# US 10,946,093 B2 · Methods of treating cancer using PD-1 axis binding antagonists and MEK inhibitors

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- Number: US 10,946,093 B2
- Document ID: US10946093B2
- Status: Granted
- Kind: B2
- Application number: 15/399,118
- Filed: 2017-01-05
- Published: 2017-04-27
- Granted: 2021-03-16
- Earliest claimed: 2014-07-15
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Melissa Junttila
- Web page: https://patentgrep.com/patent/US10946093B2

## CPC

- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 31/4523: containing further heterocyclic ring systems
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/2803: {against the immunoglobulin superfamily}
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/542: {oral/gastrointestinal}
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/72: Increased effector function due to an Fc-modification
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention describes combination treatment comprising a PD-1 axis binding antagonist and a MEK inhibitor and methods for use thereof, including methods of treating conditions where enhanced immunogenicity is desired such as increasing tumor immunogenicity for the treatment of cancer.

## Claims

### Claim 1

A method for treating or delaying progression of a melanoma that is resistant to a B-raf antagonist in an individual, the method comprising administering to the individual an effective amount of a PD-L1 binding antagonist and a MEK inhibitor, wherein:
the individual has been previously treated with the B-raf antagonist for melanoma and the melanoma is resistant to the B-raf antagonist,
the MEK inhibitor is GDC-0973 or a pharmaceutically acceptable salt or solvate thereof, and
the PD-L1 antagonist is an anti-PD-L1 antibody comprising a heavy chain comprising HVR-H1 sequence of SEQ ID NO: 15, HVR-H2 sequence of SEQ ID NO: 16, and HVR-H3 sequence of SEQ ID NO: 3; and a light chain comprising HVR-L1 sequence of SEQ ID NO: 17, HVR-L2 sequence of SEQ ID NO: 18, and HVR-L3 sequence of SEQ ID NO: 19.

### Claim 2 (depends on 1)

The method of claim 1, further comprising diagnosing the individual as having a melanoma that is resistant to the B-raf antagonist, wherein the diagnosing occurs prior to administering the effective amount of the PD-L1 binding antagonist and the MEK inhibitor.

### Claim 3 (depends on 1)

The method of claim 1, wherein the melanoma in the individual has progressed within 1 month, 6 months, 1 year, or 5 years after completing a B-raf antagonist-based therapy regimen.

### Claim 4 (depends on 1)

The method of claim 1, wherein the B-raf antagonist is a small molecule inhibitor.

### Claim 5 (depends on 4)

The method of claim 4, wherein the B-raf antagonist is dabrafenib, vemurafenib, GSK 2118436, RAF265, XL281, ARQ736, BAY73-4506, sorafenib, PLX4720, PLX-3603, GSK2118436, GDC-0879, or N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide.

### Claim 6 (depends on 4)

The method of claim 4, wherein the B-raf antagonist is a selective B-raf antagonist of B-raf V600.

### Claim 7 (depends on 6)

The method of claim 6, wherein the selective B-raf antagonist of B-raf V600 is a selective antagonist of B-raf V600E.

### Claim 8 (depends on 6)

The method of claim 6, wherein the selective B-raf antagonist of B-raf V600 is a selective antagonist of B-raf V600E, B-raf V600K, and/or V600D.

### Claim 9 (depends on 6)

The method of claim 6, wherein the selective B-raf antagonist of B-raf V600 is a selective antagonist of B-raf V600R.

### Claim 10 (depends on 1)

The method of claim 1, wherein the melanoma contains a BRAF V600E mutation, a BRAF wildtype, a KRAS wildtype, or an activating KRAS mutation.

### Claim 11 (depends on 1)

The method of claim 1, wherein the treatment results in a sustained response in the individual after cessation of the treatment.

### Claim 12 (depends on 1)

The method of claim 1, wherein the melanoma is metastatic.

### Claim 13 (depends on 1)

The method of claim 1, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1, PD-L1 to B7-1, or PD-L1 to both PD-1 and B7-1.

### Claim 14 (depends on 1)

The method of claim 1, wherein the anti-PD-L1 antibody is a monoclonal antibody.

### Claim 15 (depends on 1)

The method of claim 1, wherein the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab, Fab′-SH, Fv, scFv, and F(ab′)2 fragments.

### Claim 16 (depends on 1)

The method of claim 1, wherein the anti-PD-L1 antibody is a humanized antibody.

### Claim 17 (depends on 1)

The method of claim 1, wherein the PD-L1 binding antagonist is YW243.55.S70 or atezolizumab.

### Claim 18 (depends on 1)

The method of claim 1, wherein the anti-PD-L1 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 24 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 21.

### Claim 19 (depends on 1)

The method of claim 1, wherein the MEK inhibitor is administered continuously.

### Claim 20 (depends on 1)

The method of claim 1, wherein the MEK inhibitor is administered intermittently.

### Claim 21 (depends on 1)

The method of claim 1, wherein the MEK inhibitor is administered before the PD-L1 binding antagonist.

### Claim 22 (depends on 1)

The method of claim 1, wherein the MEK inhibitor is administered simultaneously with the PD-L1 binding antagonist.

### Claim 23 (depends on 1)

The method of claim 1, wherein the MEK inhibitor is administered after the PD-L1binding antagonist.

### Claim 24 (depends on 1)

The method of claim 1, wherein the PD-L1 binding antagonist and/or the MEK inhibitor is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.