Treatment of PD-L1-Negative Melanoma Using an Anti-PD-1 Antibody and an Anti-CTLA-4 Antibody

• US 20160340428A1
• Filed: 04/28/2016
• Published: 11/24/2016
• Est. Priority Date: 04/28/2015
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: YANG, Arvin
• Granted Patent: US 10,174,113 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2039/55 characterised by the host/recipient, e.g. newborn with maternal antibodies
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G01N 2333/70503 Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
• CPC Class Codes: G01N 33/5743 of skin, e.g. melanoma
• CPC Class Codes: G01N 33/577 involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies; monoclonal antibodies per se are classified with their corresponding antigens; G01N33/53 - G01N33/576 take precedence

Abstract

The invention provides a method of treating a melanoma comprising (i) identifying a patient having a PD-L1-negative melanoma and (ii) administering to the patient a combination of an anti-PD-1 antibody or an antigen-binding portion thereof and an anti-CTLA-4 antibody or an antigen-binding portion thereof. The methods of the invention can extend progression-free survival for over 8 months and/or reduces the tumor size at least about 10%, about 20%, about 30%, about 40%, or about 50% compared to the tumor size prior to the administration.

Claims

1. A method for treating a melanoma tumor in a subject in need thereof comprising:

identifying a patient having a PD-L1-negative melanoma tumor; and

(ii) administering to the patient;

(a) an anti-PD-1 antibody or an antigen-binding portion thereof that binds specifically to a human PD-1; and

(b) an anti-CTLA-4 antibody or an antigen-binding portion thereof that binds specifically to a human CTLA-4.

47. A kit for treating a patient afflicted with a melanoma tumor, the kit comprising:

(a) a dosage ranging from 0.1 to 10 mg/kg body weight of an anti-PD-1 antibody or an antigen-binding portion thereof;

(b) a dosage ranging from 0.1 to 10 mg/kg body weight of an anti-CTLA-4 antibody or an antigen-binding portion thereof; and

(c) instructions for using the anti-PD-1 antibody or the antigen-binding portion thereof and the anti-CTLA-4 antibody or the antigen-binding portion thereof in the method of claim 1.

2. A method for treating a melanoma tumor in a patient in need thereof comprising administering to the patient:

(a) an anti-PD-1 antibody or an antigen-binding portion thereof that binds specifically to a human PD-1; and

(b) an anti-CTLA-4 antibody or an antigen-binding portion thereof that binds specifically to a human CTLA-4,

wherein the patient is identified as having a PD-L1-negative melanoma tumor prior to the administration.

8. The method of claim 2, wherein the patient is characterized by (i) extended progression-free survival for over 8 months following the administration, (ii) tumor size reduction at least about 10% compared to the tumor size prior to the administration, or (iii) both (i) and (ii).

14. The method of claim 2 further comprising measuring a PD-L1 expression on the melanoma tumor prior to the administration.

16. The method of claim 14, wherein the measuring comprises providing a test tissue sample obtained from the patient, the test tissue sample comprising tumor cells and/or tumor-infiltrating inflammatory cells.

17. The method of claim 16, wherein the measuring further comprises assessing the proportion of cells in the test tissue sample that express PD-L1 on the cell surface.

18. The method of claim 17, wherein the test tissue sample is a formalin-fixed paraffin-embedded (FFPE) tissue sample, and wherein the presence of PD-L1 is determined using an automated IHC assay.

20. The method of claim 18, wherein the IHC assay is performed using an anti-PD-L1 monoclonal antibody that specifically binds to the PD-L1 and wherein the anti-PD-L1 monoclonal antibody is selected from the group consisting of 28-8, 28-1, 28-12, 29-8, 5H1, and any combination thereof.

21. The method of claim 2, wherein the PD-L1-negative melanoma tumor is characterized by having less than about 5% of tumor cells showing binding to the anti-PD-L1 antibody or an antigen-binding portion thereof.

22. The method of claim 2, wherein the anti-PD-1 antibody or antigen-binding portion thereof cross-competes with nivolumab for binding to human PD-1.

25. The method of claim 2, wherein the anti-PD-1 antibody is nivolumab.

27. The method of claim 2, wherein the anti-PD-1 antibody or antigen-binding portion thereof is administered at a dose ranging from 0.1 to 10.0 mg/kg body weight once every 2, 3 or 4 weeks.

28. The method of claim 27, wherein the anti-PD-1 antibody or antigen-binding portion thereof is administered at a dose of 1 or 3 mg/kg body weight once every 3 weeks.

29. The method of claim 2, wherein the anti-CTLA-4 antibody or antigen-binding portion thereof cross-competes with ipilimumab for binding to human CTLA-4.

32. The method of claim 2, wherein the anti-CTLA-4 antibody is ipilimumab.

34. The method of claim 2, wherein the anti-CTLA-4 antibody or antigen-binding portion thereof is administered at a dose ranging from 0.1 to 10.0 mg/kg body weight once every 2, 3 or 4 weeks.

36. The method of claim 34, wherein the anti-PD-1 antibody or an antigen-binding portion thereof is administered at a dose of 1 mg/kg body weight once every 3 weeks and the anti-CTLA-4 antibody or an antigen-binding portion thereof is administered at a dose of 3 mg/kg body weight once every 3 weeks.

46. The method of claim 2, further comprising administering an anti-cancer agent.

3-7. -7. (canceled)

9-12. -12. (canceled)

13. A method for selecting a patient suitable for an anti-PD-1 antibody and anti-CTLA-4 antibody combination therapy comprising:

identifying a patient having a PD-L1-negative melanoma tumor; and

(ii) instructing a healthcare provider to administer to the patient;

(a) an anti-PD-1 antibody or an antigen-binding portion thereof that binds specifically to a human PD-1; and

(b) an anti-CTLA-4 antibody or an antigen-binding portion thereof that binds specifically to a human CTLA-4.

15. (canceled)

19. (canceled)

23-24. -24. (canceled)

26. (canceled)

30-31. -31. (canceled)

33. (canceled)

35. (canceled)

37-45. -45. (canceled)