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 a melanoma that is resistant to a B-raf antagonist in an individual, the method comprising administering to the individual an effective amount of a PD-L1 binding antagonist and a MEK inhibitor, wherein:
the individual has been previously treated with the B-raf antagonist for melanoma and the melanoma is resistant to the B-raf antagonist,
the MEK inhibitor is GDC-0973 or a pharmaceutically acceptable salt or solvate thereof, and
the PD-L1 antagonist is an anti-PD-L1 antibody comprising 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.
2. The method of claim 1 , further comprising diagnosing the individual as having a melanoma that is resistant to the B-raf antagonist, wherein the diagnosing occurs prior to administering the effective amount of the PD-L1 binding antagonist and the MEK inhibitor.
3. The method of claim 1 , wherein the melanoma in the individual has progressed within 1 month, 6 months, 1 year, or 5 years after completing a B-raf antagonist-based therapy regimen.
4. The method of claim 1 , wherein the B-raf antagonist is a small molecule inhibitor.
5. The method of claim 4 , wherein the B-raf antagonist is dabrafenib, vemurafenib, GSK 2118436, RAF265, XL281, ARQ736, BAY73-4506, sorafenib, PLX4720, PLX-3603, GSK2118436, GDC-0879, or N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide.
6. The method of claim 4 , wherein the B-raf antagonist is a selective B-raf antagonist of B-raf V600.
7. The method of claim 6 , wherein the selective B-raf antagonist of B-raf V600 is a selective antagonist of B-raf V600E.
8. The method of claim 6 , wherein the selective B-raf antagonist of B-raf V600 is a selective antagonist of B-raf V600E, B-raf V600K, and/or V600D.
9. The method of claim 6 , wherein the selective B-raf antagonist of B-raf V600 is a selective antagonist of B-raf V600R.
10. The method of claim 1 , wherein the melanoma contains a BRAF V600E mutation, a BRAF wildtype, a KRAS wildtype, or an activating KRAS mutation.
11. The method of claim 1 , wherein the treatment results in a sustained response in the individual after cessation of the treatment.
12. The method of claim 1 , wherein the melanoma is metastatic.
13. The method of claim 1 , wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1, PD-L1 to B7-1, or PD-L1 to both PD-1 and B7-1.
14. The method of claim 1 , wherein the anti-PD-L1 antibody is a monoclonal antibody.
15. The method of claim 1 , wherein the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab, Fab′-SH, Fv, scFv, and F(ab′) 2 fragments.
16. The method of claim 1 , wherein the anti-PD-L1 antibody is a humanized antibody.
17. The method of claim 1 , wherein the PD-L1 binding antagonist is YW243.55.S70 or atezolizumab.
18. 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.
19. The method of claim 1 , wherein the MEK inhibitor is administered continuously.
20. The method of claim 1 , wherein the MEK inhibitor is administered intermittently.
21. The method of claim 1 , wherein the MEK inhibitor is administered before the PD-L1 binding antagonist.
22. The method of claim 1 , wherein the MEK inhibitor is administered simultaneously with the PD-L1 binding antagonist.
23. The method of claim 1 , wherein the MEK inhibitor is administered after the PD-L1binding antagonist.
24. The method of claim 1 , wherein the PD-L1 binding antagonist and/or the MEK inhibitor is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.