Combination therapies

Patent metadata

Field	Value
Publication number	US-11890285-B2
Application number	US-202017029654-A
Country	US
Kind code	B2
Filing date	Sep 23, 2020
Priority date	Sep 24, 2019
Publication date	Feb 6, 2024
Grant date	Feb 6, 2024

Abstract

The present invention relates to combination therapies for treating KRas G12C cancers. In particular, the present invention relates to methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a an agent that blocks Programmed Death-1 receptor (PD-1) and Programmed Death Ligand-1 (PD-L1) signaling and a KRAS G12C inhibitor of Formula (I), Formula I-A or Formula I-B, kits comprising the compositions and methods of use therefor.

First claim

What is claimed is:

1. A method of treating a KRas G12C-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a PD-1/PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab, and a compound of formula:

or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , wherein the PD-1/PD-L1 inhibitor is a PD-1 inhibitor.

3. The method of claim 2 , wherein the PD-1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, and tislelizumab.

4. The method of claim 3 , wherein the PD-1 inhibitor is nivolumab.

5. The method of claim 4 , wherein the therapeutically effective amount of nivolumab in the combination is about 240 mg administered every two weeks.

6. The method of claim 4 , wherein the therapeutically effective amount of nivolumab in the combination is about 480 mg administered every four weeks.

7. The method of claim 3 , wherein the PD-1 inhibitor is pembrolizumab.

8. The method of claim 7 , wherein the therapeutically effective amount of pembrolizumab in the combination is about 200 mg administered every three weeks.

9. The method of claim 7 , wherein the KRas G12C-associated cancer is non-small cell lung cancer (NSCLC).

10. The method of claim 3 , wherein the wherein the PD-1 inhibitor is cemiplimab.

11. The method of claim 10 , wherein the therapeutically effective amount of pembrolizumab in the combination is about 350 mg administered every three weeks.

12. The method of claim 3 , wherein the PD-1 inhibitor is tislelizumab.

13. The method of claim 12 , wherein the therapeutically effective amount of tislelizumab in the combination is about 200 mg administered every three weeks.

14. The method according to claim 1 , wherein the PD-1/PD-L1 inhibitor is a PD-L1 inhibitor.

15. The method of claim 14 , wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, and durvalumab.

16. The method of claim 15 , wherein the PD-L1 inhibitor is atezolizumab.

17. The method of claim 16 , wherein the therapeutically effective amount of atezolizumab in the combination is about 1200 mg administered every three weeks.

18. The method of claim 15 , wherein the PD-L1 inhibitor is avelumab.

19. The method of claim 18 , wherein the therapeutically effective amount of avelumab in the combination is about 10 mg/kg administered every two weeks or 800 mg every two weeks.

20. The method of claim 15 , wherein the PD-L1 inhibitor is durvalumab.

21. The method of claim 20 , wherein the therapeutically effective amount of durvalumab in the combination is about 10 mg/kg administered every two weeks.

22. The method according to claim 1 , wherein the PD-1/PD-L1 inhibitor and the compound of formula:

or a pharmaceutically acceptable salt thereof are administered on the same day.

23. The method according to claim 1 , wherein the PD-1/PD-L1 inhibitor and the compound of formula:

or a pharmaceutically acceptable salt thereof are administered on different days.

24. The method according to claim 1 , wherein the compound of formula:

or a pharmaceutically acceptable salt thereof is administered at a maximum tolerated dose.

25. The method according to claim 1 , wherein the PD-1/PD-L1 inhibitor and the compound of formula:

or a pharmaceutically acceptable salt thereof are each administered at a maximum tolerated dose.

26. The method of according to claim 1 , wherein the therapeutically effective amount of the combination of the PD-1/PD-L1 inhibitor and the compound of formula:

or a pharmaceutically acceptable salt thereof results in an increased duration of overall survival, an increased duration of progression free survival, an increase in tumor growth regression, an increase in tumor growth inhibition or an increased duration of stable disease in the subjects relative to treatment with only the compound of formula:

or a pharmaceutically acceptable salt thereof.

27. The method according to claim 1 , wherein the therapeutically effective amount of the combination of the PD-1/PD-L1 inhibitor and the compound of formula:

or a pharmaceutically acceptable salt thereof results in a durable complete response.

28. A pharmaceutical composition comprising a therapeutically effective amount of a PD-1/PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab and a compound of formula:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

29. The method according to claim 1 , wherein the method incudes a durable complete response in the subject having a KRas G12C-associated cancer.

30. A method of treating a KRas G12C-associated cancer in a subject in need thereof, wherein the KRas G12C-associated cancer is resistant to treatment with a PD-1/PD-L1 inhibitor, comprising administering to the subject a therapeutically effective amount of a combination of a PD-1/PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab or a pharmaceutical composition thereof, and a compound of formula:

or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

31. A method for treating a KRas G12C-associated cancer and determined to have previously developed resistance to treatment with a PD-1/PD-L1 inhibitor that include administering to the subject a therapeutically effective amount of a combination of a PD-1/PD-L1 inhibitor selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, tislelizumab, atezolizumab, avelumab, and durvalumab or a pharmaceutical composition thereof, and a compound of formula:

or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

32. A method for suppressing resistance to treatment with a PD-1/PD-L1 inhibitor in a subject having a KRas G12C-associated cancer that include administering to the su

Assignees

• Mirati Therapeutics Inc

Inventors

• Briere David
• Christensen James Gail
• Olson Peter

Classifications

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P35/04

  specific for metastasis · CPC title

• C07K16/2818

  against CD28 or CD152 · CPC title

• C07K16/2827

  against B7 molecules, e.g. CD80, CD86 · CPC title

• A61K39/39541 Primary

  against normal tissues, cells · CPC title