Methods of treating cancer using PD-1 axis binding antagonists and MEK inhibitors
The present invention describes combination treatment comprising a PD-1 axis binding antagonist and a MEK inhibitor and methods for use thereof, including methods of treating conditions where enhanced immunogenicity is desired such as increasing tumor immunogenicity for the treatment of cancer.
1. A method for treating or delaying progression of colorectal cancer or melanoma in an individual comprising administering to the individual an effective amount of an anti-PD-L1 antibody and a MEK inhibitor, wherein the MEK inhibitor is selected from the group consisting of G02442104, G-38963, G02443714, G00039805 and GDC-0973, or a pharmaceutically acceptable salt or solvate thereof.
2. The method of claim 1 , wherein the anti-PD-L1 antibody inhibits the binding of PD-L1 to PD-1.
3. The method of claim 1 , wherein the anti-PD-L1 antibody inhibits the binding of PD-L1 to B7-1.
4. The method of claim 1 , wherein the anti-PD-L1 antibody inhibits the binding of PD-L1 to both PD-1 and B7-1.
5. The method of claim 1 , wherein the anti-PD-L1 antibody is selected from the group consisting of: YW243.55.S70, MPDL3280A, and MDX-1105.
6. The method of claim 1 , wherein the anti-PD-L1 antibody comprises a heavy chain comprising HVR-H1 sequence of SEQ ID NO:15, HVR-H2 sequence of SEQ ID NO:16, and HVR-H3 sequence of SEQ ID NO:3; and a light chain comprising HVR-L1 sequence of SEQ ID NO:17, HVR-L2 sequence of SEQ ID NO:18, and HVR-L3 sequence of SEQ ID NO:19.
7. The method of claim 1 , wherein the anti-PD-L1 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:24 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:21.
8. The method of claim 1 , wherein the MEK inhibitor is G02443714, G02442104 or G00039805.
9. The method of claim 1 , wherein the cancer contains a BRAF V600E mutation.
10. The method of claim 1 , wherein the cancer contains a BRAF wildtype.
11. The method of claim 1 , wherein the colorectal cancer contains a KRAS wildtype.
12. The method of claim 1 , wherein the colorectal cancer contains an activating KRAS mutation.
13. The method of claim 1 , wherein the treatment results in a sustained response in the individual after cessation of the treatment.
14. The method of claim 1 , wherein the MEK inhibitor is administered continuously.
15. The method of claim 1 , wherein the MEK inhibitor is administered intermittently.
16. The method of claim 1 , wherein the MEK inhibitor is administered before the anti-PD-L1 antibody.
17. The method of claim 1 , wherein the MEK inhibitor is administered simultaneous with the anti-PD-L1 antibody.
18. The method of claim 1 , wherein the MEK inhibitor is administered after the anti-PD-L1 antibody.
19. The method of claim 1 , wherein the anti-PD-L1 antibody is a monoclonal antibody.
20. The method of claim 1 , wherein the anti-PD-L1 antibody is a humanized antibody.
21. The method of claim 1 , wherein the anti-PD-L1 antibody is a human antibody.
22. The method of claim 1 , wherein the anti-PD-L1 antibody is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.
23. A method for treating or delaying progression of colorectal cancer in an individual comprising administering to the individual an effective amount of GDC-0973, or a pharmaceutically acceptable salt thereof, and an effective amount of an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody comprises a heavy chain comprising an HVR-H1 sequence of SEQ ID NO:15, an HVR-H2 sequence of SEQ ID NO:16, and an HVR-H3 sequence of SEQ ID NO:3; and a light chain comprising an HVR-L1 sequence of SEQ ID NO:17;, an HVR-L2 sequence of SEQ ID NO:18, and an HVR-L3 sequence of SEQ ID NO:19.
24. The method of claim 23 , wherein the heavy chain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:24 and the light chain comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO:21.
25. The method of claim 23 , wherein the anti-PDL1 antibody is MPDL3280A.
26. A method for treating or delaying progression of melanoma in an individual comprising administering to the individual an effective amount of GDC-0973, or a pharmaceutically acceptable salt thereof, and an effective amount of an anti-PD-L1 antibody, wherein the melanoma is BRAF wildtype, and wherein the anti-PD-L1 antibody comprises a heavy chain comprising an HVR-H1 sequence of SEQ ID NO:15, an HVR-H2 sequence of SEQ ID NO:16, and an HVR-H3 sequence of SEQ ID NO:3; and a light chain comprising an HVR-L1 sequence of SEQ ID NO:17, an HVR-L2 sequence of SEQ ID NO:18, and an HVR-L3 sequence of SEQ ID NO:19.
27. The method of claim 26 , wherein the heavy chain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:24 and the light chain comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO:21.
28. The method of claim 26 , wherein the anti-PDL1 antibody is MPDL 3280A.
29. The method of claim 1 , wherein the MEK inhibitor is s G02442104, or a pharmaceutically acceptable salt or solvate thereof.
30. The method of claim 1 , wherein the MEK inhibitor is G-38963, or a pharmaceutically acceptable salt or solvate thereof.
31. The method of claim 1 , wherein the MEK inhibitor is G02443714, or a pharmaceutically acceptable salt or solvate thereof.
32. The method of claim 1 , wherein the MEK inhibitor is G00039805, or a pharmaceutically acceptable salt or solvate thereof.
33. The method of claim 1 , wherein the MEK inhibitor is GDC-0973, or a pharmaceutically acceptable salt or solvate thereof.