Treatment of patients with c-MET exon 14 skipping mutations

Abstract

The present invention relates to the treatment of subjects with cancers that have c-Met exon 14 skipping mutations.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 62 / 975,406, filed February 12, 2020. The disclosure of the foregoing application is incorporated herein by reference in its entirety.

[0002] (Reference to electronically submitted sequence listing) This application contains a Sequence Listing that has been submitted electronically via EFS-Web as a Sequence Listing in ASCII format having a size of 19 kb, with filename "JBI6242USNP1SEQLIST.TXT" and a creation date of January 19, 2021. The Sequence Listing submitted via EFS-Web is a part of the present specification and is incorporated herein by reference in its entirety.

[0003] FIELD OF THE INVENTION The present invention relates to the treatment of subjects with c-Met exon 14 skipping mutations.

[0004] (background) The individual roles of both EGFR and c-Met in cancer are well established, making these targets attractive for combination therapy. Both receptors signal through the same survival and anti-apoptotic pathways (ERK and AKT), and thus inhibiting the pair together may limit the potential activation of compensatory pathways, thereby improving overall efficacy.

[0005] Mutations in c-Met are associated with many cancers, including those of the kidney, stomach, nervous system, sarcoma, and lung. These cancers often involve mutations that result in higher activity or expression or deletion of negative regulatory sites. For example, deletion of exon 14 and a negative regulatory site at Tyr1003 are associated with a significant percentage of non-small cell lung cancers (NSCLC) and adenocarcinomas.

[0006] Relapse or resistance to existing therapeutics is common. Therefore, improved therapeutics or combinations of therapeutics and patient stratification biomarkers are needed to develop more effective treatments for diseases such as EGFR- or c-Met-positive cancers.

[0007] (overview) The present disclosure provides methods 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 having a cancer that is positive for the c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody.

[0008] The present disclosure also provides a method of treating a subject having cancer with a bispecific anti-EGFR / c-Met antibody, comprising: providing a biological sample from a subject; determining whether or not the sample contains a c-Met exon 14 skipping mutation; administering or providing for administration the bispecific anti-EGFR / c-Met antibody to a subject determined to have a c-Met exon 14 skipping mutation.

[0009] The present disclosure provides methods 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 having a cancer that is positive for the c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody.

[0010] In one embodiment, the disclosure provides a method of treating a subject having cancer with a bispecific anti-EGFR / c-Met antibody, comprising: a) providing a biological sample from a subject; b) determining the presence or absence of a c-Met exon 14 skipping mutation in the sample; c) administering or providing for administration the bispecific anti-EGFR / c-Met antibody to a subject determined to have a c-Met exon 14 skipping mutation.

[0011] In one embodiment, the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second domain that specifically binds to c-Met comprises HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12.

[0012] In one embodiment, the first domain that specifically binds to EGFR comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain that specifically binds to c-Met comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0013] In one embodiment, the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype.

[0014] In one embodiment, the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19, and a second light chain (LC2) of SEQ ID NO: 20.

[0015] In one embodiment, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 1% to about 15%.

[0016] In one embodiment, the subject is relapsed or refractory to treatment with one or more previous anti-cancer therapies.

[0017] In one embodiment, the one or more prior anti-cancer therapies include one or more chemotherapeutic agents, checkpoint inhibitors, targeted anti-cancer agents, or kinase inhibitors, or any combination thereof.

[0018] In one embodiment, the one or more prior anticancer therapies comprise carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, PD-(L)1 axis inhibitors, inhibitors of EGFR, inhibitors of c-Met, inhibitors of HER2, inhibitors of HER3, inhibitors of HER4, inhibitors of VEGFR, inhibitors of AXL, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib, or any combination thereof.

[0019] In one embodiment, the subject is treatment naive.

[0020] In one embodiment, the cancer positive for c-Met exon 14 skipping mutation is CDK4 amplified, EGFR amplified, KRAS amplified, MDM2 amplified, TERT amplified, NF1 R2450 amplified, * ;RAD50 L597Vfs * 5, positive for MET c.3082+3A>G, EGFR, wild-type EGFR, EGFR activating mutations, elevated circulating HGF levels, c-MET amplification, or mutant KRAS, or any combination thereof;

[0021] In one embodiment, the EGFR activating mutation is a substitution of L718Q, G719A, G719X (where X is any amino acid), L861X (where X is any amino acid), L858R, E746K, L747S, E749Q, A750P, A755V, V765M, C797S, L858P, or T790M, a deletion of E746 to A750, a deletion of R748 to P753, an insertion of Ala (A) between M766 and A767, an insertion of Ser, Val, and Ala (SVA) between S768 and V769, a deletion of P770M, or a substitution of L770M. insertion of Asn and Ser (NS) between exon 2 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, or one or more insertions in EGFR exon 20, or any combination thereof.

[0022] In one embodiment, the mutant KRAS comprises a G12V, G12C, G12A, or G12D substitution, or any combination thereof.

[0023] In one embodiment, the cancer is lung cancer, gastric cancer, colorectal cancer, brain cancer, cancer of epithelial cells, breast cancer, ovarian cancer, colorectal cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, head and neck cancer, pharyngeal cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, esophageal cancer, vaginal cancer, cervical cancer, spleen cancer, testicular cancer, stomach cancer, cancer of the thymus, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC), or sporadic or hereditary papillary renal cell carcinoma (PRCC), or any combination thereof.

[0024] In one embodiment, the lung cancer is non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), or lung adenocarcinoma, lung sarcomatoid carcinoma, or any combination thereof.

[0025] In one embodiment, the method comprises further administering to the subject one or more anti-cancer therapies.

[0026] In one embodiment, the one or more anti-cancer therapies comprise chemotherapy, radiation therapy, surgery, a targeted anti-cancer therapy, or a kinase inhibitor, or any combination thereof.

[0027] In one embodiment, 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.

[0028] In one embodiment, the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

[0029] In one embodiment, the c-Met exon 14 skipping mutation is a de novo mutation.

[0030] In one embodiment, the c-Met exon 14 skipping mutation is an acquired mutation.

[0031] In one embodiment, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 140 mg to about 1750 mg.

[0032] In one embodiment, 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, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, or 1400 mg.

[0033] In one embodiment, the bispecific anti-EGFR / c-Met antibody is administered twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks.

[0034] An embodiment of the present disclosure is a method of treating a subject having cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject a combination therapy, the 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 (II):

[0035] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.

[0036] In one embodiment, the bispecific anti-EGFR / c-Met antibody comprises a first domain that binds to EGFR, comprising heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and a second domain that binds to c-Met, comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12.

[0037] In one embodiment, the first domain that binds to EGFR comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain that binds to c-Met comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0038] In one embodiment, the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype.

[0039] In one embodiment, the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19, and a second light chain (LC2) of SEQ ID NO: 20.

[0040] In one embodiment, the bispecific anti-EGFR / c-Met antibody has a biantennary glycan structure with a fucose content of about 1% to about 15%.

[0041] In one embodiment, the compound of Formula (II), or a 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).

[0042] In one embodiment, the subject is relapsed or refractory to treatment with one or more previous anti-cancer therapies.

[0043] In one embodiment, the one or more prior anti-cancer therapies include one or more chemotherapeutic agents, checkpoint inhibitors, targeted anti-cancer agents, or kinase inhibitors, or any combination thereof.

[0044] In one embodiment, the one or more prior anticancer therapies comprise carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, PD-(L)1 axis inhibitors, inhibitors of EGFR, inhibitors of c-Met, inhibitors of HER2, inhibitors of HER3, inhibitors of HER4, inhibitors of VEGFR, inhibitors of AXL, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib, or any combination thereof.

[0045] In one embodiment, the subject is treatment naive.

[0046] In one embodiment, the cancer positive for c-Met exon 14 skipping mutation is CDK4 amplified, EGFR amplified, KRAS amplified, MDM2 amplified, TERT amplified, NF1 R2450 amplified, * ;RAD50 L597Vfs * 5, positive for MET c.3082+3A>G, EGFR, wild-type EGFR, EGFR activating mutations, elevated circulating HGF levels, c-MET amplification, or mutant KRAS, or any combination thereof;

[0047] In one embodiment, the EGFR activating mutation is a substitution of L718Q, G719A, G719X (where X is any amino acid), L861X (where X is any amino acid), L858R, E746K, L747S, E749Q, A750P, A755V, V765M, C797S, L858P, or T790M, a deletion of E746 to A750, a deletion of R748 to P753, an insertion of Ala (A) between M766 and A767, an insertion of Ser, Val, and Ala (SVA) between S768 and V769, a deletion of P770M, or a substitution of L770M. insertion of Asn and Ser (NS) between exon 2 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, or one or more insertions in EGFR exon 20, or any combination thereof.

[0048] In one embodiment, the mutant KRAS comprises a G12V, G12C, G12A, or G12D substitution, or any combination thereof.

[0049] In one embodiment, the cancer is lung cancer, gastric cancer, colorectal cancer, brain cancer, cancer of epithelial cells, breast cancer, ovarian cancer, colorectal cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, head and neck cancer, pharyngeal cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, esophageal cancer, vaginal cancer, cervical cancer, spleen cancer, testicular cancer, stomach cancer, cancer of the thymus, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC), or sporadic or hereditary papillary renal cell carcinoma (PRCC), or any combination thereof.

[0050] In one embodiment, the lung cancer is non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), or lung adenocarcinoma, lung sarcomatoid carcinoma, or any combination thereof.

[0051] In one embodiment, the method comprises further administering to the subject one or more anti-cancer therapies.

[0052] In one embodiment, the one or more anti-cancer therapies comprise chemotherapy, radiation therapy, surgery, a targeted anti-cancer therapy, or a kinase inhibitor, or any combination thereof.

[0053] In one embodiment, 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.

[0054] In one embodiment, the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

[0055] In one embodiment, the c-Met exon 14 skipping mutation is a de novo mutation.

[0056] In one embodiment, the c-Met exon 14 skipping mutation is an acquired mutation.

[0057] In one embodiment, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 140 mg to about 1750 mg.

[0058] In one embodiment, 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, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, or 1400 mg.

[0059] In one embodiment, the bispecific anti-EGFR / c-Met antibody is administered twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks. [Brief explanation of the drawings]

[0060] [Figure 1] Efficacy of an EGFR / c-Met antibody (JNJ-372) in a tumor model harboring a c-Met exon 14 skipping mutation. Tumor shrinkage was evident in mice treated with JNJ-372, whereas tumors expanded in animals treated with erlotinib or cetuximab. [Figure 2] CT scans are shown at baseline (top panel), 6 weeks of treatment (middle panel), and 12 weeks of treatment (bottom panel) with 1050 mg of JNJ-372. Tumor size is indicated in each panel. [Figure 3A] The mean tumor volume (Figure 3A) and mean body weight (Figure 3B) in mice bearing tumors harboring c-Met exon 14 skipping mutations and treated with JNJ-61186372 (JNJ-372), capmatinib, or isotype control (LU2503) are shown. Arrows indicate the end of individual animals due to tumor size, and vertical dashed lines represent the end of treatment. [Figure 3B] The mean tumor volume (Figure 3A) and mean body weight (Figure 3B) in mice bearing tumors harboring c-Met exon 14 skipping mutations and treated with JNJ-61186372 (JNJ-372), capmatinib, or isotype control (LU2503) are shown. Arrows indicate the end of individual animals due to tumor size, and vertical dashed lines represent the end of treatment. [Figure 4A] Figure 4A shows the mean tumor volume (Figure 4A) and mean body weight (Figure 4B) in mice bearing tumors harboring c-Met exon 14 skipping mutations and treated with JNJ-61186372 (JNJ-372), capmatinib, JNJ-61186372 and capmatinib, or isotype control (LU2503). Arrows indicate the end of individual animals due to tumor size, and vertical dashed lines indicate the end of treatment. [Figure 4B]Figure 4A shows the mean tumor volume (Figure 4A) and mean body weight (Figure 4B) in mice bearing tumors harboring c-Met exon 14 skipping mutations and treated with JNJ-61186372 (JNJ-372), capmatinib, JNJ-61186372 and capmatinib, or isotype control (LU2503). Arrows indicate the end of individual animals due to tumor size, and vertical dashed lines indicate the end of treatment. [Figure 5] Protein levels determined by Western blot are shown in LU2503 tumors grown in mice treated with JNJ-61186372 (JNJ-372), capmatinib, JNJ-61186372 and capmatinib, or isotype control. [Figure 6A] Protein levels determined by Western blot, quantified using Image J software, and normalized to β-tubulin are shown in LU2503 tumors grown in mice treated with JNJ-61186372 ("372"), capmatinib ("cap"), JNJ-61186372 and capmatinib ("372+cap"), or isotype control ("Iso Ctrl"). [Figure 6B] Protein levels determined by Western blot, quantified using Image J software, and normalized to β-tubulin are shown in LU2503 tumors grown in mice treated with JNJ-61186372 ("372"), capmatinib ("cap"), JNJ-61186372 and capmatinib ("372+cap"), or isotype control ("Iso Ctrl"). [Figure 7A] Protein levels determined by Western blot, quantified using Image J software, and normalized to β-tubulin are shown in LU2503 tumors grown in mice treated with JNJ-61186372 ("372"), capmatinib ("cap"), JNJ-61186372 and capmatinib ("372+cap"), or isotype control ("Iso Ctrl"). [Figure 7B]Protein levels determined by Western blot, quantified using Image J software, and normalized to β-tubulin are shown in LU2503 tumors grown in mice treated with JNJ-61186372 ("372"), capmatinib ("cap"), JNJ-61186372 and capmatinib ("372+cap"), or isotype control ("Iso Ctrl"). [Figure 7C] Protein levels determined by Western blot, quantified using Image J software, and normalized to β-tubulin are shown in LU2503 tumors grown in mice treated with JNJ-61186372 ("372"), capmatinib ("cap"), JNJ-61186372 and capmatinib ("372+cap"), or isotype control ("Iso Ctrl"). [Figure 8] 1 shows the mean tumor volume in mice bearing tumors with a c-Met exon 14 skipping mutation (DFCI-440) and treated with JNJ-61186372 (JNJ-372), capmatinib, JNJ-61186372 and capmatinib, or isotype control.

[0061] (Detailed description) definition All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if fully set forth.

[0062] It should be understood that the terms used herein are used for the purpose of describing particular embodiments only and are not intended to be limiting. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0063] Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present invention, exemplary materials and methods are described herein. In describing and claiming the present invention, the following terminology will be used.

[0064] When lists are presented, it is to be understood that each individual element of that list and every combination of that list is a separate embodiment, unless otherwise specified. For example, a list of embodiments presented as "A, B, or C" should be interpreted to include the embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0065] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a cell" includes a combination of two or more cells, and the like.

[0066] The conjunction "and / or" between multiple listed elements is understood to encompass both individual and combined alternatives. For example, when two elements are connected by "and / or," the first alternative refers to the first element being applicable without the second element. The second alternative refers to the second element being applicable without the first element. The third alternative refers to the first and second elements being applicable together. Any one of these alternatives is understood to be within the meaning and therefore meets the requirements of the term "and / or" as used herein. The simultaneous applicability of two or more of the alternatives is also understood to be within the meaning and therefore meets the requirements of the term "and / or."

[0067] The transitional phrases "comprising," "consisting essentially of," and "consisting" are intended to connote their generally accepted meanings in patent language, i.e., (i) "comprising" is synonymous with "comprising," "containing," or "characterized by" and is inclusive or open-ended, not excluding additional, unrecited elements or method steps; (ii) "consisting of" excludes any element, step, or ingredient not specified in the claim; and (iii) "consisting essentially of" limits the scope of the claim to the specified materials or steps and those that do not materially affect the "basic and novel characteristic(s)" of the claimed invention. Embodiments described with the phrase "comprising" (or its equivalents) also provide, as embodiments, those described independently with the terms "consisting of" and "consisting essentially of."

[0068] "Co-administration," "administration with," "administration in combination," "in combination with," and the like are intended to encompass administration of selected therapeutic agents or drugs to a single patient, and include therapeutic regimens in which the therapeutic agents or drugs are administered by the same or different routes of administration or at the same or different times.

[0069] "Isolated" refers to a homogenous population of molecules (e.g., synthetic polynucleotides, polypeptides, vectors, or viruses) that have been substantially separated and / or purified away from other components of the system in which they are produced, such as recombinant cells, as well as proteins that have been subjected to at least one purification or isolation step. "Isolated" refers to molecules that are substantially free of other cellular material and / or chemicals and includes molecules isolated to greater degrees of purity, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% purity.

[0070] "Treating," "treating," or "treatment" of a disease or disorder, such as cancer, refers to achieving one or more of the following: reducing the severity and / or duration of the disorder, inhibiting the worsening of symptoms characteristic of the disorder being treated, limiting or preventing the recurrence of the disorder in a subject who previously had the disorder, or limiting or preventing the recurrence of symptoms in a subject who was previously symptomatic for the disorder.

[0071] "Preventing," "preventing," "prevention," or "prophylaxis" of a disease or disorder means barring the disorder from occurring in a subject.

[0072] "Diagnosing" or "diagnosis" refers to a method of determining whether a subject is afflicted with a given disease or condition, or whether they may develop a given disease or condition in the future, or whether they are likely to respond to treatment for a previously diagnosed disease or condition, i.e., stratifying a patient population for likelihood of responding to treatment. Diagnosis is typically made by a physician based on a general guideline for the disease being diagnosed or other criteria that indicate a subject is likely to respond to a particular treatment.

[0073] "Responsive," "responsiveness," or "likely to respond" refers to any kind of improvement or positive response, whether detectable or undetectable, such as a reduction or amelioration of one or more symptoms, a decrease in the extent of the disease, a stabilized (i.e., not worsening) disease state, prevention of the spread of the disease, a delay or slowing of the progression of the disease, an improvement or palliation of the disease state, and remission (whether partial or total).

[0074] "Newly diagnosed" refers to a subject who has been diagnosed with an EGFR or c-Met expressing cancer but has not yet received treatment for multiple myeloma.

[0075] A "therapeutically effective amount" refers to an amount effective to obtain a desired therapeutic result at the dosage and for the period required. A therapeutically effective amount may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of a single therapeutic agent or combination of therapeutic agents to elicit a desired response in an individual. Exemplary indicators of an effective single therapeutic agent or combination of therapeutic agents include, for example, improved health of the patient.

[0076] "Refractory" refers to a disease that does not respond to treatment. A refractory disease can be resistant to treatment before or at the start of treatment, or a refractory disease can become resistant during treatment.

[0077] "Relapse" refers to the return of a disease or signs and symptoms of a disease after a period of improvement following prior treatment with a therapeutic agent.

[0078] A "subject" includes any human or non-human animal. "Non-human animals" include all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. The terms "subject" and "patient" are used interchangeably herein.

[0079] "About" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on the limitations of how the value is measured or determined, i.e., the measurement system. Unless expressly stated otherwise in the examples or elsewhere in the specification in the context of a particular assay, result, or embodiment, "about" means within one standard deviation or a range of up to 5%, whichever is greater, according to practice in the art.

[0080] "Cancer" refers to an abnormal growth of cells that tends to grow uncontrolled and, in some cases, metastasize (spread) to other areas of the patient's body.

[0081] "EGFR- or c-Met-expressing cancer" refers to a cancer that has detectable expression of EGFR or c-Met, or that has mutations or amplifications of EGFR or c-Met. EGFR or c-Met expression, amplification, and mutation status can be detected using known methods, such as sequencing, fluorescent in situ hybridization, immunohistochemistry, flow cytometry, or Western blotting, using tumor biopsies or blood samples. Expression can also be detected by sequencing circulating tumor DNA (ctDNA).

[0082] "Epidermal growth factor receptor" or "EGFR" refers to human EGFR (also known as HER1 or ErbB1) having the amino acid sequence set forth in GenBank Accession No. NP_005219 (Ullrich et al., Nature 309:418-425, 1984), as well as naturally occurring variants thereof.

[0083] As used herein, "hepatocyte growth factor receptor" or "c-Met" or "MET" refers to human c-Met having the amino acid sequence set forth in GenBank Accession No. NP_001120972 and naturally occurring variants thereof.

[0084] A "bispecific anti-EGFR / c-Met antibody" or "bispecific EGFR / c-Met antibody" refers to a bispecific antibody having a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met. The domains that specifically bind to EGFR and c-Met are typically VH / VL paired, and the bispecific anti-EGFR / c-Met antibody is monovalent with respect to binding to EGFR and c-Met.

[0085] "Specific binding" or "specifically binds" or "specific binding" or "binding" refers to an antibody binding to an antigen or an epitope within the antigen with higher affinity than other antigens. Typically, antibodies bind with an equilibrium dissociation constant (K D) is the K for binding to a nonspecific antigen (e.g., BSA, casein) D At least 100 times smaller than approximately 5 × 10 -8 M or less, for example, about 1 × 10 -9 M or less, approximately 1×10 -10 M or less, approximately 1×10 -11 M or less, approximately 1×10 -12 K below M D Antibodies bind to an antigen or an epitope within that antigen at a constant dissociation constant (dissociation constant). Dissociation constants can be measured using known protocols. However, antibodies that bind to an antigen or an epitope within that antigen may have cross-reactivity to other related antigens, e.g., the same antigen (homologues) from other species, such as humans or monkeys, e.g., Macaca fascicularis (cynomolgus monkeys) or Pan troglodytes (chimpanzees). Monospecific antibodies bind to one antigen or one epitope, while bispecific antibodies bind to two different antigens or two different epitopes.

[0086] The term "antibody" has a broad meaning and includes immunoglobulin molecules, including monoclonal antibodies, including murine, human, humanized, and chimeric monoclonal antibodies; antigen-binding fragments; multispecific antibodies, such as bispecific, trispecific, and tetraspecific antibodies; dimeric, tetrameric, or multimeric antibodies; single-chain antibodies; domain antibodies; and any other modified form of an immunoglobulin molecule containing an antigen-binding site of the required specificity. A "full-length antibody" is composed of two heavy chains (HC) and two light chains (LC), and multimers thereof (e.g., IgM), interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region (comprising domains CH1, hinge, CH2, and CH3). Each light chain is composed of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further divided into hypervariable regions, called complementarity-determining regions (CDRs), interspersed with framework regions (FR). Each VH and VL is composed of three CDR and four FR segments, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0087] "Complementarity-determining regions (CDRs)" are regions of an antibody that bind to an antigen. CDRs can be defined using various descriptions, such as Kabat (Wu et al. (1970) J Exp Med 132:211-50) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al. (1987) J Mol Biol 196:901-17), IMGT (Lefranc et al. (2003) Dev Comp Immunol 27:55-77), and AbM (Martin and Thornton (1996) J B Mol Biol 263:800-15). The correspondence between various descriptions and the numbering of variable regions has been described (see, e.g., Lefranc et al. (2003) Dev Comp Immunol 27:55-77; Honegger and Pluckthun, (2001) J Mol Biol 309:657-70; the International ImMunoGeneTics (IMGT) database; web resource, http: / / www_imgt_org). CDRs can be delineated using available programs such as abYsis by UCL Business PLC. As used herein, the terms "CDR," "HCDR1," "HCDR2," "HCDR3," "LCDR1," "LCDR2," and "LCDR3" include CDRs defined by any of the Kabat, Chothia, IMGT, or AbM methods described above, unless otherwise expressly stated herein.

[0088] Immunoglobulins can be assigned to five major classes, IgA, IgD, IgE, IgG, and IgM, depending on the amino acid sequence of the heavy chain constant domain. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chain of any vertebrate species can be assigned to one of two clearly distinct types, kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0089] "Antigen-binding fragment" refers to a portion of an immunoglobulin molecule that binds to an antigen. Antigen-binding fragments may be synthetic, enzymatically obtainable, or genetically engineered polypeptides, and include the minimum recognition unit consisting of amino acid residues reproducing the CDRs of an antibody, such as VH, VL, VH and VL, Fab, F(ab')2, Fd, and Fv fragments, domain antibodies (dAbs) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, and FR3-CDR3-FR4 portions, HCDR1, HCDR2, and / or HCDR3, and LCDR1, LCDR2, and / or LCDR3. The VH and VL domains can be linked to each other via synthetic linkers to form various types of single chain antibody designs; when the VH and VL domains are expressed as separate single chain antibody constructs, the VH / VL domains can pair intramolecularly or intermolecularly to form monovalent antigen-binding sites, such as single chain Fvs (scFvs) or diabodies, as described, for example, in WO 1998 / 44001, WO 1988 / 01649, WO 1994 / 13804, and WO 1992 / 01047.

[0090] "Monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibody molecules, i.e., individual antibodies comprising the population, which are identical except for possible, well-known alterations, such as removal of the C-terminal lysine from the antibody heavy chain, or post-translational modifications such as amino acid isomerization or deamidation, oxidation of methionine, or deamidation of asparagine or glutamine. Monoclonal antibodies typically bind to one antigenic epitope. Bispecific monoclonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibodies may be monospecific or multispecific, such as bispecific, and may be monovalent, bivalent, or multivalent.

[0091] "Recombinant" refers to DNA, antibodies, and other proteins that are prepared, expressed, produced, or isolated by recombinant means when segments from different sources are joined to produce the recombinant DNA, antibody, or protein.

[0092] "Bispecific" refers to an antibody that specifically binds to two different antigens or two different epitopes within the same antigen. Bispecific antibodies may be cross-reactive to other related antigens, e.g., the same antigen (homologues) from other species such as humans or monkeys, e.g., cynomolgus monkeys (Macaca cynomolgus, cyno) or chimpanzees, or may bind to an epitope shared between two or more different antigens.

[0093] "Antagonist" or "inhibitor" refers to a molecule that, when bound to a cellular protein, inhibits at least one response or activity induced by the protein's natural ligand. A molecule is an antagonist when at least one response or activity is inhibited by at least about 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more than the at least one response or activity inhibited in the absence of the antagonist (e.g., a negative control), or when the inhibition is statistically significant compared to the inhibition in the absence of the antagonist.

[0094] "PD-(L)1 axis inhibitor" refers to a molecule that inhibits PD-1 downstream signaling. The PD-(L)1 axis inhibitor may be a molecule that binds to PD-1, PD-L1, or PD-L2.

[0095] A "biological sample" refers to a collection of fluids, cells, or tissues present within a subject, as well as similar fluids, cells, or tissues isolated from a subject. Exemplary samples are biological fluids, such as blood, serum and serous fluid, plasma, lymph, urine, saliva, cyst fluid, tears, feces, sputum, mucosal secretions of secretory tissues and organs, vaginal secretions, ascites, fluids of the pleural, pericardial, peritoneal, abdominal cavities, and other body cavities, fluids collected by bronchial lavage, synovial fluid, liquid solutions in contact with a subject or biological source, such as cell and organ culture media, including cell or organ conditioned media, lavage fluids, tissue biopsies, tumor tissue samples, fine needle aspirations, surgically resected tissues, organ cultures, or cell cultures.

[0096] As used herein, "low fucose" or "low fucose content" refers to an antibody having a fucose content of about 1% to 15%.

[0097] As used herein, "normal fucose" or "normal fucose content" refers to an antibody having a fucose content of greater than about 50%, typically greater than 80% or greater than 85%.

[0098] A "c-Met exon 14 deletion" or a "c-Met exon 14 skipping mutation" refers to a mutation in the c-Met gene that removes at least a portion of exon 14 of c-Met, or a c-Met transcript that is spliced ​​to remove at least a portion of exon 14 of c-Met. The deleted portion may include the portion encoding the negative regulatory site Tyr1003 in the juxtamembrane region of the c-Met protein. The exon 14 region of the c-Met gene encompasses nucleotides 3284 to 3424 in the full-length nucleotide sequence of GenBank Accession No. NM_000245 or residues 964 to 1009 in the full-length c-Met amino acid sequence of GenBank Accession No. NP_000236. Various mutations at the DNA level can result in exon 14 skipping (see, for example, Kong-Beltran et al. (2006) Cancer Res. 66; Dhanasekharan et al. (2014) Nature Communication 10:1038; Awad et al., J Clin Oncology 34:721, 2016). Exon 14 of c-Met encodes 47 amino acids.

[0099] A "pharmaceutical composition" refers to a composition comprising an active ingredient, such as a bispecific EGFR / c-Met antibody, and one or more pharmaceutically acceptable carriers, i.e., for example, the EGFR TK inhibitor capmatinib, or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0100] A "pharmaceutically acceptable carrier" or "excipient" refers to an ingredient in a pharmaceutical composition, other than an active ingredient, that is not toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, stabilizers, or preservatives. Pharmaceutically acceptable carriers include, but are not limited to, diluents, disintegrants, or glidants; or diluents, disintegrants, wetting agents, glidants, or lubricants.

[0101] "Solvates" and "hydrates" are solvent addition forms that the compounds of the present invention can form, whereby the multi-component compound contains both a host molecule (e.g., a compound of Formula (I) or a salt thereof) and a guest molecule (water ("hydrate") or another solvent ("solvate")) incorporated into the structure.

[0102] "Tautomers" or "tautomeric forms" refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as protic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via rearrangement of some of the bonding electrons.

[0103] Methods of the present disclosure JNJ-61186372 (JNJ-372), also known as amivantamab, is an IgG1 anti-EGFR / c-Met bispecific antibody described in US Pat. No. 9,593,164.

[0104] The present disclosure is based, at least in part, on the discovery that JNJ-372 is effective in treating subjects with c-Met exon skipping mutations.

[0105] c-Met exon 14 skipping mutations affect splice acceptor or donor sites, resulting in in-frame exon 14 skipping, resulting in the deletion of the juxtamembrane domain of c-Met, known as the negative regulatory domain of c-Met (see, e.g., Descarentries et al., J Thoracic Oncology 13:1873-1883, 2018), rendering c-Met constitutively active. Over 160 mutations affecting c-Met exon 14 have been described (see, e.g., Cortot et al., J Natl Cancer Insti 109:djw262, 2017). c-Met exon 14 skipping mutations can be identified using next-generation sequencing (NGS) of patient samples. Exon 14 skipping mutations can arise de novo or as resistance mutations to previous treatments such as third generation TKIs. c-Met exon 14 encodes the amino acid sequence DLGSELVRYDARVHTPHLDRLVSARSVSPTTEMVSNESVDYRATFPE (SEQ ID NO: 21).

[0106] The present disclosure provides methods 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 having a cancer that is positive for the c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody.

[0107] Cancers in which c-Met exon 14 skipping mutations have been identified include lung cancer, gastric cancer, colorectal cancer, and brain cancers, such as non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), lung adenocarcinoma, and lung sarcomatoid carcinoma (PSC). Any other cancer with a c-Met exon skipping mutation may also be treated with the bispecific EGFR / c-Met antibodies of the present disclosure.

[0108] The present disclosure also provides a method of treating a subject having a lung cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject having a lung cancer that is positive for the c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody.

[0109] The present disclosure also provides a method of treating a subject with NSCLC that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with NSCLC that is positive for the c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody.

[0110] The present disclosure also provides a method of treating a subject with SCLC that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with SCLC that is positive for the c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody.

[0111] The present disclosure also provides a method of treating a subject having a lung adenocarcinoma that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject having a lung adenocarcinoma that is positive for the c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody.

[0112] The present disclosure also provides a method of treating a subject with PSC that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with PSC that is positive for the c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody.

[0113] The present disclosure also provides a method of treating a subject having gastric cancer that is positive for a c-Met exon 14 skipping mutation, the method comprising administering to the subject having gastric cancer that is positive for the c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody.

[0114] The present disclosure also provides a method of treating a subject having colorectal cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject having colorectal cancer that is positive for the c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody.

[0115] The present disclosure also provides a method of treating a subject having a brain cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject having a brain cancer that is positive for the c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody.

[0116] The present disclosure also provides a method of treating a subject having cancer with a bispecific anti-EGFR / c-Met antibody, comprising: providing a biological sample from the subject; determining whether or not the sample contains a c-Met exon 14 skipping mutation; administering or providing for administration the bispecific anti-EGFR / c-Met antibody to a subject determined to have a c-Met exon 14 skipping mutation.

[0117] In some embodiments, the biological sample is a blood sample.

[0118] In some embodiments, the biological sample is a tumor tissue biopsy.

[0119] In some embodiments, the bispecific anti-EGFR / c-Met antibody It comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, the first domain comprising heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second domain comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12.

[0120] In some embodiments, the first domain that specifically binds to EGFR comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain that specifically binds to c-Met comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0121] In some embodiments, the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype.

[0122] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19, and a second light chain (LC2) of SEQ ID NO: 20.

[0123] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure with a fucose content of about 1% to about 15%.

[0124] Antibodies with low fucose content can be produced using various methods that have been reported to successfully express relatively highly defucosylated antibodies with biantennary complex Fc oligosaccharides, such as: controlling the osmolarity of the culture medium (Konno et al., Cytotechnology 64(:249-65, 2012); applying the variant CHO line Lec13 as a host cell line (Shields et al., J Biol Chem 277:26733-26740, 2002); applying the variant CHO line EB66 as a host cell line (Olivier et al., MAbs;2(4), 2010; electronic publication ahead of print, PMID:20562582); applying the rat hybridoma cell line YB2 / 0 as a host cell line (Shinkawa et al., J Biol Chem 278:3466-3473, 2003), introduction of small interfering RNA specific for the α1,6-fucosyltransferase (FUT8) gene (Mori et al., Biotechnol Bioeng 88:901-908, 2004), or co-expression of β-1,4-N-acetylglucosaminyltransferase III and Golgi α-mannosidase II or kifunensin, a potent α-mannosidase I inhibitor (Ferrara et al., J Biol Chem 281:5032-5036, 2006; Ferrara et al., Biotechnol Bioeng 93:851-861, 2006; Xhou et al., Biotechnol Bioeng 99:652-65, 2008). In general, reducing the fucose content in antibody glycans enhances antibody-mediated cellular cytotoxicity (ADCC).

[0125] The present disclosure also provides a method of treating a subject having a cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject having a cancer that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, and the second domain comprises an HCDR1 of SEQ ID NO: 7, an HCDR2 of SEQ ID NO: 8, an HCDR3 of SEQ ID NO: 9, an LCDR1 of SEQ ID NO: 10, an LCDR2 of SEQ ID NO: 11, and an LCDR3 of SEQ ID NO: 12.

[0126] The present disclosure also provides a method of treating a subject with lung cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with lung cancer that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, and the second domain comprises an HCDR1 of SEQ ID NO: 7, an HCDR2 of SEQ ID NO: 8, an HCDR3 of SEQ ID NO: 9, an LCDR1 of SEQ ID NO: 10, an LCDR2 of SEQ ID NO: 11, and an LCDR3 of SEQ ID NO: 12.

[0127] The present disclosure also provides a method of treating a subject with NSCLC that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with NSCLC that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, and the second domain comprises an HCDR1 of SEQ ID NO: 7, an HCDR2 of SEQ ID NO: 8, an HCDR3 of SEQ ID NO: 9, an LCDR1 of SEQ ID NO: 10, an LCDR2 of SEQ ID NO: 11, and an LCDR3 of SEQ ID NO: 12.

[0128] The present disclosure also provides a method of treating a subject with SCLC that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with SCLC that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, and the second domain comprises an HCDR1 of SEQ ID NO: 7, an HCDR2 of SEQ ID NO: 8, an HCDR3 of SEQ ID NO: 9, an LCDR1 of SEQ ID NO: 10, an LCDR2 of SEQ ID NO: 11, and an LCDR3 of SEQ ID NO: 12.

[0129] The present disclosure also provides a method of treating a subject with lung adenocarcinoma that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with lung adenocarcinoma that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, and the second domain comprises an HCDR1 of SEQ ID NO: 7, an HCDR2 of SEQ ID NO: 8, an HCDR3 of SEQ ID NO: 9, an LCDR1 of SEQ ID NO: 10, an LCDR2 of SEQ ID NO: 11, and an LCDR3 of SEQ ID NO: 12.

[0130] The present disclosure also provides a method of treating a subject with PSC that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with PSC that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, and the second domain comprises an HCDR1 of SEQ ID NO: 7, an HCDR2 of SEQ ID NO: 8, an HCDR3 of SEQ ID NO: 9, an LCDR1 of SEQ ID NO: 10, an LCDR2 of SEQ ID NO: 11, and an LCDR3 of SEQ ID NO: 12.

[0131] The present disclosure also provides a method of treating a subject with gastric cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with gastric cancer that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, and the second domain comprises an HCDR1 of SEQ ID NO: 7, an HCDR2 of SEQ ID NO: 8, an HCDR3 of SEQ ID NO: 9, an LCDR1 of SEQ ID NO: 10, an LCDR2 of SEQ ID NO: 11, and an LCDR3 of SEQ ID NO: 12.

[0132] The present disclosure also provides a method of treating a subject with colorectal cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with colorectal cancer that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, and the second domain comprises an HCDR1 of SEQ ID NO: 7, an HCDR2 of SEQ ID NO: 8, an HCDR3 of SEQ ID NO: 9, an LCDR1 of SEQ ID NO: 10, an LCDR2 of SEQ ID NO: 11, and an LCDR3 of SEQ ID NO: 12.

[0133] The present disclosure also provides a method of treating a subject with brain cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with brain cancer that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, an HCDR3 of SEQ ID NO: 3, an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, and the second domain comprises an HCDR1 of SEQ ID NO: 7, an HCDR2 of SEQ ID NO: 8, an HCDR3 of SEQ ID NO: 9, an LCDR1 of SEQ ID NO: 10, an LCDR2 of SEQ ID NO: 11, and an LCDR3 of SEQ ID NO: 12.

[0134] The present disclosure provides a method of treating a subject having a cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject having a cancer that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0135] The present disclosure also provides a method of treating a subject with lung cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with lung cancer that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0136] The present disclosure also provides a method of treating a subject with NSCLC that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with NSCLC that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0137] The present disclosure also provides a method of treating a subject with SCLC that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with SCLC that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0138] The present disclosure also provides a method of treating a subject with lung adenocarcinoma that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with lung adenocarcinoma that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0139] The present disclosure also provides a method of treating a subject with PSC that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with PSC that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0140] The present disclosure also provides a method of treating a subject with gastric cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with gastric cancer that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0141] The present disclosure also provides a method of treating a subject with colorectal cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with colorectal cancer that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0142] The present disclosure also provides a method of treating a subject with a brain cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with a brain cancer that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0143] The present disclosure provides a method of treating a subject having a cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject having a cancer that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype and comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0144] The present disclosure also provides a method of treating a subject with lung cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with lung cancer that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype and comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0145] The present disclosure also provides a method of treating a subject with NSCLC that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with NSCLC that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype and comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0146] The present disclosure also provides a method of treating a subject with SCLC that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with SCLC that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype and comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0147] The present disclosure also provides a method of treating a subject with lung adenocarcinoma that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with lung adenocarcinoma that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype and comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0148] The present disclosure also provides a method of treating a subject with gastric cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with gastric cancer that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype and comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0149] The present disclosure also provides a method of treating a subject with colorectal cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with colorectal cancer that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype and comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0150] The present disclosure also provides a method of treating a subject with brain cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with brain cancer that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype and comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0151] In some embodiments, the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype. Some variation (e.g., known allotypes) exists within the IgG1 constant domain, with variation at positions 214, 356, 358, 422, 431, 435, or 436 (residue numbering according to EU numbering) (see, e.g., IMGT Web resource; IMGT Repertoire (IG and TR); Proteins and alleles; allotypes). The bispecific anti-EGFR / c-Met antibody may be of any IgG1 allotype, such as G1m17, G1m3, G1m1, G1m2, G1m27, or G1m28.

[0152] The present disclosure also provides a method of treating a subject having a cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject having a cancer that is positive for the c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises an HC1 of SEQ ID NO: 17, an LC1 of SEQ ID NO: 18, an HC2 of SEQ ID NO: 19, and an LC2 of SEQ ID NO: 20.

[0153] The present disclosure also provides a method of treating a subject having lung cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject having lung cancer that is positive for the c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises an HC1 of SEQ ID NO: 17, an LC1 of SEQ ID NO: 18, an HC2 of SEQ ID NO: 19, and an LC2 of SEQ ID NO: 20.

[0154] The present disclosure also provides a method of treating a subject with NSCLC that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with NSCLC that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises an HC1 of SEQ ID NO: 17, an LC1 of SEQ ID NO: 18, an HC2 of SEQ ID NO: 19, and an LC2 of SEQ ID NO: 20.

[0155] The present disclosure also provides a method of treating a subject with SCLC that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with SCLC that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises an HC1 of SEQ ID NO: 17, an LC1 of SEQ ID NO: 18, an HC2 of SEQ ID NO: 19, and an LC2 of SEQ ID NO: 20.

[0156] The present disclosure also provides a method of treating a subject with lung adenocarcinoma that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with lung adenocarcinoma that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises an HC1 of SEQ ID NO: 17, an LC1 of SEQ ID NO: 18, an HC2 of SEQ ID NO: 19, and an LC2 of SEQ ID NO: 20.

[0157] The present disclosure also provides a method of treating a subject with PSC that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with PSC that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises an HC1 of SEQ ID NO: 17, an LC1 of SEQ ID NO: 18, an HC2 of SEQ ID NO: 19, and an LC2 of SEQ ID NO: 20.

[0158] The present disclosure also provides a method of treating a subject with gastric cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with gastric cancer that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises an HC1 of SEQ ID NO: 17, an LC1 of SEQ ID NO: 18, an HC2 of SEQ ID NO: 19, and an LC2 of SEQ ID NO: 20.

[0159] The present disclosure also provides a method of treating a subject with colorectal cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject with colorectal cancer that is positive for the c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises an HC1 of SEQ ID NO: 17, an LC1 of SEQ ID NO: 18, an HC2 of SEQ ID NO: 19, and an LC2 of SEQ ID NO: 20.

[0160] The present disclosure also provides a method of treating a subject having a brain cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject having a brain cancer that is positive for the c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises an HC1 of SEQ ID NO: 17, an LC1 of SEQ ID NO: 18, an HC2 of SEQ ID NO: 19, and an LC2 of SEQ ID NO: 20.

[0161] In some embodiments, the subject is relapsed or refractory to treatment with one or more previous anti-cancer therapies.

[0162] In some embodiments, the subject has acquired a c-Met exon 14 skipping mutation as a result of treatment with one or more prior anti-cancer therapies.

[0163] In some embodiments, the subject has acquired a c-Met exon 14 skipping mutation as a result of treatment with a kinase inhibitor.

[0164] In some embodiments, the subject has acquired a c-Met exon 14 skipping mutation as a result of treatment with an EGFR kinase inhibitor.

[0165] In some embodiments, the subject has acquired a c-Met exon 14 skipping mutation as a result of treatment with a c-Met kinase inhibitor.

[0166] In some embodiments, the one or more prior anti-cancer therapies include one or more chemotherapeutic agents, checkpoint inhibitors, targeted anti-cancer agents, or kinase inhibitors, or any combination thereof.

[0167] In some embodiments, 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.

[0168] In some embodiments, the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

[0169] In some embodiments, the one or more prior anticancer therapies comprise carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, PD-(L)1 axis inhibitors, EGFR inhibitors, c-Met inhibitors, HER2 inhibitors, HER3 inhibitors, HER4 inhibitors, VEGFR inhibitors, AXL inhibitors, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib, or any combination thereof.

[0170] In some embodiments, the subject is resistant or has acquired resistance to an EGFR inhibitor. Exemplary EGFR inhibitors to which cancers may develop resistance include the anti-EGFR antibodies cetuximab (ERBITUX®), panchinumumab (VECTIBIX®), matuzumab, and nimotuzumab; the small molecule EGFR inhibitors erlotinib (TARCEVA®), gefitinib (IRESSA®), EKB-569 (pelitinib, an irreversible EGFR TKI); the pan-ErbB and other receptor tyrosine kinase inhibitors lapatinib (EGFR and HER2 inhibitor), pelitinib (EGFR and HER2 inhibitor), vandetanib (ZD6474, ZACTIMA™, an EGFR, VEGFR2, and RET TKI); PF00299804 (dacomitinib, an irreversible pan-ErbB TKI); and CI-1033 (an irreversible pan-erbB TKI). TKI), afatinib (BIBW2992, irreversible pan-ErbB TKI), AV-412 (dual EGFR and ErbB2 inhibitor), EXEL-7647 (EGFR, ErbB2, GEVGR, and EphB4 inhibitor), CO-1686 (irreversible mutant-selective EGFR TKI), AZD9291 (irreversible mutant-selective EGFR TKI), and HKI-272 (neratinib, irreversible EGFR / ErbB2 inhibitor).

[0171] Various qualitative and / or quantitative methods can be used to determine whether a subject is resistant to, has developed resistance to, or is likely to develop resistance to anticancer therapy. Symptoms that may be associated with resistance to anticancer therapy include a decline or plateau in the patient's health, an increase in tumor size, a halt or slowdown in tumor growth reduction, and / or the spread of cancerous cells from one location to other organs, tissues, or cells in the body. The re-establishment or worsening of various cancer-related symptoms, such as loss of appetite, cognitive impairment, depression, dyspnea, fatigue, hormone disruption, neutropenia, pain, peripheral neuropathy, and sexual dysfunction, may also be indicators that a subject has developed or is likely to develop resistance to anticancer therapy. Cancer-related symptoms may vary depending on the type of cancer. For example, symptoms associated with cervical cancer may include abnormal bleeding, abnormal heavy vaginal discharge, pelvic pain unrelated to the regular menstrual cycle, bladder pain or pain during urination, and bleeding during regular menstrual periods, sexual intercourse, vaginal douching, or pelvic examination. Symptoms related to lung cancer can include persistent cough, hemoptysis, shortness of breath, wheezing chest pain, loss of appetite, unintentional weight loss and fatigue.Symptoms related to liver cancer can include loss of appetite and weight, abdominal pain, especially in the upper right part of the abdomen, which can extend to the back and shoulder, nausea and vomiting, general weakness and fatigue, liver enlargement, abdominal swelling (ascites), and yellowing of the skin and whites of the eyes (jaundice).Those skilled in the art of oncology can easily identify the symptoms related to specific types of cancer.

[0172] Exemplary PD-(L)1 axis inhibitors are antibodies that bind to PD-1, such as nivolumab (OPDIVO®), pembrolimumab (KEYTRUDA®), sintilimab, cemiplimab (LIBTAYO®), toripolimab, tislelizumab, spartalizumab, camrelizumab, dostralimab, genolimuzumab, or cetrelimab, or antibodies that bind to PD-L1, e.g., PD-L1 antibodies are embafolimab, atezolizumab (TECENTRIQ®), durvalumab (IMFINZI®), and avelumab (BAVENCIO®).

[0173] Commercially available antibodies can be purchased through authorized distributors or pharmacies. Amino acid sequence structures of small molecules can be found in corporate USAN and / or INN deposits from the CAS registry.

[0174] In some embodiments, the subject is treatment naive.

[0175] In some embodiments, the c-Met exon 14 skipping mutation is a de novo mutation.

[0176] In some embodiments, the cancer positive for c-Met exon 14 skipping mutation is CDK4 amplified, EGFR amplified, KRAS amplified, MDM2 amplified, TERT amplified, NF1 R2450 amplified, * ;RAD50 L597Vfs * 5, positive for MET c.3082+3A>G, EGFR, wild-type EGFR, EGFR activating mutations, elevated circulating HGF levels, c-MET amplification, or mutant KRAS, or any combination thereof;

[0177] EGFR activating mutations that may be associated with cancer include point mutations, deletion mutations, insertion mutations, inversions, or gene amplifications that increase at least one biological activity of EGFR, such as increased tyrosine kinase activity, formation of receptor homodimers and heterodimers, or enhanced ligand binding. The mutations can be located in any part of the EGFR gene or regulatory regions associated with the EGFR gene, including mutations in exons 18, 19, 20, or 21 or mutations in the kinase domain. Other examples of EGFR activating mutations are known in the art (see, e.g., U.S. Patent Application Publication No. 2005 / 0272083). Information regarding EGFR and other ErbB receptors, including receptor homodimers and heterodimers, receptor ligands, autophosphorylation sites, and signaling molecules involved in ErbB-mediated signal transduction, is known in the art (see, e.g., Hynes and Lane, Nature Reviews Cancer 5:341-354, 2005).

[0178] In some embodiments, the EGFR activating mutation is a substitution of L718Q, G719A, G719X (where X is any amino acid), L861X (where X is any amino acid), L858R, E746K, L747S, E749Q, A750P, A755V, V765M, C797S, L858P, or T790M, a deletion of E746 to A750, a deletion of R748 to P753, an insertion of Ala (A) between M766 and A767, an insertion of Ser, Val, and Ala (SVA) between S768 and V769, a deletion of P769, or a substitution of P769. These include an insertion of Asn and Ser (NS) between positions 772 and H773, an insertion of one or more amino acids between positions 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, or one or more insertions in EGFR exon 20, or any combination thereof. Subjects with EGFR exon 20 mutations (insertion of one or more amino acids) are generally resistant to EGFR tyrosine kinase inhibitors (TKIs) (see, e.g., WO 2018 / 094225).

[0179] Exemplary c-Met activating mutations include point mutations, deletion mutations, insertion mutations, inversions, or gene amplifications that increase at least one biological activity of the c-Met protein, such as increased tyrosine kinase activity, receptor homodimer and heterodimer formation, and enhanced ligand binding. The mutations can be located in any part of the c-Met gene or in regulatory regions associated with the gene, such as mutations in the kinase domain of c-Met. Exemplary c-Met activating mutations are mutations at residue positions N375, V13, V923, R175, V136, L229, S323, R988, S1058 / T1010, and E168. Methods for detecting EGFR and c-Met mutations or gene amplifications are well known.

[0180] In some embodiments, the mutant KRAS comprises a G12V, G12C, G12A, or G12D substitution, or any combination thereof.

[0181] In some embodiments, cancers that are positive for c-Met exon 14 skipping mutations include lung cancer, gastric cancer, colorectal cancer, brain cancer, epithelial cell cancer-derived breast cancer, ovarian cancer, colorectal cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, head and neck cancer, pharyngeal cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, esophageal cancer, vaginal cancer, cervical cancer, splenic cancer, testicular cancer, stomach cancer, thymic cancer, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC), or sporadic or hereditary papillary renal cell carcinoma (PRCC), or any combination thereof. In some embodiments, cancers that are positive for c-Met exon 14 skipping mutations include lung cancer. In some embodiments, cancers that are positive for c-Met exon 14 skipping mutations include gastric cancer. In some embodiments, cancers that are positive for c-Met exon 14 skipping mutations include colorectal cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises brain cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises epithelial cell cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises breast cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises ovarian cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises colorectal cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises anal cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises prostate cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises kidney cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises bladder cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises head and neck cancer, hi some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises pharyngeal cancer.In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises nasal cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises pancreatic cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises skin cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises oral cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises tongue cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises esophageal cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises vaginal cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises cervical cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises splenic cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises testicular cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises gastric cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises thymic cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises colon cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises thyroid cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises liver cancer. In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises hepatocellular carcinoma (HCC). In some embodiments, the cancer positive for c-Met exon 14 skipping mutations comprises sporadic or hereditary papillary renal cell carcinoma (PRCC).

[0182] In some embodiments, the NSCLC comprises squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. In some embodiments, the cells of the NSCLC have an epithelial phenotype. In some embodiments, the NSCLC has acquired resistance to treatment with one or more EGFR inhibitors.

[0183] In NSCLC, specific mutations in the EGFR gene are associated with a high response rate (70–80%) to EGFR tyrosine kinase inhibitors (EGFR TKIs). A five-amino acid deletion within exon 19 or the point mutation L858R in EGFR is associated with sensitivity to EGFR TKIs (Nakata and Gotoh, Expert Opin Ther Targets 16:771–781, 2012). These mutations result in ligand-independent activation of EGFR kinase activity. Activating EGFR mutations occur in 10–30% of NSCLC patients and are significantly more common in East Asians, women, never-smokers, and patients with adenocarcinoma histology (Janne and Johnson Clin Cancer Res 12(14 Suppl):4416s–4420s, 2006). EGFR gene amplification also strongly correlates with response after EGFR TKI treatment (Cappuzzo et al., J Natl Cancer Inst 97:643-55, 2005). EGFR exon 20 insertions are associated with EGFR TKI resistance.

[0184] Although the majority of patients with EGFR-mutated NSCLC initially respond to EGFR TKI therapy, virtually all develop resistance, preventing a sustained response. 50–60% of patients acquire resistance due to a second-site point mutation (T790M) in the kinase domain of EGFR. Nearly 60% of all tumors resistant to EGFR tyrosine kinase inhibitors have increased c-Met expression, c-Met amplification, or increased expression of its only known ligand, HGF (Turke et al., Cancer Cell, 17:77–88, 2010).

[0185] In some embodiments, the subject is further administered one or more anti-cancer therapies.

[0186] In some embodiments, the one or more anti-cancer therapies comprise chemotherapy, radiation therapy, surgery, a targeted anti-cancer therapy, or a kinase inhibitor, or any combination thereof.

[0187] In some embodiments, 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. In some embodiments, the kinase inhibitor is an inhibitor of EGFR. In some embodiments, the kinase inhibitor is an inhibitor of c-Met. In some embodiments, the kinase inhibitor is an inhibitor of HER2. In some embodiments, the kinase inhibitor is an inhibitor of HER3. In some embodiments, the kinase inhibitor is an inhibitor of HER4. In some embodiments, the kinase inhibitor is an inhibitor of VEGFR. In some embodiments, the kinase inhibitor is an inhibitor of AXL.

[0188] In some embodiments, the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

[0189] In some embodiments, the kinase inhibitor is erlotinib. In some embodiments, the kinase inhibitor is gefitinib. In some embodiments, the kinase inhibitor is lapatinib. In some embodiments, the kinase inhibitor is vandetanib. In some embodiments, the kinase inhibitor is afatinib. In some embodiments, the kinase inhibitor is osimertinib. In some embodiments, the kinase inhibitor is lazertinib. In some embodiments, the kinase inhibitor is poziotinib. In some embodiments, the kinase inhibitor is criotinib. In some embodiments, the kinase inhibitor is cabozantinib. In some embodiments, the kinase inhibitor is capmatinib. In some embodiments, the kinase inhibitor is axitinib. In some embodiments, the kinase inhibitor is lenvatinib. In some embodiments, the kinase inhibitor is nintedanib. In some embodiments, the kinase inhibitor is regorafenib. In some embodiments, the kinase inhibitor is pazopanib. In some embodiments, the kinase inhibitor is sorafenib. In some embodiments, the kinase inhibitor is sunitinib.

[0190] Anti-cancer therapies that may be administered in combination with bispecific anti-EGFR / c-Met antibodies in the methods of the present disclosure include any one or more chemotherapeutic agents or other anti-cancer therapeutic agents known to those of skill in the art. Chemotherapeutic agents are chemical compounds useful in the treatment of cancer, including growth inhibitors or other cytotoxic agents, such as alkylating agents, antimetabolites, anti-microtubule inhibitors, topoisomerase inhibitors, receptor tyrosine kinase inhibitors, angiogenesis inhibitors, and the like. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamers, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine. Methylamelamine; nitrogen mustards, such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, phenesterine, prednimustine, trofosfamide, uracil mustard, etc.; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, etc.;Antibiotics such as aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomycin, nigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, etc.; antimetabolites such as methotrexate and 5-FU; folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate, etc.; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, etc.; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, etc.; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone, etc.; adrenocortical hormone synthesis inhibitors such as aminoglutethimide, mitotane, trilostane, etc.; folic acid supplements (folic acid replenishers, such as folinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; Bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; fenamet;Pirarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; a member of the taxoid or taxane family, such as paclitaxel (TAXOL®), docetaxel (TAX OTERE® and its analogs; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; Xeloda; ibandronate; CPT-11, topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoic acid; esperamicin; capecitabine;Inhibitors of receptor tyrosine kinase and / or angiogenesis include sorafenib (NEXAVAR®), sunitinib (SUTENT®), pazopanib (VOTRIENT™), toceranib (PALLADIA™), vandetanib (ZACTIMA™), cediranib (RECENTIN®), regorafenib (BAY73-4506), axitinib (AG013736), lestaurtinib (CEP-701), erlotinib (TARCEVA®), gefitinib (IRESSA™), afatinib (BIBW 2992), lapatinib (TYKERB®), neratinib (HKI-272), and the like, as well as pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing. Also included within this definition are antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens, including tamoxifen, raloxifene, aromatase-inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY 117018, onapristone, and toremifene (FARESTON®); and antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing. Other conventional cytotoxic compounds disclosed in Wiemann et al., 1985, Medical Oncology (Calabresi et al., eds.), Chapter 10, McMillan Publishing, are also applicable to the methods of the present invention.

[0191] Administration Bispecific anti-EGFR / c-Met antibodies can be administered in a pharmaceutically acceptable carrier. "Carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the antibody of the present invention is administered. Such vehicles can be liquids such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. For example, 0.4% saline and 0.3% glycine can be used to formulate bispecific anti-EGFR / c-Met antibodies. These solutions are sterile and generally free of particulate matter. They can be sterilized by conventional, well-known sterilization techniques (e.g., filtration). For parenteral administration, the carrier can include sterile water, and other excipients may be added to enhance solubility or preserve the integrity. Injectable suspensions or solutions can also be prepared using aqueous carriers with appropriate additives. Suitable vehicles and formulations (including other human proteins, e.g., human serum albumin) are described, for example, in Remington: The Science and Practice of Pharmacy, 21 st Edition, Troy, DB ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing pp 691-1092, see in particular pp. 958-989.

[0192] The mode of administration may be any suitable route that delivers the bispecific anti-EGFR-c-Met antibody to the host, for example, parenteral administration, such as intradermal, intramuscular, intraperitoneal, intravenous, or subcutaneous, pulmonary, transmucosal (oral, intranasal, intravaginal, rectal), using tablet, capsule, liquid, powder, gel, or particulate formulations, which may be contained in syringes, implantable devices, osmotic pumps, cartridges, micropumps, or other means well known in the art and recognized by those of skill in the art. Site-specific administration can be achieved, for example, by intratumoral, intraarticular, intrabronchial, intraabdominal, intracapsular, intrachondral, intrasinus, intracavity, intracerebellar, intraventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravascular, intravesical, intralesional, intravaginal, intrarectal, buccal, sublingual, intranasal, or transdermal delivery.

[0193] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 140 mg to about 1750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 140 mg to about 1750 mg.

[0194] In some embodiments, the bispecific anti-EGFR / c-Met antibody is about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1210 mg, about 1220 mg, about 1230 mg, about 1240 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, about 1290 mg, about 1300 mg, about 1310 mg, about 1320 mg, about 1330 mg, about 1340 mg, about 1350 mg, about 1360 mg, about 1370 mg, about 1380 mg, about 1390 mg, about 1400 mg, about 1410 mg, about 1420 mg, about 1430 mg, about 1440 mg, about 1450 mg, about 1460 mg, about 1470 mg, about 1480 mg, about 1490 mg, about 1500 mg,About 1510mg, about 1520mg, about 1530mg, about 1540mg, about 1550mg, about 1560mg, about 1570mg, about 1580mg, about 1590mg, about 1600mg, about 1610mg, 1620mg, about 1630mg , about 1640mg, about 1650mg, about 1660mg, about 1670mg, about 1680mg, about 1690mg, about 1700mg, about 1710mg, about 1720mg, about 1730mg, about 1740mg, about 1750mg, about 1760 mg, about 1770 mg, about 1780 mg, about 1790 mg, about 1800 mg, about 1810 mg, about 1820 mg, about 1830 mg, about 1840 mg, about 1850 mg, about 1860 mg, about 1870 mg, about 1880 mg, 1890 mg, about 1900 mg, about 1910 mg, about 1920 mg, about 1930 mg, about 1940 mg, about 1950 mg, about 1960 mg, about 1970 mg, about 1980 mg, about 1990 mg, or about 2000 mg.

[0195] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg, about 700 mg, about 1050 mg, or about 1400 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 700 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 750 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 800 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 850 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 900 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 950 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1000 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1050 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1100 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1150 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1200 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1250 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1300 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1350 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1400 mg.

[0196] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once a week. In some embodiments, about 1050 mg of the bispecific anti-EGFR / c-Met antibody is administered once a week. In some embodiments, about 1400 mg of the bispecific anti-EGFR / c-Met antibody is administered once a week.

[0197] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once every two weeks. In some embodiments, about 1050 mg of the bispecific anti-EGFR / c-Met antibody is administered once every two weeks. In some embodiments, about 1400 mg of the bispecific anti-EGFR / c-Met antibody is administered once every two weeks.

[0198] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered twice a week. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once a week. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once every two weeks. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once every three weeks. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once every four weeks.

[0199] In the case of combination therapy, one or more anti-cancer agents may be administered using the recommended doses and administration of the anti-cancer agents.

[0200] Generation of bispecific anti-EGFR / c-Met antibodies for use in the methods of the disclosure An exemplary bispecific anti-EGFR / c-Met antibody that can be used in the methods of the present disclosure is JNJ-372. JNJ-372 is characterized by the following amino acid sequence: EGFR binding arm >SEQ ID NO: 1 (HCDR1, EGFR binding arm) TYGMH >SEQ ID NO: 2 (HCDR2, EGFR binding arm) VIWDDGSYKYYGDSVKG >SEQ ID NO: 3 (HCDR3, EGFR binding arm) DGITMVRGVMKDYFDY >SEQ ID NO: 4 (LCDR1, EGFR binding arm) RASQDISSALV >SEQ ID NO: 5 (LCDR2, EGFR binding arm) DASSLES >SEQ ID NO: 6 (LCDR3, EGFR binding arm) QQFNSYPLT >SEQ ID NO: 7 (HCDR1, c-Met binding arm) SYGIS >SEQ ID NO: 8 (HCDR2, c-Met binding arm) WISAYNGYTNYAQKLQG >SEQ ID NO: 9 (HCDR3, c-Met binding arm) DLRGTNYFDY >SEQ ID NO: 10 (LCDR1, c-Met binding arm) RASQGISNWLA >SEQ ID NO: 11 (LCDR2, c-Met binding arm) AASSLLS >SEQ ID NO: 12 (LCDR3, c-Met binding arm) QQANSFPIT >SEQ ID NO: 13 (VH, EGFR binding arm) QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS >SEQ ID NO: 14 (VL, EGFR binding arm) AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK >SEQ ID NO: 15 (VH, c-Met binding arm) QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSS >SEQ ID NO: 16 (VL, c-Met binding arm) DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK >SEQ ID NO: 17 HC1 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFD YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK >SEQ ID NO: 18 LC1 AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC >SEQ ID NO: 19 HC2 QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK >SEQ ID NO: 20 LC2 DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0201] Other publicly available bispecific anti-EGFR / c-Met antibodies may be used in the methods of the disclosure, so long as they exhibit similar characteristics when compared to JNJ-372, as described in U.S. Patent No. 9,593,164. Bispecific anti-EGFR / c-Met antibodies that can be used in the methods of the disclosure can also be generated by combining publicly available EGFR-binding VH / VL domains and c-Met-binding VH / VL domains and testing the resulting bispecific antibody for its characteristics as described in U.S. Patent No. 9,593,164.

[0202] The bispecific anti-EGFR / c-Met antibodies used in the methods of the present disclosure can be generated using Fab arm exchange (or half molecule exchange) between two monospecific bivalent antibodies by introducing substitutions into the heavy chain CH3 interface of each half molecule to favor heterodimer formation of two antibody half molecules with different specificities, for example, in a cell-free environment in vitro or using coexpression. The Fab arm exchange reaction is the result of disulfide bond isomerization and dissociation-association of the CH3 domains. The heavy chain disulfide bonds in the hinge region of the parent monospecific antibodies are reduced. The resulting free cysteine ​​of one of the parent monospecific antibodies forms an intra-heavy chain disulfide bond with a cysteine ​​residue of the second parent monospecific antibody molecule, while the CH3 domain of the parent antibody is released and reformed by dissociation-association. The CH3 domain of the Fab arm may be engineered to favor heterodimer formation over homodimer formation. The resulting product is a bispecific antibody with two Fab arms or half molecules, each binding a different epitope, i.e., an epitope in EGFR and an epitope in c-Met. For example, bispecific antibodies of the present invention can be produced using the techniques described in WO 2011 / 131746. For IgG1 antibodies, the mutation F405L in one heavy chain and K409R in the other heavy chain can be used. For IgG2 antibodies, wild-type IgG2 and IgG2 antibodies with F405L and R409K substitutions can be used. For IgG4 antibodies, wild-type IgG4 and IgG4 antibodies with F405L and R409K substitutions can be used. To generate a bispecific antibody, a first monospecific bivalent antibody and a second monospecific bivalent antibody are engineered to have the aforementioned mutations in the Fc region, and the antibodies are incubated together under reducing conditions sufficient to allow cysteines in the hinge region to undergo disulfide bond isomerization, thereby generating the bispecific antibody by Fab arm exchange. Incubation conditions can optimally be returned to non-reducing conditions.Exemplary reducing agents that can be used are 2-mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine, and β-mercaptoethanol. For example, incubation at a temperature of at least 20°C, in the presence of at least 25 mM 2-MEA or at least 0.5 mM dithiothreitol, at a pH of 5-8, e.g., pH 7.0 or 7.4, for at least 90 minutes can be used.

[0203] Bispecific anti-EGFR / c-Met antibodies for use in the methods of the present disclosure can also be generated using designs such as knobs-in-holes (Genentech), CrossMAb (Roche) and electrostatically-matched (Chugai, Amgen, NovoNordisk, Oncomed), LUZ-Y (Genentech), Strand Exchange Engineered Domain body (SEEDbody) (EMD Serono), and Biclonic (Merus).

[0204] In the "knobs-in-holes" approach (see, e.g., WO 2006 / 028936), selected amino acids that form the interface of the CH3 domain of human IgG can be mutated at positions that affect CH3 domain interactions to promote heterodimer formation. Amino acids with small side chains (holes) are introduced into the heavy chain of an antibody that specifically binds to a first antigen, and amino acids with large side chains (knobs) are introduced into the heavy chain of an antibody that specifically binds to a second antigen. After co-expression of the two antibodies, heterodimers form as a result of the preferential interaction of heavy chains with "holes" and heavy chains with "knobs." Exemplary CH3 substitution pairs that form knobs and holes are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V (expressed as modified position in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain).

[0205] In addition to utilizing a "knobs-in-holes" approach to promote Fab arm exchange, CrossMAb technology utilizes CH1 / CL domain exchange in one of the half-arms to ensure correct light chain pairing in the resulting bispecific antibody (see, e.g., U.S. Pat. No. 8,242,247).

[0206] Other crossover strategies may be used to generate full-length bispecific antibodies of the invention by swapping variable or constant domains, or both, in one or both arms between the heavy and light chains of the bispecific antibody, or within the heavy chain, including, for example, VH-CH1 and VL-CL, VH and VL, CH3 and CL, and CH3 and CH1, as described in WO 2009 / 080254, WO 2009 / 080251, WO 2009 / 018386, and WO 2009 / 080252.

[0207] Other approaches, such as promoting heavy chain heterodimerization using electrostatic interactions by substituting positively charged residues on one CH3 surface and negatively charged residues on the second CH3 surface, may also be used, as described in U.S. Patent Application Publication Nos. 2010 / 0015133, 2009 / 0182127, 2010 / 028637, or 2011 / 0123532. In another approach, heterodimerization can be achieved by using the following substitutions: L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407V, as described in U.S. Patent Application Publication No. 2012 / 0149876 or U.S. Patent Application Publication No. 2013 / 0195849. A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W (expressed as modified position in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain).

[0208] SEEDbody technology may be used to generate bispecific antibodies of the invention. SEEDbodies have selected IgG residues in their constant domains substituted with IgA residues to promote heterodimerization, as described in U.S. Patent Application Publication No. 2007 / 0287170.

[0209] Mutations are typically made at the DNA level on molecules such as antibody constant domains, using standard methods.

[0210] An embodiment of the present disclosure is a method of treating a subject having cancer, 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):

[0211] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.

[0212] An embodiment of the disclosure is a method of treating a subject having an EGFR or c-Met expressing cancer, comprising administering to the subject a combination therapy comprising a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody and a therapeutically effective amount of a compound of Formula (I):

[0213] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.

[0214] An embodiment of the present disclosure provides a method for treating a patient suffering from atopic dermatitis, comprising administering to a patient 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):

[0215] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.

[0216] An embodiment of the present disclosure provides a method for treating a patient suffering from atopic dermatitis, comprising administering to a patient 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):

[0217] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.

[0218] An embodiment of the present disclosure provides a method for treating a patient suffering from atopic dermatitis, comprising administering to a patient 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):

[0219] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, for use in treating a subject having cancer harboring a c-Met exon 14 skipping mutation.

[0220] An embodiment of the present disclosure provides a method for treating a patient suffering from atopic dermatitis, comprising administering to a patient 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):

[0221] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer, particularly for treating cancer in a subject.

[0222] An embodiment of the present disclosure provides a method for treating a patient suffering from atopic dermatitis, comprising administering to a patient 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):

[0223] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer, particularly for treating cancer comprising a c-Met exon 14 skipping mutation in a subject.

[0224] An embodiment of the present disclosure provides a method for treating a patient suffering from atopic dermatitis, comprising administering to a patient 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):

[0225] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.

[0226] An embodiment of the present disclosure provides a method for treating a patient suffering from atopic dermatitis, comprising administering to a patient 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):

[0227] [ka] or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, as a combined preparation for simultaneous, separate or sequential use in the treatment of cancer, particularly in the treatment of cancer in a subject.

[0228] An embodiment of the present disclosure provides a method for treating a patient suffering from atopic dermatitis, comprising administering to a patient 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):

[0229] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer, particularly for treating cancer harboring a c-Met exon 14 skipping mutation in a subject.

[0230] An embodiment of the present disclosure provides for the treatment of cancer, particularly in the treatment of cancer in a subject, comprising administering to a subject a compound of formula (I), particularly a therapeutically effective amount of a compound of formula (I):

[0231] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.

[0232] Embodiments of the present disclosure provide for the treatment of EGFR or c-Met expressing cancers, particularly cancers harboring c-Met exon 14 skipping mutations in a subject, comprising administering to a subject a compound of formula (I), particularly a therapeutically effective amount of a compound of formula (I):

[0233] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.

[0234] In each embodiment, the bispecific anti-EGFR / c-Met antibody and the capmatinib compound, or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, may be administered simultaneously (e.g., as part of the same pharmaceutical composition or in separate pharmaceutical compositions) or at different times, as described herein.

[0235] Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts, such as acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinol, hydrobromide, hydrochloride, and hydroxynaphthoate. Pharmaceutically acceptable basic / cationic salts include sodium, potassium, calcium, magnesium, diethanolamine, N-methylglucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine, and triethanolamine salts.

[0236] Pharmaceutically acceptable acid salts are formed by reaction of the free base form of the compound of formula (I) with a suitable inorganic or organic acid, including, but not limited to, hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, succinic acid, maleic acid, formic acid, acetic acid, propionic acid, fumaric acid, citric acid, tartrate, lactic acid, benzoate, salicylic acid, glutamic acid, aspartic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, naphthalenesulfonic acids, e.g., 2-naphthalenesulfonic acid, or hexanoic acid. Pharmaceutically acceptable acid addition salts of compounds of formula (I) may include or be, for example, hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), or hexanoate salts.

[0237] The free acid or free base form of the compound of formula (I) can be prepared from the corresponding base addition salt or acid addition salt form, respectively. For example, a compound of the present invention in an acid addition salt form can be converted into the corresponding free base form by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). A compound of the present invention in a base addition salt form can be converted into the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

[0238] In some embodiments, the compound of Formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof has the formula (II):

[0239] [ka] or a solvate, hydrate, or tautomer thereof.

[0240] In some embodiments, the cancer is a c-Met-expressing cancer.

[0241] In some embodiments, the cancer comprises a c-Met exon 14 skipping mutation.

[0242] Exemplary c-Met exon 14 skipping mutations include mutations in the c-Met gene that result in the deletion of at least a portion of exon 14 of c-Met, or c-Met transcripts that are spliced ​​to delete at least a portion of exon 14 of c-Met. The deleted portion may include a portion encoding the negative regulatory site Tyr1003 in the juxtamembrane region of the c-Met protein. The exon 14 region of the c-Met gene encompasses nucleotides 3284 to 3424 in the full-length nucleotide sequence of GenBank Accession No. NM_000245 or residues 964 to 1009 in the full-length c-Met amino acid sequence of GenBank Accession No. NP_000236. Various mutations at the DNA level can result in exon 14 skipping (see, for example, Kong-Beltran et al. (2006) Cancer Res. 66; Dhanasekharan et al. (2014) Nature Communication 10:1038; Awad et al., J Clin Oncology 34:721, 2016). Exon 14 of c-Met encodes 47 amino acids.

[0243] Methods for detecting c-Met mutations are well known.

[0244] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a first domain that binds to EGFR, comprising heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, LCDR3 of SEQ ID NO: 6, and a second domain that binds to c-Met, comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12.

[0245] In some embodiments, the first domain that binds to EGFR comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain that binds to c-Met comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0246] In some embodiments, the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype. Some variation (e.g., known allotypes) exists within the IgG1 constant domain, with variation at positions 214, 356, 358, 422, 431, 435, or 436 (residue numbering according to EU numbering) (see, e.g., IMGT Web resource; IMGT Repertoire (IG and TR); Proteins and alleles; allotypes). The bispecific anti-EGFR / c-Met antibody may be of any IgG1 allotype, such as G1m17, G1m3, G1m1, G1m2, G1m27, or G1m28.

[0247] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises an HC1 of SEQ ID NO: 17, an LC1 of SEQ ID NO: 18, an HC2 of SEQ ID NO: 19, and an LC2 of SEQ ID NO:20.

[0248] In some embodiments, the subject has a newly diagnosed cancer.

[0249] In some embodiments, the subject has a newly diagnosed c-Met-expressing cancer.

[0250] In some embodiments, the subject has a newly diagnosed cancer that comprises a c-Met exon 14 skipping mutation.

[0251] In some embodiments, the subject is tyrosine kinase inhibitor (TKI) treatment naive.

[0252] In some embodiments, the subject is EGFR tyrosine kinase inhibitor (TKI) treatment naive.

[0253] In some embodiments, the subject is refractory or relapsed to treatment with an EGFR TKI.

[0254] In some embodiments, the subject is resistant or has acquired resistance to treatment with a previous anti-cancer therapy.

[0255] In some embodiments, the previous anti-cancer therapy is a chemotherapy, a targeted anti-cancer therapy, or a kinase inhibitor.

[0256] In some embodiments, the TKI is an inhibitor of EGFR, c-Met, HER2, HER3, HER4, VEGFR, or AXL.

[0257] In some embodiments, the TKI is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, poziotinib, cliotinib, cabozantinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

[0258] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), epithelial cell carcinoma, breast cancer, ovarian cancer, lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, small cell lung cancer, colorectal cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, head and neck cancer, pharyngeal cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, esophageal cancer, vaginal cancer, cervical cancer, spleen cancer, testicular cancer, stomach cancer, thymic cancer, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC), or sporadic or hereditary papillary renal cell carcinoma (PRCC). In some embodiments, the cancer is metastatic cancer.

[0259] In some embodiments, the cancer is NSCLC. In some embodiments, the cancer is an epithelial cell carcinoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is lung adenocarcinoma. In some embodiments, the cancer is lung squamous cell carcinoma. In some embodiments, the cancer is small cell lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is anal cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is pharyngeal cancer. In some embodiments, the cancer is nasal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is oral cancer. In some embodiments, the cancer is tongue cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is vaginal cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is splenic cancer. In some embodiments, the cancer is testicular cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is thymic cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is HCC. In some embodiments, the cancer is PRCC.

[0260] In some embodiments, the NSCLC comprises squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. In some embodiments, the cells of the NSCLC have an epithelial phenotype. In some embodiments, the NSCLC has acquired resistance to treatment with one or more EGFR inhibitors.

[0261] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 200 mg to about 2000 mg.

[0262] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg to about 1400 mg.

[0263] In some embodiments, the bispecific anti-EGFR / c-Met antibody is about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1210 mg, about 1220 mg, about 1230 mg, about 1240 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, about 1290 mg, about 1300 mg, about 1310 mg, about 1320 mg, about 1330 mg, about 1340 mg, about 1350 mg, about 1360 mg, about 1370 mg, about 1380 mg, about 1390 mg, about 1400 mg, about 1410 mg, about 1420 mg, about 1430 mg, about 1440 mg, about 1450 mg, about 1460 mg, about 1470 mg, about 1480 mg, about 1490 mg, about 1500 mg,About 1510mg, about 1520mg, about 1530mg, about 1540mg, about 1550mg, about 1560mg, about 1570mg, about 1580mg, about 1590mg, about 1600mg, about 1610mg, 1620mg, about 1630mg , about 1640mg, about 1650mg, about 1660mg, about 1670mg, about 1680mg, about 1690mg, about 1700mg, about 1710mg, about 1720mg, about 1730mg, about 1740mg, about 1750mg, about 1760 mg, about 1770 mg, about 1780 mg, about 1790 mg, about 1800 mg, about 1810 mg, about 1820 mg, about 1830 mg, about 1840 mg, about 1850 mg, about 1860 mg, about 1870 mg, about 1880 mg, 1890 mg, about 1900 mg, about 1910 mg, about 1920 mg, about 1930 mg, about 1940 mg, about 1950 mg, about 1960 mg, about 1970 mg, about 9810 mg, about 1990 mg, or about 2000 mg.

[0264] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg, about 700 mg, about 1050 mg, or about 1400 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 700 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1050 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1400 mg.

[0265] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once a week.

[0266] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once every two weeks.

[0267] In some embodiments, the compound of Formula (I), or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof (e.g., the compound of Formula (II), capmatinib hydrochloride), is administered at a dose of about 50 mg to about 500 mg. The doses of the compound of Formula (I), or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof described herein refer to the amount of free base of the compound of Formula (I) in the dose. For example, according to embodiments where the dose includes capmatinib hydrochloride (the compound of Formula (II)), the dose refers to the amount of free base of capmatinib (the compound of Formula (I)).

[0268] In some embodiments, the compound of Formula (I), or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg to about 400 mg. In some embodiments, the compound of Formula (I), or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, is administered at a dose of about 100 mg to about 500 mg. In some embodiments, the compound of Formula (I), or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg to about 450 mg. In some embodiments, the compound of Formula (I), or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, is administered at a dose of about 250 mg to about 300 mg. In some embodiments, the compound of Formula (I), or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, is administered in a dose of about 100 mg to about 400 mg.

[0269] In some embodiments, the compound of Formula (II), or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, is administered at a dose of about 50 mg to about 400 mg. In some embodiments, the compound of Formula (II), or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, is administered at a dose of about 100 mg to about 500 mg. In some embodiments, the compound of Formula (II), or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, is administered at a dose of about 200 mg to about 450 mg. In some embodiments, the compound of Formula (II), or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, is administered at a dose of about 250 mg to about 300 mg. In some embodiments, the compound of Formula (II), or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, is administered at a dose of about 100 mg to about 400 mg.

[0270] In some embodiments, the compound of Formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II), capmatinib hydrochloride) is administered at a dose of at least about 50 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, or at least about 500 mg.

[0271] In some embodiments, the compound of Formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof (e.g., the compound of Formula (II), capmatinib hydrochloride) is administered once daily.

[0272] In some embodiments, the compound of Formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof (e.g., the compound of Formula (II), capmatinib hydrochloride) is administered twice daily.

[0273] In some embodiments, the subject is further administered a third anti-cancer therapy.

[0274] In some embodiments, the third anti-cancer therapy is a chemotherapy, a targeted anti-cancer therapy, or a kinase inhibitor.

[0275] Anti-cancer therapies that may be administered in combination with the bispecific anti-EGFR / c-Met antibody and capmatinib in the methods of the present disclosure include any one or more chemotherapeutic agents or other anti-cancer therapeutic agents known to those of skill in the art. Chemotherapeutic agents are chemical compounds useful in the treatment of cancer, including growth inhibitors or other cytotoxic agents, such as alkylating agents, antimetabolites, anti-microtubule inhibitors, topoisomerase inhibitors, receptor tyrosine kinase inhibitors, angiogenesis inhibitors, and the like. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamers, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine. Methylamelamine; nitrogen mustards, such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, phenesterine, prednimustine, trofosfamide, uracil mustard, etc.; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, etc.;Antibiotics such as aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomycin, nigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, etc.; antimetabolites such as methotrexate and 5-FU; folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate, etc.; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, etc.; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, etc.; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone, etc.; adrenocortical hormone synthesis inhibitors such as aminoglutethimide, mitotane, trilostane, etc.; folic acid supplements (folic acid replenishers, such as folinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; Bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; fenamet;Pirarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; a member of the taxoid or taxane family, such as paclitaxel (TAXOL®), docetaxel (TAX OTERE® and its analogs; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; Xeloda; ibandronate; CPT-11, topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoic acid; esperamicin; capecitabine;Inhibitors of receptor tyrosine kinase and / or angiogenesis include sorafenib (NEXAVAR®), sunitinib (SUTENT®), pazopanib (VOTRIENT™), toceranib (PALLADIA™), vandetanib (ZACTIMA™), cediranib (RECENTIN®), regorafenib (BAY73-4506), axitinib (AG013736), lestaurtinib (CEP-701), erlotinib (TARCEVA®), gefitinib (IRESSA™), afatinib (BIBW 2992), lapatinib (TYKERB®), neratinib (HKI-272), and the like, as well as pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing. Also included within this definition are antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens, including tamoxifen, raloxifene, aromatase-inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY 117018, onapristone, and toremifene (FARESTON®); and antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing. Other conventional cytotoxic compounds disclosed in Wiemann et al., 1985, Medical Oncology (Calabresi et al., eds.), Chapter 10, McMillan Publishing, are also applicable to the methods of the present invention.

[0276] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered prior to administration of the compound of Formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.

[0277] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered prior to administration of the compound of formula (II) or a solvate, hydrate, or tautomer thereof.

[0278] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered after administration of the compound of Formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.

[0279] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered after administration of the compound of formula (II) or a solvate, hydrate, or tautomer thereof.

[0280] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered one or more times after administration of the compound of Formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.

[0281] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered one or more times after administration of the compound of formula (II) or a solvate, hydrate, or tautomer thereof.

[0282] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more times after administration of the compound of Formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.

[0283] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more times following administration of the compound of Formula (II) or a solvate, hydrate, or tautomer thereof.

[0284] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intermittently after administration of the compound of Formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.

[0285] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intermittently following administration of the compound of formula (II) or a solvate, hydrate, or tautomer thereof.

[0286] The length of time between administration of the bispecific anti-EGFR / c-Met antibody and administration of a compound of Formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, or Formula (II) or a solvate, hydrate, or tautomer thereof, or a third anti-cancer therapy can be a few minutes, e.g., about 1, 2, 5, 10, 30, or 60 minutes, or a few hours, e.g., about 2, 4, 6, 10, 12, 24, or 36 hours, or e.g., about 2, 4, 7, 14, 21, 28, 35, 42, 49, 56 days, or more.

[0287] The bispecific anti-EGFR / c-Met antibody and a pharmaceutically acceptable salt of a compound of Formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, or a third anti-cancer agent may be administered as a pharmaceutical composition.

[0288] The bispecific anti-EGFR / c-Met antibody and the compound of formula (II) or a solvate, hydrate, or tautomer thereof, or the third anti-cancer agent may be administered as a pharmaceutical composition.

[0289] The bispecific anti-EGFR / c-Met antibody can be formulated into a pharmaceutical composition comprising the bispecific anti-EGFR / c-Met antibody and a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier can be one or more diluents, adjuvants, excipients, vehicles, etc. Such vehicles can be liquids such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. For example, the bispecific anti-EGFR / c-Met antibody can be formulated using 0.4% saline and 0.3% glycine. These solutions are sterile and generally free of particulate matter. They can be sterilized by conventional, well-known sterilization techniques (e.g., filtration).

[0290] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered by intravenous injection. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered by subcutaneous injection.

[0291] In some embodiments, the compound of Formula (I), or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, or the compound of Formula (II), or a solvate, hydrate, or tautomer thereof, is administered as an oral formulation, such as a solid oral formulation, including, for example, a powder, capsule, and tablet.

[0292] For example, in the case of oral solid preparations such as powders, capsules, and tablets of the compound of formula (I) or the compound of formula (II), suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. Oral solid preparations may be coated with a substance such as sugar, or may be enteric coated to adjust the primary absorption site. For parenteral administration, the carrier may comprise sterile water, and other excipients may be added to increase solubility or preserve the solubility. Injectable suspensions or solutions may also be prepared using aqueous carriers with appropriate additives. Suitable vehicles and formulations (including other human proteins, for example, human serum albumin) are described, for example, in Remington: The Science and Practice of Pharmacy, 21 st Edition, Troy, DB ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing pp 691-1092, see in particular pp. 958-989.

[0293] The compositions may contain pharmaceutically acceptable auxiliary substances required to approximate physiological conditions, such as pH adjusting and buffering agents, stabilizers, thickeners, lubricants, and coloring agents. The concentration of the bispecific anti-EGFR / c-Met antibody in the pharmaceutical formulation may vary from less than about 0.5% by weight, usually at least about 1% by weight, up to 15%, 20%, 30%, 40%, or 50% by weight, and may be selected primarily based on the required dose, fluid volume, viscosity, and the like, in accordance with the particular mode of administration selected. Pharmaceutical compositions, including solid forms, may contain from about 0.1 mg to about 2000 mg, e.g., about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, about 600 mg, or about 1000 mg of the active ingredient.

[0294] The mode of administration may be any suitable route of delivery of the antibody to the host, e.g., parenteral administration, e.g., intradermal, intramuscular, intraperitoneal, intravenous, or subcutaneous, pulmonary, transmucosal (oral, intranasal, intravaginal, rectal), using tablet, capsule, liquid, powder, gel, particle formulations, which may be contained in syringes, implantable devices, osmotic pumps, cartridges, micropumps, or other means well known in the art and recognized by those of skill in the art. Site-specific administration can be achieved, for example, by intratumoral, intraarticular, intrabronchial, intraabdominal, intracapsular, intrachondral, intrasinus, intracavity, intracerebellar, intraventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravascular, intravesical, intralesional, intravaginal, intrarectal, buccal, sublingual, intranasal, or transdermal delivery.

[0295] The invention will now be described with reference to the following specific, non-limiting examples.

[0296] Embodiment The following sections describe specific embodiments of the present invention. 1) A method of treating a subject having a cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject having a cancer that is positive for the c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody. 2) A method of treating a subject with cancer with a bispecific anti-EGFR / c-Met antibody, comprising: a) providing a biological sample from a subject; b) determining the presence or absence of a c-Met exon 14 skipping mutation in the sample; c) administering or providing for administration the bispecific anti-EGFR / c-Met antibody to a subject determined to have a c-Met exon 14 skipping mutation. 3) The method of embodiment 1 or 2, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second domain that specifically binds to c-Met comprises HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12. 4) The method of embodiment 3, wherein the first domain that specifically binds to EGFR comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain that specifically binds to c-Met comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16. 5) The method of any one of embodiments 1 to 4, wherein the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype. 6) The method of any one of embodiments 1 to 5, wherein the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19, and a second light chain (LC2) of SEQ ID NO: 20. 7) The method of any one of embodiments 1 to 6, wherein the bispecific anti-EGFR / c-Met antibody has a biantennary glycan structure with a fucose content of about 1% to about 15%. 8) The method of any one of embodiments 1 to 7, wherein the subject is relapsed or refractory to treatment with one or more previous anti-cancer therapies. 9) The method of embodiment 8, wherein the one or more previous anti-cancer therapies comprise one or more chemotherapeutic agents, checkpoint inhibitors, targeted anti-cancer agents, or kinase inhibitors, or any combination thereof. 10) The method of embodiment 8, wherein the one or more previous anticancer therapies comprise carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, a PD-(L)1 axis inhibitor, an EGFR inhibitor, a c-Met inhibitor, a HER2 inhibitor, a HER3 inhibitor, a HER4 inhibitor, a VEGFR inhibitor, an AXL inhibitor, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib, or any combination thereof. 11) The method of any one of embodiments 1 to 7, wherein the subject is treatment-naive. 12) Cancers positive for c-Met exon 14 skipping mutations include CDK4 amplification, EGFR amplification, KRAS amplification, MDM2 amplification, TERT amplification, and NF1 R2450. * ;RAD50 L597Vfs *5. The method of any one of embodiments 1 to 11, wherein the patient is positive for MET c.3082 +3A>G, EGFR, wild-type EGFR, an EGFR activating mutation, elevated circulating HGF levels, c-MET amplification, or mutant KRAS, or any combination thereof. 13) The EGFR activating mutation is a substitution of L718Q, G719A, G719X (X is any amino acid), L861X (X is any amino acid), L858R, E746K, L747S, E749Q, A750P, A755V, V765M, C797S, L858P, or T790M, a deletion of E746 to A750, a deletion of R748 to P753, an insertion of Ala (A) between M766 and A767, an insertion of Ser, Val, or Ala (SVA) between S768 and V769, or a substitution of P772 and H773. 13. The method of embodiment 12, comprising an insertion of Asn and Ser (NS) between, an 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, or one or more insertions in EGFR exon 20, or any combination thereof. 14) The method of embodiment 12, wherein the mutant KRAS comprises a G12V, G12C, G12A, or G12D substitution, or any combination thereof. 15) The method according to any one of embodiments 1 to 14, wherein the cancer is lung cancer, gastric cancer, colorectal cancer, brain cancer, cancer derived from epithelial cells, breast cancer, ovarian cancer, colorectal cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, head and neck cancer, pharyngeal cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, esophageal cancer, vaginal cancer, cervical cancer, splenic cancer, testicular cancer, stomach cancer, thymic cancer, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC), or sporadic or hereditary papillary renal cell carcinoma (PRCC), or any combination thereof. 16) The method of embodiment 15, wherein the lung cancer is non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), or lung adenocarcinoma, lung sarcomatoid carcinoma, or any combination thereof. 17) The method of any one of embodiments 1 to 16, further comprising administering to the subject one or more anti-cancer therapies. 18) The method of embodiment 17, wherein the one or more anti-cancer therapies comprise chemotherapy, radiation therapy, surgery, targeted anti-cancer therapy, or kinase inhibitors, or any combination thereof. 19) The method of embodiment 18, 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. 20) The method of embodiment 19, wherein the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib. 21) The method of any one of embodiments 1 to 20, wherein the c-Met exon 14 skipping mutation is a de novo mutation. 22) The method of any one of embodiments 1 to 21, wherein the c-Met exon 14 skipping mutation is an acquired mutation. 23) The method of any one of embodiments 1 to 22, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 140 mg to about 1750 mg. 24) The method of any one of embodiments 1 to 23, 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, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, or 1400 mg. 25) The method of any one of embodiments 1 to 24, wherein the bispecific anti-EGFR / c-Met antibody is administered twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks. 26) A method of treating a subject having cancer positive for a c-Met exon 14 skipping mutation, comprising administering to the subject a combination therapy, the 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):

[0297] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof. 27) The method of embodiment 26, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that binds to EGFR, the first domain comprising heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and a second domain that binds to c-Met, the second domain comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12. 28) The method of embodiment 27, wherein the first domain that binds to EGFR comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain that binds to c-Met comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16. 29) The method of any one of embodiments 26 to 28, wherein the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype. 30) The method of any one of embodiments 26 to 29, wherein the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19, and a second light chain (LC2) of SEQ ID NO: 20. 31) The method of any one of embodiments 26 to 30, wherein the bispecific anti-EGFR / c-Met antibody has a biantennary glycan structure with a fucose content of about 1% to about 15%. 32) The method of any one of embodiments 26-31, wherein the compound of formula (II), or a 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). 33) The method of any one of embodiments 26 to 32, wherein the subject is relapsed or refractory to treatment with one or more previous anticancer therapies. 34) The method of embodiment 33, wherein the one or more previous anti-cancer therapies include one or more chemotherapeutic agents, checkpoint inhibitors, targeted anti-cancer agents, or kinase inhibitors, or any combination thereof. 35) The method of embodiment 33, wherein the one or more previous anticancer therapies comprise carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, PD-(L)1 axis inhibitors, EGFR inhibitors, c-Met inhibitors, HER2 inhibitors, HER3 inhibitors, HER4 inhibitors, VEGFR inhibitors, AXL inhibitors, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib, or any combination thereof. 36) The method of any one of embodiments 26 to 32, wherein the subject is treatment-naive. 37) Cancers positive for c-Met exon 14 skipping mutations include CDK4 amplification, EGFR amplification, KRAS amplification, MDM2 amplification, TERT amplification, and NF1 R2450. * ;RAD50 L597Vfs *5. The method of any one of embodiments 26 to 36, wherein the patient is positive for MET c.3082+3A>G, EGFR, wild-type EGFR, an EGFR activating mutation, elevated circulating HGF levels, c-MET amplification, or mutant KRAS, or any combination thereof. 38) The EGFR activating mutation is a substitution of L718Q, G719A, G719X (X is any amino acid), L861X (X is any amino acid), L858R, E746K, L747S, E749Q, A750P, A755V, V765M, C797S, L858P, or T790M, a deletion of E746 to A750, a deletion of R748 to P753, an insertion of Ala (A) between M766 and A767, an insertion of Ser, Val, or Ala (SVA) between S768 and V769, or a substitution of P772 and H773. 38. The method of embodiment 37, comprising an insertion of Asn and Ser (NS) between, an 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, or one or more insertions in EGFR exon 20, or any combination thereof. 39) The method of embodiment 37, wherein the mutant KRAS comprises a G12V, G12C, G12A, or G12D substitution, or any combination thereof. 40) The method of any one of embodiments 26 to 39, wherein the cancer is lung cancer, stomach cancer, colorectal cancer, brain cancer, cancer derived from epithelial cells, breast cancer, ovarian cancer, colorectal cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, head and neck cancer, pharyngeal cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, esophageal cancer, vaginal cancer, cervical cancer, splenic cancer, testicular cancer, stomach cancer, thymic cancer, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC), or sporadic or hereditary papillary renal cell carcinoma (PRCC), or any combination thereof. 41) The method of embodiment 40, wherein the lung cancer is non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), or lung adenocarcinoma, lung sarcomatoid carcinoma, or any combination thereof. 42) The method of any one of embodiments 26 to 41, further comprising administering to the subject one or more anti-cancer therapies. 43) The method of embodiment 42, wherein the one or more anti-cancer therapies include chemotherapy, radiation therapy, surgery, targeted anti-cancer therapy, or kinase inhibitors, or any combination thereof. 44) The method of embodiment 43, 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. 45) The method of embodiment 44, wherein the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib. 46) A method according to any one of embodiments 26 to 45, wherein the c-Met exon 14 skipping mutation is a de novo mutation. 47) A method according to any one of embodiments 26 to 46, wherein the c-Met exon 14 skipping mutation is an acquired mutation. 48) The method of any one of embodiments 26 to 47, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 140 mg to about 1750 mg. 49) The method of any one of embodiments 26 to 48, 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, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, or 1400 mg. 50) The method of any one of embodiments 26 to 49, wherein the bispecific anti-EGFR / c-Met antibody is administered twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks.

[0298] Example 1. JNJ-372 was effective in a c-Met-driven PDX model The efficacy of JNJ-372 was tested in PDX models harboring c-Met exon 14 skipping mutations. Erlotinib and cetuximab were used for comparison. In these experiments, JNJ-372 was expressed in wild-type CHO cells, thus exhibiting the fucose content characteristic of wild-type CHO cells.

[0299] Tumor fragments were harvested from stock mice inoculated with selected primary human NSCLC tissues and used to inoculate BALB / c nude mice. To develop tumors, primary human NSCLC model (LU2503) fragments (passage number 5, 2–4 mm in diameter) were subcutaneously inoculated into the right flank of each mouse. The average tumor size was approximately 151.5 mm. 3 Treatment was initiated when tumor size reached 100 μg / kg. Mice were randomly assigned to four experimental groups according to tumor size. Each group consisted of 10 mice, with 5 mice per cage. This day was designated as day 0. The tumor-bearing mice were administered the test articles from day 0 to day 25 according to the prescribed regimen shown in Table 1.

[0300] [Table 1]

[0301] The primary endpoint was to determine whether tumor growth could be slowed or whether tumor-bearing mice could be cured. Tumor size was measured twice a week in two dimensions using calipers and calculated using the formula: V = 0.5a × b 2 where a and b are the long and short diameters of the tumor, respectively, to calculate the volume in mm 3The tumor size was then used to calculate TC and T / C values. TC was the percentage of the mean tumor size in a treatment group that exceeded a given size (e.g., 1000 mm). 3 The T / C value (%) was calculated using T as the time (days) required for the mean tumor size to reach 2000 mm ), and C was the time (days) required for the mean tumor size in the control group to reach the same size. The T / C value (%) was an index of antitumor efficacy. T and C were the mean volumes of the treatment and control groups, respectively, on a given day. The study was terminated when scheduled dosing was completed, and the mean tumor volume in the vehicle-treated control group was 2000 mm . 3 The difference between the mean tumor size of the comparison groups was analyzed for significance using SPSS software. P<0.05 was considered statistically significant.

[0302] Tumor sizes (expressed as mean + SEM) within treatment groups at various time points during treatment are shown in Table 2. Tumor growth inhibition is summarized in Table 3. When tumors reached a given size (1000 mm 3 ) was calculated. Figure 1 shows tumor volume over time.

[0303] [Table 2]

[0304] [Table 3]

[0305] In Group 2 (erlotinib 50 mg / kg, 5 days on, 2 days off), Group 3 (cetuximab 10 mg / kg, BIW × 4), and Group 4 (JNJ-372 10 mg / kg, BIW × 4), the body weight changes on Day 27 of treatment were −8%, 3.6%, and 6.6%, respectively (data not shown).

[0306] The mean tumor size in vehicle-treated mice was 2160.5 mm on day 27. 3The study was terminated on day 28. JNJ-372 treatment at 10 mg / kg BIW x 4 produced a significant antitumor response compared with vehicle treatment (P<0.0001). JNJ-372 treatment at 10 mg / kg BIW x 4 reduced the mean tumor size to 48.35 mm 3 The TC could not be calculated due to tumor shrinkage. In summary, JNJ-372 at 10 mg / kg BIW × 4 produced significant antitumor activity against the primary human NSCLC tumor xenograft model LU2503 in this study.

[0307] Example 2. JNJ-372 inhibited tumor growth in patients with c-Met exon 14 skipping mutations We evaluated the potential clinical utility of JNJ-372 in NSCLC with altered MET drivers. JNJ-372 used in clinical trials was produced in a cell line, resulting in an antibody with a fucose content of less than 15%.

[0308] Eligible patients with metastatic NSCLC received JNJ-372 at escalating doses (140 mg to 1750 mg) in Part 1 or at the RP2D in expansion cohorts in Part 2. JNJ-372 was administered intravenously (IV) on days 1, 2, 8, 15, and 22 of Cycle 1 and days 1 and 15 of subsequent cycles in 28-day cycles. Disease response was assessed every 6 weeks by investigator assessment according to RECIST v.1.1 criteria.

[0309] Patient 1, a 76-year-old with heavily pretreated metastatic adenosquamous NSCLC harboring a MET exon 14 skipping mutation, was initially diagnosed with metastatic disease. After multiple chemotherapy regimens (carboplatin and paclitaxel, carboplatin and gemcitabine, cisplatin and vinorelbine, and docetaxel), localized radiation therapy, and nivolumab, next-generation sequencing (NGS) revealed a MET exon 14 deletion; NF1 R2450; CDK4 amplification; MDM2 amplification; EPHB1 amplification; FRS2 amplification; and RAD50 N598fs. *The patient received a trial of palbociclib without response and then received crizotinib for 11 months, with stable disease as the best response. Post-crizotinib biopsy of the left axillary lymph node revealed metastatic lung adenosquamous carcinoma, and next-generation sequencing (HopeSeq) revealed CDK4 amplification; EGFR amplification; KRAS amplification; MET exon 14 deletion; MET c.3082+3A>G; MDM2 amplification; and NF1 R2450. * ;RAD50 L597Vfs * The patient's tumor size was 5%; TERT amplification; and PD-L1 5%. This suggested EGFR and KRAS amplification as potential mechanisms of resistance to crizotinib, as previously reported. The patient began treatment with 1050 mg of JNJ-372 in the phase 1 portion of the study. A restaging CT scan at week 6 showed a partial response (PR), with a 32% tumor reduction (9.1 to 6.2 cm) compared to the baseline CT scan. A CT scan at week 12 confirmed continued PR with a 41% tumor reduction (5.4 cm). At the final visit, the patient tolerated treatment well with mild toxicity through four cycles and remained on the 1050 mg dose. Figure 2 shows the CT scans at weeks 6 and 12 post-treatment demonstrating a partial response.

[0310] The first case of primary MET exon 14 deletion NSCLC that experienced resistance to crizotinib was reported herein, with a confirmed partial response to JNJ-372 in a phase 1 trial after multiple lines of therapy, suggesting a potential new treatment option for patients with MET exon 14 deletions.

[0311] Example 3. JNJ-372 was effective in inhibiting c-Met-driven NSCLC PDX tumor growth in LU2503. The efficacy of JNJ-372 and the small molecule c-Met inhibitor capmatinib (Selleck, S2788) was evaluated in the LU2503 NSCLC PDX model, which harbors a c-Met exon 14 skipping mutation. The LU2503 PDX model was established by CrownBio and described in Yang M, Shan B, Li Q, Song X, Cai J, Deng J, et al. Overcoming erlotinib resistance with tailored treatment regimens in patient-derived xenografts from naive Asian NSCLC patients. International Journal of Cancer. 2013;132:E74-84. LU2503 tumor fragments were harvested from stock tumor-bearing mice (passage R17P12) and used to inoculate BALB / c nude mice. To develop tumors, PDX LU2503 tumor fragments (approximately 2–3 mm in diameter) were subcutaneously inoculated into the right hind flank of each mouse.

[0312] After the establishment of palpable lesions, tumor growth was measured twice weekly. Once tumor volumes reached approximately 200 mm3, animals were randomly assigned to relevant study groups, each containing eight mice. Randomization was performed according to tumor size within each group, with the day of randomization designated as day 0. Treatment began on the same day as randomization, according to the study design in Table 4.

[0313] [Table 4] ip: intraperitoneal; po: oral administration; BIW: twice weekly; BID: twice daily

[0314] The endpoint of the study was to compare tumor growth in each group at the end of treatment with subsequent tumor elongation after dosing was stopped. Tumor size was measured twice weekly in two dimensions using calipers, and volume was expressed in mm using the formula: V = (L × W × W) / 2, where V is tumor volume, L is tumor length (longest tumor dimension), and W is tumor width (longest tumor dimension perpendicular to L). 3Tumor sizes (expressed as mean + SEM) within treatment groups at different time points during treatment are shown in Table 5, and tumor growth curves over time are shown in Figure 3A.

[0315] [Table 5] a: Data represent mean tumor volume ± standard error of the mean (SEM).

[0316] Tumor growth inhibition (TGI%) is an indicator of antitumor activity and was calculated as Δ% inhibition = 100 × ((C-C) - (T-T)) / (C-C), where T and C were the mean tumor volumes of the treatment and control groups, respectively, on the day the mean tumor volume (TV) in the vehicle group reached the humane endpoint (>2000 mm, day 13). Tumor growth inhibition is summarized in Table 6. To compare the mean tumor volumes of the treatment groups with the vehicle control group, we first used a Bartlett test to confirm the assumption of homogeneity of variance among all groups. Since the p-value for the Bartlett test was <0.05, a Kruskal-Wallis test was performed for overall equality of medians among all groups (<0.05). Post-hoc testing was then further performed by performing a Conover nonparametric test with a one-step p-value adjustment (P < 0.05 was considered statistically significant). Body weight changes were monitored and are shown in Figure 3B.

[0317] [Table 6] a: Data represent mean tumor volume ± SEM. b: % D inhibition calculated as follows:

[0318]

number

[0319] As shown in Figure 3A, JNJ-372 at 10 mg / kg BIW x 3 and capmatinib at 10 mg / kg BID x 21 both produced significant antitumor activity (108.44% and 109.78% TGI, respectively) against primary LU2503 human NSCLC tumor xenografts in this study. During the non-treatment monitoring phase after day 21, all eight capmatinib-treated animals showed faster tumor regrowth compared to JNJ-372-treated animals (six of the eight animals showed no measurable tumors by the end of the study).

[0320] Example 4. JNJ-372 in combination with a MET-TKI (capmatinib) showed deeper and more durable tumor inhibition in LU2503. To investigate whether there was any additional benefit when JNJ-372 was combined with a MET-TKI, a follow-up study in LU2503 included combined treatment with JNJ-372 and capmatinib. Tumor fragments from stock mice (passage R18P2) were subcutaneously implanted into the right hind flank of BALB / c nude mice to propagate tumors.

[0321] The average tumor size is approximately 150-200 mm 3 When tumor size reached 100 mg / kg / day, treatment was initiated in the efficacy study according to the following design (Table 7). Animals were randomly assigned to four experimental groups according to tumor size, with eight mice in each group. Tumor size was measured and body weight was monitored twice weekly as described in Example 3. Tumor size (expressed as mean + SEM) within the treatment groups at various time points during treatment is shown in Table 8, tumor growth curves over time are shown in Figure 4A, and body weight changes are graphically depicted in Figure 4B.

[0322] [Table 7] ip: intraperitoneal; po: oral administration; BIW: twice weekly; BID: twice daily

[0323] [Table 8] a: Data represent mean tumor volume ± SEM. BIW: twice weekly; BID: twice daily

[0324] The isotype and vehicle control groups were terminated on day 14 when the mean tumor size reached 1400 mm. Tumor growth inhibition (TGI%) in each treatment group was calculated using the formula Δ% inhibition = 100 × ((C-C) - (T-T)) / (C-C) and is shown in Table 9. T and C were the mean tumor volumes of the treatment and control groups, respectively. Statistical analysis was performed using the same method as in Example 3.

[0325] [Table 9] a: Data represent mean tumor volume ± SEM. b: % D inhibition calculated as follows:

[0326]

number

[0327] While all three treatment groups induced rapid tumor regression, the combination of JNJ-372 and capmatinib produced a longer, more durable response compared with the monotherapies in this study: two of eight animals in the JNJ-372 group experienced regrowth at approximately day 70, and all animals in the combination group remained tumor-free until the end of the study (>120 days).

[0328] A combination study evaluating pharmacodynamic parameters of LU2503 was conducted, with treatment initiated when tumors reached approximately 450-500 mm3. Samples were collected in all treatment groups at time points according to the design in Table 10. Snap-frozen tumors were homogenized in RIPA buffer containing a cocktail of protease and phosphatase inhibitors. For Western blotting, 50 mg of total protein (100 mg for phospho-EGFR) was loaded per lane (see Figure 5). Using the manufacturer's recommended method, protein levels of total MET (Cell Signaling, 8198S), EGFR (Cell Signaling, 4267S), phosphoMET-Tyr1234 / 1235 (Cell Signaling, 3077S), phosphoMET-Tyr1349 (Cell Signaling, 3133S), phosphoEGFR-Tyr1068 (Cell Signaling, 3777S), and phosphoEGFR-Tyr1173 (Cell Signaling, 4407S) were detected using the indicated primary antibodies and the following secondary antibodies: IRDye800CW goat anti-rabbit (Li-Cor, 925-32211) and IRDye680RD goat anti-mouse (Li-Cor, 925-68070). In Figures 6A-6B and 7A-7C, protein levels were quantified using ImageJ software and normalized to the loading control β-tubulin.

[0329] [Table 10] ip: intraperitoneal; po: oral administration; BIW: twice weekly; BID: twice daily

[0330] Consistent with its published mechanism of action, JNJ-372 caused downregulation of total EGFR and MET receptors. Unexpectedly, the JNJ-372 / capmatinib combination further reduced both EGFR and MET receptor levels. A similar synergistic effect in inhibiting phospho-EGFR and phospho-MET signaling was observed in the combination group. In summary, the more robust PD marker inhibition with combination treatment is consistent with the observed efficacy and merits further investigation.

[0331] Example 5. JNJ-372 was effective in inhibiting tumor growth in the DFCI-440 MET exon 14 skipping NSCLC PDX model. The efficacy of JNJ-372, the small molecule MET inhibitor captinib (Advanced Chemblock, Burlingame, CA), and their combination was compared in the NSCLC PDX model DFCI-440, a patient explant (PDX) model of NSCLC harboring a MET exon 14 skipping mutation developed at Dana-Farber Cancer Institute (Boston, MA). Tumor fragments were harvested from stock tumor-bearing mice and used to inoculate female NSG™ mice. To develop tumors, PDX DFCI-440 tumor fragments (approximately 2–3 mm in diameter) were subcutaneously inoculated into the right hind flank of each mouse.

[0332] After the establishment of palpable lesions, tumor growth was measured twice weekly. Once tumor volumes reached 150-250 mm, animals were randomly assigned to relevant study groups, each containing eight mice. The day of randomization was designated day 0; treatment began on day 0 and followed the dosing schedule in Table 11.

[0333] [Table 11] LFI: low fucose isotype; HPMC: hydroxypropyl methylcellulose; ip: intraperitoneal; po: oral administration;

[0334] The endpoint of the study was to compare tumor growth in each group at the end of treatment with subsequent tumor elongation after dosing was stopped. Tumor size was measured twice weekly in two dimensions using calipers, and volume was expressed in mm using the formula: V = (L × W × W) / 2, where V is tumor volume, L is tumor length (longest tumor dimension), and W is tumor width (longest tumor dimension perpendicular to L). 3 The tumor size (expressed as mean + SEM) for each group over time is shown in Figure 8.

[0335] As shown in Figure 8, both JNJ-372 and capmatinib as single agents significantly inhibited DFCI-440 tumor growth and caused these tumors to regress. After treatment was stopped, tumors in mice treated with JNJ-372 or capmatinib as single agents resumed growth. However, treatment with the combination of JNJ-372 and capmatinib also effectively inhibited tumor growth and resulted in tumor regression, and the combined treatment completely eliminated tumors in 8 of 8 mice, even after treatment was stopped. The following aspects may be included. [1] A method of treating a subject having a cancer that is positive for a c-Met exon 14 skipping mutation, comprising administering to the subject having a cancer that is positive for a c-Met exon 14 skipping mutation a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody. [2] A method of treating a subject with cancer with a bispecific anti-EGFR / c-Met antibody, comprising: a) providing a biological sample from said subject; b) determining the presence or absence of a c-Met exon 14 skipping mutation in the sample; c) administering or providing for administration the bispecific anti-EGFR / c-Met antibody to the subject determined to have a c-Met exon 14 skipping mutation; A method comprising: 3. The method of claim 1, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met, wherein the first domain comprises heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second domain that specifically binds to c-Met comprises HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12. [4] The method of claim 3, wherein the first domain that specifically binds to EGFR comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain that specifically binds to c-Met comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16. [5] The method according to any one of claims 1 to 4, wherein the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype. [6] The method of any one of claims 1 to 5, wherein the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19, and a second light chain (LC2) of SEQ ID NO: 20. [7] The method of any one of claims 1 to 6, wherein the bispecific anti-EGFR / c-Met antibody comprises a biantennary glycan structure having a fucose content of about 1% to about 15%. [8] The method of any one of claims 1 to 7, wherein the subject is relapsed or resistant to treatment with one or more previous anticancer therapies. [9] The method of claim 8, wherein the one or more prior anticancer therapies include one or more chemotherapeutic agents, checkpoint inhibitors, targeted anticancer agents, or kinase inhibitors, or any combination thereof. 10. The method of claim 8, wherein the one or more prior anticancer therapies comprise carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, a PD-(L)1 axis inhibitor, an EGFR inhibitor, a c-Met inhibitor, a HER2 inhibitor, a HER3 inhibitor, a HER4 inhibitor, a VEGFR inhibitor, an AXL inhibitor, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib, or any combination thereof.

[11] The method of any one of claims 1 to 7, wherein the subject is treatment-naive.

[12] Cancers positive for c-Met exon 14 skipping mutations include CDK4 amplification, EGFR amplification, KRAS amplification, MDM2 amplification, TERT amplification, and NF1 R2450. * ;RAD50 L597Vfs * 5, MET c.3082+3A>G, EGFR, wild-type EGFR, an EGFR activating mutation, elevated circulating HGF levels, c-MET amplification, or mutant KRAS, or any combination thereof.

[13] The EGFR activating mutation is a substitution of L718Q, G719A, G719X (X is any amino acid), L861X (X is any amino acid), L858R, E746K, L747S, E749Q, A750P, A755V, V765M, C797S, L858P, or T790M, a deletion of E746 to A750, a deletion of R748 to P753, an insertion of Ala (A) between M766 and A767, an insertion of Ser, Val, or Ala (SVA) between S768 and V769, or an insertion of Ala (A) between P772 and H773. 13. The method of claim 12, wherein the EGFR exon 20 insertion comprises an insertion of Asn and Ser (NS) into the EGFR exon 20 site, an 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, or one or more insertions in EGFR exon 20, or any combination thereof.

[14] The method of claim 12, wherein the mutant KRAS comprises a G12V, G12C, G12A, or G12D substitution, or any combination thereof.

[15] The method of any one of claims 1 to 14, wherein the cancer is lung cancer, gastric cancer, colorectal cancer, brain cancer, cancer derived from epithelial cells, breast cancer, ovarian cancer, colorectal cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, head and neck cancer, pharyngeal cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, esophageal cancer, vaginal cancer, cervical cancer, splenic cancer, testicular cancer, stomach cancer, thymic cancer, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC), or sporadic or hereditary papillary renal cell carcinoma (PRCC), or any combination thereof.

[16] The method of claim 15, wherein the lung cancer is non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), or lung adenocarcinoma, lung sarcomatoid carcinoma, or any combination thereof.

[17] A method according to any one of claims 1 to 16, further comprising administering one or more anti-cancer therapies to the subject.

[18] The method of claim 17, wherein the one or more anticancer therapies include chemotherapy, radiation therapy, surgery, targeted anticancer therapy, or a kinase inhibitor, or any combination thereof.

[19] The method of claim 18, 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.

[20] The method of claim 19, wherein the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

[21] The method of any one of claims 1 to 20, wherein the c-Met exon 14 skipping mutation is a de novo mutation.

[22] A method according to any one of claims 1 to 21, wherein the c-Met exon 14 skipping mutation is an acquired mutation.

[23] The method of any one of claims 1 to 22, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 140 mg to about 1750 mg. 24. The method of any one of claims 1 to 23, 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, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, or 1400 mg. 25. The method of any one of claims 1 to 24, wherein the bispecific anti-EGFR / c-Met antibody is administered twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks.

[26] A method of treating a subject having cancer positive for a c-Met exon 14 skipping mutation, comprising administering to the subject a combination therapy, the 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 (II):

change

[29] The method according to any one of claims 26 to 28, wherein the bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype. 30. The method of any one of claims 26 to 29, wherein the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19, and a second light chain (LC2) of SEQ ID NO: 20.

[31] The method of any one of claims 26 to 30, wherein the bispecific anti-EGFR / c-Met antibody has a biantennary glycan structure with a fucose content of about 1% to about 15%.

[32] The method according to any one of claims 26 to 31, wherein the compound of formula (II) or a 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).

[33] The method of any one of claims 26 to 32, wherein the subject is relapsed or resistant to treatment with one or more previous anticancer therapies.

[34] The method of claim 33, wherein the one or more prior anticancer therapies include one or more chemotherapeutic agents, checkpoint inhibitors, targeted anticancer agents, or kinase inhibitors, or any combination thereof.

[35] The method of claim 33, wherein the one or more prior anticancer therapies comprise carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, PD-(L)1 axis inhibitor, EGFR inhibitor, c-Met inhibitor, HER2 inhibitor, HER3 inhibitor, HER4 inhibitor, VEGFR inhibitor, AXL inhibitor, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib, or any combination thereof.

[36] A method according to any one of claims 26 to 32, wherein the subject is treatment-naive.

[37] Cancers positive for c-Met exon 14 skipping mutations include CDK4 amplification, EGFR amplification, KRAS amplification, MDM2 amplification, TERT amplification, and NF1 R2450. * ;RAD50 L597Vfs * 5. The method of any one of claims 26 to 36, wherein the patient is positive for MET c.3082+3A>G, EGFR, wild-type EGFR, an EGFR activating mutation, elevated circulating HGF levels, c-MET amplification, or mutant KRAS, or any combination thereof.

[38] The EGFR activating mutation is a substitution of L718Q, G719A, G719X (X is any amino acid), L861X (X is any amino acid), L858R, E746K, L747S, E749Q, A750P, A755V, V765M, C797S, L858P, or T790M, a deletion of E746 to A750, a deletion of R748 to P753, an insertion of Ala (A) between M766 and A767, an insertion of Ser, Val, or Ala (SVA) between S768 and V769, or an insertion of Ala (A) between P772 and H773. 38. The method of claim 37, wherein the EGFR exon 20 insertion comprises an insertion of Asn and Ser (NS) into the EGFR exon 20 site, an 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, or one or more insertions in EGFR exon 20, or any combination thereof.

[39] The method of claim 37, wherein the mutant KRAS comprises a G12V, G12C, G12A, or G12D substitution, or any combination thereof.

[40] The method of any one of claims 26 to 39, wherein the cancer is lung cancer, gastric cancer, colorectal cancer, brain cancer, cancer derived from epithelial cells, breast cancer, ovarian cancer, colorectal cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, head and neck cancer, pharyngeal cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, esophageal cancer, vaginal cancer, cervical cancer, splenic cancer, testicular cancer, stomach cancer, thymic cancer, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC), or sporadic or hereditary papillary renal cell carcinoma (PRCC), or any combination thereof.

[41] The method of claim 40, wherein the lung cancer is non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), or lung adenocarcinoma, lung sarcomatoid carcinoma, or any combination thereof.

[42] A method according to any one of claims 26 to 41, further comprising administering to the subject one or more anti-cancer therapies.

[43] The method of claim 42, wherein the one or more anticancer therapies include chemotherapy, radiation therapy, surgery, targeted anticancer therapy, or a kinase inhibitor, or any combination thereof.

[44] The method of claim 43, 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.

[45] The method of claim 44, wherein the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

[46] The method of any one of claims 26 to 45, wherein the c-Met exon 14 skipping mutation is a de novo mutation.

[47] The method of any one of claims 26 to 46, wherein the c-Met exon 14 skipping mutation is an acquired mutation.

[48] ​​The method of any one of claims 26 to 47, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 140 mg to about 1750 mg. 49. The method of any one of claims 26-48, 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, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, or 1400 mg.

[50] The method of any one of claims 26 to 49, wherein the bispecific anti-EGFR / c-Met antibody is administered twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks.

Claims

1. 1. A pharmaceutical composition for use in a method of treating a subject having a cancer positive for a c-Met exon 14 skipping mutation, said pharmaceutical composition comprising a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody; The antibody a 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; a second domain comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO:7, an HCDR2 comprising the amino acid sequence of SEQ ID NO:8, an HCDR3 comprising the amino acid sequence of SEQ ID NO:9, an LCDR1 comprising the amino acid sequence of SEQ ID NO:10, an LCDR2 comprising the amino acid sequence of SEQ ID NO:11, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:12; Including, The method comprises administering to the subject the pharmaceutical composition.

2. A pharmaceutical composition for use according to claim 1, comprising: The method further comprises determining the presence or absence of a c-Met exon 14 skipping mutation in a biological sample from the subject before administering the pharmaceutical composition.

3. A pharmaceutical composition for use according to claim 1 or 2, wherein the first domain 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 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.

4. The bispecific anti-EGFR / c-Met antibody is (a) is an IgG1 isotype; (b) comprising a first heavy chain (HC1) comprising the amino acid sequence of SEQ ID NO: 17, a first light chain (LC1) comprising the amino acid sequence of SEQ ID NO: 18, a second heavy chain (HC2) comprising the amino acid sequence of SEQ ID NO: 19, and a second light chain (LC2) comprising the amino acid sequence of SEQ ID NO: 20; or (c) comprising a biantennary glycan structure having a fucose content of about 1% to about 15%; A pharmaceutical composition for use according to any one of claims 1 to 3.

5. the subject is relapsed or refractory to treatment with one or more prior anti-cancer therapies; and optionally, (a) the one or more prior anti-cancer therapies comprise one or more chemotherapeutic agents, checkpoint inhibitors, targeted anti-cancer therapies, kinase inhibitors, or any combination thereof; or (b) The pharmaceutical composition for use of any one of claims 1 to 4, wherein the one or more prior anticancer therapies comprise carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, PD-(L)1 axis inhibitors, EGFR inhibitors, c-Met inhibitors, HER2 inhibitors, HER3 inhibitors, HER4 inhibitors, VEGFR inhibitors, AXL inhibitors, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, sunitinib, or any combination thereof.

6. The pharmaceutical composition for use according to any one of claims 1 to 4, wherein the subject is treatment naive.

7. Cancers positive for c-Met exon 14 skipping mutations include CDK4 amplification, EGFR amplification, KRAS amplification, MDM2 amplification, TERT amplification, and NF1 R2450. ＊ , RAD50 L597Vfs ＊ 5. Positive for MET c.3082+3A>G, EGFR, wild-type EGFR, EGFR activating mutations, elevated circulating HGF levels, c-MET amplification, mutant KRAS, or any combination thereof; optionally, (a) the EGFR activating mutation is a substitution of L718Q, G719A, G719X (wherein X is any amino acid), L861X (wherein X is any amino acid), L858R, E746K, L747S, E749Q, A750P, A755V, V765M, C797S, L858P, or T790M; a deletion of E746 to A750; a deletion of R748 to P753; an insertion of Ala (A) between M766 and A767; an insertion of Ser, Val, and Ala (SVA) between S768 and V769; an insertion of Asn and Ser (NS) 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; or (b) the pharmaceutical composition for use according to any one of claims 1 to 6, wherein the mutant KRAS comprises a G12V, G12C, G12A, G12D substitution, or any combination thereof.

8. 8. The pharmaceutical composition for use according to any one of claims 1 to 7, 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, pharyngeal cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, esophageal cancer, vaginal cancer, cervical cancer, spleen cancer, testicular cancer, thymus cancer, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC), sporadic or hereditary papillary renal cell carcinoma (PRCC), or any combination thereof.

9. 9. The pharmaceutical composition for use according to claim 8, wherein the lung cancer is non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), lung adenocarcinoma, lung sarcomatoid carcinoma, or any combination thereof.

10. The pharmaceutical composition for use according to any one of claims 1 to 9, wherein said method further comprises administering to said subject one or more anti-cancer therapies.

11. the one or more anti-cancer therapies comprise chemotherapy, radiation therapy, surgery, targeted anti-cancer therapy, kinase inhibitor, or any combination thereof; and optionally (a) 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; or (b) The pharmaceutical composition for use according to claim 10, wherein the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

12. The pharmaceutical composition for use according to any one of claims 1 to 11, wherein the c-Met exon 14 skipping mutation is a de novo mutation or an acquired mutation.

13. The method comprises administering the bispecific anti-EGFR / c-Met antibody to: (a) at a dose of about 140 mg to about 1750 mg; (b) at a dose of about 700 mg, about 750 mg, about 800 mg, about 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, or 1400 mg; or (c) twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks; 13. The pharmaceutical composition for use according to any one of claims 1 to 12, comprising administering

14. 1. A pharmaceutical composition for use in a method of treating a subject having a cancer that is positive for a c-Met exon 14 skipping mutation, comprising: the pharmaceutical composition comprises a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody; The method comprises administering to the subject a combination therapy, the combination therapy comprising the pharmaceutical composition and a therapeutically effective amount of a compound of formula (II): 【Chemistry 1】 or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.

15. 1. A pharmaceutical composition for use in a method of treating a subject having a cancer that is positive for a c-Met exon 14 skipping mutation, comprising: The pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (II): 【Chemistry 2】 or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, The method comprises administering to the subject a combination therapy, the combination therapy comprising the pharmaceutical composition and a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody.

16. the bispecific anti-EGFR / c-Met antibody comprises a 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 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; and optionally 16. The pharmaceutical composition for use according to claim 14 or 15, wherein the first domain 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 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.

17. The bispecific anti-EGFR / c-Met antibody is (a) is an IgG1 isotype; (b) comprising a first heavy chain (HC1) comprising the amino acid sequence of SEQ ID NO: 17, a first light chain (LC1) comprising the amino acid sequence of SEQ ID NO: 18, a second heavy chain (HC2) comprising the amino acid sequence of SEQ ID NO: 19, and a second light chain (LC2) comprising the amino acid sequence of SEQ ID NO: 20; or (c) having a biantennary glycan structure with a fucose content of about 1% to about 15%; A pharmaceutical composition for use according to any one of claims 14 to 16.

18. 18. The pharmaceutical composition for use according to any one of claims 14 to 17, wherein the compound of formula (II), or a 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).

19. the subject is relapsed or refractory to treatment with one or more prior anti-cancer therapies, and optionally (a) the one or more prior anti-cancer therapies comprise one or more chemotherapeutic agents, checkpoint inhibitors, targeted anti-cancer agents, kinase inhibitors, or any combination thereof; or (b) The pharmaceutical composition for use of any one of claims 14 to 18, wherein the one or more prior anticancer therapies comprise carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, PD-(L)1 axis inhibitors, EGFR inhibitors, c-Met inhibitors, HER2 inhibitors, HER3 inhibitors, HER4 inhibitors, VEGFR inhibitors, AXL inhibitors, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, sunitinib, or any combination thereof.

20. The pharmaceutical composition for use according to any one of claims 14 to 18, wherein the subject is treatment naive.

21. Cancers positive for c-Met exon 14 skipping mutations include CDK4 amplification, EGFR amplification, KRAS amplification, MDM2 amplification, TERT amplification, and NF1 R2450. ＊ , RAD50 L597Vfs ＊ 5. Positive for MET c.3082+3A>G, EGFR, wild-type EGFR, EGFR activating mutations, elevated circulating HGF levels, c-MET amplification, mutant KRAS, or any combination thereof; optionally, (a) the EGFR activating mutation is a substitution of L718Q, G719A, G719X (X is any amino acid), L861X (X is any amino acid), L858R, E746K, L747S, E749Q, A750P, A755V, V765M, C797S, L858P, or T790M; a deletion of E746 to A750; a deletion of R748 to P753; an insertion of Ala (A) between M766 and A767; an insertion of Ser, Val, and Ala (SVA) between S768 and V769; and H773, an 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; or (b) the mutant KRAS comprises a G12V, G12C, G12A, G12D substitution, or any combination thereof; A pharmaceutical composition for use according to any one of claims 14 to 20.

22. 22. The pharmaceutical composition for use according to any one of claims 14 to 21, 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, pharyngeal cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, esophageal cancer, vaginal cancer, cervical cancer, spleen cancer, testicular cancer, thymus cancer, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC), sporadic or hereditary papillary renal cell carcinoma (PRCC), or any combination thereof.

23. 23. The pharmaceutical composition for use according to claim 22, wherein the lung cancer is non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), lung adenocarcinoma, lung sarcomatoid carcinoma, or any combination thereof.

24. 24. The pharmaceutical composition for use according to any one of claims 14 to 23, wherein said method further comprises administering to said subject one or more anti-cancer therapies.

25. the one or more anti-cancer therapies comprise chemotherapy, radiation therapy, surgery, targeted anti-cancer therapy, kinase inhibitor, or any combination thereof; and optionally (a) 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; or (b) the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib; 25. A pharmaceutical composition for use according to claim 24.

26. The pharmaceutical composition for use according to any one of claims 14 to 25, wherein the c-Met exon 14 skipping mutation is a de novo mutation or an acquired mutation.

27. The bispecific anti-EGFR / c-Met antibody is (a) at a dose of about 140 mg to about 1750 mg; (b) at a dose of about 700 mg, about 750 mg, about 800 mg, about 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, or 1400 mg; or (c) twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks; The pharmaceutical composition for use according to any one of claims 14 to 26, wherein the pharmaceutical composition is used for administration.

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