# US 11,439,645 B2 · Combination therapy including a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers

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- Number: US 11,439,645 B2
- Document ID: US11439645B2
- Status: Granted
- Kind: B2
- Application number: 16/687,563
- Filed: 2019-11-18
- Published: 2020-07-16
- Granted: 2022-09-13
- Earliest claimed: 2018-11-19
- Assignees: Amgen Inc.
- Applicants: Amgen Inc.
- Inventors: James Russell Lipford; Jude Robert Canon; Anne Y. Saiki; Karen Louise Rex
- Web page: https://patentgrep.com/patent/US11439645B2

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 35/00: Antineoplastic agents
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- C07K 16/2818: {against CD28 or CD152}
- 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 provides combination therapy that includes an KRASG12C inhibitor, such as or a pharmaceutically acceptable salt thereof, and one or more additional pharmaceutically active agents, particularly for the treatment of cancers. The invention also relates to pharmaceutical compositions that contain an KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers.

## Claims

### Claim 1

A method of treating cancer mediated by a KRAS G12C mutation in a patient, the method comprising administering to the patient a therapeutically effective amount of (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an AKT inhibitor, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendix cancer, endometrial cancer, esophageal cancer, gastric cancer, small intestine cancer, nasal cavity cancer, paranasal sinus cancer, bile duct cancer, skin cancer, or intraocular melanoma.

### Claim 2 (depends on 1)

The method of claim 1, wherein the AKT inhibitor is AZD5363.

### Claim 3 (depends on 1)

The method of claim 1, wherein the cancer is non-small cell lung cancer.

### Claim 4 (depends on 1)

The method of claim 1, wherein the cancer is pancreatic cancer.

### Claim 5 (depends on 1)

The method of claim 1, wherein the cancer is colorectal cancer.

### Claim 6 (depends on 2)

The method of claim 2, wherein the cancer is non-small cell lung cancer.

### Claim 7 (depends on 2)

The method of claim 2, wherein the cancer is pancreatic cancer.

### Claim 8 (depends on 2)

The method of claim 2, wherein the cancer is colorectal cancer.

### Claim 9 (depends on 1)

The method of claim 1, wherein (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and the AKT inhibitor are administered simultaneously.

### Claim 10 (depends on 1)

The method of claim 1, wherein (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and the AKT inhibitor are administered separately.

### Claim 11 (depends on 3)

The method of claim 3, wherein (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and the AKT inhibitor are administered simultaneously.

### Claim 12 (depends on 3)

The method of claim 3, wherein (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and the AKT inhibitor are administered separately.

### Claim 13 (depends on 4)

The method of claim 4, wherein (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and the AKT inhibitor are administered simultaneously.

### Claim 14 (depends on 4)

The method of claim 4, wherein (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and the AKT inhibitor are administered separately.

### Claim 15 (depends on 5)

The method of claim 5, wherein (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and the AKT inhibitor are administered simultaneously.

### Claim 16 (depends on 5)

The method of claim 5, wherein (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and the AKT inhibitor are administered separately.

### Claim 17 (depends on 2)

The method of claim 2, wherein (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and AZD5363 are administered simultaneously.

### Claim 18 (depends on 6)

The method of claim 6, wherein (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and AZD5363 are administered separately.

### Claim 19 (depends on 7)

The method of claim 7, wherein (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and AZD5363 are administered simultaneously.

### Claim 20 (depends on 7)

The method of claim 7, wherein (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and AZD5363 are administered separately.

### Claim 21 (depends on 8)

The method of claim 8, wherein (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and AZD5363 are administered simultaneously.

### Claim 22 (depends on 8)

The method of claim 8, wherein (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and AZD5363 are administered separately.

### Claim 23 (depends on 1)

The method of claim 1, wherein (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one is administered as a solid dosage form.

### Claim 24 (depends on 2)

The method of claim 2, wherein AZD5363 is administered as a solid dosage form.

### Claim 25 (depends on 23)

The method of claim 23, wherein the solid dosage form is a tablet.

### Claim 26 (depends on 24)

The method of claim 24, wherein the solid dosage form is a tablet.

### Claim 27 (depends on 25)

The method of claim 25, wherein the tablet is administered orally.

### Claim 28 (depends on 26)

The method of claim 26, wherein the tablet is administered orally.

### Claim 29 (depends on 2)

The method od claim 2, wherein (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and AZD5363 are administered separately.

### Claim 30 (depends on 6)

The method od claim 6, wherein (1M)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one and AZD5363 are administered simultaneously.