Combination of a PD-1 antagonist and a VEGFR inhibitor for treating cancer

Patent metadata

Field	Value
Publication number	US-10570202-B2
Application number	US-201515115730-A
Country	US
Kind code	B2
Filing date	Feb 3, 2015
Priority date	Feb 4, 2014
Publication date	Feb 25, 2020
Grant date	Feb 25, 2020

Abstract

The present disclosure describes combination therapies comprising an antagonist of Programmed Death 1 receptor (PD-1) and a VEGFR inhibitor, and the use of the combination therapies for the treatment of cancer, and in particular for treating cancers that express PD-L1.

First claim

The invention claimed is:

1. A method for treating a cancer in an individual comprising administering to the individual a combination therapy which comprises an antagonist of a Programmed Death 1 protein (PD-1) and a vascular endothelial growth factor receptor (VEGFR) inhibitor, wherein the PD-1 antagonist is an anti-PD-1 monoclonal antibody which comprises a heavy chain and a light chain, wherein the heavy and light chains comprise SEQ ID NO:21 and SEQ ID NO:22, respectively, and further wherein the VEGFR inhibitor is N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the individual is a human.

3. The method of claim 1 , wherein the cancer is a solid tumor.

4. The method of claim 1 , wherein the cancer is renal cell carcinoma.

5. The method of claim 1 , wherein the PD-1 antagonist is Pembrolizumab and the VEGFR inhibitor is axitinib.

6. A kit which comprises a first container, a second container and a package insert, wherein the first container comprises at least one dose of a medicament comprising an antagonist of a Programmed Death 1 protein (PD-1), the second container comprises at least one dose of a medicament comprising a vascular endothelial growth factor receptor (VEGFR) inhibitor, and the package insert comprises instructions for treating an individual for cancer using the medicaments, wherein the PD-1 antagonist is an anti-PD-1 monoclonal antibody which comprises a heavy chain and a light chain, wherein the heavy and light chains comprise SEQ ID NO:21 and SEQ ID NO:22, respectively, and further wherein the VEGFR inhibitor is N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide or a pharmaceutically acceptable salt thereof.

7. The kit of claim 6 , wherein the instructions state that the medicaments are intended for use in treating an individual having a cancer that tests positive for Program Death-Ligand 1 (PD-L1) expression by an immunohistochemical (IHC) assay.

8. The kit of claim 6 , wherein the individual is a human.

9. The kit of claim 6 , wherein the PD-1 antagonist is Pembrolizumab formulated as a liquid medicament and the VEGFR inhibitor is axitinib formulated as a 1 mg tablet or a 5 mg tablet.

10. The method of claim 1 , wherein the cancer is bladder cancer, breast cancer, clear cell kidney cancer, head/neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell cancer, small-cell lung cancer (SCLC), triple negative breast cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL).

11. The method of claim 10 , wherein the cancer is advanced renal cell carcinoma.

12. A method for treating a human individual diagnosed with a cancer, comprising administering to the individual a combination therapy which comprises Pembrolizumab and axitinib, wherein (a) axitinib is administered at a dose of 5 mg twice daily (BID) and Pembrolizumab is administered at a dose selected from the group consisting of 1 mg/kg every three weeks (Q3W), 2 mg/kg Q3W and 200 mg Q3W or (b) axitinib is administered at a dose of 3 mg BID and Pembrolizumab is administered at a dose selected from the group consisting of 1 mg/kg Q3W, 2 mg/kg Q3W and 200 mg Q3W.

13. The kit of claim 6 , wherein the cancer is bladder cancer, breast cancer, clear cell kidney cancer, head/neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell cancer, small-cell lung cancer (SCLC), triple negative breast cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL).

14. The method of claim 12 , wherein said cancer is renal cell carcinoma.

15. The method of claim 12 , wherein said Pembrolizumab is provided at a dose of 200 mg Q3W.

16. The method for treating a human individual diagnosed with a cancer of claim 12 , comprising administering to the individual a combination therapy which comprises Pembrolizumab and axitinib, wherein axitinib is administered at a dose of 5 mg twice daily (BID) and Pembrolizumab is administered at a dose of 1 mg/kg every three weeks (Q3W).

17. The method for treating a human individual diagnosed with a cancer of claim 12 , comprising administering to the individual a combination therapy which comprises Pembrolizumab and axitinib, wherein axitinib is administered at a dose of 5 mg twice daily (BID) and Pembrolizumab is administered at a dose of 2 mg/kg Q3W.

18. The method for treating a human individual diagnosed with a cancer of claim 12 , comprising administering to the individual a combination therapy which comprises Pembrolizumab and axitinib, wherein axitinib is administered at a dose of 5 mg twice daily (BID) and Pembrolizumab is administered at a dose of 200 mg Q3W.

19. The method for treating a human individual diagnosed with a cancer of claim 12 , comprising administering to the individual a combination therapy which comprises Pembrolizumab and axitinib, wherein axitinib is administered at a dose of 3 mg twice daily (BID) and Pembrolizumab is administered at a dose of 1 mg/kg every three weeks (Q3W).

20. The method for treating a human individual diagnosed with a cancer of claim 12 , comprising administering to the individual a combination therapy which comprises Pembrolizumab and axitinib, wherein axitinib is administered at a dose of 3 mg twice daily (BID) and Pembrolizumab is administered at a dose of 2 mg/kg Q3W.

21. The method for treating a human individual diagnosed with a cancer of claim 12 , comprising administering to the individual a combination therapy which comprises Pembrolizumab and axitinib, wherein axitinib is administered at a dose of 3 mg twice daily (BID) and Pembrolizumab is administered at a dose of 200 mg Q3W.

22. The kit of claim 9 , wherein the PD-1 antagonist is Pembrolizumab formulated as a liquid medicament and the VEGFR inhibitor is axitinib formulated as a 1 mg tablet.

23. The kit of claim 9 , wherein the PD-1 antagonist is Pembrolizumab formulated as a liquid medicament and the VEGFR inhibitor is axitinib formulated as a 5 mg tablet.

24. A method for treating renal cell carcinoma in an individual comprising administering to the individual a combination therapy which comprises an antagonist of a Programmed Death 1 protein (PD-1) and a vascular endothelial growth factor receptor (VEGFR) inhibitor, wherein the PD-1 antagonist is Pembrolizumab, and further wherein the VEGFR inhibitor is axitinib.

25. A method for treating advanced renal cell carcinoma in an individual comprising administering to the individual a combination therapy which comprises an antagonist of a Programmed Death 1 protein (PD-1) and a vascular endothelial growth fact

Assignees

• Pfizer
• Merck Sharp & Dohme
• Merck Sharpe & Dohme Corp

Inventors

• Martini Jean-Francois Andre
• Tarazi Jamal Christo
• Perini Rodolfo Fleury
• Mauro David J

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P13/12

  of the kidneys · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title