall percent agreement (OPA), at least 80% positive percent agreement (PPA), and / or at least 80% negative percent agreement (NPA) with the SP142 Assay in the same indication and using the same scoring algorithm and cutoff. In a specific embodiment, the AHC has at least 80%, at least 85%, at least 90%, or at least 95% OPA with the SP142 assay. In another specific embodiment, the AHC has at least 80%, at least 85%, at least 90%, or at least 95% PPA with the SP142 assay. In another specific embodiment, the AHC has at least 80%, at least 85%, at least 90%, or at least 95% NPA with the SP142 assay. In another specific embodiment, the AHC has at least 80%, at least 85%, at least 90%, or at least 95% PPA with the SP142 Assay and at least 80%, at least 85%, at least 90%, or at least 95% NPA with the SP142 Assay. In an embodiment, the OPA, PPA, and / or NPA are measured using an immune proportion (IC) scoring method at a single cutoff that has been shown to be predictive for response to a PD-1 axis binding antagonist in the tested indication. In another embodiment, the OPA, PPA, and / or NPA are measured using a >5% IC 2 / 3 cutoff in a bladder cancer indication (e.g., locally advanced or metastatic UC).

[0213] As is also described herein, an immune-agnostic PD-L1 assay is any AHC assay (e.g., an IHC assay) specific for human PD-L1 protein that is not an immune-directed PD-L1 assay. Exemplary commercially-available immune-agnostic PD-L1 assays include the PD-L1 IHC 22C3 PHARMDX assay (Agilent) (hereafter, “22C3 Assay”), the VENTANA PD-L1 (SP263) Assay (Roche) (hereafter, “SP263 Assay”), and the PD-L1 IHC 28-8 PHARMDX assay (Agilent) (hereafter, “28-8 Assay”). In an embodiment, the immune-agnostic PD-L1 assay is an AHC assay (e.g., an IHC assay) that has at least 80% OPA, at least 80% PPA, and / or at least 80% NPA with one or more of the 22C3 Assay, the SP263 Assay, and the 28-8 Assay in the same indication and using the same scoring algorithm and cutoff. In a specific embodiment, the AHC has at least 80%, at least 85%, at least 90%, or at least 95% OPA with the 22C3 assay. In another specific embodiment, the AHC has at least 80%, at least 85%, at least 90%, or at least 95% PPA with the 22C3 assay. In another specific embodiment, the AHC has at least 80%, at least 85%, at least 90%, or at least 95% NPA with the 22C3 assay. In another specific embodiment, the AHC has at least 80%, at least 85%, at least 90%, or at least 95% PPA with the 22C3 assay and at least 80%, at least 85%, at least 90%, or at least 95% NPA with the 22C3 assay. In an embodiment, the OPA, PPA, and / or NPA are measured using a combined positive score (CPS) scoring method at a single cutoff that has been shown to be predictive for response to a PD-1 axis binding antagonist in the tested indication. In another embodiment, the OPA, PPA, and / or NPA are measured using a >10% CPS cutoff in a bladder cancer indication (e.g., locally advanced or metastatic UC).

[0214] In one example, provided herein is an assay for determining the presence or expression level of PD-L1 in a tumor sample obtained from a patient suffering from a cancer, the assay comprising: (a) determining the presence or expression level of PD-L1 in a tumor sample obtained from the patient using an immune-directed PD-L1 assay (e.g., the SP142 assay); and (b) determining the presence or expression level of PD-L1 in the tumor sample obtained from the patient using an immune-agnostic PD- L1 assay (e.g., the 22C3 Assay, the SP263 Assay or the 28-8 Assay). In some examples, assessment of the presence and / or expression level of PD-L1 , and / or patient selection, may involve the use of one AHC assay (e.g., IHC assay).

[0215] Any suitable scoring algorithm may be used. For example, the scoring algorithm may be the immune cell scoring algorithm set forth in Table 1 herein, e.g., as used in an SP142 Assay. In some examples the scoring algorithm may be a Combined Positive Score (CPS), e.g., as used in a 22C3 Assay. It is to be understood that a CPS may be determined using other PD-L1 AHC assays (e.g., other PD-L1 IHC assays), e.g., an IHC assay comprising use of VENTANA SP263 or 28-8. Other scoring algorithms for PD-L1 assays are known in the art, e.g., TPS, percent of tumor cells (TC), and the tumor cell scoring algorithm set forth in Table 2 herein. A description of different exemplary scoring algorithms for PD-L1 assays that may be used is shown in Fig. 1 of Zajac et al. Diagnostic Pathology.

[0216] Any suitable cutoff may be used. For example, in some examples, the cutoff is IC > 1 %, e.g., as described in Table 1 herein. In some examples, the cutoff is CPS >1 .

[0217] In some examples, the tumor sample obtained from the patient has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise 1 % or more of the tumor sample using a PD-L1 IHC assay comprising the VENTANA SP142 anti-PD-L1 diagnostic antibody.

[0218] In some examples, the tumor sample obtained from the patient has the presence of discernible PD-L1 staining of any intensity in tumor-infiltrating immune cells covering > 1 % of tumor area occupied by tumor cells, associated intratumoral, and contiguous peritumoral stroma, as determined by the PD-L1 IHC assay comprising the VENTANA SP142 anti-PD-L1 diagnostic antibody.

[0219] In some examples, the tumor sample obtained from the patient has a CPS of >1 using a PD-L1 IHC assay comprising the Dako 22C3 anti-PD-L1 diagnostic antibody, the VENTANA SP263 anti-PD-L1 diagnostic antibody, or the 28-8 anti-PD-L1 diagnostic antibody. In some examples, the tumor sample obtained from the patient has a CPS of >10 using a PD-L1 IHC assay comprising the Dako 22C3 anti-PD- L1 diagnostic antibody.

[0220] The present disclosure provides methods of treating a subject from which a tumor sample (e.g., a sample (e.g., biopsy) of the pancreatic cancer tumor (e.g., PDAC tumor)) has been determined to be PD- L1 -positive.

[0221] A PD-L1 -positive tumor sample is a tumor sample that expresses any detectable level of PD-L1 protein. The sample from the subject may thus be determined to be PD-L1 -positive using any suitable method for detecting protein, e.g., immunostaining (e.g., using immunohistochemistry (IHC) or immunofluorescence), e.g., using one or a combination of the AHC assays described above. For example, in some aspects, the tumor sample from the subject is determined to be PD-L1 -positive by an immunohistochemical (IHC) assay comprising staining with an anti-PD-L1 antibody suitable for staining (e.g., an assay comprising staining with the anti-PD-L1 antibody SP263, SP142, 22C3, or 28-8, e.g., a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, a Ventana SP142 IHC assay, or a pharmDx 28-8 IHC assay).

[0222] Any suitable tumor sample may be used, e.g., a formalin-fixed and paraffin-embedded (FFPE) tumor sample, an archival tumor sample, a fresh tumor sample, or a frozen tumor sample. The tumor sample may contain, e.g., tumor-infiltrating immune cells, tumor cells, stromal cells, and any combinations thereof. In one aspect, the protein expression level of PD-L1 in the tumor sample from the subject has been determined using the VENTANA PD-L1 (SP263) CDx Assay, and the tumor sample has been determined to have a PD-L1 tumor area positive (TAP) score of equal to or greater than 1 %. Methods for calculating TAP score are described, e.g., in Liu et al., Diagn. Pathol., 18: 48, 2023.

[0223] Briefly, a tumor area positive (TAP) score is calculated as follows:

[0224] TAP=(%PD-L1 positive TC and IC) I (Tumor area) wherein TCs are tumor cells and ICs are immune cells.

[0225] In some aspects, the tumor sample has been determined to have a PD-L1 TAP score of at least 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%, or has been determined to have a PD-L1 TAP score of greater than 50% (e.g., has been determined to have a PD-L1 TAP score of 1 -5%, 5-10%, 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45- 50%, or greater than 50%), e.g., as determined using an immunohistochemical (IHC) assay comprising staining with an anti-PD-L1 antibody suitable for staining, e.g., as determined using the VENTANA PD-L1 (SP263) CDx Assay. In some aspects, the tumor sample has been determined to have a PD-L1 TAP score of at least 1 % as determined using an IHC assay comprising staining with the anti-PD-L1 antibody SP263, e.g., as determined using the VENTANA PD-L1 (SP263) CDx Assay.

[0226] Further methods for detecting PD-L1 expression are known in the art. For example, PD-L1 expression may be determined as described in U.S. Patent Application Publication Nos.

[0227] US20180030138A1 and US20180037655A1 , which are each incorporated by reference in their entirety.

[0228] As a general principle, in some aspects, a PD-L1 -positive tumor is a tumor in which PD-L1 expression in the tumor and / or immune cell compartment is equal to or greater than 1 % in the analyzed tumor area.

[0229] In some aspects, PD-L1 expression is characterized in terms of the percentage of a tumor sample comprised by tumor-infiltrating immune cells expressing a detectable expression level of PD-L1 , as the percentage of tumor-infiltrating immune cells in a tumor sample expressing a detectable expression level of PD-L1 , and / or as the percentage of tumor cells in a tumor sample expressing a detectable expression level of PD-L1 . It is to be understood that in any of the preceding examples, the percentage of the tumor sample comprised by tumor-infiltrating immune cells may be in terms of the percentage of tumor area covered by tumor-infiltrating immune cells in a section of the tumor sample obtained from the subject, for example, as assessed by IHC using an anti-PD-L1 antibody (e.g., the SP142 antibody). Any suitable anti-PD-L1 antibody may be used, including, e.g., SP142 (Ventana), SP263 (Ventana), 22C3 (Dako), 28-8 (Dako), E1 L3N (Cell Signaling Technology), 4059 (ProSci, Inc.), h5H1 (Advanced Cell Diagnostics), and 9A1 1 . In some examples, the anti-PD-L1 antibody is SP142. In other examples, the anti-PD-L1 antibody is SP263. In some examples, the anti-PD-L1 antibody is 22C3. In some examples, the anti-PD-L1 antibody is 28-8.

[0230] In some examples, a tumor sample obtained from the subject has a detectable expression level of PD-L1 in greater than 0%, but less than 1 %, of the tumor cells in the tumor sample; in 1 % or more of the tumor cells in the tumor sample; in from 1 % to less than 5% of the tumor cells in the tumor sample; in 5% or more of the tumor cells in the tumor sample; in from 5% to less than 50% of the tumor cells in the tumor sample; or in 50% or more of the tumor cells in the tumor sample.

[0231] In some examples, a tumor sample obtained from the subject has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than 0%, but less than 1 %, of the tumor sample; more than 1 % of the tumor sample; from 1 % to less than 5% of the tumor sample; more than 5% of the tumor sample; from 5% to less than 10% of the tumor sample; or more than 10% of the tumor sample.

[0232] In some aspects, a tumor sample obtained from the subject has a detectable expression level of PD-L1 of greater than or equal to 1 % (e.g., about 1 % or more, 2% or more, 3% or more, 5% or more, 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 1 1 % or more, 12% or more, 13% or more, 14% or more, 15% or more, 16% or more, 17% or more, 18% or more, 19% or more, 20% or more, 21 % or more, 22% or more, 23% or more, 24% or more, 25% or more, 26% or more, 27% or more, 28% or more, 29% or more, 30% or more, 31 % or more, 32% or more, 33% or more, 34% or more, 35% or more, 36% or more, 37% or more, 38% or more, 39% or more, 40% or more, 41 % or more, 42% or more, 43% or more, 44% or more, 45% or more, 46% or more, 47% or more, 48% or more, 49% or more, 50% or more, 51 % or more, 52% or more, 53% or more, 54% or more, 55% or more, 56% or more, 57% or more, 58% or more, 59% or more, 60% or more, 61 % or more, 62% or more, 63% or more, 64% or more, 65% or more, 66% or more, 67% or more, 68% or more, 69% or more, 70% or more, 71 % or more, 72% or more, 73% or more, 74% or more, 75% or more, 76% or more, 77% or more, 78% or more, 79% or more, 80% or more, 81 % or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91 % or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more) in the tumor and / or immune cell compartment in the analyzed tumor area as determined using the anti-PD-L1 antibody SP263.

[0233] In some aspects, a tumor sample obtained from the subject has a detectable expression level of PD-L1 of greater than or equal to 1 % (e.g., about 1 % or more, 2% or more, 3% or more, 5% or more, 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 1 1 % or more, 12% or more, 13% or more, 14% or more, 15% or more, 16% or more, 17% or more, 18% or more, 19% or more, 20% or more, 21 % or more, 22% or more, 23% or more, 24% or more, 25% or more, 26% or more, 27% or more, 28% or more, 29% or more, 30% or more, 31 % or more, 32% or more, 33% or more, 34% or more, 35% or more, 36% or more, 37% or more, 38% or more, 39% or more, 40% or more, 41 % or more, 42% or more, 43% or more, 44% or more, 45% or more, 46% or more, 47% or more, 48% or more, 49% or more, 50% or more, 51 % or more, 52% or more, 53% or more, 54% or more, 55% or more, 56% or more, 57% or more, 58% or more, 59% or more, 60% or more, 61 % or more, 62% or more, 63% or more, 64% or more, 65% or more, 66% or more, 67% or more, 68% or more, 69% or more, 70% or more, 71 % or more, 72% or more, 73% or more, 74% or more, 75% or more, 76% or more, 77% or more, 78% or more, 79% or more, 80% or more, 81 % or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91 % or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more) in the tumor and / or immune cell compartment in the analyzed tumor area as determined using the anti-PD-L1 antibody 28-8.

[0234] In some aspects, a tumor sample obtained from the subject has a detectable expression level of PD-L1 of greater than or equal to 1 % (e.g., about 1 % or more, 2% or more, 3% or more, 5% or more, 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 1 1 % or more, 12% or more, 13% or more, 14% or more, 15% or more, 16% or more, 17% or more, 18% or more, 19% or more, 20% or more, 21 % or more, 22% or more, 23% or more, 24% or more, 25% or more, 26% or more, 27% or more, 28% or more, 29% or more, 30% or more, 31 % or more, 32% or more, 33% or more, 34% or more, 35% or more, 36% or more, 37% or more, 38% or more, 39% or more, 40% or more, 41 % or more, 42% or more, 43% or more, 44% or more, 45% or more, 46% or more, 47% or more, 48% or more, 49% or more, 50% or more, 51 % or more, 52% or more, 53% or more, 54% or more, 55% or more, 56% or more, 57% or more, 58% or more, 59% or more, 60% or more, 61 % or more, 62% or more, 63% or more, 64% or more, 65% or more, 66% or more, 67% or more, 68% or more, 69% or more, 70% or more, 71 % or more, 72% or more, 73% or more, 74% or more, 75% or more, 76% or more, 77% or more, 78% or more, 79% or more, 80% or more, 81 % or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91 % or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more) in the tumor and / or immune cell compartment in the analyzed tumor area as determined using the anti-PD-L1 antibody 22C3.

[0235] In some aspects, a tumor sample obtained from the subject has a detectable expression level of PD-L1 of greater than or equal to 1 % (e.g., about 1 % or more, 2% or more, 3% or more, 5% or more, 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 1 1 % or more, 12% or more, 13% or more, 14% or more, 15% or more, 16% or more, 17% or more, 18% or more, 19% or more, 20% or more, 21 % or more, 22% or more, 23% or more, 24% or more, 25% or more, 26% or more, 27% or more, 28% or more, 29% or more, 30% or more, 31 % or more, 32% or more, 33% or more, 34% or more, 35% or more, 36% or more, 37% or more, 38% or more, 39% or more, 40% or more, 41 % or more, 42% or more, 43% or more, 44% or more, 45% or more, 46% or more, 47% or more, 48% or more, 49% or more, 50% or more, 51 % or more, 52% or more, 53% or more, 54% or more, 55% or more, 56% or more, 57% or more, 58% or more, 59% or more, 60% or more, 61 % or more, 62% or more, 63% or more, 64% or more, 65% or more, 66% or more, 67% or more, 68% or more, 69% or more, 70% or more, 71 % or more, 72% or more, 73% or more, 74% or more, 75% or more, 76% or more, 77% or more, 78% or more, 79% or more, 80% or more, 81 % or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91 % or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more) in the tumor and / or immune cell compartment in the analyzed tumor area as determined using the anti-PD-L1 antibody SP142.

[0236] In some examples, tumor samples may be scored for PD-L1 positivity in tumor-infiltrating immune cells and / or in tumor cells according to the criteria for diagnostic assessment shown in Table 1 and / or Table 2, respectively.

[0237] Table 1. Tumor-infiltrating immune cell (IC) IHC diagnostic criteria

[0238] Table 2. Tumor cell (TC) IHC diagnostic criteria

[0239] In some instances, the IC score has been determined to be ICO, IC1 , IC2, or IC3 (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the IC score has been determined to be IC1 , IC2, or IC3 (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay).

[0240] In some instances, the IC score has been determined to be TCO, TC1 , TC2, or TC3 (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the IC score has been determined to be TC1 , TC2, or TC3 (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the IHC assay uses anti-PD-L1 antibody SP142. In some instances, the IHC assay uses anti-PD-L1 antibody SP263. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the IHC assay uses anti-PD-L1 antibody 28-8.

[0241] In some instances, the proportion of tumor area occupied by PD-L1 -expressing ICs has been determined to be greater than, or equal to, 1% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the proportion of tumor area occupied by PD-L1 -expressing ICs has been determined to be greater than, or equal to, 5% (e.g., as determined using the Ventana (SP142) PD- L1 IHC assay). In some instances, the proportion of tumor area occupied by PD-L1 -expressing ICs has been determined to be greater than, or equal to, 10% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the proportion of tumor area occupied by PD-L1 -expressing ICs has been determined to be greater than, or equal to, 1 % and less than 50% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the proportion of tumor area occupied by PD-L1 -expressing ICs has been determined to be greater than, or equal to, 1% and less than 30% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay).

[0242] In some instances, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has a detectable protein expression level of PD-L1 . In some instances, the detectable protein expression level of PD-L1 has been determined by an IHC assay. In some instances, the IHC assay uses anti-PD-L1 antibody SP142. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 5% of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 1 % of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 1 % and less than 5% of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumorinfiltrating immune cells that comprise greater than, or equal to, 5% and less than 10% of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 10% of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 1% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 1% and less than 5% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 5% and less than 50% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 50% of the tumor cells in the tumor sample.

[0243] In some instances, in any of the methods, uses, or compositions for use described herein, the subject has a PD-L1 high tumor (e.g., a PD-L1 tumor proportion score (TPS) greater than or equal to 50% in a tumor sample as determined by an IHC with the SP263 antibody). In some instances, the PD-L1 selected tumor is a tumor that has been determined to have TPS greater than or equal to 50% by an immunohistochemical (IHC) assay. In some instances, the IHC assay uses the anti-PD-L1 antibody SP263, SP142, 22C3, or 28-8. In some instances, the IHC assay uses anti-PD-L1 antibody SP263. In some instances, the IHC assay uses anti-PD-L1 antibody SP142. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the TPS has been determined to be greater than, or equal to, 50% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TPS has been determined to be less than 50% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TPS has been determined to be greater than, or equal to, 1% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TPS has been determined to be greater than, or equal to, 1% and less than 50% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay).

[0244] In some instances, the IHC assay uses the anti-PD-L1 antibody 22C3. In some instances, the IHC assay is the pharmDx 22C3 IHC assay. In some instances, the PD-L1 -positive tumor cell fraction is greater than, or equal to, 1% as determined by positive staining with the anti-PD-L1 antibody 22C3. In some embodiments, the tumor sample has been determined to have a combined positive score (CPS) of greater than, or equal to, 10 or a tumor proportion score (TPS) of greater than or equal to 1% in the tumor sample, e.g., as determined using the anti-PD-L1 antibody 22C3 as part of the pharmDx 22C3 IHC assay. In some embodiments, the tumor sample has been determined to have a CPS of greater than, or equal to, 10 or a TPS of greater than or equal to 1% and less than 50% in the tumor sample, e.g., as determined using the anti-PD-L1 antibody 22C3 as part of the pharmDx 22C3 IHC assay. In some embodiments, the tumor sample has been determined to have a CPS of greater than, or equal to, 20 or a TPS of greater than or equal to 50% in the tumor sample, e.g., as determined using the anti-PD-L1 antibody 22C3 as part of the pharmDx 22C3 IHC assay. In some embodiments, tumor samples that have been determined to have a CPS of greater than, or equal to, 1 are comparable to tumor samples that have a TIC of greater than, or equal to, 5%.

[0245] In some instances, the IHC assay uses the anti-PD-L1 antibody 28-8. In some instances, the IHC assay is the pharmDx 28-8 IHC assay. In some instances, the PD-L1 -positive tumor cell fraction is greater than, or equal to, 1% as determined by positive staining with the anti-PD-L1 antibody 28-8.

[0246] In some instances, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has been determined to be PD-L1 -positive by an assay that detects a nucleic acid expression level of PD-L1 . In some instances, the nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique, ISH, or a combination thereof.

[0247] IV. ANTI-TIGIT ANTAGONIST ANTIBODIES

[0248] The invention provides anti-TIG IT antagonist antibodies useful for treating cancer in a subject (e.g., a human) having a cancer (e.g., a pancreatic cancer, e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC).

[0249] In some instances, the anti-TIG IT antagonist antibody is tiragolumab (CAS Registry Number: 1918185-84-8). Tiragolumab (Genentech) is also known as MTIG7192A.

[0250] In certain instances, the anti-TIGIT antagonist antibody includes at least one, two, three, four, five, or six HVRs selected from: (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4), (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and / or (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6), or a combination of one or more of the above HVRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 1 -6.

[0251] In some instances, anti-TIGIT antagonist antibodies may include (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). In some instances, the anti-TIGIT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 17) or an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 18); and / or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFS GSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIK (SEQ ID NO: 19). In some instances, the anti-TIG IT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 17 and / or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 19. In some instances, the anti-TIGIT antagonist antibody has a VH domain comprising the amino acid sequence of SEQ ID NO: 17 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some instances, the anti-TIGIT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 18 and / or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 19. In some instances, the anti-TIGIT antagonist antibody has a VH domain comprising the amino acid sequence of SEQ ID NO: 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

[0252] In some instances, the anti-TIGIT antagonist antibody includes a heavy chain and a light chain sequence, wherein: (a) the heavy chain comprises the amino acid sequence: EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 33); and (b) the light chain comprises the amino acid sequence: DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFS GSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVC LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSS PVTKSFNRGEC (SEQ ID NO: 34).

[0253] In some instances, the anti-TIGIT antagonist antibody further comprises at least one, two, three, or four of 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); and / or an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 7-10. In some instances, for example, the antibody further comprises 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); and an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

[0254] In some instances, the anti-TIG IT antagonist antibody further comprises at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of XiVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11 ), wherein Xi 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); and / or an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 11 -14. The anti-TIGIT antagonist antibody may further include, for example, at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 15); 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); and / or an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 12- 15. In some instances, the anti-TIGIT antagonist antibody includes an FR-H1 comprising the amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 15); 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); and an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14). In another instance, for example, the anti-TIGIT antagonist antibody may further include at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 16); 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); and / or an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 12-14 and 16. In some instances, the anti-TIGIT antagonist antibody includes an FR-H1 comprising the amino acid sequence of QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 16); 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); and an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).

[0255] In another aspect, an anti-TIGIT antagonist antibody is provided, wherein the antibody comprises a VH as in any of the instances provided above, and a VL as in any of the instances provided above, wherein one or both of the variable domain sequences include post-translational modifications.

[0256] In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to rabbit TIGIT, in addition to human TIGIT. In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to both human TIGIT and cynomolgus monkey (cyno) TIGIT. In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to human TIGIT, cyno TIGIT, and rabbit TIGIT. In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to human TIGIT, cyno TIGIT, and rabbit TIGIT, but not murine TIGIT.

[0257] In some instances, the anti-TIGIT antagonist antibody binds human TIGIT with a KD of about 10 nM or lower and cyno TIGIT with a KD of about 10 nM or lower (e.g., binds human TIGIT with a KD of about 0.1 nM to about 1 nM and cyno TIGIT with a KD of about 0.5 nM to about 1 nM, e.g., binds human TIGIT with a KD of about 0.1 nM or lower and cyno TIGIT with a KD of about 0.5 nM or lower).

[0258] In some instances, the anti-TIGIT antagonist antibody specifically binds TIGIT and inhibits or blocks TIGIT interaction with poliovirus receptor (PVR) (e.g., the antagonist antibody inhibits intracellular signaling mediated by TIGIT binding to PVR). In some instances, the antagonist antibody inhibits or blocks binding of human TIGIT to human PVR with an IC50 value of 10 nM or lower (e.g., 1 nM to about 10 nM). In some instances, the anti-TIGIT antagonist antibody specifically binds TIGIT and inhibits or blocks TIGIT interaction with PVR, without impacting PVR-CD226 interaction. In some instances, the antagonist antibody inhibits or blocks binding of cyno TIGIT to cyno PVR with an IC50 value of 50 nM or lower (e.g., 1 nM to about 50 nM, e.g., 1 nM to about 5 nM). In some instances, the anti-TIGIT antagonist antibody inhibits and / or blocks the interaction of CD226 with TIGIT. In some instances, the anti-TIGIT antagonist antibody inhibits and / or blocks the ability of TIGIT to disrupt CD226 homodimerization.

[0259] In some instances, the methods or uses described herein may include using or administering an isolated anti-TIGIT antagonist antibody that competes for binding to TIGIT with any of the anti-TIGIT antagonist antibodies described above. For example, the method may include administering an isolated anti-TIGIT antagonist antibody that competes for binding to TIGIT with an anti-TIGIT antagonist antibody having the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1 ); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4), (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). The methods described herein may also include administering an isolated anti-TIGIT antagonist antibody that binds to the same epitope as an anti-TIGIT antagonist antibody described above.

[0260] In some aspects, the anti-TIGIT antagonist antibody exhibits Fc-mediated effector function, e.g., participates in antibody-dependent cellular cytotoxicity (ADCC). In some aspects, the anti-TIGIT antagonist antibody is an antibody having intact Fc-mediated effector function (e.g., tiragolumab, vibostolimab, etigilimab, EQS084448, or TJ-T6) or enhanced effector function (e.g., SGN-TGT).

[0261] In other aspects, the anti-TIGIT antagonist antibody is an antibody that lacks Fc-mediated effector function (e.g., domvanalimab, BMS-986207, ASP8374, or COM902).

[0262] In some aspects, the anti-TIGIT antagonist antibody is an IgG class antibody. In some aspects, the anti-TIG IT antagonist antibody is an lgG1 class antibody, e.g., tiragolumab, vibostolimab, domvanalimab, BMS-986207, etigilimab, BGB-A1217, SGN-TGT, EOS084448 (EOS-448), TJ-T6, or AB308. In some aspects, the antibody is a human monoclonal full-length IgG 1 class antibody comprising an Fc region.

[0263] In some aspects, the anti-TIG IT antagonist antibody is a human, monoclonal full-length lgG1 subclass antibody comprising a human IgG 1 Fc region, a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 17, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 19.

[0264] In other aspects, the anti-TIG IT antagonist antibody is an lgG4 class antibody, e.g., ASP8374 or COM902.

[0265] The anti-TIG IT antagonist antibodies (e.g., tiragolumab) useful in this invention, including compositions containing such antibodies, may be used in combination with a PD-1 axis binding antagonist (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antagonist antibodies, e.g., atezolizumab), PD-1 binding antagonists (e.g., anti-PD-1 antagonist antibodies, e.g., pembrolizumab), and PD-L2 binding antagonists (e.g., anti-PD-L2 antagonist antibodies)).

[0266] In some embodiments, the anti-TIG IT antagonist antibody functions to inhibit TIGIT signaling. In some embodiments, the anti-TIG IT antagonist antibody inhibits the binding of TIGIT to its binding partners. Exemplary TIGIT binding partners include CD155 (PVR), CD112 (PVRL2 or Nectin-2), and CD113 (PVRL3 or Nectin-3). In some embodiments, the anti-TIGIT antagonist antibody is capable of inhibiting binding between TIGIT and CD155. In some embodiments, the anti-TIGIT antagonist antibody may inhibit binding between TIGIT and CD112. In some embodiments, the anti-TIGIT antagonist antibody inhibits binding between TIGIT and CD113. In some embodiments, the anti-TIGIT antagonist antibody inhibits TIGIT-mediated cellular signaling in immune cells. In some embodiments, the anti-TIGIT antagonist antibody inhibits TIGIT by depleting regulatory T cells (e.g., when engaging a FcyR).

[0267] In some embodiments, the anti-TIGIT antibody is a monoclonal antibody. In some embodiments, the anti-TIGIT antibody is an antibody fragment selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some embodiments, the anti-TIGIT antibody is a humanized antibody. In some embodiments, the anti-TIGIT antibody is a human antibody. In some embodiments, the anti-TIGIT antibody described herein binds to human TIGIT. In some embodiments, the anti-TIGIT antibody is an Fc fusion protein.

[0268] In some embodiments, the anti-TIGIT antibody is selected from the group consisting of tiragolumab (MTIG7192A, RG6058 or RO7092284), vibostolimab (MK-7684), ASP8374 (PTZ-201 ), EOS884448 (EOS-448), SEA-TGT (SGN-TGT)), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), IBI939, domvanalimab (AB154), M6223, AB308, AB154, TJ-T6, MG1131 , NB6253, HLX301 , HLX53, SL-9258 (TIGIT-Fc-LIGHT), STW264, and YBL-012. In some embodiments, the anti- TIGIT antibody is selected from the group consisting of tiragolumab (MTIG7192A, RG6058 or RO7092284), vibostolimab (MK-7684), ASP8374 (PTZ-201), EOS-448, and SEA-TGT (SGN-TGT). The anti-TIGIT antibody may be tiragolumab (MTIG7192A, RG6058 or RO7092284).

[0269] In some embodiments, the anti-TIGIT antibody comprises at least one, two, three, four, five, or six complementarity determining regions (CDRs) of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIGIT antibody comprises the six CDRs of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIG IT antibody comprises the six CDRs of any one of the antibodies selected from the group consisting of tiragolumab, ASP8374 (PTZ-201 ), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domvanalimab (AB154), vibostolimab (MK-7684), and SEA-TGT (SGN-TGT).

[0270] In some embodiments, the anti-TIG IT antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) sequence of any one of the anti- TIG IT antibodies disclosed herein and the light chain comprises a light chain variable region (VL) of the same antibody. In some embodiments, the anti-TIG IT antibody comprises the VH and VL of an anti- TIGIT antibody selected from the group consisting of tiragolumab, ASP8374 (PTZ-201 ), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domvanalimab (AB154), vibostolimab (MK-7684), and SEA-TGT (SGN-TGT).

[0271] In some embodiments, the anti-TIG IT antibody comprises the heavy chain and the light chain of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIG IT antibody comprises the heavy chain and the light chain of an anti-TIGIT antibody selected from the group consisting of tiragolumab, ASP8374 (PTZ-201 ), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domvanalimab (AB154), vibostolimab (MK- 7684), and SEA-TGT (SGN-TGT).

[0272] A. Dosing of anti-TIGIT antagonist antibodies

[0273] As a general proposition, the therapeutically effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) administered to a subject having a cancer (e.g., a pancreatic cancer) will be in the range of about 0.01 to about 50 mg / kg of subject body weight, whether by one or more administrations. In some embodiments, the therapeutically effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) administered to a subject is in the range of 0.01 to 50 mg / kg of subject body weight, whether by one or more administrations.

[0274] In some exemplary embodiments, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered in a dose of about 0.01 to about 45 mg / kg, about 0.01 to about 40 mg / kg, about 0.01 to about 35 mg / kg, about 0.01 to about 30 mg / kg, about 0.01 to about 25 mg / kg, about 0.01 to about 20 mg / kg, about 0.01 to about 15 mg / kg, about 0.01 to about 10 mg / kg, about 0.01 to about 5 mg / kg, or about 0.01 to about 1 mg / kg administered daily, weekly, every two weeks, every three weeks, or every four weeks, for example. In exemplary embodiments, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered in a dose of 0.01 to 45 mg / kg, 0.01 to 40 mg / kg, 0.01 to 35 mg / kg, 0.01 to 30 mg / kg, 0.01 to 25 mg / kg, 0.01 to 20 mg / kg, 0.01 to 15 mg / kg, 0.01 to 10 mg / kg, 0.01 to 5 mg / kg, or 0.01 to 1 mg / kg administered daily, weekly, every two weeks, every three weeks, or every four weeks, for example.

[0275] In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered on about Day 1 (e.g., Day -3, Day -2, Day -1 , Day 1 , Day 2, or Day 3) of a dosing cycle. In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of between about 30 mg to about 1200 mg (e.g., between about 30 mg to about 1100 mg, e.g., between about 60 mg to about 1000 mg, e.g., between about 100 mg to about 900 mg, e.g., between about 200 mg to about 800 mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to about 800 mg, e.g., between about 400 mg to about 750 mg, e.g., between about 450 mg to about 750 mg, e.g., between about 500 mg to about 700 mg, e.g., between about 550 mg to about 650 mg, e.g., 600 mg ± 10 mg, e.g., 600 ± 6 mg, e.g., 600 ± 5 mg, e.g., 600 ± 3 mg, e.g., 600 ± 1 mg, e.g., 600 ± 0.5 mg, e.g., 600 mg) every three weeks (Q3W). In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of between about 30 mg to about 600 mg (e.g., between about 50 mg to between 600 mg, e.g., between about 60 mg to about 600 mg, e.g., between about 100 mg to about 600 mg, e.g., between about 200 mg to about 600 mg, e.g., between about 200 mg to about 550 mg, e.g., between about 250 mg to about 500 mg, e.g., between about 300 mg to about 450 mg, e.g., between about 350 mg to about 400 mg, e.g., about 375 mg) every three weeks. In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of about 600 mg every three weeks. In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of 600 mg every three weeks. In some instances, the fixed dose of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) administered in a combination therapy (e.g., a combination treatment with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) may be reduced as compared to a standard dose of the anti-TIGIT antagonist antibody administered as a monotherapy.

[0276] In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of between about 10 mg to about 1000 mg (e.g., between about 20 mg to about 1000 mg, e.g., between about 50 mg to about 900 mg, e.g., between about 100 mg to about 850 mg, e.g., between about 200 mg to about 800 mg, e.g., between about 300 mg to about 600 mg, e.g., between about 400 mg to about 500 mg, e.g., between about 405 mg to about 450 mg, e.g., between about 410 mg to about 430 mg, e.g., about 420 mg) every two weeks (Q2W). In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of about 420 mg every two weeks (e.g., 420 mg ± 10 mg, e.g., 420 ± 6 mg, e.g., 420 ± 5 mg, e.g., 420 ± 3 mg, e.g., 420 ± 1 mg, e.g., 420 ± 0.5 mg, e.g., 420 mg every two weeks).

[0277] In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of between about 200 mg to about 2000 mg (e.g., between about 200 mg to about 1600 mg, e.g., between about 250 mg to about 1600 mg, e.g., between about 300 mg to about 1600 mg, e.g., between about 400 mg to about 1500 mg, e.g., between about 500 mg to about 1400 mg, e.g., between about 600 mg to about 1200 mg, e.g., between about 700 mg to about 1100 mg, e.g., between about 800 mg to about 1000 mg, e.g., between about 800 mg to about 900 mg, e.g., about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, or about 900 mg) every four weeks (Q4W). In some instances, the effective amount of anti-TIG IT antagonist antibody (e.g., an anti-TIG IT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of about 840 mg every four weeks (e.g., 840 mg ± 10 mg, e.g., 840 ± 6 mg, e.g., 840 ± 5 mg, e.g., 840 ± 3 mg, e.g., 840 ± 1 mg, e.g., 840 ± 0.5 mg, e.g., 840 mg every four weeks).

[0278] In some instances, the dose of the anti-TIG IT antagonist antibody (e.g., an anti-TIG IT antagonist antibody as disclosed herein, e.g., tiragolumab) is a tiered dose based on a subject’s body weight (e.g., body weight (BW) > 40 kg: 600 mg, BW > 15 kg and < 40 kg: 400 mg, and BW < 15 kg: 300 mg).

[0279] In some instances, the dose of the anti-TIG IT antagonist antibody (e.g., an anti-TIG IT antagonist antibody as disclosed herein, e.g., tiragolumab) administered in a combination therapy (e.g., a combination treatment with a PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) may be reduced as compared to a standard dose of the anti-TIG IT antagonist antibody administered as a monotherapy.

[0280] In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIG IT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered intravenously. Alternatively, in some embodiments, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered subcutaneously. In some instances, tiragolumab is administered to the subject intravenously at a dose of about 420 mg every 2 weeks, about 600 mg every 3 weeks, or about 840 mg of every 4 weeks. In some instances, tiragolumab is administered to the subject intravenously at a dose of 420 mg every 2 weeks, 600 mg every 3 weeks, or 840 mg of every 4 weeks. In some embodiments, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered to the subject subcutaneously at a dose of about 880 mg (e.g., at a dose of 880 mg), e.g., is administered subcutaneously at a dose of 880 mg every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered to the subject subcutaneously at a dose of about 1000 mg (e.g., at a dose of 1000 mg), e.g., is administered subcutaneously at a dose of 1000 mg every 2 weeks, every 3 weeks, or every 4 weeks.

[0281] In some instances, the dose of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) administered in a combination therapy (e.g., a combination treatment with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab))) may be reduced as compared to a standard dose of the anti-TIGIT antagonist antibody administered as a monotherapy. In some instances, the dose of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) administered in a combination therapy (e.g., a combination treatment with a PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)), with or without one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and / or a non-platinum-based chemotherapeutic agent (e.g., an alkylating agent (e.g., cyclophosphamide), a taxane (e.g., paclitaxel or nab-paclitaxel), and / or a topoisomerase II inhibitor (e.g., doxorubicin))) and / or G-CSF or GM-CSF, may be reduced as compared to a standard dose of the anti-TIGIT antagonist antibody administered as a monotherapy. In some instances, a subject is administered a total of 1 to 60 doses of an anti-TIG IT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, or 60 doses. In some instances, a subject is administered a total of 1 to 60 doses of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), e.g., 1 to 60 doses, 1 to 55 doses, 1 to 50 doses, 1 to 45 doses, 1 to 40 doses, 1 to 35 doses, 1 to 30 doses, 1 to 25 doses, 1 to 20 doses, 1 to 15 doses, 1 to 10 doses, 1 to 5 doses, 2 to 60 doses, 2 to 55 doses, 2 to 50 doses, 2 to 45 doses, 2 to 40 doses, 2 to 35 doses, 2 to 30 doses, 2 to 25 doses, 2 to 20 doses, 2 to 15 doses, 2 to 10 doses, 2 to 5 doses, 3 to 60 doses, 3 to 55 doses, 3 to 50 doses, 3 to 45 doses, 3 to 40 doses, 3 to 35 doses, 3 to 30 doses, 3 to 25 doses, 3 to 20 doses, 3 to 15 doses, 3 to 10 doses, 3 to 5 doses, 4 to 60 doses, 4 to 55 doses, 4 to 50 doses, 4 to 45 doses, 4 to 40 doses, 4 to 35 doses, 4 to 30 doses, 4 to 25 doses, 4 to 20 doses, 4 to 15 doses, 4 to 10 doses, 4 to 5 doses, 5 to 60 doses, 5 to 55 doses, 5 to 50 doses, 5 to 45 doses, 5 to 40 doses, 5 to 35 doses, 5 to 30 doses, 5 to 25 doses, 5 to 20 doses, 5 to 15 doses, 5 to 10 doses, 10 to 60 doses, 10 to 55 doses, 10 to 50 doses, 10 to 45 doses, 10 to 40 doses, 10 to 35 doses, 10 to 30 doses, 10 to 25 doses, 10 to 20 doses, 10 to 15 doses, 15 to 60 doses, 15 to 55 doses, 15 to 50 doses, 15 to 45 doses, 15 to 40 doses, 15 to 35 doses, 15 to 30 doses, 15 to 25 doses, 15 to 20 doses, 20 to 60 doses, 20 to 55 doses, 20 to 50 doses, 20 to 45 doses, 20 to 40 doses, 20 to 35 doses, 20 to 30 doses, 20 to 25 doses, 25 to 60 doses, 25 to 55 doses, 25 to 50 doses, 25 to 45 doses, 25 to 40 doses, 25 to 35 doses, 25 to 30 doses, 30 to 60 doses, 30 to 55 doses, 30 to 50 doses, 30 to 45 doses, 30 to 40 doses, 30 to 35 doses, 35 to 60 doses, 35 to 55 doses, 35 to 50 doses, 35 to 45 doses, 35 to 40 doses, 40 to 60 doses, 40 to 55 doses, 40 to 50 doses, 40 to 45 doses, 45 to 50 doses, 50 to 60 doses, or 55 to 60 doses. In particular instances, the doses may be administered intravenously.

[0282] The anti-TIGIT antagonist antibody may be administered in any suitable manner known in the art. In some instances, the anti-TIGIT antagonist antibody is administered on about Day 1 (e.g., Day -3, Day - 2, Day -1 , Day 1 , Day 2, or Day 3) of a dosing cycle. In some instances, the anti-TIGIT antagonist antibody may be administered on the same day. In some instances, the PD-1 axis binding antagonist is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some instances, the anti-TIGIT antagonist antibody is administered intravenously. In some instances, the anti-TIGIT antagonist antibody is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some instances, the anti-TIGIT antagonist antibody is administered intravenously. In some instances, there is a first observation period following administration of anti-TIGIT antagonist antibody. In some instances, the observation period is between about 30 minutes to about 60 minutes in length. In some instances, the anti-TIGIT antagonist antibody is administered intravenously or subcutaneously.

[0283] In one example, tiragolumab may be administered intravenously over 60 minutes; if the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. In any of the preceding examples, each dosing cycle may have any suitable length, e.g., about 7 days (about 5, 6, 7, 8, or 9 days), about 14 days (e.g., about 12, 13, 14, 15, or 16 days), about 21 days (e.g., about 18, 19, 20, 21 , 22, 23, or 24 days), about 28 days (about 25, 26, 27, 28, 29, 30, or 31 days), or longer. In some instances, each dosing cycle is about 28 days.

[0284] V. PD-1 AXIS BINDING ANTAGONISTS

[0285] The invention provides PD-1 axis binding antagonists useful for treating cancer in a subject (e.g., a human) having a cancer (e.g., a pancreatic cancer, e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC).

[0286] PD-1 axis binding antagonists may include PD-L1 binding antagonists, PD-1 binding antagonists, and PD-L2 binding antagonists. Any suitable PD-1 axis binding antagonist may be used for treating a subject having a cancer (e.g., a pancreatic cancer, e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC).

[0287] A. PD-L 1 Binding Antagonists

[0288] In some instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners. In other instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 . In yet other instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to B7-1 . In some instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1 . The PD-L1 binding antagonist may be, without limitation, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule. In some instances, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 (e.g., GS-4224, INCB086550, MAX-10181 , INCB090244, CA-170, or ABSK041 ). In some instances, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and VISTA. In some instances, the PD-L1 binding antagonist is CA-170 (also known as AUPM-170). In some instances, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and TIM3. In some instances, the small molecule is a compound described in WO 2015 / 033301 and / or WO 2015 / 033299.

[0289] In some instances, the PD-L1 binding antagonist is an anti-PD-L1 antibody. A variety of anti-PD- L1 antibodies are contemplated and described herein. In any of the instances herein, the isolated anti- PD-L1 antibody can bind to a human PD-L1 , for example a human PD-L1 as shown in UniProtKB / Swiss- Prot Accession No. Q9NZQ7-1 , or a variant thereof. In some instances, the anti-PD-L1 antibody is capable of inhibiting binding between PD-L1 and PD-1 and / or between PD-L1 and B7-1 . In some instances, the anti-PD-L1 antibody is a monoclonal antibody. In some instances, the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some instances, the anti-PD-L1 antibody is a humanized antibody. In some instances, the anti-PD-L1 antibody is a human antibody. Exemplary anti-PD-L1 antibodies include atezolizumab, MDX- 1105, MEDI4736 (durvalumab), MSB0010718C (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, and HS-636. Examples of anti-PD-L1 antibodies useful in the methods of this invention and methods of making them are described in International Patent Application Publication No. WO 2010 / 077634 and U.S. Patent No. 8,217,149, each of which is incorporated herein by reference in its entirety.

[0290] In some instances, the anti-PD-L1 antibody comprises:

[0291] (a) an HVR-H1 , HVR-H2, and HVR-H3 sequence of GFTFSDSWIH (SEQ ID NO: 20), AWISPYGGSTYYADSVKG (SEQ ID NO: 21 ) and RHWPGGFDY (SEQ ID NO: 22), respectively, and

[0292] (b) an HVR-L1 , HVR-L2, and HVR-L3 sequence of RASQDVSTAVA (SEQ ID NO: 23), SASFLYS (SEQ ID NO: 24) and QQYLYHPAT (SEQ ID NO: 25), respectively.

[0293] In one embodiment, the anti-PD-L1 antibody comprises:

[0294] (a) a heavy chain variable region (VH) comprising the amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGR FTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO: 26), and

[0295] (b) the light chain variable region (VL) comprising the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 27).

[0296] In some instances, the anti-PD-L1 antibody comprises (a) a VH comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of SEQ ID NO: 26; (b) a VL comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of SEQ ID NO: 27; or (c) a VH as in (a) and a VL as in (b).

[0297] In one embodiment, the anti-PD-L1 antibody comprises atezolizumab, which comprises:

[0298] (a) the heavy chain amino acid sequence:

[0299] EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGR FTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKST SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK PSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD

[0300] KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 28), and

[0301] (b) the light chain amino acid sequence:

[0302] DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC (SEQ ID NO: 29).

[0303] In some instances, the anti-PD-L1 antibody is avelumab (CAS Registry Number: 1537032-82-8). Avelumab, also known as MSB0010718C, is a human monoclonal lgG1 anti-PD-L1 antibody (Merck KGaA, Pfizer).

[0304] In some instances, the anti-PD-L1 antibody is durvalumab (CAS Registry Number: 1428935-60- 7). Durvalumab, also known as MEDI4736, is an Fc-optimized human monoclonal IgG 1 kappa anti-PD- L1 antibody (Medlmmune, AstraZeneca) described in WO 2011 / 066389 and US 2013 / 034559.

[0305] In some instances, the anti-PD-L1 antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO 2007 / 005874. In some instances, the anti-PD-L1 antibody is LY3300054 (Eli Lilly).

[0306] In some instances, the anti-PD-L1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti- PD-L1 antibody.

[0307] In some instances, the anti-PD-L1 antibody is KN035 (Suzhou Alphamab). KN035 is singledomain antibody (dAB) generated from a camel phage display library.

[0308] In some instances, the anti-PD-L1 antibody comprises a cleavable moiety or linker that, when cleaved (e.g., by a protease in the tumor microenvironment), activates an antibody antigen-binding domain to allow it to bind its antigen, e.g., by removing a non-binding steric moiety. In some instances, the anti-PD-L1 antibody is CX-072 (CytomX Therapeutics).

[0309] In some instances, the anti-PD-L1 antibody comprises the six HVR sequences (e.g., the three heavy chain HVRs and the three light chain HVRs) and / or the heavy chain variable domain and light chain variable domain from an anti-PD-L1 antibody described in US 20160108123, WO 2016 / 000619, WO 2012 / 145493, U.S. Pat. No. 9,205,148, WO 2013 / 181634, or WO 2016 / 061142.

[0310] In a still further specific aspect, the anti-PD-L1 antibody has reduced or minimal effector function. In a still further specific aspect, the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation. In still a further instance, the effector-less Fc mutation is an N297A or D265A / N297A substitution in the constant region. In still a further instance, the effector-less Fc mutation is an N297A substitution in the constant region. In some instances, the isolated anti-PD-L1 antibody is aglycosylated. Glycosylation of antibodies is typically either N-linked or O- linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N- acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. Removal of glycosylation sites from an antibody is conveniently accomplished by altering the amino acid sequence such that one of the abovedescribed tripeptide sequences (for N-linked glycosylation sites) is removed. The alteration may be made by substitution of an asparagine, serine or threonine residue within the glycosylation site with another amino acid residue (e.g., glycine, alanine, or a conservative substitution).

[0311] B. PD- 1 Binding Antagonists

[0312] In some instances, the PD-1 axis binding antagonist is a PD-1 binding antagonist. For example, in some instances, the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners. In some instances, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 . In other instances, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2. In yet other instances, the PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2. The PD-1 binding antagonist may be, without limitation, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule. In some instances, the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). For example, in some instances, the PD-1 binding antagonist is an Fc-fusion protein. In some instances, the PD-1 binding antagonist is AMP-224. AMP-224, also known as B7-DCIg, is a PD- L2-Fc fusion soluble receptor described in WO 2010 / 027827 and WO 201 1 / 066342. In some instances, the PD-1 binding antagonist is a peptide or small molecule compound. In some instances, the PD-1 binding antagonist is AUNP-12 (PierreFabre / Aurigene). See, e.g., WO 2012 / 168944, WO 2015 / 036927, WO 2015 / 044900, WO 2015 / 033303, WO 2013 / 144704, WO 2013 / 132317, and WO 201 1 / 161699. In some instances, the PD-1 binding antagonist is a small molecule that inhibits PD-1 .

[0313] In some instances, the PD-1 binding antagonist is an anti-PD-1 antibody. A variety of anti-PD-1 antibodies can be utilized in the methods and uses disclosed herein. In any of the instances herein, the PD-1 antibody can bind to a human PD-1 or a variant thereof. In some instances, the anti-PD-1 antibody is a monoclonal antibody. In some instances, the anti-PD-1 antibody is an antibody fragment selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some instances, the anti-PD-1 antibody is a humanized antibody. In other instances, the anti-PD-1 antibody is a human antibody. Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (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-1 1 10, AK-103, and hAb21 .

[0314] In some instances, the anti-PD-1 antibody is nivolumab (CAS Registry Number: 946414-94-4). Nivolumab (Bristol-Myers Squibb / Ono), also known as MDX-1 106-04, MDX-1 106, ONO-4538, BMS- 936558, and OPDIVO®, is an anti-PD-1 antibody described in WO 2006 / 121 168.

[0315] In some instances, the anti-PD-1 antibody is pembrolizumab (CAS Registry Number: 1374853- 91 -4). Pembrolizumab (Merck), also known as MK-3475, Merck 3475, lambrolizumab, SCH-900475, and KEYTRUDA®, is an anti-PD-1 antibody described in WO 2009 / 1 14335.

[0316] In some instances, the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca). MEDI-0680 is a humanized lgG4 anti-PD-1 antibody.

[0317] In some instances, the anti-PD-1 antibody is PDR001 (CAS Registry No. 1859072-53-9; Novartis). PDR001 is a humanized lgG4 anti-PD-1 antibody that blocks the binding of PD-L1 and PD-L2 to PD-1 .

[0318] In some instances, the anti-PD-1 antibody is REGN2810 (Regeneron). REGN2810 is a human anti-PD-1 antibody.

[0319] In some instances, the anti-PD-1 antibody is BGB-108 (BeiGene).

[0320] In some instances, the anti-PD-1 antibody is BGB-A317 (BeiGene).

[0321] In some instances, the anti-PD-1 antibody is JS-001 (Shanghai Junshi). JS-001 is a humanized anti-PD-1 antibody.

[0322] In some instances, the anti-PD-1 antibody is STI-A1 1 10 (Sorrento). STI-A1 1 10 is a human antiPD-1 antibody.

[0323] In some instances, the anti-PD-1 antibody is INCSHR-1210 (Incyte). INCSHR-1210 is a human lgG4 anti-PD-1 antibody.

[0324] In some instances, the anti-PD-1 antibody is PF-06801591 (Pfizer). In some instances, the anti-PD-1 antibody is TSR-042 (also known as ANB011 ; Tesaro / AnaptysBio).

[0325] In some instances, the anti-PD-1 antibody is AM0001 (ARMO Biosciences).

[0326] In some instances, the anti-PD-1 antibody is ENUM 244C8 (Enumeral Biomedical Holdings). ENUM 244C8 is an anti-PD-1 antibody that inhibits PD-1 function without blocking binding of PD-L1 to PD-1.

[0327] In some instances, the anti-PD-1 antibody is ENUM 388D4 (Enumeral Biomedical Holdings). ENUM 388D4 is an anti-PD-1 antibody that competitively inhibits binding of PD-L1 to PD-1 .

[0328] In some instances, the anti-PD-1 antibody comprises the six HVR sequences (e.g., the three heavy chain HVRs and the three light chain HVRs) and / or the heavy chain variable domain and light chain variable domain from an anti-PD-1 antibody described in WO 2015 / 112800, WO 2015 / 112805, WO 2015 / 112900, US 20150210769 , WO2016 / 089873, WO 2015 / 035606, WO 2015 / 085847, WO 2014 / 206107, WO 2012 / 145493, US 9,205,148, WO 2015 / 119930, WO 2015 / 119923, WO 2016 / 032927, WO 2014 / 179664, WO 2016 / 106160, and WO 2014 / 194302.

[0329] In a still further specific aspect, the anti-PD-1 antibody has reduced or minimal effector function. In a still further specific aspect, the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation. In still a further instance, the effector-less Fc mutation is an N297A or D265A / N297A substitution in the constant region. In some instances, the isolated anti-PD-1 antibody is aglycosylated.

[0330] C. PD-L2 Binding Antagonists

[0331] In some instances, the PD-1 axis binding antagonist is a PD-L2 binding antagonist. In some instances, the PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its ligand binding partners. In a specific aspect, the PD-L2 binding ligand partner is PD-1 . The PD-L2 binding antagonist may be, without limitation, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule.

[0332] In some instances, the PD-L2 binding antagonist is an anti-PD-L2 antibody. In any of the instances herein, the anti-PD-L2 antibody can bind to a human PD-L2 or a variant thereof. In some instances, the anti-PD-L2 antibody is a monoclonal antibody. In some instances, the anti-PD-L2 antibody is an antibody fragment selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some instances, the anti-PD-L2 antibody is a humanized antibody. In other instances, the anti-PD-L2 antibody is a human antibody. In a still further specific aspect, the anti-PD-L2 antibody has reduced or minimal effector function. In a still further specific aspect, the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation. In still a further instance, the effector-less Fc mutation is an N297A or D265A / N297A substitution in the constant region. In some instances, the isolated anti-PD-L2 antibody is aglycosylated.

[0333] D. Dosing of PD- 1 axis binding antagonists

[0334] As a general proposition, the therapeutically effective amount of a PD-1 axis binding antagonist (e.g., atezolizumab) administered to a subject having a cancer (e.g., a pancreatic cancer, e.g., PDAC, e.g., metastatic PDAC) will be in the range of about 0.01 to about 50 mg / kg of subject body weight, whether by one or more administrations.

[0335] In some exemplary embodiments, the PD-1 axis binding antagonist (e.g., atezolizumab) is administered in a dose of about 0.01 to about 45 mg / kg, about 0.01 to about 40 mg / kg, about 0.01 to about 35 mg / kg, about 0.01 to about 30 mg / kg, about 0.01 to about 25 mg / kg, about 0.01 to about 20 mg / kg, about 0.01 to about 15 mg / kg, about 0.01 to about 10 mg / kg, about 0.01 to about 5 mg / kg, or about 0.01 to about 1 mg / kg administered daily, weekly, every two weeks, every three weeks, or every four weeks, for example.

[0336] In some instances, the dose of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose based on a subject’s body weight (e.g., 15 mg / kg). In some instances, the dose of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose based on a subject’s body surface area (e.g., body surface area (BSA) > 1 .25 m2: 600 mg, BSA > 0.75 m2and < 1 .25 m2: 450 mg, BSA > 0.5 m2and < 0.75 m2: 350 mg, and BSA < 0.5 m2: 300 mg).

[0337] In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of between about 80 mg to about 1600 mg (e.g., between about 100 mg to about 1600 mg, e.g., between about 200 mg to about 1600 mg, e.g., between about 300 mg to about 1600 mg, e.g., between about 400 mg to about 1600 mg, e.g., between about 500 mg to about 1600 mg, e.g., between about 600 mg to about 1600 mg, e.g., between about 700 mg to about 1600 mg, e.g., between about 800 mg to about 1600 mg, e.g., between about 900 mg to about 1500 mg, e.g., between about 1000 mg to about 1400 mg, e.g., between about 1050 mg to about 1350 mg, e.g., between about 1 100 mg to about 1300 mg, e.g., between about 1 150 mg to about 1250 mg, e.g., between about 1 175 mg to about 1225 mg, e.g., between about 1 190 mg to about 1210 mg, e.g., 1200 mg ± 5 mg, e.g., 1200 ± 2.5 mg, e.g., 1200 ± 1 .0 mg, e.g., 1200 ± 0.5 mg, e.g., 1200) every three weeks. In some embodiments, the effective amount of the PD-1 axis binding antagonist is atezolizumab at a fixed dose of about 1200 mg every three weeks. In some embodiments, the effective amount of the PD-1 axis binding antagonist is pembrolizumab at a fixed dose of about 200 mg every three weeks or, alternatively, pembrolizumab at a fixed dose of about 400 mg every six weeks.

[0338] In some instances, the fixed dose of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered in a combination therapy (e.g., a combination treatment with an anti-TIG IT antagonist antibody, such as an anti-TIG IT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced as compared to a standard dose of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered as a monotherapy.

[0339] In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01 mg / kg to about 50 mg / kg of the subject’s body weight (e.g., between about 0.01 mg / kg to about 45 mg / kg, e.g., between about 0.1 mg / kg to about 40 mg / kg, e.g., between about 1 mg / kg to about 35 mg / kg, e.g., between about 2.5 mg / kg to about 30 mg / kg, e.g., between about 5 mg / kg to about 25 mg / kg, e.g., between about 10 mg / kg to about 20 mg / kg, e.g., between about 12.5 mg / kg to about 15 mg / kg, e.g., about 15 ± 2 mg / kg, about 15 ± 1 mg / kg, about 15 ± 0.5 mg / kg, about 15 ± 0.2 mg / kg, or about 15 ± 0.1 mg / kg, e.g., about 15 mg / kg) every three weeks. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., an anti- PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 0.01 mg / kg to about 15 mg / kg of the subject’s body weight (e.g., between about 0.1 mg / kg to about 15 mg / kg, e.g., between about 0.5 mg / kg to about 15 mg / kg, e.g., between about 1 mg / kg to about 15 mg / kg, e.g., between about 2.5 mg / kg to about 15 mg / kg, e.g., between about 5 mg / kg to about 15 mg / kg, e.g., between about 7.5 mg / kg to about 15 mg / kg, e.g., between about 10 mg / kg to about 15 mg / kg, e.g., between about 12.5 mg / kg to about 15 mg / kg, e.g., between about 14 mg / kg to about 15 mg / kg, e.g., about 15 ± 1 mg / kg, e.g., about 15 ± 0.5 mg / kg, e.g., about 15 ± 0.2 mg / kg, e.g., about 15 ± 0.1 mg / kg, e.g., about 15 mg / kg) every three weeks. In some instances, the effective amount of PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of about 15 mg / kg administered every three weeks. In some instances, the dose of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered in a combination therapy (e.g., a combination treatment with an anti-TIG IT antagonist antibody, such as an anti-TIG IT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced as compared to a standard dose of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered as a monotherapy.

[0340] In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of between about 20 mg to about 1600 mg (e.g., between about 40 mg to about 1500 mg, e.g., between about 200 mg to about 1400 mg, e.g., between about 300 mg to about 1400 mg, e.g., between about 400 mg to about 1400 mg, e.g., between about 500 mg to about 1300 mg, e.g., between about 600 mg to about 1200 mg, e.g., between about 700 mg to about 1 100 mg, e.g., between about 800 mg to about 1000 mg, e.g., between about 800 mg to about 900 mg, e.g., about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, or about 900 mg) every two weeks (Q2W). In some instances, the effective amount of the PD-1 axis binding antagonist is atezolizumab at a fixed dose of about 840 mg every two weeks (e.g., 840 mg ± 10 mg, e.g., 840 ± 6 mg, e.g., 840 ± 5 mg, e.g., 840 ± 3 mg, e.g., 840 ± 1 mg, e.g., 840 ± 0.5 mg, e.g., 840 mg every two weeks). In some embodiments, the effective amount of the PD-1 axis binding antagonist is avelumab at a fixed dose of about 800 mg every two weeks. In some embodiments, the effective amount of the PD-1 axis binding antagonist is nivolumab at a fixed dose of about 240 mg every two weeks.

[0341] In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of between about 500 mg to about 3000 mg (e.g., between about 500 mg to about 2800 mg, e.g., between about 600 mg to about 2700 mg, e.g., between about 650 mg to about 2600 mg, e.g., between about 700 mg to about 2500 mg, e.g., between about 1000 mg to about 2400 mg, e.g., between about 1 100 mg to about 2300 mg, e.g., between about 1200 mg to about 2200 mg, e.g., between about 1300 mg to about 2100 mg, e.g., between about 1400 mg to about 2000 mg, e.g., between about 1500 mg to about 1900 mg, e.g., between about 1600 mg to about 1800 mg, e.g., between about 1620 mg to about 1700 mg, e.g., between about 1640 mg to about 1690 mg, e.g., between about 1660 mg to about 1680 mg, about 1680 mg, e.g., about 1600 mg, about 1610 mg, about 1620 mg, about 1630 mg, about 1640 mg, about 1650 mg, about 1660 mg, about 1670 mg, about 1680 mg, about 1690 mg, or about 1700 mg) every four weeks (Q4W). In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of 1680 mg every four weeks (e.g., 1680 mg ± 10 mg, e.g., 1680 ± 6 mg, e.g., 1680 ± 5 mg, e.g., 1680 ± 3 mg, e.g., 1680 ± 1 mg, e.g., 1680 ± 0.5 mg, e.g., 1680 mg every four weeks). In some embodiments, the effective amount of the PD-1 axis binding antagonist is nivolumab at a fixed dose of about 480 mg every four weeks.

[0342] In some instances, the dose of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein (e.g., tiragolumab) may be reduced as compared to a standard dose of the anti-PD-L1 antagonist antibody administered as a monotherapy. In some instances, the dose of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab), with or without one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and / or a non-platinum-based chemotherapeutic agent (e.g., an alkylating agent (e.g., cyclophosphamide), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and / or a topoisomerase II inhibitor (e.g., doxorubicin))) and / or G-CSF or GM-CSF may be reduced as compared to a standard dose of the PD-1 axis binding antagonist administered as a monotherapy.

[0343] In some instances, a subject is administered a total of 1 to 60 doses of a PD-1 axis binding antagonist (e.g., atezolizumab), e.g., 1 to 60 doses, 1 to 55 doses, 1 to 50 doses, 1 to 45 doses, 1 to 40 doses, 1 to 35 doses, 1 to 30 doses, 1 to 25 doses, 1 to 20 doses, 1 to 15 doses, 1 to 10 doses, 1 to 5 doses, 2 to 60 doses, 2 to 55 doses, 2 to 50 doses, 2 to 45 doses, 2 to 40 doses, 2 to 35 doses, 2 to 30 doses, 2 to 25 doses, 2 to 20 doses, 2 to 15 doses, 2 to 10 doses, 2 to 5 doses, 3 to 60 doses, 3 to 55 doses, 3 to 50 doses, 3 to 45 doses, 3 to 40 doses, 3 to 35 doses, 3 to 30 doses, 3 to 25 doses, 3 to 20 doses, 3 to 15 doses, 3 to 10 doses, 3 to 5 doses, 4 to 60 doses, 4 to 55 doses, 4 to 50 doses, 4 to 45 doses, 4 to 40 doses, 4 to 35 doses, 4 to 30 doses, 4 to 25 doses, 4 to 20 doses, 4 to 15 doses, 4 to 10 doses, 4 to 5 doses, 5 to 60 doses, 5 to 55 doses, 5 to 50 doses, 5 to 45 doses, 5 to 40 doses, 5 to 35 doses, 5 to 30 doses, 5 to 25 doses, 5 to 20 doses, 5 to 15 doses, 5 to 10 doses, 10 to 60 doses, 10 to 55 doses, 10 to 50 doses, 10 to 45 doses, 10 to 40 doses, 10 to 35 doses, 10 to 30 doses, 10 to 25 doses, 10 to 20 doses, 10 to 15 doses, 15 to 60 doses, 15 to 55 doses, 15 to 50 doses, 15 to 45 doses, 15 to 40 doses, 15 to 35 doses, 15 to 30 doses, 15 to 25 doses, 15 to 20 doses, 20 to 60 doses, 20 to 55 doses, 20 to 50 doses, 20 to 45 doses, 20 to 40 doses, 20 to 35 doses, 20 to 30 doses, 20 to 25 doses, 25 to 50 doses, 25 to 45 doses, 25 to 40 doses, 25 to 35 doses, 25 to 30 doses, 30 to 60 doses, 30 to 55 doses, 30 to 50 doses, 30 to 45 doses, 30 to 40 doses, 30 to 35 doses, 35 to 60 doses, 35 to 55 doses, 35 to 50 doses, 35 to 45 doses, 35 to 40 doses, 40 to 60 doses, 40 to 55 doses, 40 to 50 doses, 40 to 45 doses, 45 to 50 doses, 50 to 60 doses, or 55 to 60 doses. In particular instances, the doses may be administered intravenously.

[0344] In some instances, atezolizumab is administered to the subject intravenously at a dose of about 840 mg every 2 weeks, about 1200 mg every 3 weeks, or about 1680 mg of every 4 weeks. For example, in some aspects, atezolizumab is administered to the subject intravenously at a dose of 1200 mg every 3 weeks. In some aspects, atezolizumab is administered to the subject intravenously at a dose of 840 mg every 2 weeks. In some aspects, atezolizumab is administered to the subject intravenously at a dose of 1680 mg every 4 weeks. In some embodiments, the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered to the subject subcutaneously at a dose of about 1875 mg (e.g., at a dose of 1875 mg), e.g., is administered subcutaneously at a dose of 1875 mg every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered to the subject subcutaneously at a dose of about 2000 mg (e.g., at a dose of 2000 mg), e.g., is administered subcutaneously at a dose of 2000 mg every 2 weeks, every 3 weeks, or every 4 weeks.

[0345] The PD-1 axis binding antagonist and / or any additional therapeutic agent(s) may be administered in any suitable manner known in the art. For example, the PD-1 axis binding antagonist and / or any additional therapeutic agent(s) may be administered sequentially (on different days) or concurrently (on the same day or during the same treatment cycle). In some instances, the PD-1 axis binding antagonist is administered prior to the additional therapeutic agent. In other instances, the PD-1 axis binding antagonist is administered after the additional therapeutic agent. In some instances, the PD-1 axis binding antagonist and / or any additional therapeutic agent(s) may be administered on the same day. In some instances, the PD-1 axis binding antagonist may be administered prior to an additional therapeutic agent that is administered on the same day. For example, the PD-1 axis binding antagonist may be administered prior to chemotherapy on the same day. In another example, the PD-1 axis binding antagonist may be administered prior to both chemotherapy and another drug (e.g., bevacizumab) on the same day. In other instances, the PD-1 axis binding antagonist may be administered after an additional therapeutic agent that is administered on the same day. In yet other instances, the PD-1 axis binding antagonist is administered at the same time as the additional therapeutic agent. In some instances, the PD-1 axis binding antagonist is in a separate composition as the additional therapeutic agent. In some instances, the PD-1 axis binding antagonist is in the same composition as the additional therapeutic agent. In some instances, the PD-1 axis binding antagonist is administered through a separate intravenous line from any other therapeutic agent administered to the subject on the same day.

[0346] The PD-1 axis binding antagonist and any additional therapeutic agent(s) may be administered by the same route of administration or by different routes of administration. In some instances, the PD-1 axis binding antagonist is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some instances, the additional therapeutic agent is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.

[0347] In a preferred embodiment, the PD-1 axis binding antagonist is administered intravenously. In one example, atezolizumab may be administered intravenously over 60 minutes; if the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. In some examples, the PD-1 axis binding antagonist is not administered as an intravenous push or bolus.

[0348] VI. CHEMOTHERAPEUTIC AGENTS

[0349] Therapeutically effective amounts of various chemotherapeutic agents are known in the art and contemplated in the present invention. In particular instances, one or more chemotherapeutic agents (e.g., a taxane (e.g., nab-paclitaxel), and / or an antimetabolite (e.g., gemcitabine)) are administered according to the doses recited herein. Taxanes

[0350] In some aspects, the methods provided herein comprise administration of one or more dosing cycles of a taxane. Taxanes are chemotherapeutic agents that may bind to tubulin, promoting microtubule assembly and stabilization, and / or prevent microtubule depolymerization. Taxanes included herein include taxoid 10-deacetylbaccatin III and / or derivatives thereof. Exemplary taxanes include, but are not limited to, paclitaxel (i.e., TAXOL®, CAS # 33069-62-4), docetaxel (i.e., TAXOTERE®, CAS # 1 14977-28-5), larotaxel, cabazitaxel, milataxel, tesetaxel, and / or orataxel. In some embodiments, the taxane is an albumin-coated nanoparticle (e.g., nano-albumin bound (nab)-paclitaxel, i.e., ABRAXANE® and / or nab-docetaxel, ABI-008). In some embodiments, the taxane is nab-paclitaxel (ABRAXANE®). In some embodiments, the taxane is formulated in CREMAPHOR® (e.g., TAXOL®) and / or in Tween such as polysorbate 80 (e.g., TAXOTERE®). In some embodiments, the taxane is liposome-encapsulated taxane. In some embodiments, the taxane is a prodrug form and / or conjugated form of taxane (e.g., DHA covalently conjugated to paclitaxel, paclitaxel poliglumex, and / or linoleyl carbonate-paclitaxel). In some embodiments, the paclitaxel is formulated with substantially no surfactant (e.g., in the absence of CREMAPHOR and / or Tween-such as TOCOSOL® paclitaxel).

[0351] In some instances, paclitaxel is administered as part of the methods of the present invention. Paclitaxel may have the following structure:

[0352] In some instances, the methods or uses include administration of nano-albumin bound (nab)-paclitaxel.

[0353] Dosing of taxanes

[0354] A therapeutically effective amount of a taxane (e.g., paclitaxel or nab-paclitaxel (ABRAXANE®)) administered to a human will be in the range of about 25 to about 300 mg / m2(e.g., about 25 mg / m2, about 50 mg / m2, about 75 mg / m2, about 80 mg / m2, about 90 mg / m2, about 100 mg / m2, about 1 10 mg / m2, about 120 mg / m2, about 125 mg / m2, about 130 mg / m2, about 140 mg / m2, about 150 mg / m2, about 160 mg / m2, about 170 mg / m2, about 175 mg / m2, about 180 mg / m2, about 190 mg / m2, about 200 mg / m2, about 225 mg / m2, about 250 mg / m2, about 275 mg / m2, or about 300 mg / m2(e.g., 25 mg / m2, 50 mg / m2, 75 mg / m2, 80 mg / m2, 90 mg / m2, 100 mg / m2, 1 10 mg / m2, 120 mg / m2, 125 mg / m2, 130 mg / m2, 140 mg / m2, 150 mg / m2, 160 mg / m2, 170 mg / m2, 175 mg / m2, 180 mg / m2, 190 mg / m2, 200 mg / m2, 225 mg / m2, 250 mg / m2, 275 mg / m2, or 300 mg / m2)) whether by one or more administrations (e.g., intravenous (IV) administrations). For example, in some embodiments, about 175 mg / m2of paclitaxel (e.g., 175 mg / m2of paclitaxel) is administered. In some embodiments, the taxane (e.g., paclitaxel or nab-paclitaxel (ABRAXANE®)) is administered to the subject or population of subjects intravenously (e.g., over a 3-hour infusion). In some embodiments, the taxane (e.g., paclitaxel or nab-paclitaxel (ABRAXANE®)) may be administered weekly, every 2 weeks, every 3 weeks, every 4 weeks, on days 1 , 8 and 15 of each 21 -day cycle, or on days 1 , 8, and 15 of each 28-day cycle.

[0355] In some embodiments, the taxane is administered to the subject or population of subjects on about Day 1 (e.g., on Day -3, Day -2, Day -1 , Day 1 , Day 2, or Day 3) of a 21 -day dosing cycle. In some embodiments, the taxane is administered to the subject or population of subjects every three weeks. In some embodiments, nab-paclitaxel (ABRAXANE®) is administered to the subject or population of subjects on about Day 1 of a 21 -day dosing cycle.

[0356] In some embodiments, the taxane is administered to the subject or population of subjects three times every four weeks. For example, in some embodiments, the taxane is administered to the subject or population of subjects on or about Days 1 , 8, and 15 of each of one or more 28-day dosing cycles, e.g., on Day 1 ± 3 days, Day 8 ± 3 days, and Day 15 ± 3 days of each of one or more 28-day dosing cycles.

[0357] In some embodiments, paclitaxel is administered at a dose of between about 175 mg / m2to about 200 mg / m2(e.g., between 175 mg / m2to 200 mg / m2) every three weeks. In some embodiments, paclitaxel is administered at a dose of about 175 mg / m2(e.g., at a dose of at a dose of 175 mg / m2) every three weeks. In some embodiments, paclitaxel is administered at a dose of about 200 mg / m2(e.g., a dose of 200 mg / m2) every three weeks. In some embodiments, paclitaxel is administered at 200 mg / m2IV every 3 weeks. In some embodiments, about 100 mg / m2(e.g., 100 mg / m2) of nab-paclitaxel (ABRAXANE®) is administered.

[0358] In some embodiments, nab-paclitaxel (ABRAXANE®) is administered at 100 mg / m2IV every week. In some embodiments, nab-paclitaxel (ABRAXANE®) is administered at 100 mg / m2IV three times every four weeks (e.g., on Days 1 , 8, and 15 of each of one or more 28-day dosing cycles). In some embodiments, nab-paclitaxel (ABRAXANE®) is administered intravenously at a dose of about 125 mg / m2(e.g., at a dose of 125 mg / m2) three times every four weeks (e.g., on or about Days 1 , 8, and 15 of each of one or more 28-day dosing cycles, e.g., on Day 1 ± 3 days, Day 8 ± 3 days, and Day 15 ± 3 days).

[0359] Antimetabolites

[0360] In some aspects, the methods provided herein comprise administration of one or more dosing cycles of an antimetabolite. Antimetabolites interfere with and inhibit (wholly or partially) an endogenous (normal) metabolic process within a cell (e.g., a cancer cell). Antimetabolites include gemcitabine, pemetrexed, capecitabine, hydroxyurea, methotrexate, fluorouracil, cladribine, mercaptopurine, and pralatrexate.

[0361] Gemcitabine is an exemplary antimetabolite used in the methods described herein and has the following structure:

[0362]

[0363] In some instances, pemetrexed can be administered as part of the methods of the present invention. Pemetrexed has the following structure:

[0364] Dosing of antimetabolites

[0365] In some instances, the effective amount of an antimetabolite (e.g., pemetrexed or gemcitabine) administered as part of the methods described herein is from 10-10000 mg / m2(e.g., from 20-8000 mg / m2, from 30-5000 mg / m2, from 40-2500 mg / m2, from 50-2000 mg / m2, from 100-1500 mg / m2, or from 400- 1200 mg / m2, e.g., about 20 mg / m2, about 30 mg / m2, about 40 mg / m2, about 50 mg / m2, about 60 mg / m2, about 70 mg / m2, about 80 mg / m2, about 90 mg / m2, about 100 mg / m2, about 1 10 mg / m2, about 120 mg / m2, about 130 mg / m2, about 140 mg / m2, about 150 mg / m2, about 160 mg / m2, about 170 mg / m2, about 180 mg / m2, about 190 mg / m2, about 200 mg / m2, about 250 mg / m2, about 300 mg / m2, about 400 mg / m2, about 500 mg / m2, about 600 mg / m2, about 700 mg / m2, about 800 mg / m2, about 900 mg / m2, about 1000 mg / m2, about 1 100 mg / m2, about 1200 mg / m2, about 1250 mg / m2, about 1300 mg / m2, about 1400 mg / m2, about 1500 mg / m2, about 1750 mg / m2, about 2000 mg / m2, about 3000 mg / m2, about 4000 mg / m2, about 5000 mg / m2, about 6000 mg / m2, about 7000 mg / m2, about 8000 mg / m2, about 9000 mg / m2, or about 10000 mg / m2). In some instances, the effective amount of the antimetabolite (e.g., pemetrexed or gemcitabine) is between about 500 mg / m2to about 1250 mg / m2(e.g., 20 mg / m2, 30 mg / m2, 40 mg / m2, 50 mg / m2, 60 mg / m2, 70 mg / m2, 80 mg / m2, 90 mg / m2, 100 mg / m2, 1 10 mg / m2, 120 mg / m2, 130 mg / m2, 140 mg / m2, 150 mg / m2, 160 mg / m2, 170 mg / m2, 180 mg / m2, 190 mg / m2, 200 mg / m2, 250 mg / m2, 300 mg / m2, 400 mg / m2, 500 mg / m2, 600 mg / m2, 700 mg / m2, 800 mg / m2, 900 mg / m2, 1000 mg / m2, 1 100 mg / m2, 1200 mg / m2, 1250 mg / m2, 1300 mg / m2, 1400 mg / m2, 1500 mg / m2, 1750 mg / m2, 2000 mg / m2, 3000 mg / m2, 4000 mg / m2, 5000 mg / m2, 6000 mg / m2, 7000 mg / m2, 8000 mg / m2, 9000 mg / m2, or 10000 mg / m2). In some instances, the effective amount of the antimetabolite (e.g., pemetrexed or gemcitabine) is about 500 mg / m2. In some instances, the effective amount of the antimetabolite (e.g., pemetrexed or gemcitabine) is about 1000 mg / m2. In some instances, the effective amount of the antimetabolite (e.g., pemetrexed or gemcitabine) is about 1250 mg / m2. In some instances, the effective amount of the antimetabolite (e.g., pemetrexed or gemcitabine) is 500 mg / m2. In some instances, the effective amount of the antimetabolite (e.g., pemetrexed or gemcitabine) is 1000 mg / m2. In some instances, the effective amount of the antimetabolite (e.g., pemetrexed or gemcitabine) is 1250 mg / m2.

[0366] In some instances, the effective amount of pemetrexed administered as part of the methods described herein is from 10-1000 mg / m2(e.g., from 20-900 mg / m2, from 30-800 mg / m2, from 40-700 mg / m2, from 50-650 mg / m2, from 100-600 mg / m2, or from 200-550 mg / m2, e.g., about 20 mg / m2, about 30 mg / m2, about 40 mg / m2, about 50 mg / m2, about 60 mg / m2, about 70 mg / m2, about 80 mg / m2, about 90 mg / m2, about 100 mg / m2, about 1 10 mg / m2, about 120 mg / m2, about 130 mg / m2, about 140 mg / m2, about 150 mg / m2, about 160 mg / m2, about 170 mg / m2, about 180 mg / m2, about 190 mg / m2, about 200 mg / m2, about 250 mg / m2, about 300 mg / m2, about 400 mg / m2, about 500 mg / m2, about 600 mg / m2, about 700 mg / m2, about 800 mg / m2, about 900 mg / m2, or about 1000 mg / m2). In some instances, the effective amount of pemetrexed is about 500 mg / m2. In some instances, the effective amount of pemetrexed is about 500 mg / m2every three weeks. In some instances, the effective amount of pemetrexed is 500 mg / m2. In some instances, the effective amount of pemetrexed is 500 mg / m2every three weeks.

[0367] In some embodiments, the pemetrexed is administered to the subject or population of subjects intravenously (e.g., over a 10-minute infusion). In some embodiments, the pemetrexed is administered to the subject or population of subjects every three weeks. In some embodiments, the pemetrexed is administered to the subject or population of subjects on about Day 1 (e.g., Day -3, Day -2, Day -1 , Day 1 , Day 2, or Day 3) of a 21 -day dosing cycle.

[0368] In some instances, the effective amount of gemcitabine administered as part of the methods described herein is from 10-10000 mg / m2(e.g., from 20-8000 mg / m2, from 30-5000 mg / m2, from 40-2500 mg / m2, from 50-2000 mg / m2, from 100-1500 mg / m2, or from 400-1250 mg / m2, e.g., about 20 mg / m2, about 30 mg / m2, about 40 mg / m2, about 50 mg / m2, about 60 mg / m2, about 70 mg / m2, about 80 mg / m2, about 90 mg / m2, about 100 mg / m2, about 1 10 mg / m2, about 120 mg / m2, about 130 mg / m2, about 140 mg / m2, about 150 mg / m2, about 160 mg / m2, about 170 mg / m2, about 180 mg / m2, about 190 mg / m2, about 200 mg / m2, about 250 mg / m2, about 300 mg / m2, about 400 mg / m2, about 500 mg / m2, about 600 mg / m2, about 700 mg / m2, about 800 mg / m2, about 900 mg / m2, about 1000 mg / m2, about 1 100 mg / m2, about 1200 mg / m2, about 1250 mg / m2, about 1300 mg / m2, about 1400 mg / m2, about 1500 mg / m2, about 1750 mg / m2, about 2000 mg / m2, about 3000 mg / m2, about 4000 mg / m2, about 5000 mg / m2, about 6000 mg / m2, about 7000 mg / m2, about 8000 mg / m2, about 9000 mg / m2, or about 10000 mg / m2(e.g., 20 mg / m2, 30 mg / m2, 40 mg / m2, 50 mg / m2, 60 mg / m2, 70 mg / m2, 80 mg / m2, 90 mg / m2, 100 mg / m2, 1 10 mg / m2, 120 mg / m2, 130 mg / m2, 140 mg / m2, 150 mg / m2, 160 mg / m2, 170 mg / m2, 180 mg / m2, 190 mg / m2, 200 mg / m2, 250 mg / m2, 300 mg / m2, 400 mg / m2, 500 mg / m2, 600 mg / m2, 700 mg / m2, 800 mg / m2, 900 mg / m2, 1000 mg / m2, 1 100 mg / m2, 1200 mg / m2, 1250 mg / m2, 1300 mg / m2, 1400 mg / m2, 1500 mg / m2, 1750 mg / m2, 2000 mg / m2, 3000 mg / m2, 4000 mg / m2, 5000 mg / m2, 6000 mg / m2, 7000 mg / m2, 8000 mg / m2, 9000 mg / m2, or 10000 mg / m2)). In some instances, the effective amount of gemcitabine is between about 500 mg / m2to about 1250 mg / m2. In some instances, the effective amount of gemcitabine is about 500 mg / m2. In some instances, the effective amount of gemcitabine is about 1000 mg / m2(e.g., is 1000 mg / m2). In some instances, the effective amount of gemcitabine is about 1250 mg / m2(e.g., is 1250 mg / m2). In some instances, the effective amount of gemcitabine is about 1000 mg / m2on Days 1 and 8 of a 21 -day dosing cycle. In some instances, the effective amount of gemcitabine is about 1250 mg / m2on Days 1 and 8 of a 21 -day dosing cycle.

[0369] In some embodiments, the gemcitabine is administered to the subject or population of subjects intravenously (e.g., over a 30-minute infusion). In some instances, the gemcitabine is administered to the subject or population of subjects on about Day 1 (e.g., Day -3, Day -2, Day -1 , Day 1 , Day 2, or Day 3) of a 21 -day dosing cycle. In some instances, the gemcitabine is administered to the subject or population of subjects on about Day 1 and about Day 8 (e.g., Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, or Day 1 1 ) of a 21 -day dosing cycle.

[0370] In some embodiments, gemcitabine is administered intravenously at a dose of about 1000 mg / m2(e.g., at a dose of 1000 mg / m2) three times every four weeks (e.g., on or about Days 1 , 8, and 15 of each of one or more 28-day dosing cycles, e.g., on Day 1 ± 3 days, Day 8 ± 3 days, and Day 15 ± 3 days).

[0371] VII. PHARMACEUTICAL COMPOSITIONS, FORMULATIONS, AND KITS

[0372] Any of the anti-cancer agents described herein (e.g., a PD-1 axis binding antagonist (e.g., atezolizumab), an anti-TIG IT antagonist antibody (e.g., tiragolumab), a taxane (e.g., nab-paclitaxel), and an antimetabolite (e.g., gemcitabine)) can be used in pharmaceutical compositions and formulations. Pharmaceutical compositions and formulations of a PD-1 axis binding antagonist (e.g., atezolizumab), an anti-TIGIT antagonist antibody (e.g., tiragolumab); a taxane (e.g., nab-paclitaxel); and an antimetabolite (e.g., gemcitabine) can be prepared by mixing one, two, three, four, or more than four agents having the desired degree of purity with one or more optional pharmaceutically acceptable carriers {Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include insterstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Patent Publication Nos. 2005 / 0260186 and 2006 / 0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases. Exemplary lyophilized antibody formulations are described in U.S. Patent No. 6,267,958.

[0373] Aqueous antibody formulations include those described in US Patent No. 6,171 ,586 and WO 2006 / 044908, the latter formulations including a histidine-acetate buffer.

[0374] An exemplary atezolizumab formulation comprises glacial acetic acid, L-histidine, polysorbate 20, and sucrose, with a pH of 5.8. For example, atezolizumab may be provided in a 20 mL vial containing 1200 mg of atezolizumab that is formulated in glacial acetic acid (16.5 mg), L-histidine (62 mg), polysorbate 20 (8 mg), and sucrose (821 .6 mg), with a pH of 5.8. In another example, atezolizumab may be provided in a 14 mL vial containing 840 mg of atezolizumab that is formulated in glacial acetic acid (11 .5 mg), L-histidine (43.4 mg), polysorbate 20 (5.6 mg), and sucrose (575.1 mg) with a pH of 5.8.

[0375] An exemplary tiragolumab formulation comprises a histidine solution containing polysorbate 20, sucrose, L-methionine, and WFI. Tiragolumab may be provided in a 15-mL vial containing 10 mL of tiragolumab drug product at an approximate concentration of tiragolumab antibody of 60 mg / mL.

[0376] In addition, exemplary intravenous (IV) and subcutaneous (SC) fixed dose combination (FDC) doses and formulations of tiragolumab and atezolizumab are provided in WO 2023 / 122665 A1 .

[0377] The formulation herein may also contain more than one active ingredients as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to further provide an additional therapeutic agent. Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended.

[0378] Active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Flemington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0379] Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, for example, films, or microcapsules. The formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.

[0380] In some aspects, the invention provides kits that include (a) a PD-1 axis binding antagonist (e.g., atezolizumab) for use in combination with an anti-TIGIT antagonist antibody (e.g., tiragolumab), (b) an anti-TIG IT antagonist antibody (e.g., tiragolumab) for use in combination with a PD-1 axis binding antagonist (e.g., atezolizumab), or (c) a PD-1 axis binding antagonist (e.g., atezolizumab) and an anti- TIGIT antagonist antibody (e.g., tiragolumab) for treating a subject having a cancer (e.g., a pancreatic cancer, e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC) according to any of the methods described herein. In some aspects, the kits further include one or more chemotherapeutic agents, e.g., one or both of a taxane (e.g., nab-paclitaxel) and an antimetabolite (e.g., gemcitabine). In some instances, the article of manufacture or kit further comprises package insert comprising instructions for using (a) a PD-1 axis binding antagonist (e.g., atezolizumab) for use in combination with an anti-TIGIT antagonist antibody (e.g., tiragolumab), (b) an anti-TIGIT antagonist antibody (e.g., tiragolumab) for use in combination with a PD-1 axis binding antagonist (e.g., atezolizumab), (c) a PD-1 axis binding antagonist (e.g., atezolizumab) and an anti-TIGIT antagonist antibody (e.g., tiragolumab); or (d) a PD-1 axis binding antagonist, an anti-TIGIT antagonist antibody, and / or one or more chemotherapeutic agents to treat or delay progression of a cancer (e.g., a pancreatic cancer, e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC) in a patient.

[0381] Accordingly, in some aspects, the invention provides kits that include (a) atezolizumab for use in combination with tiragolumab, (b) tiragolumab for use in combination with atezolizumab, (c) atezolizumab and tiragolumab; or (d) tiragolumab, atezolizumab, nab-paclitaxel, and / or gemcitabine for treating a subject having a cancer (e.g., a pancreatic cancer, e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC) according to any of the methods described herein. In some instances, the article of manufacture or kit further comprises a package insert comprising instructions for using (a) atezolizumab in combination with tiragolumab, (b) tiragolumab in combination with atezolizumab, or (c) atezolizumab and tiragolumab to treat or delay progression of a cancer (e.g., a pancreatic cancer, e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC) in a patient.

[0382] In some instances, (i) a PD-1 axis binding antagonist (e.g., atezolizumab) and an anti-TIGIT antagonist antibody (e.g., tiragolumab) or (ii) a PD-1 axis binding antagonist (e.g., atezolizumab), an anti- TIGIT antagonist antibody (e.g., tiragolumab) and one or more chemotherapeutic agents (e.g., one or both of a taxane (e.g., nab-paclitaxel) and an antimetabolite (e.g., gemcitabine)) are in the same container or separate containers. Suitable containers include, for example, bottles, vials, bags and syringes. The container may be formed from a variety of materials such as glass, plastic (such as polyvinyl chloride or polyolefin), or metal alloy (such as stainless steel or hastelloy). In some instances, the container holds the formulation and the label on, or associated with, the container may indicate directions for use. The article of manufacture or kit may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. In some instances, the article of manufacture further includes one or more of another agent (e.g., an additional chemotherapeutic agent or anti-neoplastic agent). Suitable containers for the one or more agents include, for example, bottles, vials, bags and syringes.

[0383] EXAMPLES

[0384] Example 1 : A Phase Ib / ll, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Of Tiragolumab And Atezolizumab In Combination With Chemotherapy In PD-L1 -Selected Participants With Untreated Metastatic Pancreatic Ductal Adenocarcinoma

[0385] A. Study Summary and Rationale

[0386] GO45216 is a Phase Ib / ll, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of tiragolumab plus atezolizumab in combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and gemcitabine compared with tiragolumab placebo and atezolizumab placebo (hereafter referred to as double placebo) in combination with nab- paclitaxel and gemcitabine in patients with PD-L1 -positive untreated, metastatic pancreatic ductal adenocarcinoma (PDAC).

[0387] In this study, PD-L1 positivity is defined as > 1% tumor area positive (TAP) score by investigational VENTANA PD-L1 (SP263) Companion Diagnostic (CDx) Assay. Schematic diagrams showing the study design are provided in FIGS. 1 A, 1 B, and 2.

[0388] Current treatment options for patients with metastatic PDAC have remained largely unchanged for more than a decade and are primarily limited to gemcitabine-based or fluoropyrimidine-based multichemotherapy drug regimens, which are associated with limited improvement for overall survival (OS). Therefore, there is a high unmet need for novel and transformative treatment options for patients with metastatic PDAC.

[0389] B. Objectives and Endpoints

[0390] The study has primary endpoints of PFS and OS (see Table 3, below). Primary and secondary objectives for the study are expressed using an estimand framework in accordance with the International Conference on Harmonization (ICH) E9 (R1 ) statistical principles for clinical trials (ICH 2020) (Tables 3 and 4).

[0391] Table 3. Primary Objectives and Corresponding Estimands

[0392] Secondary objectives and corresponding endpoints are described in Table 4, below.

[0393] Table 4. Secondary Objectives and Corresponding Endpoints

[0394] Exploratory objectives and corresponding endpoints are described in Table 5, below.

[0395] Table 5. Exploratory Objectives and Corresponding Endpoints

[0396] C. Overall Design and Study Population

[0397] Several key aspects of the study design and study population are summarized in Table 6, below. Briefly, male and female participants age > 18 years old with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 who have PD-L1 positive, untreated metastatic PDAC are eligible for the study. PD-L1 positive status is defined as PD-L1 TAP > 1% by the investigational VENTANA PD- L1 (SP263) CDx Assay, as performed by a central laboratory.

[0398] Table 6. Overall Study Design

[0399] For the Phase lb part of the trial, after approximately 100 participants have been enrolled and followed for at least 16 weeks, an interim efficacy analysis is performed by an independent Data Monitoring Committee (iDMC). The iDMC may recommend continuing into the Phase II part of the study (to ungate the enrollment of an additional 50 participants for a total of 150 participants) if the pre-specified threshold for

[0400] Phase II expansion is met at this interim analysis (see FIG. 2). The iDMC has the authority to deviate from the criteria by considering the totality of the benefit-risk profile. D. Study Treatment

[0401] Randomization is at a 1 :1 ratio to one of two treatment arms: Arm A and Arm B.

[0402] Arm A (Experimental Arm):

[0403] The dosing regimen for Arm A is as follows: tiragolumab 840 mg plus atezolizumab 1680 mg administered by intravenous (IV) co-infusion on Day 1 of each 28-day cycle, followed by nab-paclitaxel 125 mg / m2IV infusion and gemcitabine 1000 mg / m2IV infusion on Days 1 , 8, and 15 of each 28-day cycle.

[0404] Arm B (Control Arm):

[0405] The dosing regimen for Arm B is as follows: double placebo administered by IV co-infusion on Day 1 of each 28-day cycle, followed by nab-paclitaxel 125 mg / m2IV and gemcitabine 1000 mg / m2IV infusion on Days 1 , 8, and 15 of each 28-day cycle.

[0406] Nab-paclitaxel plus gemcitabine is a globally approved treatment regimen that is considered an acceptable standard of care (SOC) and is indicated in the National Comprehensive Cancer Network (NCCN)- and European Society for Medical Oncology (ESMO)-recommended initial therapy regimen for untreated participants with metastatic PDAC.

[0407] Randomization is stratified according to the following stratification factors:

[0408] • Geographic region (Asia vs. rest of world (ROW)).

[0409] • Eastern Cooperative Oncology Group (ECOG) Performance Status (0 vs. 1 ).

[0410] Dose Modification:

[0411] Modification of the tiragolumab and atezolizumab doses are not permitted.

[0412] For management of drug-related toxicities, the dose of nab-paclitaxel may be reduced by 25 mg / m2(one dose level) up to two times and the dose of gemcitabine may be reduced by 200 mg / m2(one dose level) up to two times. Further dose modifications are described in Example 3(D), below.

[0413] Duration of Participation:

[0414] Participants continue to receive treatment until unacceptable toxicity or loss of clinical benefit as determined after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status (e.g., symptomatic deterioration such as pain secondary to disease).

[0415] Because of the possibility of an initial increase in tumor burden caused by immune cell infiltration in the setting of a T-cell response (termed pseudoprogression) with atezolizumab and tiragolumab treatment, radiographic progression per Response Evaluation Criteria in Solid Tumors, Version 1 .1 (RECIST v1 .1 ) (Eisenhauer et al., EurJ Cancer, 45: 228-247, 2009) may not be indicative of true disease progression. In the absence of unacceptable toxicity, participants who meet criteria for disease progression per RECIST v1 .1 will be permitted to continue treatment if they meet all the following criteria:

[0416] • Evidence of clinical benefit, as determined by an investigator following a review of all available data. • Absence of symptoms or signs (including laboratory values, such as new or worsening hypercalcemia) indicating unequivocal progression of disease.

[0417] • Absence of decline in ECOG Performance Status that can be attributed to disease progression.

[0418] • Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that cannot be managed by protocol-allowed medical interventions.

[0419] Tumor assessments are performed at baseline and at regular intervals during study treatment. Additional scans are performed as clinically indicated. Tumor assessments continue until disease progression, regardless of whether treatment was discontinued (e.g., for toxicity). Participants who meet RECIST v1 .1 criteria for progression and receive treatment beyond progression undergo tumor assessments until loss of clinical benefit. In the absence of disease progression, tumor assessments continue regardless of whether participants start new anti-cancer therapy, until consent is withdrawn, death or termination of the study, whichever occurs first. Following disease progression, participants are followed for survival and subsequent anti-cancer therapies until death, loss to follow-up, withdrawal of consent, or study termination, whichever occurs first.

[0420] In order not to confound the OS endpoint, crossover from Arm B to Arm A (FIGS. 1 and 3) is not allowed.

[0421] All participants are closely monitored for adverse events throughout the study, and adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0). The severity of cytokine release syndrome (CRS) is also graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) CRS Consensus Grading Scale.

[0422] To characterize the pharmacokinetic (PK) properties and / or immunogenicity of study treatments, blood samples are taken at various timepoints before and during study treatment administration. Blood and tissue samples are also collected at baseline and during the study for exploratory biomarker research.

[0423] After discontinuing treatment, participants continue to be followed for survival status. The total duration of study participation for each individual is expected to range from 1 day to more than 24 months.

[0424] Further details of the study design are provided in Examples 3 and 4, below.

[0425] E. End of Study Definition

[0426] A participant is considered to have completed the study if he or she has completed all phases of the study, including the last survival follow-up visit.

[0427] The end of this study is defined as the date of the last visit of the last participant in the study or the date at which the last data point required for statistical analysis (i.e. , OS analysis) or safety follow-up is received from the last participant, whichever occurs later.

[0428] The end of the study is expected to occur 4 to 5 years after the last participant is enrolled. Example 2: Study Population

[0429] Approximately 100-150 participants with untreated, PD-L1 -positive metastatic pancreatic ductal adenocarcinoma (PDAC) are enrolled during the global enrollment phase of the GO45216 study.

[0430] A. Inclusion criteria

[0431] Potential participants are eligible to be included in the study only if all of the following criteria apply:

[0432] • Age > 18 years.

[0433] • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 .

[0434] • Histologically or cytologically confirmed metastatic PDAC. The definitive diagnosis of metastatic PDAC is made by evaluating the histopathologic data within the context of clinical and radiographic data. Individuals with endocrine or acinar pancreatic carcinoma are not eligible for the study.

[0435] • No prior systemic treatment for PDAC. Individuals with prior surgery and radiation are permitted; individuals with prior neoadjuvant or adjuvant systemic treatment are not permitted.

[0436] • Life expectancy of > 3 months.

[0437] • Tumor PD-L1 expression with SP263 TAP > 1%, as determined by the investigational Ventana PD- L1 (SP263) CDx Assay, documented through central testing of a representative tumor tissue, in either a previously obtained archival tumor tissue or tissue obtained from a biopsy at screening. Baseline tumor tissue samples from the primary lesion or a metastatic lesion are collected from all individuals, by means of a biopsy performed at study entry or archival tumor tissue, provided the tissue was obtained within 6 months prior to enrollment and the individual has not received any anti-cancer therapy since the tissue was acquired.

[0438] • Measurable disease (at least one target lesion) according to RECIST v1 .1 . Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation.

[0439] • Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:

[0440] -Absolute neutrophil count ANC > 1.5 x 109 / L (> 1500 / pL) without granulocyte colony-stimulating factor support within 2 weeks prior to Day 1 of Cycle 1 . Individuals with benign ethnic neutropenia (BEN) are eligible: ANC > 1.3 x 109 / L (> 1300 / pL). BEN (also known as constitutional neutropenia) is an inherited cause of mild or moderate neutropenia that is not associated with any increased risk for infections or other clinical manifestations (Atallah-Yunes et al., Blood Rev, 37: 100586, 2019).

[0441] - Lymphocyte count > 0.5 x 109 / L (> 500 / pL).

[0442] - Platelet count > 100 x 109 / L (> 100,000 / pL) without transfusion.

[0443] - Hemoglobin > 90 g / L (> 9 g / dL). Individuals may be transfused to meet this criterion.

[0444] - AST, ALT, ALP < 2.5 x upper limit of normal (ULN), with the following exceptions: individuals with documented liver metastases: AST and ALT < 5 x ULN; individuals with documented liver or bone metastases: ALP < 5 x ULN.

[0445] - Total bilirubin < 1.5 x ULN with the following exceptions: individuals with known Gilbert disease: total bilirubin < 3 x ULN. - Creatinine clearance > 50 mL / min (calculated using the Cockcroft-Gault formula).

[0446] - Albumin > 25 g / L (> 2.5 g / dL)

[0447] - For individuals not receiving therapeutic anticoagulation: INR and aPTT < 1 .5 x ULN.

[0448] • For individuals receiving therapeutic anticoagulation: stable anticoagulant regimen.

[0449] • Negative HIV test at screening with the following exception: individuals with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4+ T cell count > 200 / pL, and have an undetectable viral load.

[0450] • Individuals meeting one of the following criteria for hepatitis B virus (HBV): (1 ) Negative hepatitis B surface antigen (HbsAg) test at screening, accompanied by either (i) positive hepatitis B surface antibody (HbsAb) or (ii) negative HbsAb and negative total hepatitis B core antibody (HbcAb); or (2) positive HbsAg test or positive total HbcAb and negative HbsAb tests, followed by quantitative hepatitis B virus (HBV) DNA test < 500 ILJ / rnL. For individuals with active HBV, initiation of anti-HBV treatment at least 14 days prior to randomization and willingness to continue anti-HBV treatment during the study per local standard of care (SOC) treatment.

[0451] • Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening.

[0452] • Negative Epstein-Barr virus (EBV) viral capsid antigen IgM test at screening. An EBV PCR test should be performed as clinically indicated to screen for acute infection or suspected chronic active infection. Individuals with a positive EBV PCR test are excluded.

[0453] • For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs.

[0454] • For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm.

[0455] B. Exclusion criteria

[0456] Potential participants are excluded from the study if any of the following criteria apply:

[0457] • Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including but not limited to anti-CTLA-4, anti-PD-1 , anti-PD-L1 , and anti-TIGIT therapeutic antibodies.

[0458] • Treatment with investigational therapy within 28 days prior to initiation of study treatment.

[0459] • Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and IL- 2) within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment.

[0460] • Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (TNF) agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: (i) individuals who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible; and (ii) individuals who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study. • Adverse events from prior anti-cancer therapy that have not resolved to Grade < 1 or better, with the exception of alopecia of any grade and Grade < 2 peripheral neuropathy.

[0461] • Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Individuals with indwelling catheters (e.g., PLEURX®) are allowed.

[0462] • Uncontrolled tumor-related pain. Individuals requiring narcotic pain medication must be on a stable regimen at study entry. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to initiation of study treatment. Individuals should be recovered from the effects of radiation. There is no required minimum recovery period. Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not presently associated with spinal cord compression) should be considered for loco-regional therapy, if appropriate, prior to initiation of study treatment.

[0463] • Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases. Asymptomatic individuals with treated CNS lesions are eligible, provided that all of the following criteria are met: measurable disease, per RECIST v1 .1 , must be present outside of the CNS; the individual has no history of intracranial hemorrhage or spinal cord hemorrhage; the individual has not undergone stereotactic radiotherapy within 7 days prior to initiation of study treatment, whole-brain radiotherapy within 14 days prior to initiation of study treatment, or neurosurgical resection within 28 days prior to initiation of study treatment; the individual has no ongoing requirement for corticosteroids as therapy for CNS disease (if the individual is receiving anti-convulsant therapy, the dose is considered stable); metastases are limited to the cerebellum or the supratentorial region (i.e. , no metastases to the midbrain, pons, medulla, or spinal cord); and there is no evidence of interim progression between completion of CNS-directed therapy and initiation of study treatment. Asymptomatic individuals with CNS metastases newly detected at screening are eligible for the study after receiving radiotherapy and / or surgery, with no need to repeat the screening brain scan.

[0464] • History of leptomeningeal disease.

[0465] • Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1 .5 mmol / L, calcium > 12 mg / dL, or corrected calcium greater than ULN).

[0466] • Active or history of autoimmune disease or immune deficiency, including but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, granulomatosis with polyangiitis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions: individuals with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study; individuals with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study; individuals with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., participants with psoriatic arthritis are excluded) are eligible for the study provided all of the following conditions are met: (i) rash must cover < 10% of body surface area; (ii) disease is well controlled at baseline and requires only low-potency topical corticosteroids; and (iii) there has been no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.

[0467] • History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug- induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

[0468] • Known or clinically significant liver disease, including alcoholic hepatitis, cirrhosis, fatty liver disease, and inherited liver disease.

[0469] • Known active tuberculosis.

[0470] • Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina.

[0471] • Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study. Placement of a central venous access catheter (e.g., port or similar) is not considered a major surgical procedure and is therefore permitted.

[0472] • History of malignancy other than pancreatic adenocarcinoma within 2 years prior to initiation of study treatment, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5- year overall survival (OS) rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, breast ductal carcinoma in situ, or Stage I uterine cancer.

[0473] • Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that could impact participant safety.

[0474] • Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Individuals receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or COPD exacerbation) are eligible for the study.

[0475] • Prior allogeneic stem cell or solid organ transplantation.

[0476] • Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the participant at high risk from treatment complications.

[0477] • Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab or tiragolumab treatment or within 5 months after the final dose of atezolizumab and 90 days after the final dose of tiragolumab.

[0478] • History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins.

[0479] • Known hypersensitivity to CHO cell products or to any component of the atezolizumab or tiragolumab formulation.

[0480] • Known allergy or hypersensitivity to any component of the study drug, including nab-paclitaxel and gemcitabine formulations. • Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 5 months after the final dose of atezolizumab, 90 days after the final dose of tiragolumab, 1 month after the final dose of nab-paclitaxel, and 6 months after the final dose of gemcitabine. C. Screen Failures

[0481] Individuals who do not meet the criteria for participation in the study (screen failure) may qualify for two re-screening opportunities (for a total of three screenings per individual).

[0482] Example 3: Study Treatment The investigational medicinal products (IMPs) for the GO45216 study are tiragolumab, atezolizumab, tiragolumab placebo, and atezolizumab placebo. Table 7 provides a description of assigned study treatments.

[0483] Table ?. Study Treatment Description IMP = investigational medicinal product; AxMP = auxiliary medicinal product; NIMP = non-investigational medicinal product; Q4W = every 4 weeks.

[0484] “Study treatment” refers to the combination of treatments assigned to participants as part of the study (i.e., tiragolumab / placebo plus atezolizumab / placebo plus nab-paclitaxel plus gemcitabine).

[0485] A. Tiragolumab and Atezolizumab or Double Placebo Co-Infusion

[0486] Tiragolumab at a fixed dose of 840 mg is mixed in the same IV bag with atezolizumab at a fixed dose of 1680 mg for administration by co-infusion on Day 1 of each 28-day cycle. Alternatively, a double placebo is mixed in the same IV bag for administration by IV co-infusion on Day 1 of each 28-day cycle. Tiragolumab plus atezolizumab and double placebo co-infusions are administered per the instructions outlined in Table 8.

[0487] Table 8. Administration of First and Subsequent Infusions of Tiragolumab Mixed with Atezolizumab, or Double Placebo

[0488] B. Nab-Paclitaxel and Gemcitabine

[0489] On Days 1 , 8, and 15 of each 28-day cycle, participants receive nab-paclitaxel 125 mg / m2, administered by IV infusion over 30 (± 5) minutes, followed by gemcitabine 1000 mg / m2, administered by IV infusion over 30 (± 5) minutes. On Day 1 of Cycle 1 , nab-paclitaxel is administered 60 minutes after completion of the tiragolumab plus atezolizumab or double placebo co-infusion to allow for the observation period. The interval between subsequent infusions is 30 minutes if the previous tiragolumab plus atezolizumab or double placebo co-infusion was well tolerated without an infusion-related reaction (IRR), or 60 minutes if the participant experienced an IRR with the previous tiragolumab plus atezolizumab or double placebo co-infusion.

[0490] Nab-paclitaxel and gemcitabine are administered according to institutional standards in a monitored setting where there is immediate access to trained personnel and adequate equipment and medicine to manage potential serious reactions.

[0491] C. Treatment Assignment and Blinding

[0492] GO45216 is a randomized, double-blind, placebo-controlled study. Participants are randomly assigned in a 1 :1 ratio to one of two treatment arms: Arm A (tiragolumab and atezolizumab plus nab- paclitaxel and gemcitabine) or Arm B (double placebo plus nab-paclitaxel and gemcitabine). Randomization is stratified by geographic region (Asia vs. rest of world (ROW)) and ECOG Performance Status, and occurs through use of a permuted-block randomization method to ensure a balanced assignment between two treatment arms within each stratum and overall. It is recommended that participants receive their first dose of study treatment on the day of randomization if possible. If this is not possible, the first dose should occur within 7 days of randomization.

[0493] Study site personnel and participants are blinded to treatment assignment during the study.

[0494] D. Dose Modification

[0495] Modification of the tiragolumab and atezolizumab doses are not permitted. Tiragolumab and atezolizumab treatment may be interrupted because of toxicity or for reasons other than toxicity (e.g., surgical procedures).

[0496] For management of drug-related toxicities, the dose of nab-paclitaxel may be reduced by 25 mg / m2(one dose level) up to two times and the dose of gemcitabine may be reduced by 200 mg / m2(one dose level) up to two times.

[0497] If further dose reduction is indicated for nab-paclitaxel and / or gemcitabine after two dose reductions because of toxicities, that drug (or both drugs, if applicable) should be discontinued, but the participant may continue other study treatments. After dose reduction, the dose may be escalated during subsequent administrations.

[0498] Nab-paclitaxel and gemcitabine treatment may be interrupted for reasons other than toxicity (e.g., surgical procedures). In some cases, the Day 8 dose may be interrupted or permanently withheld because of toxicities. The acceptable length of treatment interruption or withhold must be based on an assessment of benefit-risk and in alignment with the local prescribing information.

[0499] Example 4: Statistical Considerations

[0500] A. Statistical Hypotheses

[0501] The purpose of the GO45216 study is hypothesis generation regarding the effect of tiragolumab plus atezolizumab in combination with nab-paclitaxel and gemcitabine relative to the current standard of care (SOC). The study is a Phase Ib / ll study with primary endpoints of progression-free survival (PFS) and overall survival (OS). The null (Ho) and alternative (HA) hypotheses regarding PFS and OS are tested at the significance level of 0.1 each and can be phrased in terms of the population hazard ratio (HR) X between the experimental arm and the control arm: Ho: A = 1 versus HA: X 1 .

[0502] B. Sample Size Determination

[0503] The GO45216 study is a Phase Ib / ll study with 100 participants planned for enrolling in the stage of Phase lb and additionally 50 participants planned for enrolling in the stage of Phase II after gating. Overall, approximately 100-150 patients are enrolled in the study.

[0504] For the Phase lb part of the study, after 100 participants have been enrolled and followed for at least approximately 16 weeks, an interim efficacy analysis is performed and the study may be expanded to a Phase II study by enrolling approximately an additional 50 participants.

[0505] For the Phase II part of the study with approximately 150 participants total, though the study is not designed to make explicit power and type I error control, the assumption for sample size justification are as follows: Log-rank test will be used; PFS and OS event time follows the exponential distribution; median PFS of 5.5 months in Arm B and 8.5 months in the Arm A (corresponding to a target PFS hazard ratio (HR) of 0.65); median OS of 10 months in Arm B and 15.2 months in the Arm A (corresponding to a target PFS HR of 0.66); the dropout rate is 2.5% over 12 months for PFS; the dropout rate is 2.5% over 12 months for OS; two-sided a of 0.1 for each of PFS and OS; accrual over a period of 39 months (including an approximately 9-month enrollment hold between fully enrolling the Phase lb part and start of the Phase II expansion).

[0506] The primary analysis of the primary endpoint of PFS occurs when approximately 100 PFS events (67% of 150 participants) have been observed or until last participant in the Phase II expansion enrolled and followed for at least 16 weeks, whichever comes later. The 100 PFS events provide a 70% power to detect a target PFS HR of 0.65 at a two-sided significance level of 0.1 . It is projected that an observed HR of 0.72 or less for PFS will result in a statistically significant difference at the significance level of 0.1 between the treatment arms based on the log-rank test. That is, an HR of 0.72 will be the minimally detectable difference for the analysis; this corresponds to an improvement of 2.1 months in median PFS from 5.5 months in Arm B to 7.6 months in Arm A. The primary analysis of PFS is expected to occur at approximately 39 months after the first patient is randomized.

[0507] The primary analysis of the primary endpoint of OS occurs when approximately 100 OS events (67% of 150 participants) have been observed. The 100 OS events provide a 67% power to detect a target OS HR of 0.66 at a two-sided significance level of 0.1 . It is projected that an observed HR of 0.72 or less for OS will result in a statistically significant difference at the significance level of 0.1 between the treatment arms based on the log-rank test. This corresponds to approximately an improvement of 3.9 months in median OS from 10 months in Arm B to 13.9 months in Arm A. The primary analysis of OS is expected to occur at approximately 44 months after the first patient is randomized.

[0508] C. Analysis Sets

[0509] The participant analysis sets for the purposes of analyses are (1 ) the Full Analysis Set (FAS), consisting of all randomized participants (participants are included in the analyses according to the treatment to which they were assigned); and (2) the Safety Analysis Set (SAS), consisting of all participants exposed to study treatment (participants are analyzed according to the treatment that they actually received).

[0510] D. Statistical Analyses

[0511] General Considerations

[0512] All efficacy analyses are performed on the FAS, unless otherwise specified. The analyses are grouped according to the treatment assigned at randomization, regardless of whether the participant receives any assigned study treatment.

[0513] The treatment policy is used to address the intercurrent events of both early treatment discontinuation and start of non-protocol anti-cancer therapy prior to occurrence of the respective event of interest.

[0514] Safety analyses are performed on the safety analysis set and are grouped by the actual treatment received, regardless of the initial treatment assignment at randomization. Specifically, a participant is included in Arm A in the safety analyses if the participant receives any amount of tiragolumab or atezolizumab.

[0515] Estimation Methods for the Primary Estimands

[0516] The primary efficacy endpoints of the study are investigator-assessed PFS per RECIST v1 .1 and OS. PFS is defined as the time between the date of randomization and the date of first documented disease progression or death, whichever occurs first. Participants who have not experienced disease progression or who have not died at the time of analysis are censored at the time of the last tumor assessment. Participants with no post-baseline tumor assessment are censored at the date of randomization.

[0517] OS is defined as the time from randomization to death from any cause. Data for participants who are alive at the time of the data cutoff will be censored at the last date they were known to be alive. Data from participants without post-baseline information are censored at the date of randomization.

[0518] PFS and OS are compared between treatment arms with use of the stratified log-rank test. The HR and its 90% confidence interval (Cl) for PFS and OS are estimated with use of a stratified Cox proportional-hazards regression model. The stratification factors are geographic region (Asia vs. rest of world (ROW)) and ECOG Performance Status (0 vs. 1 ). Kaplan-Meier methodology is used to estimate the median PFS and OS for each treatment arm with 90% Cl constructed by the Brookmeyer Crowley methodology. Kaplan-Meier curves are constructed to provide a visual description of the difference between treatment arms.

[0519] Results from an unstratified analysis for log-rank test and Cox proportional hazards regression model for both PFS and OS, respectively, are also provided.

[0520] Safety Analyses

[0521] Safety is assessed through summaries of exposure to study treatment, adverse events, changes in laboratory test results, and changes in vital signs and ECGs.

[0522] All verbatim adverse event terms are mapped to MedDRA thesaurus terms, and adverse event severity is graded according to NCI CTCAE v5.0. Cytokine release syndrome (CRS) is also graded according to the ASTCT CRS Consensus Grading Scale.

[0523] Overall Survival Rate at 12 and 24 Months

[0524] OS rate at 12 and 24 months is defined as the probability of not experiencing death at 12 and 24 months after randomization, respectively. The OS rate is estimated according to the Kaplan-Meier methodology along with its 90% Cl being estimated via Greenwood’s formula for variance.

[0525] Objective Response Rate

[0526] Confirmed objective response rate (ORR) is defined as the proportion of participants who have achieved an objective response, characterized by a complete response (CR) or partial response (PR), on two consecutive occasions 4 weeks apart. ORR is calculated by treatment arm with its 90% Cl being constructed by the Clopper-Pearson method. Participants without post-baseline overall response assessments are counted as non-responders. The analysis population for ORR is all randomized participants with measurable disease at baseline. An estimate of the difference in the ORR between the treatment arms is computed along with its 90% Cl by using the normal approximation. The Mantel-Haenszel test is used to evaluate the ORR difference between the treatment arms, stratified by the protocol-defined stratification factors.

[0527] Duration of Response

[0528] Duration of response (DOR) is defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first. Data for participants who have not experienced disease progression or death are censored at the last tumor assessment date. If no tumor assessments were performed after the date of the first occurrence of CR or PR, data are censored at the date of the first occurrence of CR or PR.

[0529] The analysis of DOR includes only participants who achieved an objective response during the study and is estimated with the use of the Kaplan-Meier methodology.

[0530] Disease Control Rate

[0531] Disease control rate (DCR) is defined as the proportion of participants with stable disease (SD) for > 12 weeks or a complete response (CR) or partial response (PR), as determined according to RECIST v1 .1 . DCR is calculated for all randomized participants with measurable disease at baseline, with its 90% Cl being constructed by the Clopper-Pearson method.

[0532] E. Interim Analyses

[0533] An interim efficacy analysis for both PFS and OS is conducted to enable the gating decision to continue into Phase II. The interim analysis is time-driven; the analysis is planned when 100 participants have enrolled in the Phase lb part and have been followed for at least approximately 16 weeks. This is expected to occur approximately 25 months after the first participant in (21 -month enrollment + 4-month follow-up after last participant in Phase lb), when 70 PFS events and 50 OS events are expected. The gating criteria are as follows:

[0534] • Scenario 1 : If observing HR > 0.8 for both PFS and OS at the Phase lb interim analysis, trial enrollment stops due to futility. The final analysis is done at approximately 70 OS events that occur in 100 participants.

[0535] • Scenario 2: If observing HR < 0.6 for both PFS and OS at the Phase lb interim analysis, then the trial enrollment stops due to efficacy, and the final analysis is done at 70 OS events that occur in 100 participants.

[0536] • Scenario 3: Otherwise, that is, both Scenarios 1 and 2 are not met, the trial expands and enroll an additional 50 participants to Phase II for further evaluation.

[0537] The study may continue into a Phase II study if the pre-specified efficacy threshold for Phase II expansion is met at this interim analysis.

[0538] After Phase II expansion, there are no planned interim analyses of the primary endpoint of PFS. The final analysis of the primary endpoint of PFS occurs when approximately 100 PFS events (67% of 150 participants) have been observed (this is estimated to occur approximately 39 months after the first participant is enrolled in the study), or until last participant in the Phase II expansion enrolled and followed for at least 16 weeks, whichever comes later.

[0539] After Phase II expansion, there is one planned interim analysis of the primary endpoint of OS at the time of PFS final. The final analysis of the primary endpoint of OS occurs when approximately 100 OS events (67% of 150 participants) have been observed. This is estimated to occur approximately 44 months after the first participant is enrolled in the study.

[0540] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated in their entirety by reference.

Claims

WHAT IS CLAIMED IS:1 . A method of treating a subject having a pancreatic cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIG IT antagonist antibody and an anti-PD-L1 antagonist antibody, wherein a tumor sample from the subject has been determined to be PD-L1 -positive; and wherein:(a) 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); and an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6); and(b) 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); and an HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO: 25).

2. The method of claim 1 , wherein the pancreatic cancer is a pancreatic ductal adenocarcinoma (PDAC).

3. The method of claim 2, wherein the PDAC is a metastatic PDAC.

4. The method of any one of claims 1 -3, wherein the subject has not received prior systemic therapy for pancreatic cancer.

5. The method of any one of claims 1 -4, 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; and(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.

6. The method of any one of claims 1 -5, 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; and(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.

7. The method of claim 6, 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.

8. The method of claim 7, 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.

9. The method of any one of claims 1 -8, 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.

10. The method of any one of claims 1 -8, wherein the anti-TIGIT antagonist antibody is tiragolumab.1 1 . The method of any one of claims 1 -10, wherein the method comprises administering the anti- TIGIT antagonist antibody to the subject at a dose of about 840 mg every four weeks.

12. The method of any one of claims 1 -1 1 , 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; and(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.

13. The method of claim 12, 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.

14. The method of any one of claims 1 -13, 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.

15. The method of any one of claims 1 -13, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

16. The method of any one of claims 1 -15, wherein the method comprises administering the anti-PD- L1 antagonist antibody to the subject at a dose of about 1680 mg every four weeks.

17. The method of any one of claims 1 -16, wherein the method comprises co-administering the anti- TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody.

18. The method of any one of claims 1 -17, wherein the length of each of the one or more dosing cycles is 28 days.

19. The method of claim 18, wherein the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are administered on about Day 1 of each dosing cycle.

20. The method of any one of claims 1 -19, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.21 . The method of claim 20, wherein the method comprises administering to the subject a taxane and an antimetabolite.

22. The method of claim 21 , wherein the taxane is nab-paclitaxel.

23. The method of claim 22, wherein the length of each of the one or more dosing cycles is 28 days, and wherein nab-paclitaxel is administered three times over the course of each 28-day dosing cycle.

24. The method of claim 23, wherein nab-paclitaxel is administered on Days 1 , 8, and 15 of each 28- day dosing cycle.

25. The method of any one of claims 22-24, wherein nab-paclitaxel is administered at a dose of about 125 mg / m2.

26. The method of any one of claims 21 -25, wherein the antimetabolite is gemcitabine.

27. The method of claim 26, wherein the length of each of the one or more dosing cycles is 28 days, and wherein gemcitabine is administered three times over the course of each 28-day dosing cycle.

28. The method of claim 27, wherein gemcitabine is administered on Days 1 , 8, and 15 of each 28- day dosing cycle.

29. The method of any one of claims 26-28, wherein gemcitabine is administered at a dose of about 1000 mg / m2.

30. The method of any one of claims 19, 24, and 28, wherein, on Day 1 of each 28-day dosing cycle, the method comprises (i) administering the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonistantibody before administering nab-paclitaxel and (ii) administering nab-paclitaxel before administering gemcitabine.31 . The method of any one of claims 1 -30, wherein the method comprises administering to the subject the anti-TIG IT antagonist antibody, the anti-PD-L1 antagonist antibody, the taxane, and / or the antimetabolite intravenously.

32. The method of any one of claims 1 -31 , wherein the tumor sample from the subject has been determined to be PD-L1 -positive by an immunohistochemical (IHC) assay comprising staining with an anti-PD-L1 antibody suitable for staining.

33. The method of claim 32, wherein the anti-PD-L1 antibody suitable for staining is the anti-PD-L1 antibody SP263, SP142, 22C3, or 28-8.

34. The method of claim 33, wherein the 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.

35. The method of any one of claims 32-34, wherein the anti-PD-L1 antibody suitable for staining is the anti-PD-L1 antibody SP263, and the protein expression level of PD-L1 has been determined using the VENTANA PD-L1 (SP263) CDx Assay.

36. The method of claim 35, wherein the tumor sample obtained from the subject has been determined to have a PD-L1 tumor area positive (TAP) score of equal to or greater than 1 %.

37. The method of any one of claims 1 -31 , wherein the tumor sample from the subject has been determined to be PD-L1 -positive by an assay that detects a nucleic acid expression level of PD-L1 .

38. The method of claim 37, wherein the nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique, ISH, or a combination thereof.

39. A method of treating a subject having a pancreatic cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of atezolizumab, tiragolumab, nab- paclitaxel, and gemcitabine, wherein a tumor sample from the subject has been determined to have a PD- L1 tumor area positive (TAP) score of equal to or greater than 1 % using the VENTANA PD-L1 (SP263) CDx Assay, and wherein the pancreatic cancer is a metastatic pancreatic ductal adenocarcinoma (PDAC).

40. The method of claim 39, wherein the method comprises administering tiragolumab to the subject at a dose of about 840 mg every four weeks; administering atezolizumab to the subject at a dose of about1680 mg every four weeks; administering nab-paclitaxel to the subject at a dose of about 125 mg / m2; and administering gemcitabine to the subject at a dose of about 1000 mg / m2.41 . The method of claim 39 or 40, wherein the method comprises co-administering atezolizumab and tiragolumab.

42. The method of any one of claims 39-41 , wherein the length of each of the one or more dosing cycles is 28 days, and wherein tiragolumab is administered on about Day 1 of each dosing cycle; atezolizumab is administered on about Day 1 of each dosing cycle; nab-paclitaxel is administered on Days 1 , 8, and 15 of each 28-day dosing cycle; and gemcitabine is administered on Days 1 , 8, and 15 of each 28-day dosing cycle.

43. The method of any one of claims 1 -42, wherein the treating results in an increase in progression- free survival (PFS) as compared to a reference PFS.

44. The method of claim 43, wherein the reference PFS is the mean or median PFS of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine and not comprising administration of an anti-TIG IT antagonist antibody and an anti-PD-L1 antagonist antibody.

45. The method of any one of claims 1 -44, wherein the treating results in an increase in overall survival (OS) as compared to a reference OS.

46. The method of claim 45, wherein the reference OS is the mean or median OS of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine and not comprising administration of an anti-TIG IT antagonist antibody and an anti-PD-L1 antagonist antibody.

47. The method of any one of claims 1 -46, wherein the treating results in an increase in OS rate at 12 months as compared to a reference 12-month OS rate.

48. The method of claim 47, wherein the reference 12-month OS rate is the 12-month OS rate of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIG IT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

49. The method of any one of claims 1 -48, wherein the treating results in an increase in OS rate at 24 months as compared to a reference 24-month OS rate.

50. The method of claim 49, wherein the reference 24-month OS rate is the 24-month OS rate of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIG IT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.51 . The method of any one of claims 1 -50, wherein the treating results in an increase in objective response rate (ORR) as compared to a reference ORR.

52. The method of claim 51 , wherein the reference ORR is the mean or median ORR of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIG IT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

53. The method of any one of claims 1 -52, wherein the treating results in an increase in duration of response (DOR) as compared to a reference DOR.

54. The method of claim 53, wherein the reference DOR is the mean or median DOR of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIG IT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

55. The method of any one of claims 1 -54, wherein the treating results in an increase in disease control rate (DCR) as compared to a reference DCR.

56. The method of claim 55, wherein the reference DCR is the DCR of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIGIT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

57. The method of any one of claims 1 -56, wherein the subject is a human.

58. An anti-TIG IT antagonist antibody and / or an anti-PD-L1 antagonist antibody for use in a method of treating a subject having a pancreatic cancer, wherein the method comprises administering to the subject a dosing regimen comprising one or more dosing cycles of the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody, wherein a tumor sample from the subject has been determined to be PD-L1 -positive; and wherein:(a) 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); and an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6); and(b) 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); and an HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO: 25).

59. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 58, wherein the pancreatic cancer is a pancreatic ductal adenocarcinoma (PDAC).

60. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 59, wherein the PDAC is a metastatic PDAC.61 . The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-60, wherein the subject has not received prior systemic therapy for pancreatic cancer.

62. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-61 , 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; and(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.

63. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-62, 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; and(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.

64. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 63, wherein the anti-TIGIT antagonist antibody comprises:(c) a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and(d) a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

65. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 64, wherein the anti-TIGIT antagonist antibody comprises:(c) a VH domain comprising the amino acid sequence of SEQ ID NO: 17; and(d) a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

66. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-65, 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.

67. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-65, wherein the anti-TIGIT antagonist antibody is tiragolumab.

68. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-67, wherein the anti-TIGIT antagonist antibody is to be administered to the subject at a dose of about 840 mg every four weeks.

69. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-68, 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; and(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.

70. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 69, wherein the anti-PD-L1 antagonist antibody comprises:(c) a VH domain comprising the amino acid sequence of SEQ ID NO: 26; and(d) a VL domain comprising the amino acid sequence of SEQ ID NO: 27.71 . The anti-TIG IT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-70, 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.

72. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-70, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

73. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-72, wherein the anti-PD-L1 antagonist antibody is to be administered to the subject at a dose of about 1680 mg every four weeks.

74. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-73, wherein the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are to be co-administered.

75. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-74, wherein the length of each of the one or more dosing cycles is 28 days.

76. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 75, wherein the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are to be administered on about Day 1 of each dosing cycle.

77. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-76, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.

78. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 77, wherein a taxane and an antimetabolite are to be administered to the subject.

79. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 78, wherein the taxane is nab-paclitaxel.

80. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 79, wherein the length of each of the one or more dosing cycles is 28 days, and wherein nab-paclitaxel is to be administered three times over the course of each 28-day dosing cycle.81 . The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 80, wherein nab-paclitaxel is to be administered on Days 1 , 8, and 15 of each 28-day dosing cycle.

82. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 79-81 , wherein nab-paclitaxel is to be administered at a dose of about 125 mg / m2.

83. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 78-82, wherein the antimetabolite is gemcitabine.

84. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 83, wherein the length of each of the one or more dosing cycles is 28 days, and wherein gemcitabine is to be administered three times over the course of each 28-day dosing cycle.

85. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 84, wherein gemcitabine is to be administered on Days 1 , 8, and 15 of each 28-day dosing cycle.

86. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 83-85, wherein gemcitabine is to be administered at a dose of about 1000 mg / m2.

87. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 76, 81 , and 85, wherein, on Day 1 of each 28-day dosing cycle, (i) the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are to be administered before nab-paclitaxel and (ii) nab- paclitaxel is to be administered before gemcitabine.

88. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-87, wherein the anti-TIGIT antagonist antibody, the anti-PD-L1 antagonist antibody, the taxane, and / or the antimetabolite are to be administered to the subject intravenously.

89. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-88, wherein the tumor sample from the subject has been determined to be PD-L1 -positive by an immunohistochemical (IHC) assay comprising staining with an anti-PD-L1 antibody suitable for staining.

90. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 89, wherein the anti-PD-L1 antibody suitable for staining is the anti-PD-L1 antibody SP263, SP142, 22C3, or 28-8.91 . The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 90, wherein the 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.

92. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 89-91 , wherein the anti-PD-L1 antibody suitable for staining is the anti-PD-L1 antibody SP263, andthe protein expression level of PD-L1 has been determined using the VENTANA PD-L1 (SP263) CDx Assay.

93. The anti-TIG IT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 92, wherein the tumor sample obtained from the subject has been determined to have a PD-L1 tumor area positive (TAP) score of equal to or greater than 1 %.

94. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-88, wherein the tumor sample from the subject has been determined to be PD-L1 -positive by an assay that detects a nucleic acid expression level of PD-L1 .

95. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 94, wherein the nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique, ISH, or a combination thereof.

96. Atezolizumab and / or tiragolumab for use in a method of treating a subject having a pancreatic cancer, wherein the method comprises administering to the subject a dosing regimen comprising one or more dosing cycles of atezolizumab, tiragolumab, nab-paclitaxel, and gemcitabine, wherein a tumor sample from the subject has been determined to have a PD-L1 tumor area positive (TAP) score of equal to or greater than 1 % using the VENTANA PD-L1 (SP263) CDx Assay, and wherein the pancreatic cancer is a metastatic pancreatic ductal adenocarcinoma (PDAC).

97. The atezolizumab and / or tiragolumab for use of claim 96, wherein tiragolumab is to be administered to the subject at a dose of about 840 mg every four weeks; atezolizumab is to be administered to the subject at a dose of about 1680 mg every four weeks; nab-paclitaxel is to be administered to the subject at a dose of about 125 mg / m2; and gemcitabine is to be administered to the subject at a dose of about 1000 mg / m2.

98. The atezolizumab and / or tiragolumab for use of claim 96 or 97, wherein atezolizumab and tiragolumab are to be co-administered.

99. The atezolizumab and / or tiragolumab for use of any one of claims 96-98, wherein the length of each of the one or more dosing cycles is 28 days, and wherein tiragolumab is to be administered on about Day 1 of each dosing cycle; atezolizumab is to be administered on about Day 1 of each dosing cycle; nab- paclitaxel is to be administered on Days 1 , 8, and 15 of each 28-day dosing cycle; and gemcitabine is to be administered on Days 1 , 8, and 15 of each 28-day dosing cycle.

100. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-95, wherein the treating results in an increase in progression-free survival (PFS) as compared to a reference PFS.101 . The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 100, wherein the reference PFS is the mean or median PFS of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIGIT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

102. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-95, 100, and 101 , wherein the treating results in an increase in overall survival (OS) as compared to a reference OS.

103. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 102, wherein the reference OS is the mean or median OS of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIGIT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody .

104. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-95 and 100-103, wherein the treating results in an increase in OS rate at 12 months as compared to a reference 12-month OS rate.

105. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 104, wherein the reference 12-month OS rate is the 12-month OS rate of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIGIT antagonist antibody and does not comprise administration of an anti-PD- L1 antagonist antibody.

106. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-95 and 100-105, wherein the treating results in an increase in OS rate at 24 months as compared to a reference 24-month OS rate.

107. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 106, wherein the reference 24-month OS rate is the 24-month OS rate of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIGIT antagonist antibody and does not comprise administration of an anti-PD- L1 antagonist antibody.

108. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-95 and 100-107, wherein the treating results in an increase in objective response rate (ORR) as compared to a reference ORR.

109. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 108, wherein the reference ORR is the mean or median ORR of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIGIT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

110. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-95 and 100-109, wherein the treating results in an increase in duration of response (DOR) as compared to a reference DOR.

111. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 110, wherein the reference DOR is the mean or median DOR of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIGIT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

112. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-95 and 100-111 , wherein the treating results in an increase in disease control rate (DCR) as compared to a reference DCR.

113. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of claim 112, wherein the reference DCR is the DCR of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab- paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti- TIGIT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

114. The anti-TIGIT antagonist antibody and / or anti-PD-L1 antagonist antibody for use of any one of claims 58-95 and 100-113, wherein the subject is a human.

115. The atezolizumab and / or tiragolumab for use of any one of claims 96-99, wherein the treating results in an increase in progression-free survival (PFS) as compared to a reference PFS.

116. The atezolizumab and / or tiragolumab for use of claim 115, wherein the reference PFS is the mean or median PFS of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel andgemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIG IT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.1 17. The atezolizumab and / or tiragolumab for use of any one of claims 96-99, 1 15, and 1 16, wherein the treating results in an increase in overall survival (OS) as compared to a reference OS.1 18. The atezolizumab and / or tiragolumab for use of claim 1 17, wherein the reference OS is the mean or median OS of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIG IT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.1 19. The atezolizumab and / or tiragolumab for use of any one of claims 96-99 and 1 15-118, wherein the treating results in an increase in OS rate at 12 months as compared to a reference 12-month OS rate.

120. The atezolizumab and / or tiragolumab for use of claim 1 19, wherein the reference 12-month OS rate is the 12-month OS rate of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIG IT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.121 . The atezolizumab and / or tiragolumab for use of any one of claims 96-99 and 1 15-120, wherein the treating results in an increase in OS rate at 24 months as compared to a reference 24-month OS rate.

122. The atezolizumab and / or tiragolumab for use of claim 121 , wherein the reference 24-month OS rate is the 24-month OS rate of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIG IT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

123. The atezolizumab and / or tiragolumab for use of any one of claims 96-99 and 1 15-122, wherein the treating results in an increase in objective response rate (ORR) as compared to a reference ORR.

124. The atezolizumab and / or tiragolumab for use of claim 123, wherein the reference ORR is the mean or median ORR of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIG IT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

125. The atezolizumab and / or tiragolumab for use of any one of claims 96-99 and 1 15-124, wherein the treating results in an increase in duration of response (DOR) as compared to a reference DOR.

126. The atezolizumab and / or tiragolumab for use of claim 125, wherein the reference DOR is the mean or median DOR of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIG IT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

127. The atezolizumab and / or tiragolumab for use of any one of claims 96-99 and 115-126, wherein the treating results in an increase in disease control rate (DCR) as compared to a reference DCR.

128. The atezolizumab and / or tiragolumab for use of claim 127, wherein the reference DCR is the DCR of a population of subjects having the pancreatic cancer who have received a treatment comprising a dosing regimen comprising one or more dosing cycles of nab-paclitaxel and gemcitabine, wherein the dosing regimen does not comprise administration of an anti-TIG IT antagonist antibody and does not comprise administration of an anti-PD-L1 antagonist antibody.

129. The atezolizumab and / or tiragolumab for use of any one of claims 96-99 and 115-128, wherein the subject is a human.

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