COMBINATION THERAPY OF A PD-1 ANTAGONIST AND LAG3 ANTAGONIST FOR TREATING PATIENTS WITH NON-MICROSATELLITE INSTABILITY-HIGH OR PROFICIENT MISMATCH REPAIR COLORECTAL CANCER

1 . A method for treating non-microsatellite instability-high (non-MSI-H) or proficient mismatch repair (pMMR) colorectal cancer in an individual comprising administering to the individual a PD-1 antagonist and a LAG3 antagonist.

2 . The method of claim 1 , wherein the PD-1 antagonist is a monoclonal antibody, or an antigen binding fragment thereof.

3 . The method of claim 1 , wherein the individual is a human and the PD-1 antagonist is a monoclonal antibody, or an antigen binding fragment thereof, which specifically binds to human PD-1 and blocks the binding of human PD-L1 to human PD-1.

4 . The method of claim 3 , wherein the PD-1 antagonist also blocks binding of human PD-L2 to human PD-1.

5 . The method of claim 4 , wherein the PD-1 antagonist is an antibody, or antigen binding fragment thereof, which comprises: (a) light chain CDRs of SEQ ID NOs: 1, 2 and 3 and (b) heavy chain CDRs of SEQ ID NOs: 6, 7 and 8.

6 . The method of claim 4 , wherein the PD-1 antagonist is an anti-PD-1 antibody which comprises a heavy chain and a light chain, and wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:9 and the light chain comprises a light chain variable region comprising SEQ ID NO: 4.

7 . The method of claim 4 , wherein the PD-1 antagonist is an anti-PD-1 antibody which comprises a heavy chain and a light chain, and wherein the heavy chain comprises SEQ ID NO:10 and the light chain comprises SEQ ID NO:5.

8 . The method of claim 4 , wherein the PD-1 antagonist is pembrolizumab.

9 . The method of claim 4 , wherein the PD-1 antagonist is a pembrolizumab variant.

10 . The method of claim 4 , wherein the PD-1 antagonist is nivolumab.

11 . The method of claim 4 , wherein the LAG3 antagonist is a monoclonal antibody, or an antigen binding fragment thereof that blocks binding of LAG3 to MHC Class II molecules.

12 . The method of claim 5 , wherein the LAG3 antagonist is an antibody, or antigen binding fragment thereof, which comprises: (a) light chain CDRs of SEQ ID NOs: 26, 27 and 28 and (b) heavy chain CDRs of SEQ ID NOs: 29, 30 and 31.

13 . The method of claim 6 , wherein the LAG3 antagonist is an anti-LAG3 monoclonal antibody which comprises a heavy chain and a light chain, and wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:25 and the light chain comprises a light chain variable region comprising SEQ ID NO: 24.

14 . The method of claim 7 , wherein the LAG3 antagonist is an anti-LAG3 antibody which comprises a heavy chain and a light chain, and wherein the heavy chain comprises SEQ ID NO:23 and the light chain comprises SEQ ID NO:22.

15 . The method of claim 8 , wherein the LAG3 antagonist is an Ab6 variant.

16 . The method of claim 10 , wherein the LAG3 antagonist is relatlimab.

17 . The method of claim 1 , wherein the PD-1 antagonist is a humanized anti-PD-1 antibody that comprises a heavy chain and a light chain, and wherein the heavy chain comprises a heavy chain variable region comprising heavy chain CDRs of SEQ ID NOs: 6, 7 and 8 and the light chain comprises a light chain variable region comprising light chain CDRs of SEQ ID NOs: 1, 2 and 3; and the LAG3 antagonist is a humanized anti-LAG3 antibody which comprises a heavy chain and a light chain, and wherein the heavy chain comprises a heavy chain variable region comprising heavy chain CDRs of SEQ ID NOs: 29, 30 and 31 and the light chain comprises a light chain variable region comprising light chain CDRs of SEQ ID NOs: 26, 27 and 28.

18 . The method of claim 1 , wherein the PD-1 antagonist is an anti-PD-1 antibody that comprises a heavy chain and a light chain, and wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:9 and the light chain comprises a light chain variable region comprising SEQ ID NO: 4; and the LAG3 antagonist is an anti-LAG3 antibody which comprises a heavy chain and a light chain, and wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:25 and the light chain comprises a light chain variable region comprising SEQ ID NO: 24.

19 . The method of claim 1 , wherein the PD-1 antagonist is an anti-PD-1 antibody that comprises a heavy chain and a light chain, and wherein the heavy chain comprises SEQ ID NO:10 and the light chain comprises SEQ ID NO: 5; and the LAG3 antagonist is an anti-LAG3 antibody which comprises a heavy chain and a light chain, and wherein the heavy chain comprises SEQ ID NO:23 and the light chain comprises SEQ ID NO: 22.

20 . The method of claim 19 , wherein the PD-1 antagonist and LAG3 antagonist are co-formulated.

21 . The method of claim 19 , wherein the PD-1 antagonist and LAG3 antagonist are co-administered.

22 . The method of claim 11 , wherein the individual has not been previously treated with anti-PD-1 or anti-PD-L 1 therapy or is confirmed progressive while receiving prior anti-PD-1 therapy.

23 . The method of claim 1 , wherein the tumor cells of the individual is PD-L1 expression positive.

24 . The method of claim 1 , wherein the individual has a Mononuclear Inflammatory Density Score for PD-L1 expression≥2.

25 . The method of claim 1 , wherein the individual has a Combined Positive Score for PD-L1 expression≥1%.

26 . The method of claim 34 , wherein the PD-L1 expression is measured by the PD-L1 IHC 22C3 pharmDx assay.

27 . The method of claim 4 , wherein the tumor cells of the individual is PD-L1 expression positive.

28 . The method of claim 11 , wherein the tumor cells of the individual is PD-L1 expression positive.

29 . The method of claim 16 , wherein the tumor cells of the individual is PD-L1 expression positive.

30 . The method of claim 11 , wherein the individual has a Mononuclear Inflammatory Density Score for PD-L1 expression≥2.

31 . The method of claim 16 , wherein the individual has a Mononuclear Inflammatory Density Score for PD-L1 expression≥2.

32 . The method of claim 11 , wherein the individual has a Combined Positive Score for PD-L1 expression≥1%.

33 . The method of claim 16 , wherein the individual has a Combined Positive Score for PD-L1 expression≥1%.

34 . The method of claim 18 , wherein the individual has a Combined Positive Score for PD-L1 expression≥1%.

35 . The method of claim 19 , wherein the individual has a Combined Positive Score for PD-L1 expression≥1%.

36 . The method of claim 35 , wherein the PD-L1 expression is measured by the PD-L1 IHC 22C3 pharmDx assay.