Combination therapies comprising SHP2 inhibitors and PD-1 inhibitors

1. A method of treating cancer in a patient in need thereof, said method comprising administering to the patient a combination comprising a therapeutically effective amount of a compound having the structure of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof:

and a PD-1 inhibitor.

2. The method of claim 1 , wherein said compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof, is administered to said patient in need from about 5 mg/kg to about 25 mg/kg.

3. The method of claim 1 , wherein said compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof is administered to said patient in need at about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, or about 25 mg/kg.

4. The method claim 1 , wherein said PD-1 inhibitor is a small molecule compound, a nucleic acid, a peptide, a protein, an antibody, a peptibody, a diabody, a minibody, a single-chain variable fragment (ScFv), or a variant thereof.

5. The method of claim 4 , wherein said PD-1 inhibitor is a PD-1 inhibitor antibody.

6. The method of claim 5 , wherein said PD-1 inhibitor antibody is nivolumab, pembrolizumab, pidilizumab, REGN2810 (SAR-439684), PDR 001, SHR-1210, or MEDI0680.

7. The method of claim 1 , wherein said method comprises administering said compound or Formula Ia, or a pharmaceutically acceptable salt or solvate thereof and said PD-1 inhibitor simultaneously or sequentially.

8. The method of claim 1 , wherein said cancer is squamous cell carcinoma, nonsquamous cell carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, head and neck cancer, urothelial cancer, breast cancer, prostate cancer, glioblastoma, colorectal cancer, pancreatic cancer, lymphoma, leiomyosarcoma, liposarcoma, synovial sarcoma, or malignant peripheral sheath tumor (MPNST).

9. The method of claim 1 , wherein said patient is treatment naïve.

10. The method of claim 1 , wherein said method comprises administering said compound of Formula Ia, or a pharmaceutically acceptable salt of solvate thereof and said PD-1 inhibitor to said patient as a first line therapy.

11. The method of claim 1 , wherein said method comprises administering said compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof; and said PD-1 inhibitor to said patient following treatment with at least one anti-cancer therapy, wherein said anti-cancer therapy is chemotherapy, radiotherapy, surgery, targeted therapy, immunotherapy, or a combination thereof.

12. The method of claim 1 , wherein said method comprises administering said compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof; and said PD-1 inhibitor to said patient as a regimen.

13. The method of claim 1 , wherein said method comprises administering said compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof to said patient orally.

14. The method of claim 1 , wherein said method comprises administering said compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof to said patient daily; and administering said PD-1 inhibitor to said patient every two weeks.

15. The method of claim 1 , wherein said method of treating cancer inhibits metastasis of said cancer in said patient.

16. The method of claim 1 , wherein said method of treating cancer prolongs the time to disease progression of said cancer in said patient.

17. The method of claim 1 , wherein said method of treating cancer prolongs the survival of said patient.

18. The method of claim 1 , wherein said method of treating cancer increases progression-free survival of said patient.

19. The method of claim 1 , wherein said method of treating cancer reduces tumor or tumor burden in said patient.

20. A method of treating cancer in a patient in need thereof, said method comprising administering to the patient a combination comprising a therapeutically effective amount of a compound having the structure of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof:

and a PD-1 inhibitor, wherein the amounts of the compound of Formula Ia and PD-1 inhibitor administered to the patient cause an in vivo synergistic effect.

21. The method of claim 20 , wherein said compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof, is administered to said patient in need from about 5 mg/kg to about 25 mg/kg.

22. The method of claim 20 , wherein said compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof is administered to said patient in need at about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, or about 25 mg/kg.

23. The method claim 20 , wherein said PD-1 inhibitor is a small molecule compound, a nucleic acid, a peptide, a protein, an antibody, a peptibody, a diabody, a minibody, a single-chain variable fragment (ScFv), or a variant thereof.

24. The method of claim 23 , wherein said PD-1 inhibitor is a PD-1 inhibitor antibody.

25. The method of claim 24 , wherein said PD-1 inhibitor is nivolumab, pembrolizumab, pidilizumab, REGN2810 (SAR-439684), PDR 001, SHR-1210, or MEDI0680.

26. The method of claim 20 , wherein said cancer is squamous cell carcinoma, nonsquamous cell carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, head and neck cancer, urothelial cancer, breast cancer, prostate cancer, glioblastoma, colorectal cancer, pancreatic cancer, lymphoma, leiomyosarcoma, liposarcoma, synovial sarcoma, or malignant peripheral sheath tumor (MPNST).

27. The method of claim 20 , wherein said patient is treatment naïve.

28. The method of claim 20 , wherein said method comprises administering said compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof, and said PD-1 inhibitor to said patient as a regimen.

29. The method of claim 20 , wherein said method comprises administering said compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof, to said patient orally.

30. The method of claim 20 , wherein said method comprises administering said compound of Formula Ia, or a pharmaceutically acceptable salt or solvate thereof, to said patient daily, and administering said PD-1 inhibitor to said patient every two weeks.

31. The method of claim 20 , wherein said method of treating cancer inhibits metastasis of said cancer in said patient, prolongs the time to disease progression of said cancer in said patient, prolongs the survival of said patient, increases progression-free survival of said patient, or reduces tumor or tumor burden in said patient.