Combination cancer treatment using a pd-1 antagonist, an ilt4 antagonist, and lenvatinib or salts thereof

Patent metadata

Field	Value
Publication number	US-2023058779-A1
Application number	US-202017790543-A
Country	US
Kind code	A1
Filing date	Dec 18, 2020
Priority date	Jan 2, 2020
Publication date	Feb 23, 2023
Grant date	—

Abstract

Provided herein are methods of treating cancer (e.g., RCC), which comprise administering to a human patient in need thereof: (a) a PD-1 antagonist; (b) an ILT4 antagonist; and (c) lenvatinib represented by Formula (I), or a pharmaceutically acceptable salt thereof. Also provided are kits containing such agents and uses of therapeutic combinations of such agents for the treatment of cancer.

First claim

1 . A method of treating cancer, comprising administering to a human patient in need thereof:
(a) a PD-1 antagonist; (b) an ILT4 antagonist; and (c) lenvatinib represented by Formula (I),

or a pharmaceutically acceptable salt thereof.

2 . The method of claim 1 , wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, non-small cell lung cancer, colorectal cancer, renal cell carcinoma (RCC), hepatocellular carcinoma, and melanoma.

3 . The method of claim 2 , wherein the cancer is advanced RCC or metastatic RCC.

4 - 12 . (canceled)

13 . The method of claim 1 , wherein the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen binding fragment thereof.

14 . The method of claim 1 , wherein the PD-1 antagonist is an anti-human PD-L1 monoclonal antibody or antigen binding fragment thereof, wherein the anti-human PD-L1 monoclonal antibody is not atezolizumab.

15 . The method of claim 13 , wherein the anti-human PD-1 monoclonal antibody is a humanized antibody or a human antibody.

16 . (canceled)

17 . The method of claim 1 , wherein the ILT4 antagonist is an anti-human ILT4 monoclonal antibody or antigen binding fragment thereof.

18 . The method of claim 17 , wherein the anti-human ILT4 monoclonal antibody is a humanized antibody or a human antibody.

19 . (canceled)

20 . The method of claim 13 , wherein the anti-human PD-1 monoclonal antibody is pembrolizumab.

21 . The method of claim 13 , wherein the anti-human PD-1 monoclonal antibody is nivolumab or cemiplimab.

22 . (canceled)

23 . The method of claim 17 , wherein the anti-human ILT4 monoclonal antibody comprises a V L CDR1, a V L CDR2, and a V L CDR3 comprising amino acid sequences as set forth in SEQ ID NOS:1, 2, and 3, respectively, and a V H CDR1, a V H CDR2, and a V H CDR3 comprising amino acid sequences as set forth in SEQ ID NOS:6, 7, and 8, respectively.

24 . The method of claim 17 , wherein the anti-human ILT4 monoclonal antibody comprises a V L region comprising an amino acid sequence as set forth in SEQ ID NO:4, and a V H region comprising an amino acid sequence as set forth in SEQ ID NO:9.

25 . The method of claim 17 , wherein the anti-human ILT4 monoclonal antibody comprises a light chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO:5 and a heavy chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO:10.

26 . The method of any one of claim 1 , wherein:
(a) the PD-1 antagonist is pembrolizumab; and (b) the ILT4 antagonist is a monoclonal antibody or antigen binding fragment thereof comprising a V L CDR1, a V L CDR2, and a V L CDR3 comprising amino acid sequences as set forth in SEQ ID NOS:1, 2, and 3, respectively, and a V H CDR1, a V H CDR2, and a V H CDR3 comprising amino acid sequences as set forth in SEQ ID NOS:6, 7, and 8, respectively.

27 . The of claims of claim 1 , wherein:
(a) the PD-1 antagonist is nivolumab or cemiplimab; and (b) the ILT4 antagonist is a monoclonal antibody or antigen binding fragment thereof comprising a V L CDR1, a V L CDR2, and a V L CDR3 comprising amino acid sequences as set forth in SEQ ID NOS:1, 2, and 3, respectively, and a V H CDR1, a V H CDR2, and a V H CDR3 comprising amino acid sequences as set forth in SEQ ID NOS:6, 7, and 8, respectively.

28 . (canceled)

29 . The method of claim 26 , wherein the human patient is administered 200 mg, 240 mg, or 2 mg/kg pembrolizumab, and wherein pembrolizumab is administered once every three weeks.

30 . The method of claim 26 , wherein the human patient is administered 400 mg pembrolizumab, and wherein pembrolizumab is administered once every six weeks.

31 . The method of claim 27 , wherein the human patient is administered 240 mg or 3 mg/kg nivolumab once every two weeks, 480 mg nivolumab once every four weeks, or 350 mg cemiplimab once every three weeks.

32 . (canceled)

33 . The method claim 29 , wherein the human patient is administered from about 100 mg to about 1600 mg of the anti-human ILT4 antibody, and wherein the anti-human ILT4 antibody is administered once every three weeks.

34 . (canceled)

35 . The method of claim 34 , wherein the human patient is administered 800 mg of the anti-human ILT4 antibody.

36 . The method of claim 29 , wherein the human patient is administered 8, 10, 12, 14, 18, 20, or 24 mg lenvatinib, and wherein lenvatinib is administered once daily.

37 . A method of treating RCC, comprising administering to a human patient in need thereof:
(a) 200 mg pembrolizumab; (b) 800 mg of an anti-human ILT4 monoclonal antibody or antigen binding fragment thereof that comprises a V L CDR1, a V L CDR2, and a V L CDR3 comprising amino acid sequences as set forth in SEQ ID NOS:1, 2, and 3, respectively, and a V H CDR1, a V H CDR2, and a V H CDR3 comprising amino acid sequences as set forth in SEQ ID NOS:6, 7, and 8, respectively; and (c) 20 mg lenvatinib.

38 . The method of claim 37 , wherein each of (a) and (b) is administered once every three weeks and wherein (c) is administered once daily.

39 . (canceled)

40 . The method of claim 39 , wherein (a) and (b) are administered on the same day, and wherein (a) and (b) are administered sequentially or concurrently.

41 . The method of claim 1 , wherein the pharmaceutically acceptable salt thereof is lenvatinib mesylate.

Assignees

• Merck Sharp & Dohme Llc
• Eisai R&D Man Co Ltd

Inventors

• Altura Rachel A
• Brandish Philip E
• Perini Rodolfo Fleury

Classifications

• C07K16/2803

  against the immunoglobulin superfamily · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• A61K45/06 Primary

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

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title