# US 12,215,160 B2 · Treatment of patients having c-met exon 14 skipping mutations

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- Number: US 12,215,160 B2
- Document ID: US12215160B2
- Status: Granted
- Kind: B2
- Application number: 17/174,386
- Filed: 2021-02-12
- Published: 2021-08-19
- Granted: 2025-02-04
- Earliest claimed: 2020-02-12
- Assignees: Janssen Biotech, Inc.
- Applicants: Janssen Biotech, Inc.
- Inventors: Roland Knoblauch; Sylvie Laquerre; Sheri Moores
- Web page: https://patentgrep.com/patent/US12215160B2

## CPC

- C07K 16/2863: {against receptors for growth factors, growth regulators}
- A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495})
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- G01N 33/5752: of the lungs
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- A61K 2039/55: {characterised by the host/recipient, e.g. newborn with maternal antibodies}
- C07K 2317/31: multispecific
- C07K 2317/41: Glycosylation, sialylation, or fucosylation
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/156: Polymorphic or mutational markers
- G01N 2333/71: for growth factors; for growth regulators
- G01N 2333/82: Translation products from oncogenes
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- 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)
- 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
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention relates to treatment of subjects having a cancer that is positive for c-Met exon 14 skipping mutations.

## Claims

### Claim 1

A method of treating a subject having a cancer that is positive for a c-Met exon 14 skipping mutation, the method comprising administering to the subject a combination therapy comprising:
a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody; and
a therapeutically effective amount of a compound of formula (I)
or a pharmaceutically acceptable solvate, hydrate, tautomer, or salt thereof, wherein the bispecific anti-EGFR/c-Met antibody comprises:
a first domain that binds EGFR, the first domain comprising a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6; and
a second domain that binds c-Met, the second domain comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 12.

### Claim 2 (depends on 1)

The method of claim 1, wherein the first domain that binds EGFR comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 14, and the second domain that binds c-Met comprises a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL comprising the amino acid sequence of SEQ ID NO: 16.

### Claim 3 (depends on 1)

The method of claim 1, wherein the bispecific anti-EGFR/c-Met antibody is an IgG1 isotype.

### Claim 4 (depends on 2)

The method of claim 2, wherein the first domain that binds EGFR comprises a heavy chain (HC1) comprising the amino acid sequence of SEQ ID NO: 17 and a light chain (LC1) comprising the amino acid sequence of SEQ ID NO: 18, and the second domain that binds c-Met comprises a heavy chain (HC2) comprising the amino acid sequence of SEQ ID NO: 19 and a light chain (LC2) comprising the amino acid sequence of SEQ ID NO: 20.

### Claim 5 (depends on 1)

The method of claim 1, wherein the bispecific anti-EGFR/c-Met antibody has a biantennary glycan structure with a fucose content of about 1% to about 15%.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound of formula (I) or the solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is 2-Fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl) imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide-hydrogen chloride-water (1/2/1).

### Claim 7 (depends on 1)

The method of claim 1, wherein the subject is relapsed or resistant to treatment with one or more prior anti-cancer therapies.

### Claim 8 (depends on 7)

The method of claim 7, wherein the one or more prior anti-cancer therapies comprise one or more chemotherapeutic agents, one or more checkpoint inhibitors, one or more targeted anti-cancer therapies, one or more kinase inhibitors, or any combination thereof.

### Claim 9 (depends on 7)

The method of claim 7, wherein the one or more prior anti-cancer therapies comprise carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, a PD-(L) 1 axis inhibitor, an inhibitor of EGFR, an inhibitor of c-Met, an inhibitor of HER2, an inhibitor of HER3, an inhibitor of HER4, an inhibitor of VEGFR, an inhibitor of AXL, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, sunitinib, or any combination thereof.

### Claim 10 (depends on 1)

The method of claim 1, wherein the subject is treatment naïve.

### Claim 11 (depends on 1)

The method of claim 1, wherein the cancer is positive for a CDK4 amplification, an EGFR amplification, a KRAS amplification, a MDM2 amplification, a TERT amplification, NF1 R2450*, RAD50 L597Vfs*5, MET c.3082+3A>G, EGFR, wild-type EGFR, an EGFR activating mutation, increased levels of circulating HGF, a c-MET amplification, a mutant KRAS, or any combination thereof.

### Claim 12 (depends on 11)

The method of claim 11, wherein the EGFR activating mutation comprises a L718Q, G719A, G719X (X being any amino acid), L861X (X being any amino acid), L858R, E746K, L747S, E749Q, A750P, A755V, V765M, C797S, L858P, or T790M substitution, deletion of E746-A750, deletion of R748-P753, insertion of Ala (A) between M766 and A767, insertion of Ser, Val, and Ala (SVA) between S768 and V769, insertion of Asn and Ser (NS) between P772 and H773, insertion of one or more amino acids between D761 and E762, A763 and Y764, Y764 and Y765, M766 and A767, A767 and V768, S768 and V769, V769 and D770, D770 and N771, N771 and P772, P772 and H773, H773 and V774, V774 and C775, one or more deletions in EGFR exon 20, one or more insertions in EGFR exon 20, or any combination thereof.

### Claim 13 (depends on 11)

The method of claim 11, wherein the mutant KRAS comprises a G12V, G12C, G12A, or G12D substitution, or any combination thereof.

### Claim 14 (depends on 1)

The method of claim 1, wherein the cancer is lung cancer, gastric cancer, colorectal cancer, brain cancer, cancer derived from epithelial cells, breast cancer, ovarian cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, head and neck cancer, pharynx cancer, cancer of the nose, pancreatic cancer, skin cancer, oral cancer, cancer of the tongue, esophageal cancer, vaginal cancer, cervical cancer, cancer of the spleen, testicular cancer, cancer of the thymus, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC), sporadic or hereditary papillary renal cell carcinoma (PRCC), or any combination thereof.

### Claim 15 (depends on 14)

The method of claim 14, wherein the lung cancer is non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), lung adenocarcinoma, pulmonary sarcomatoid carcinoma, or any combination thereof.

### Claim 16 (depends on 1)

The method of claim 1, comprising further administering one or more anti-cancer therapies to the subject.

### Claim 17 (depends on 16)

The method of claim 16, wherein the one or more anti-cancer therapies comprise a chemotherapy, radiation therapy, surgery, targeted anti-cancer therapy, kinase inhibitor, or any combination thereof.

### Claim 18 (depends on 17)

The method of claim 17, wherein the kinase inhibitor is an inhibitor of EGFR, an inhibitor of c-Met, an inhibitor of HER2, an inhibitor of HER3, an inhibitor of HER4, an inhibitor of VEGFR, or an inhibitor of AXL.

### Claim 19 (depends on 18)

The method of claim 18, wherein the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

### Claim 20 (depends on 1)

The method of claim 1, wherein the c-Met exon 14 skipping mutation is a de novo mutation.

### Claim 21 (depends on 1)

The method of claim 1, wherein the c-Met exon 14 skipping mutation is an acquired mutation.

### Claim 22 (depends on 1)

The method of claim 1, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 140 mg to about 1750 mg.

### Claim 23 (depends on 1)

The method of claim 1, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, or about 1400 mg.

### Claim 24 (depends on 22)

The method of claim 22, wherein the bispecific anti-EGFR/c-Met antibody is administered twice a week, once a week, once in two weeks, once in three weeks, or once in four weeks.

### Claim 25 (depends on 1)

The method of claim 1, wherein the pharmaceutically acceptable salt of formula (I) is the compound of formula (II):

### Claim 26

A method of treating a subject having a cancer that is positive for a c-Met exon 14 skipping mutation, the method comprising administering to the subject a combination therapy comprising:
a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody; and
and a therapeutically effective amount of the compound of formula (II)
wherein the bispecific anti-EGFR/c-Met antibody comprises:
a first domain that binds EGFR, the first domain comprising a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6; and
a second domain that binds c-Met, the second domain comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 12.

### Claim 27 (depends on 26)

The method of claim 26, wherein the first domain that binds EGFR comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 14, and the second domain that binds c-Met comprises a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL comprising the amino acid sequence of SEQ ID NO: 16.

### Claim 28 (depends on 27)

The method of claim 27, wherein the first domain that binds EGFR comprises a heavy chain (HC1) comprising the amino acid sequence of SEQ ID NO: 17 and a light chain (LC1) comprising the amino acid sequence of SEQ ID NO: 18, and the second domain that binds c-Met comprises a heavy chain (HC2) comprising the amino acid sequence of SEQ ID NO: 19 and a light chain (LC2) comprising the amino acid sequence of SEQ ID NO: 20.

### Claim 29 (depends on 26)

The method of claim 26, wherein the bispecific anti-EGFR/c-Met antibody is an IgG1 isotype.

### Claim 30 (depends on 26)

The method of claim 26, wherein the subject is relapsed or resistant to treatment with one or more prior anti-cancer therapies.

### Claim 31 (depends on 30)

The method of claim 30, wherein the one or more prior anti-cancer therapies comprise one or more chemotherapeutic agents, one or more checkpoint inhibitors, one or more targeted anti-cancer therapies, one or more kinase inhibitors, or any combination thereof.

### Claim 32 (depends on 30)

The method of claim 30, wherein the one or more prior anti-cancer therapies comprise carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, a PD-(L)1 axis inhibitor, an inhibitor of EGFR, an inhibitor of c-Met, an inhibitor of HER2, an inhibitor of HER3, an inhibitor of HER4, an inhibitor of VEGFR, an inhibitor of AXL, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, sunitinib, or any combination thereof.

### Claim 33 (depends on 26)

The method of claim 26, wherein the subject is treatment naïve.

### Claim 34 (depends on 26)

The method of claim 26, wherein the cancer is positive for a CDK4 amplification, an EGFR amplification, a KRAS amplification, a MDM2 amplification, a TERT amplification, NF1 R2450*, RAD50 L597Vfs*5, MET c.3082+3A>G, EGFR, wild-type EGFR, an EGFR activating mutation, increased levels of circulating HGF, a c-MET amplification, a mutant KRAS, or any combination thereof.

### Claim 35 (depends on 34)

The method of claim 34, wherein the EGFR activating mutation comprises a L718Q, G719A, G719X (X being any amino acid), L861X (X being any amino acid), L858R, E746K, L747S, E749Q, A750P, A755V, V765M, C797S, L858P, or T790M substitution, deletion of E746-A750, deletion of R748-P753, insertion of Ala (A) between M766 and A767, insertion of Ser, Val, and Ala (SVA) between S768 and V769, insertion of Asn and Ser (NS) between P772 and H773, insertion of one or more amino acids between D761 and E762, A763 and Y764, Y764 and Y765, M766 and A767, A767 and V768, S768 and V769, V769 and D770, D770 and N771, N771 and P772, P772 and H773, H773 and V774, V774 and C775, one or more deletions in EGFR exon 20, one or more insertions in EGFR exon 20, or any combination thereof.

### Claim 36 (depends on 34)

The method of claim 34, wherein the mutant KRAS comprises a G12V, G12C, G12A, or G12D substitution, or any combination thereof.

### Claim 37 (depends on 26)

The method of claim 26, wherein the cancer is lung cancer, gastric cancer, colorectal cancer, brain cancer, cancer derived from epithelial cells, breast cancer, ovarian cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, head and neck cancer, pharynx cancer, cancer of the nose, pancreatic cancer, skin cancer, oral cancer, cancer of the tongue, esophageal cancer, vaginal cancer, cervical cancer, cancer of the spleen, testicular cancer, cancer of the thymus, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC), sporadic or hereditary papillary renal cell carcinoma (PRCC), or any combination thereof.

### Claim 38 (depends on 37)

The method of claim 37, wherein the lung cancer is non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), lung adenocarcinoma, pulmonary sarcomatoid carcinoma, or any combination thereof.

### Claim 39 (depends on 26)

The method of claim 26, comprising further administering one or more anti-cancer therapies to the subject.

### Claim 40 (depends on 39)

The method of claim 39, wherein the one or more anti-cancer therapies comprise a chemotherapy, radiation therapy, surgery, targeted anti-cancer therapy, kinase inhibitor, or any combination thereof.

### Claim 41 (depends on 40)

The method of claim 40, wherein the kinase inhibitor is an inhibitor of EGFR, an inhibitor of c-Met, an inhibitor of HER2, an inhibitor of HER3, an inhibitor of HER4, an inhibitor of VEGFR, or an inhibitor of AXL.

### Claim 42 (depends on 41)

The method of claim 41, wherein the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

### Claim 43 (depends on 26)

The method of claim 26, wherein the c-Met exon 14 skipping mutation is a de novo mutation.

### Claim 44 (depends on 26)

The method of claim 26, wherein the c-Met exon 14 skipping mutation is an acquired mutation.

### Claim 45 (depends on 26)

The method of claim 26, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 140 mg to about 1750 mg.

### Claim 46 (depends on 45)

The method of claim 45, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, or about 1400 mg.

### Claim 47 (depends on 45)

The method of claim 45, wherein the bispecific anti-EGFR/c-Met antibody is administered twice a week, once a week, once in two weeks, once in three weeks, or once in four weeks.