Combination therapy to treat abnormal cell growth

Abstract

The present invention relates to a method for treating abnormal cell growth (e.g., cancer), a composition and oral dosage form of a KRAS G12C inhibitor combined with a FAK inhibitor and / or a MEK inhibitor, or a dual RAF / MEK inhibitor.For example, provided herein in part is a combination (e.g., a combination of compounds described herein, such as a KRAS G12C inhibitor combined with a FAK inhibitor and / or a MEK inhibitor or a dual RAF / MEK inhibitor), which can be used in a method for treating abnormal cell growth (e.g., cancer) in a subject in need thereof.

Description

[Technical Field]

[0001] Cross-reference to Related Applications This application claims priority and benefit to U.S. Provisional Patent Application No. 62 / 968,615 filed on January 31, 2020, and U.S. Provisional Patent Application No. 63 / 115,433 filed on November 18, 2020, which is incorporated herein by reference in its entirety. [Background Art]

[0002] Background Focal adhesion kinase (FAK), a cytoplasmic non-receptor tyrosine kinase, plays an essential role in cell survival, proliferation, migration, invasion and adhesion (Clark and Brugge 1995, Science 268: 233-239), and convincing evidence suggests that its abnormal activation is associated with increased metastatic potential of tumors (Owens et al. 1995, Cancer Research 55: 2752-2755). Selective inhibitors of certain non-receptor tyrosine kinases or serine / threonine kinases (e.g., cyclin-dependent kinases) such as FAK, ICK, SRC, ABL are useful in the treatment of abnormal cell growth, particularly cancer, in mammals. FAK is also known as protein-tyrosine kinase 2, namely PTK2. It has been reported that FAK expression and / or activity is upregulated in various malignant diseases, including uveal melanoma, and cancers of the thyroid, prostate, cervix, colon, rectum, oral epithelium, ovary and breast.

[0003] Kirsten's rat sarcoma 2 viral oncogene homolog (KRAS) is a small GTPase and a member of the Ras family of oncogenes. KRAS acts as a molecular switch-cycling mechanism between inactive (GDP-bound) and active (GTP-bound) states, transmitting upstream cellular signals received from multiple tyrosine kinases to downstream effectors, regulating a wide range of processes, including cell proliferation (see, e.g., Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401). Mutations in the KRAS gene are common in cancers such as pancreatic cancer, lung adenocarcinoma, colorectal cancer (CRC), gallbladder cancer, thyroid cancer, and cholangiocarcinoma (Kodaz et al., EJMO 2017). KRAS mutations are observed in approximately 30% of patients with lung adenocarcinoma, 40% of patients with CRC, and 67% of patients with pancreatic adenocarcinoma. KRAS is a major driving factor in lung adenocarcinoma and pancreatic cancer, but it is not a primary initiating event in colorectal cancer (McCormick, 2015). Components of the RAS / RAF / MEK / ERK signaling pathway also present opportunities for treating abnormal cell growth, such as cancer. Selective inhibitors of certain components of the RAS / RAF / MEK / ERK signaling pathway, such as RAS, RAF, MEK, and ERK, are useful for treating abnormal cell growth in mammals, particularly cancer. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Alamgeer et al., Current Opin Pharmcol. (2013) 13:394~401 [Overview of the project] [Means for solving the problem]

[0005] Due to the severity and breadth of diseases and disorders associated with abnormal cell growth (e.g., cancer), effective therapeutic means and methods for treatment are needed. The compounds, combinations of compounds, compositions, and methods described herein are intended for this purpose.

[0006] overview For example, combinations (e.g., combinations of compounds described herein, e.g., KRAS G12C inhibitors combined with FAK inhibitors and / or MEK inhibitors or dual RAF / MEK inhibitors) that can be used in methods to treat abnormal cell growth (e.g., cancer) in subjects requiring such treatment are partially provided herein.

[0007] Accordingly, in one embodiment, a method for treating cancer in a subject requiring treatment for cancer is provided herein, comprising the step of administering to the subject a KRAS G12C inhibitor (e.g., ARS-853, ARS-1620, ARS-3248, LY3499446, AMG-510, and MRTX849) or a pharmaceutically acceptable salt thereof in combination with a FAK inhibitor (e.g., defactinib, TAE226, BI-853520 (IN10018), GSK2256098, PF-03814735, BI-4464, VS-4718, and APG-2449) or a pharmaceutically acceptable salt thereof, thereby treating the subject.

[0008] In another embodiment, a method for treating cancer in a subject requiring treatment for cancer, comprising: a KRAS G12C inhibitor (e.g., ARS-853, ARS-1620, ARS-3248, LY3499446, AMG-510, and MRTX849) or a pharmaceutically acceptable salt thereof, and a MEK inhibitor (e.g., trametinib, cobimetinib, binimetinib, selumetinib, PD-325901, CI-1040, CH5126766, MEK162, AZD8330, GDC-0623, refametinib, pima A method is provided herein that includes the step of administering to a subject a combination of seltiveb (e.g., CH5126766) or a pharmaceutically acceptable salt thereof, thereby treating the subject.

[0009] In one embodiment, a method for treating cancer in a subject requiring treatment is disclosed herein, comprising the step of administering to the subject a KRAS G12C inhibitor (e.g., ARS-853, ARS-1620, ARS-3248, LY3499446, AMG-510, and MRTX849) or a pharmaceutically acceptable salt thereof in combination with a dual RAF / MEK inhibitor (e.g., CH5126766) or a pharmaceutically acceptable salt thereof, thereby treating the subject (subjec).

[0010] Similarly, in subjects requiring cancer treatment, a method of treating cancer comprising a KRAS G12C inhibitor (e.g., ARS-853, ARS-1620, ARS-3248, LY3499446, AMG-510, and MRTX849) or a pharmaceutically acceptable salt thereof, a FAK inhibitor (e.g., defactinib, TAE226, BI-853520 (IN10018), GSK2256098, PF-03814735, BI-4464, VS-4718, and APG-2449) or a pharmaceutically acceptable salt thereof, and a MEK inhibitor (e.g., trametinib, cobimetinib, binimetinib, selmetinib) A method is provided herein that includes the step of administering to a subject a combination of (PD-325901, CI-1040, CH5126766, MEK162, AZD8330, GDC-0623, refametinib, pimacertib, WX-554, HL-085, CH4987655, TAK-733, CInQ-03, G-573, PD184161, PD318088, PD98059, RO5068760, U0126 and SL327) or a pharmaceutically acceptable salt thereof, thereby treating the subject.

[0011] In some embodiments, the KRAS G12C inhibitor is selected from the group consisting of ARS-853, ARS-1620, ARS-3248, LY3499446, AMG-510, and MRTX849 or pharmaceutically acceptable salts thereof. In some embodiments, the KRAS G12C inhibitor is AMG-510 or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS G12C inhibitor is MRTX849 or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the FAK inhibitor is selected from the group consisting of defactinib, TAE226, BI-853520 (IN10018), GSK2256098, PF-03814735, BI-4464, VS-4718, and APG-2449 or pharmaceutically acceptable salts thereof. In some embodiments, the FAK inhibitor is defactinib or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the method further includes the step of administering a MEK inhibitor.

[0014] In some embodiments, the MEK inhibitor is selected from the group consisting of trametinib, cobimetinib, binimetinib, selumetinib, PD-325901, CI-1040, CH5126766, MEK162, AZD8330, GDC-0623, refametinib, pimacertib, WX-554, HL-085, CH4987655, TAK-733, CInQ-03, G-573, PD184161, PD318088, PD98059, RO5068760, U0126, and SL327, or pharmaceutically acceptable salts thereof.

[0015] In some embodiments, the MEK inhibitor is a dual RAF / MEK inhibitor.

[0016] In some embodiments, the MEK inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the KRAS G12C inhibitor is administered in doses of approximately 100 mg to approximately 2000 mg. In some embodiments, the KRAS G12C inhibitor is administered once daily. In some embodiments, the KRAS G12C inhibitor is administered twice daily. In some embodiments, the KRAS G12C inhibitor is administered orally.

[0018] In some embodiments, the FAK inhibitor (e.g., defactinib) is administered twice daily. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered once daily. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered in doses of approximately 100 mg to approximately 1000 mg. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered in doses of approximately 200 mg to approximately 400 mg. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered orally.

[0019] In some embodiments, the FAK inhibitor is administered before the KRAS G12C inhibitor is administered. In some embodiments, the FAK inhibitor is administered after the KRAS G12C inhibitor is administered. In some embodiments, the FAK inhibitor is administered concurrently with the KRAS G12C inhibitor.

[0020] In some embodiments, the MEK inhibitor is administered at least once a week (e.g., once a week, twice a week, three times a week, four times a week, five times a week, or six times a week). In some embodiments, the MEK inhibitor is administered once a week. In some embodiments, the MEK inhibitor is administered twice a week. In some embodiments, the MEK inhibitor is administered once a day. In some embodiments, the MEK inhibitor is administered twice a day. In some embodiments, the MEK inhibitor is administered in an amount of from about 0.1 mg to about 100 mg. In some embodiments, the MEK inhibitor is administered orally.

[0021] In some embodiments, the MEK inhibitor is a dual RAF / MEK inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered before the KRAS G12C inhibitor is administered. In some embodiments, the dual RAF / MEK inhibitor is administered after the KRAS G12C inhibitor is administered. In some embodiments, the dual RAF / MEK inhibitor is administered concurrently with the KRAS G12C inhibitor.

[0022] In some embodiments, the cancer is a cancer having a KRAS G12C mutation.

[0023] In some embodiments, the cancer is lung adenocarcinoma, non-small cell lung cancer, colorectal cancer (CRC), uterine endometrioid carcinoma, bladder urothelial carcinoma, invasive lobular breast carcinoma, cervical squamous cell carcinoma, cutaneous melanoma, endocervical adenocarcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma, biphasic type pleural mesothelioma, clear cell renal cell carcinoma, clear cell renal cell carcinoma, gastric adenocarcinoma, tubular stomach adenocarcinoma, uterine carcinosarcoma or uterine malignant mixed Müllerian tumor.

[0024] Other objects and advantages will become apparent to those skilled in the art from consideration of the following detailed description of the invention, examples and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] [Figure 1] Figure 1A shows the synergy score (Loewe model) between VS-6766 and AMG-510 or MRTX849 in KRAS G12C mutant NSCLC and CRC cell lines.

[0026] Figure 1B shows the dose-response of AMG-510 or MRTX849 alone or in combination with VS-6766 (left), and the dose-response of VS-6766 alone or in combination with AMG-510 or MRTX849 (right) on tumor cell line viability in H2122 KRAS G12C mutant NSCLC.

[0027] [Figure 2] Figure 2 shows a heat map presenting the synergy scores (Loewe model) between VS-6766 and AMG-510 or MRTX849 (left), and between defactinib and AMG-510 or MRTX849 (right) in KRAS G12C mutant NSCLC and CRC cell lines.

[0028] [Figure 3]Figure 3 shows immunoblot protein Western analysis of pERK in KRAS G12C mt NSCLC cell lines treated with 100 nM VS-6766 and 100 nM AMG-510 or MRTX849 for 4 and 48 hours, respectively.

[0029] [Figure 4] Figure 4 shows immunoblot protein Western analysis of KRAS pathway targets (pMEK, pERK, and p-p90RSK) in KRAS G12C mt NSCLC cell lines treated with 100 nM VS-6766 and 100 nM AMG-510 or MRTX849 for 4 and 48 hours, respectively.

[0030] [Figure 5] Figure 5 shows immunoblot protein Western analysis of KRAS pathway targets (pMEK and pERK), as well as quantification of pMEK and pERK by Western blot densitometry.

[0031] [Figure 6] Figure 6 shows the change in tumor volume in mice with H2122 tumors treated with VS-6766+ / - FAKi+ / - AMG-510 for 10 days.

[0032] [Figure 7] Figure 7 shows the change in tumor volume in mice with H358 tumors treated with VS-6766+ / - FAKi+ / - AMG-510 for 21 days. [Modes for carrying out the invention]

[0033] Detailed explanation As generally described herein, this disclosure provides methods and combinations of compounds useful for treating abnormal cell growth (e.g., cancer) in subjects requiring such treatment. definition

[0034] "Approximately" and "about" generally mean an acceptable degree of error in the measured quantity, taking into account the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%) of a given value or range of values, typically within 10 percent, and more typically within 5 percent.

[0035] As used herein, “pharmaceutically acceptable salt” means a salt that is free from excessive toxicity, irritation, or allergic reactions, is suitable for use in contact with human and lower animal tissues, and is within the bounds of reasonable medical judgment, with a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids, as well as inorganic and organic bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobio These include sodium sulfates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanoates, and valersates. Pharmaceutically acceptable salts derived from appropriate bases include alkali metals, alkaline earth metals, ammonium and N + (C 1~4This includes alkyl)4 salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Furthermore, pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions such as halide ions, hydroxide ions, carboxylate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions.

[0036] As used herein, “pharmaceutically acceptable carrier” means a non-toxic carrier, agent, or vehicle that does not impair the pharmacological activity of the Compound and is formulated together with the Compound. pharmaceutically acceptable carriers, agents, or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffers (such as phosphates, glycine, sorbic acid, potassium sorbate), partial glyceride mixtures of vegetable saturated fatty acids, water, salts, or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate), polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0037] As used herein, the “subject” to which administration is intended means, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)), and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0038] Diseases, disorders, and conditions are used interchangeably within this specification.

[0039] As used herein, and unless otherwise specified, the terms “to treat,” “to treat,” and “treatment” refer to any action taken while a subject is suffering from a particular disease, disorder, or condition, with the aim of reducing the severity of the disease, disorder, or condition, or delaying or slowing its progression (also known as “therapeutic treatment”).

[0040] Generally, the “effective amount” of a compound refers to an amount sufficient to induce a desired biological response. As is understood by those skilled in the art, the effective amount of the compound of the present invention can vary depending on the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and factors such as the age, weight, health, and condition of the subject.

[0041] As used herein, and unless otherwise specified, “therapeutic dose” of a compound means a sufficient amount to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutic dose of a compound means the amount of the therapeutic agent, either alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term “therapeutic dose” may include amounts that improve overall treatment, alleviate or avoid symptoms or causes of a disease or condition, or enhance the therapeutic effect of another therapeutic agent.

[0042] As used herein, “preventive action” refers to an action taken before a subject begins to develop a particular disease, disorder, or condition.

[0043] As used herein, and unless otherwise specified, “preventive dose” of a compound means an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition. A preventive dose of a compound refers to the amount of the therapeutic agent, either alone or in combination with other agents, that provides a preventive benefit in the prevention of a disease, disorder, or condition. The term “preventive dose” may include an amount that comprehensively improves prevention or enhances the preventive efficacy of another preventive agent.

[0044] The term “oral dosage form” as used herein refers to a composition or medium used to administer a drug to a subject. While oral dosage forms are typically administered orally, “oral dosage form” is intended to encompass any substance administered to a subject and absorbed across the membranes of the digestive tract, such as the mucous membrane, including, for example, the mouth, esophagus, stomach, small intestine, large intestine, and colon. For example, “oral dosage form” includes a solution administered to the stomach via the nutrient duct.

[0045] Treatment method The compound combinations described herein (e.g., FAK inhibitors and / or MEK inhibitors, or KRAS G12C inhibitors combined with dual RAF / MEK inhibitors) and their pharmaceutical compositions are generally useful in methods for treating abnormal cell growth, such as cancer.

[0046] Accordingly, in one embodiment, a method for treating cancer in a subject requiring treatment of cancer is provided herein, comprising the step of administering to the subject a KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof in combination with a FAK inhibitor or a pharmaceutically acceptable salt thereof, thereby treating the subject. In some embodiments, the method further comprises the step of administering a MEK inhibitor.

[0047] In another embodiment, the present invention provides a method for treating cancer in a subject requiring treatment for cancer, comprising the step of administering to the subject a KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof in combination with a MEK inhibitor or a pharmaceutically acceptable salt thereof, thereby treating the subject.

[0048] In one embodiment, a method for treating cancer in a subject requiring treatment is disclosed herein, comprising the step of administering to the subject a KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof in combination with a dual RAF / MEK inhibitor or a pharmaceutically acceptable salt thereof, thereby treating the subject.

[0049] Similarly, the present invention provides a method for treating cancer in a subject requiring treatment for cancer, comprising the step of administering to the subject a KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof in combination with a FAK inhibitor or a pharmaceutically acceptable salt thereof, and a MEK inhibitor or a pharmaceutically acceptable salt thereof, thereby treating the subject.

[0050] In some embodiments of the methods described herein, the response duration to a KRAS G12C inhibitor can be reduced by administering the KRAS G12C inhibitor in combination with a FAK inhibitor and / or a MEK inhibitor to subjects who require it. In some embodiments, the response duration to a KRAS G12C inhibitor can be reduced by administering the KRAS G12C inhibitor in combination with a FAK inhibitor and / or a dual RAF / MEK inhibitor to subjects who require it. In some embodiments, the combinations described herein can improve the depth and / or duration of the response (e.g., antitumor response) in subjects.

[0051] Subjects intended for the methods described herein may be identified (e.g., by screening, e.g., by sequencing) as having the KRAS G12C mutation.

[0052] KRAS G12C inhibitors Examples of KRAS G12C inhibitors include, but are not limited to: MRTX849 (adagrasiv) has the following structure: [ka] The AMG-510 (Sotrasib) has the following structure: [ka] ARS-1620 has the following structure: [ka] ARS-853 has the following structure: [ka] LY3499446(Eli Lilly); and Contains ARS-3248 (Araxes Pharma / Wellspring Biosciences).

[0053] In some embodiments, the KRAS G12C inhibitor is selected from the group consisting of ARS-853, ARS-1620, ARS-3248, LY3499446, AMG-510, and MRTX849 or pharmaceutically acceptable salts thereof. In some embodiments, the KRAS G12C inhibitor is AMG-510 or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS G12C inhibitor is MRTX849 or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the KRAS G12C inhibitor is administered at least once daily. In some embodiments, the KRAS G12C inhibitor is administered once daily. In some embodiments, the KRAS G12C inhibitor is administered twice daily. In some embodiments, the KRAS G12C inhibitor is administered orally.

[0055] In some embodiments, the KRAS G12C inhibitor is administered in doses ranging from approximately 10 mg to approximately 2000 mg, for example, approximately 100 mg to approximately 2000 mg, approximately 100 mg to approximately 1500 mg, approximately 100 mg to approximately 1000 mg, approximately 100 mg to approximately 800 mg, approximately 100 mg to approximately 600 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 200 mg, approximately 200 mg to approximately 2000 mg, approximately 200 mg to approximately 1500 mg, approximately 200 mg to approximately 1000 mg, approximately 200 mg to approximately 800 mg, approximately 200 mg to approximately 600 mg, approximately 200 mg to approximately 400 mg, and approximately 400 mg to approximately 2000 mg. g is administered in doses of approximately 400mg to 1500mg, approximately 400mg to 1000mg, approximately 400mg to 800mg, approximately 400mg to 600mg, approximately 600mg to 2000mg, approximately 600mg to 1500mg, approximately 600mg to 1000mg, approximately 600mg to 800mg, approximately 800mg to 2000mg, 800mg to 1500mg, approximately 800mg to 1000mg, approximately 600mg to 2000mg, approximately 600mg to 1500mg, approximately 600mg to 1000mg, and approximately 600mg to 800mg. In some embodiments, the KRAS G12C inhibitor is administered in doses of approximately 100mg. In some embodiments, the KRAS G12C inhibitor is administered in doses of approximately 200mg. In some embodiments, the KRAS G12C inhibitor is administered at approximately 300 mg. In some embodiments, the KRAS G12C inhibitor is administered at approximately 400 mg. In some embodiments, the KRAS G12C inhibitor is administered at approximately 500 mg. In some embodiments, the KRAS G12C inhibitor is administered at approximately 600 mg. In some embodiments, the KRAS G12C inhibitor is administered at approximately 700 mg. In some embodiments, the KRAS G12C inhibitor is administered at approximately 800 mg. In some embodiments, the KRAS G12C inhibitor is administered at approximately 900 mg. In some embodiments, the KRAS G12C inhibitor is administered at approximately 1000 mg.

[0056] FAK inhibitors Potent inhibitors of FAK protein tyrosine kinase may be used therapeutically in mammals, particularly humans, as antiproliferative agents (e.g., anticancer), antitumor agents (e.g., effective against solid tumors), and anti-angiogenic agents (e.g., halting or inhibiting vascular growth). Compounds described herein, e.g., FAK inhibitors, may be useful in the prevention and treatment of diseases or disorders described herein (e.g., abnormal cell growth, e.g., cancer (e.g., cancers described herein)). Compounds described herein, e.g., FAK inhibitors, may be useful in the prevention and treatment of non-hematological malignancies, malignant and benign tumors of the liver, kidneys, bladder, chest, stomach, ovaries, colorectal, prostate, pancreas, lungs, vulva, and thyroid, various human hyperproliferative disorders such as hepatocellular carcinoma, sarcoma, glioblastoma, head and neck, as well as in the prevention and treatment of other hyperplastic conditions such as benign hyperplasia of the skin (e.g., psoriasis) and benign hyperplasia of the prostate (e.g., BPH), as well as in the prevention and treatment of disorders such as mesothelioma. In some embodiments, the compounds described herein, such as FAK inhibitors, inhibit protein tyrosine kinase 2 (PYK2). Exemplary FAK inhibitors include, but are not limited to, defactinib having the following structures: [ka] or a pharmaceutically acceptable salt thereof. Defactinib is also known as VS-6063 (e.g., free base of VS-6063) or PF-04554878. VS-6063 and related compounds are also disclosed in U.S. Patent No. 7,928,109, the contents of which are incorporated herein by reference. In some embodiments, VS6063 may form a pharmaceutically acceptable salt (e.g., hydrochloride of VS-6063).

[0057] In some embodiments, the FAK inhibitor is VS-4718 having the following structure. [ka] Or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the FAK inhibitor is TAE226 having the following structure [ka]

[0059] Or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the FAK inhibitor has the following structure: GSK2256098 [ka] Or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the FAK inhibitor has the following structure: PF-03814735 [ka] Or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the FAK inhibitor is BI-4464 having the following structure. [ka] Or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the FAK inhibitor is BI-853520 (IN10018; Boehringer Ingelheim). In some other embodiments, the FAK inhibitor is APG-2449 (Ascentage Pharma Group).

[0064] In some embodiments, the FAK inhibitor is selected from the group consisting of defactinib, TAE226, BI-853520, GSK2256098, PF-03814735, BI-4464, VS-4718, and APG-2449, or pharmaceutically acceptable salts thereof. For example, the FAK inhibitor is defactinib or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at least once daily. For example, in some embodiments, the FAK inhibitor (e.g., defactinib) is administered twice daily. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered once daily.

[0066] In some embodiments, the FAK inhibitor (e.g., defactinib) is administered in doses of approximately 100 mg to approximately 1000 mg, for example, approximately 100 mg to approximately 800 mg, approximately 100 mg to approximately 600 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 200 mg, approximately 200 mg to approximately 1000 mg, approximately 400 mg to approximately 1000 mg, approximately 600 mg to approximately 1000 mg, approximately 800 mg to approximately 1000 mg, approximately 200 mg to approximately 800 mg, approximately 200 mg to approximately 600 mg, approximately 200 mg to approximately 400 mg, approximately 400 mg to approximately 800 mg, or approximately 400 mg to approximately 600 mg. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered in doses of approximately 200 mg to approximately 400 mg. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at approximately 100 mg. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at approximately 200 mg. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at approximately 300 mg. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at approximately 400 mg. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at approximately 500 mg. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at approximately 600 mg. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered orally.

[0067] MEK inhibitors MEK inhibitors may be small molecule or biological inhibitors of the mitogen-activated protein kinase (MAPK) enzymes MEK1 and / or MEK2 (e.g., the MAPK / ERK pathway).

[0068] Examples of MEK inhibitors include, but are not limited to, trametinib (also known as mekinist, GSK1120212), which has the following structure: [ka] Cobimetinib (also known as GDC-0973 or XL518) has the following structure: [ka] Binimethinib having the following structure: [ka] CI-1040 (also known as PD184352) has the following structure: [ka] PD-325901 has the following structure: [ka] Selumetinib (also known as AZD6244) has the following structure: [ka] MEK162 has the following structure: [ka] The AZD8330 has the following structure: [ka] TAK-733 has the following structure: [ka] GDC-0623 has the following structure: [ka] Refametinib with the following structure (also known as RDEA119; BAY869766): [ka] Pimasertib (also known as AS4987655) has the following structure: [ka] RO4987655 (also known as CH4987655) has the following structure: [ka] CH5126766 (VS-6766) has the following structure: [ka] CInQ-03 has the following structure: [ka] The G-573 has the following structure: [ka] PD184161 has the following structure: [ka] PD318088 has the following structure: [ka] PD98059 has the following structure: [ka] RO5068760 has the following structure: [ka] SL327 has the following structure: [ka] U0126 has the following structure: [ka] Includes WX-554 (Wilex) and HL-085 (Shanghai Kechow Pharma).

[0069] In some embodiments, the MEK inhibitor is selected from the group consisting of trametinib, cobimetinib, binimetinib, selumetinib, PD-325901, CI-1040, CH5126766, MEK162, AZD8330, GDC-0623, refametinib, pimacertib, WX-554, HL-085, CH4987655, TAK-733, CInQ-03, G-573, PD184161, PD318088, PD98059, RO5068760, U0126, and SL327, or pharmaceutically acceptable salts thereof.

[0070] In some embodiments, the MEK inhibitor is administered at least once a week (for example, once a week, twice a week, three times a week, four times a week, five times a week, or six times a week). In some embodiments, the MEK inhibitor is administered once a week. In some embodiments, the MEK inhibitor is administered twice a week. In some embodiments, the MEK inhibitor is administered once a day. In some embodiments, the MEK inhibitor is administered twice a day. In some embodiments, the MEK inhibitor is administered in doses of approximately 0.1 mg to approximately 100 mg, for example, approximately 0.1 mg to approximately 50 mg, approximately 0.1 mg to approximately 10 mg, approximately 0.1 mg to approximately 5 mg, approximately 0.1 mg to approximately 4 mg, approximately 0.1 mg to approximately 3 mg, approximately 0.1 mg to approximately 2 mg, approximately 0.1 mg to approximately 1 mg, approximately 1 mg to approximately 10 mg, approximately 1 mg to approximately 20 mg, approximately 1 mg to approximately 40 mg, approximately 1 mg to approximately 60 mg, approximately 1 mg to approximately 80 mg, approximately 1 mg to approximately 100 mg, approximately 10 mg to approximately 100 mg, approximately 20 mg to approximately 100 mg, approximately 40 mg to approximately 100 mg, approximately 60 mg to approximately 100 mg, or approximately 80 mg to approximately 100 mg. In some embodiments, the MEK inhibitor is administered in doses of approximately 0.1 mg, 0.2 mg, 0.5 mg, 1 mg, 1.5 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg. In some embodiments, the MEK inhibitor is administered orally.

[0071] In some embodiments, the MEK inhibitor is a dual RAF / MEK inhibitor. In some embodiments, the MEK inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, the dual RAF / MEK inhibitor is administered at least once a week (for example, once a week, twice a week, three times a week, four times a week, five times a week, or six times a week). In some embodiments, the dual RAF / MEK inhibitor is administered once a week. In some embodiments, the dual RAF / MEK inhibitor is administered twice a week. In some embodiments, the dual RAF / MEK inhibitor is administered once a day. In some embodiments, the dual RAF / MEK inhibitor is administered twice a day. In some embodiments, the dual RAF / MEK inhibitor is administered in doses ranging from approximately 0.1 mg to approximately 100 mg. In some embodiments, the dual RAF / MEK inhibitor is administered orally.

[0073] In some embodiments, the dual RAF / MEK inhibitor is administered before the KRAS G12C inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered after the KRAS G12C inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered concurrently with the KRAS G12C inhibitor.

[0074] Diseases and Disabilities Abnormal cell growth As used herein, and unless otherwise indicated, abnormal cell growth refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes (1) tumor cells (tumors) that proliferate, for example, by expressing mutated tyrosine kinases or by overexpression of receptor tyrosine kinases; (2) benign and malignant cells of other proliferative disorders in which abnormal tyrosine kinase activation occurs; (3) any tumor that proliferates, for example, by receptor tyrosine kinases; (4) any tumor that proliferates, for example, by abnormal serine / threonine kinase activation; and (5) growth abnormalities consisting of benign and malignant cells of other proliferative disorders in which abnormal serine / threonine kinase activation occurs. Abnormal cell growth can refer to cell growth in epithelial cells (e.g., carcinomas, adenocarcinomas), mesenchymal cells (e.g., sarcomas (e.g., leiomyosarcomas, Ewing's sarcomas)), hematological cells (e.g., lymphomas, leukemias, spinal cord malformations (e.g., premalignant)), or other cells (e.g., melanomas, mesotheliomas, and other tumors of unknown origin).

[0075] Neoplasm Disorders Abnormal cell growth can refer to neoplasms. A "neoplasm" is a disease or disorder characterized by cells having the ability to grow or replicate autonomously, for example, proliferative cell growth. Abnormal cell growth or division, or an abnormal mass of tissue resulting from a "neoplasm," can be benign, pre-malignant (carcinoma in situ), or malignant (cancer).

[0076] Exemplary neoplasms include carcinomas, sarcomas, metastatic disorders (e.g., tumors originating from the prostate, colon, lung, chest, and liver), hematological neoplasms such as leukemia, and metastatic tumors. Treatment with the compound can be in an amount effective in improving at least one symptom of the neoplasm, such as reducing cell proliferation or decreasing tumor volume.

[0077] cancer The original methods of the present invention may be useful in the prevention and treatment of cancer, including, for example, solid tumors, soft tissue tumors and their metastases. The disclosed methods are also useful in the treatment of non-solid cancers. Exemplary solid tumors include malignant diseases of various organ systems (e.g., sarcomas, adenocarcinomas, and carcinomas), such as those of the lungs, chest, lymphatic system, gastrointestinal tract (e.g., colon), and urogenital tract (e.g., tumors of the kidneys, urothelial or testicular tracts), pharynx, prostate, and ovaries. Exemplary adenocarcinomas include colorectal cancer, renal cell carcinoma, liver cancer (e.g., hepatocellular carcinoma), non-small cell lung cancer, pancreatic cancer (e.g., metastatic pancreatic adenocarcinoma), and small intestine cancer.

[0078] Cancer can include mesothelioma; neurofibromatosis; for example, neurofibromatosis type 2, neurofibromatosis type 1; renal cancer; lung cancer, non-small cell lung cancer; liver cancer; thyroid cancer; ovarian cancer; breast cancer; nervous system tumors; schwannomas; meningiomas; schwannomas; acoustic neuromas; adenoid cystic carcinoma; ependymoma; ependymal tumors, or any other tumors exhibiting decreased and / or mutations in merlin expression, as well as / or deletions and / or promoter hypermethylation of the NF-2 gene. In some embodiments, cancer is renal cancer.

[0079] Cancer may include cancers characterized as containing cancer stem cells, cancer-associated mesenchymal cells, or tumor-origin cancer cells. Cancer may include cancers characterized as being rich in cancer stem cells, cancer-associated mesenchymal cells, or tumor-origin cancer cells (e.g., cells that have undergone epithelial-mesenchymal transition, or tumors rich in metastatic tumors).

[0080] Cancer can be a primary tumor, that is, it can be located at the anatomical site where the tumor growth began. Cancer can also be metastatic, that is, it can appear at at least a second anatomical site other than the anatomical site where the tumor growth began. Cancer can be a recurrent cancer, that is, cancer that recurs after treatment and after a period of time when the cancer is undetectable. Recurrent cancer can be anatomically located locally in the original tumor, for example, anatomically near the original tumor, locally in the original tumor, for example, in lymph nodes located near the original tumor, or distal to the original tumor, for example, in an area away from the original tumor.

[0081] Cancers may also include, but are not limited to, epithelial carcinomas of the chest, lung, pancreas, colorectal (e.g., metastatic colorectal cancer, e.g., metastatic KRAS mutation), prostate, head and neck, melanoma (e.g., locally advanced or metastatic subcutaneous malignant melanoma with NRAS mutation), acute myeloid leukemia, and glioblastoma. Exemplary breast cancers include triple-negative breast cancer, basal-like breast cancer, low-claudin breast cancer, and treatment-resistant, invasive, inflammatory, dysplastic, and advanced HER-2 positive or ER-positive cancers.

[0082] Cancer may also include cancers that have the KRAS G12C mutation.

[0083] Cancer can also include lung adenocarcinoma, colorectal cancer (CRC), endometrioid carcinoma of the uterus, urothelial carcinoma of the bladder, invasive lobular carcinoma of the breast, squamous cell carcinoma of the cervix, cutaneous melanoma, intracervical adenocarcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma, biphasic pleural mesothelioma, clear cell carcinoma of the kidney, clear cell carcinoma of the kidney, gastric adenocarcinoma, tubular gastric adenocarcinoma, uterine carcinosarcoma, or mixed Müller tumor of the uterus.

[0084] Other cancers include, but are not limited to, uveal melanoma, brain, abdominal, esophageal, gastrointestinal, glioma, liver, tongue, neuroblastoma, osteosarcoma, ovarian, retinoblastoma, Wilms' tumor, multiple myeloma, skin, lymphoma, blood and bone marrow cancers (e.g., progressive hematological malignancies, leukemia, e.g., acute myeloid leukemia (e.g., primary or secondary), acute lymphoblastic leukemia, acute lymphoblastic leukemia, T-cell leukemia, hematological malignancies, progressive myeloproliferative disorders, myelodysplastic syndromes, relapsed or refractory multiple myeloma, progressive myeloproliferative disorders), retina, bladder, cervix, kidney, endometrium, meningioma, lymphoma, skin, uterus, lung, non-small cell lung, nasopharyngeal cancer, neuroblastoma, solid tumors, hematological malignancies, squamous cell carcinoma, testicular, thyroid, mesothelioma, brain This includes tumors of the vulva, sarcomas, intestines, oral cavity, endocrine glands, saliva, spermatocytic seminoma of the testis, sporadic medulalry thyroid carcinoma, nonproliferative testicular cells, cancers associated with malignant mast cells, non-Hodgkin lymphoma, and diffuse large B-cell lymphoma.

[0085] In some embodiments, the tumor is a solid tumor. In some embodiments, this solid tumor is locally advanced or metastatic. In some embodiments, this solid tumor is resistant to treatment (e.g., resistant) after standard treatment.

[0086] The methods described herein can alleviate, improve, or completely eliminate the disorder and / or its associated symptoms, prevent exacerbation, slow the rate of progression, or, once initially eliminated, minimize the rate of recurrence of the disorder (i.e., avoid recurrence). Suitable doses and treatment regimens may vary depending on the specific compounds, combinations, and / or pharmaceutical compositions used, as well as the mode of delivery of the compounds, combinations, and / or pharmaceutical compositions. In some embodiments, the methods statistically significant increase the mean length of survival, the mean length of progression-free survival, and / or the rate of recurrence in subjects treated with the combinations described herein.

[0087] In some embodiments, cancer can be lung cancer (e.g., non-small cell lung cancer (NSCLC), e.g., KRAS-mutated NSCLC, metastatic cancer), bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer (e.g., unresectable low-grade ovarian cancer) Ovarian cancer, advanced or metastatic ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer (e.g., triple-negative breast cancer (e.g., breast cancer that does not express genes for estrogen receptor, progesterone receptor (receipter) and Her2 / neu)), uterine cancer, fallopian tube cancer, endometrial cancer, cervix cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis This includes tumors of the axis, brainstem gliomas, pituitary adenomas, mesotheliomas (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma), or one or more combinations of the above cancers. In some embodiments, the cancer is metastatic. In some embodiments, the abnormal cell growth is locally recurrent (e.g., the subject has a locally recurrent disease, e.g., cancer). Additional treatments

[0088] In some embodiments, the methods and compositions described herein are administered in conjunction with additional treatments (e.g., cancer treatments). In one embodiment, a mixture of one or more compounds or pharmaceutical compositions may be administered to a subject in need of it, along with the combinations described herein. In yet another embodiment, one or more compounds or compositions (e.g., pharmaceutical compositions) may be administered with the combinations described herein to treat or prevent a variety of diseases, including, for example, cancer, diabetes, neurodegenerative diseases, cardiovascular diseases, blood clotting, inflammation, flushing, obesity, aging, stress, etc. In various embodiments, a combination therapy comprising the compounds or pharmaceutical compositions described herein may refer to (1) a pharmaceutical composition comprising one or more compounds combined with the combinations described herein, and (2) co-administration of one or more compounds or pharmaceutical compositions described herein with the combinations described herein, in which case the compounds or pharmaceutical compositions described herein are not formulated in the same composition. In some embodiments, the combinations described herein are administered in conjunction with additional treatments (e.g., additional cancer treatments). In some embodiments, additional treatments (e.g., additional cancer treatments) may be administered simultaneously (e.g., at the same time) or sequentially with the same or different compositions. Sequential administration refers to administering one treatment before the administration of an additional treatment, such as a second treatment (e.g., a compound or therapy) (immediately before, less than 5, 10, 15, 30, 45, 60 minutes before, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 hours or more before, 4, 5, 6, 7, 8, 9 days or more before, 1, 2, 3, 4, 5, 6, 7, 8 weeks or more before). The order of administration of the first and second compounds or therapy may also be reversed.

[0089] Exemplary cancer treatments include, for example, chemotherapy, targeted therapies such as antibody therapies, immunotherapy, and hormone therapy. Examples of each of these treatments are provided below.

[0090] chemotherapy In some embodiments, the combinations described herein are administered in conjunction with chemotherapy. Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. "Chemotherapy" usually refers to cytotoxic drugs that affect rapidly dividing cells, as opposed to generally targeted therapies. Chemotherapy drugs interfere with cell division, for example, DNA replication or the separation of newly formed chromosomes, in a variety of possible ways. Most forms of chemotherapy target rapidly dividing cells and are not specific to cancer cells, although some specificity may stem from the fact that normal cells are generally able to repair DNA damage, while many cancer cells lack the ability to repair DNA damage.

[0091] Examples of chemotherapy agents used in cancer treatment include, for example, antimetabolites (e.g., folic acid, purines, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustard, nitrosourea, platinum, alkyl sulfonates, hydrazines, triazines, aziridines, spindle toxins, cytotoxic agents, topoisomerase inhibitors, and others). Examples of drugs include acralubicin, actinomycin, alitretinon, altretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrin, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bexarotene, endamustine, bleomycin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, carbocon, carmofur, carmustine, celecoxib, chlorambucil, chlormethine, cisplatin, cladribine, and clof Farabin, Crisantaspase, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolsin, Docetaxel, Doxorubicin, Efaproxial, Elesclomol, Elsamitrucin, Enocitabine, Epirubicin, Estramustine, Etogluside, Etoposide, Fuluxuridine, Fludarabine, Fluorouracil (5FU), Fotemustine, Gemcitabine, Gliadel implant (Gliadel(implant), hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, irinotecan, ilofluben, ixabepyrone, larotaxel, leucovorin, liposomal doxorubicin, liposomal daunorubicin, ronidamin, lomustine, rucanton, mannosulfan, masopropyl alcohol, melphalan, mercaptopurine, mesna, methotrexate, methyl aminolevulinate Mitobronitol, Mitoguazone, Mitotane, Mitomycin, Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omasetaxin, Ortataxel, Oxaliplatin, Paclitaxel, Pegaspargaze, Pemetrexed, Pentostatin, Pirarubicin, Pixantrone, Plicamycin, Porfimer sodium, Prednimustine, Procarbazine This includes larcitrexed, ranimustine, rubitecan, sapacitabine, semustine, citimazine seradenovec, strataplatin, streptozosin, talaporfin, tegaflu-uracil, temoporfin, temozolomide, teniposide, tesetaxel, testolactone, tetranitrate, thiotepa, thiazophrine, thioguanine, tipifarnib, topotecan, trabectedin, triadicone, triethylenemelamine, triplatin, tretinoin, treosulfan, trophosphamide, uramustine, barrubicin, verteporfin, vinblastine, vincristine, vindesine, vinflunin, vinorelbine, vorinostat, zolubicin, and other cell proliferation inhibitors or cytotoxic agents described herein.

[0092] Some drugs work better together than alone, so two or more drugs are often administered simultaneously or sequentially. Often, two or more chemotherapy agents are used as combination chemotherapy. In some embodiments, these chemotherapy agents (including combination chemotherapy) can be used in combination with the combinations described herein.

[0093] targeted therapy In some embodiments, the combinations described herein are administered in conjunction with targeted therapies. Targeted therapies consist of the use of drugs specific to dysregulated proteins in cancer cells. Small molecule targeted therapies are generally inhibitors of enzyme domains on mutated, overexpressed, or otherwise important proteins within cancer cells. Notable examples include tyrosine kinase inhibitors such as axitinib, bosutinib, cedilanib, desatinib, erlotinib, imatinib, gefitinib, lapatinib, restautinib, nilotinib, semaxanib, sorafenib, sunitinib, and vandetanib, as well as cyclin-dependent kinase inhibitors such as albocidib and cericyclib. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody that specifically binds to proteins on the surface of cancer cells. Examples include trastuzumab (HERCEPTIN®), an anti-HER2 / neu antibody commonly used in breast cancer, and rituximab and tocitumomab, anti-CD20 antibodies commonly used in various B-cell malignancies. Other exemplary antibodies include cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, edrecolomab, and gemtuzumab. Exemplary fusion proteins include aflibercept and denileukin difutitox. In some embodiments, this targeted therapy can be used in combination with the combinations described herein.

[0094] Targeted therapies can also include small peptides acting as "homing devices" that can bind to cell surface receptors or the affected extracellular matrix surrounding the tumor. As the radionuclide decays near the cell, the radionuclide bound to these peptides (e.g., RGD) ultimately kills the cancer cell. One example of such therapies is BEXXAR®.

[0095] immunotherapy In some embodiments, the combinations described herein are administered in conjunction with immunotherapy. Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to stimulate the patient's own immune system to fight tumors. Current methods for generating an immune response against tumors include intracapsular BCG immunotherapy in the case of superficial bladder cancer, as well as the use of interferon and other cytokines to induce immune responses in subjects with renal cell carcinoma and melanoma.

[0096] Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy because the donor's immune cells often attack the tumor in the graft-versus-tumor effect. In some embodiments, this immunotherapy agent can be used in combination with the combinations described herein.

[0097] Hormone therapy In some embodiments, the combinations described are administered in conjunction with hormonal therapies. The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers. Estrogen or testosterone removal or blockade is often an important additional treatment. In some cancers, the administration of hormonal agonists such as progestogens may be therapeutically beneficial. In some embodiments, this hormonal therapy can be used in combination with the combinations described herein.

[0098] Radiation therapy The combinations described herein can be used in combination with directed energy or particle or radioisotope therapy, such as radiotherapy or radiation oncology, for the treatment of proliferative disorders, such as cancer, such as cancers associated with cancer stem cells. The combinations described herein may be administered simultaneously or sequentially to a subject together with directed energy or particle or radioisotope therapy. For example, the combinations described herein may be administered before, during, or after directed energy or particle or radioisotope therapy, or any combination thereof. Directed energy or particle therapy may include whole-body irradiation, localized irradiation, or point irradiation. Directed energy or particles may originate from accelerators, synchrotrons, nuclear reactions, vacuum tubes, lasers, or radioisotopes. This therapy may include external beam radiotherapy, remote radiotherapy, close-range radiotherapy, sealed source radiation therapy, whole-body radioisotope therapy, or unsealed source radiotherapy. This treatment may involve the ingestion or placement of radioactive isotopes, such as radioactive iodine, cobalt, cesium, potassium, bromine, fluorine, or carbon, or their proximal regions. External beam irradiation may involve exposure to directed alpha particles, electrons (e.g., beta particles), protons, neutrons, positrons, or photons (e.g., radio waves, millimeter waves, microwaves, infrared radiation, visible light, ultraviolet radiation, X-rays, or gamma-ray photons). Radiation may target any part of the subject requiring treatment.

[0099] surgery The combinations described herein can be used in combination with surgery, such as surgical examination, intervention, or biopsy, for the treatment of proliferative disorders, such as cancer, such as cancer related to cancer stem cells. The combinations described herein may be administered to the subject simultaneously or sequentially with surgery. For example, the combinations described herein may be administered before (preoperative), during or after (postoperative), or in combination thereof. The surgery may be a biopsy while one or more cells are collected for further analysis. The biopsy may be performed using, for example, a scalpel, needle, catheter, endoscope, spatula, or scissors. The biopsy may be an excision biopsy, incision biopsy, core biopsy, or needle biopsy, such as a needle aspiration biopsy. The surgery may include the removal of local tissue suspected of being or identified as cancerous. For example, the procedure may include the removal of a cancerous lesion, lump, polyp, or nevus. The procedure may include the removal of a large amount of tissue, such as breast, bone, skin, fat, or muscle. The procedure may include the removal of an organ or segment, such as the lungs, throat, tongue, bladder, cervix, ovaries, testes, lymph nodes, liver, pancreas, brain, eyes, kidneys, gallbladder, stomach, colon, rectum, or part or all of the intestines. In one embodiment, the cancer is breast cancer, such as triple-negative breast cancer, and the surgery is a mastectomy or rampectomy.

[0100] Anti-inflammatory drugs The combinations described herein may be administered together with anti-inflammatory agents. Anti-inflammatory agents include, but are not limited to, non-steroidal anti-inflammatory agents (e.g., salicylates (aspirin (acetylsalicylic acid), diflunisal, salsalate), propionic acid derivatives (ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, loxoprofen), acetate derivatives (indomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone), enolic acid (oxicam) derivatives (piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam). This may include cam), fenamic acid derivatives (fename) (mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (coxib) (celecoxib), and sulfonanilides (nimeslide). It may also include steroids (e.g., hydrocortisone (cortisol), cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone).

[0101] Pain relievers Analgesics include, but are not limited to, opiates (e.g., morphine, codeine, oxycodone, hydrocodone, dihydromorphine, pethidine, buprenorphine, tramadol, venlafaxine), paracetamol, and nonsteroidal anti-inflammatory drugs (e.g., salicylates (aspirin (acetylsalicylic acid), diflunisal, salsalate), propionic acid derivatives (ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxycoxine), This may include saprozin (loxoprofen), acetate derivatives (indomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone), enolic acid (oxicam) derivatives (piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam), fenamic acid derivatives (fenamet) (mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (coxib-type) (celecoxib), and sulfonanilide-type (nimeslide).

[0102] Antiemetics The combinations described herein may be administered with antiemetics. Antiemetics include, but are not limited to, 5-HT3 receptor antagonists (drasetron (Anzemet), granisetron (Kytril, Sancuso), ondansetron (Zofran), tropisetron (Navoban), palonosetron (Aloxi), mirtazapine (Remeron)), dopamine antagonists (domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, promethazine, prochlorpalazine, metoclopramide (Reglan), arizaprid, prochlorperazine (Compazine, Stemz)). This may include drugs such as ine, Buccastem, Stemetil, Phenotil), NK1 receptor antagonists (aprepitant (Emend)), antihistamines (cyclizine, diphenhydramine (Benadryl), dimenhydrinate (Gravol, Dramamine), meclozine (Bonine, Antivert), promethazine (Pentazine, Phenergan, Promacot), hydroxyzine), benzodiazapines (lorazepam, midazolam), anticholinergics (hyostine), and steroids (dexamethasone).

[0103] combination The phrase "in combination with" and the terms "co-administration," "co-administering," or "co-providing," as used herein, in the context of the administration of the compounds or treatments described herein, mean that two (or more) different compounds or treatments are delivered to a subject while the subject is in the course of illness due to a disease or disorder (e.g., a disease or disorder described herein, e.g., cancer), for example, that two (or more) different compounds or treatments are delivered to the subject after the subject has been diagnosed with a disease or disorder (e.g., a disease or disorder described herein, e.g., cancer) and before the disease or disorder is cured or eliminated, or before treatment is discontinued for any other reason.

[0104] In some embodiments, the delivery of one compound or treatment is still occurring when the delivery of a second one is initiated, resulting in an overlap in administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery.” In other embodiments, the delivery of one compound or treatment is completed before the delivery of the other compound or treatment is initiated. In any case, in some embodiments, the above treatment (e.g., administration of a compound, composition, or treatment) becomes more effective for combination administration. For example, the second compound or treatment is more effective. For example, an equivalent effect is observed with less of the second compound or treatment than would be observed if the second compound or treatment were administered in the absence of the first compound or treatment, or the symptoms are reduced to a greater extent with the second compound or treatment, or a similar situation is observed when using the first compound or treatment. In some embodiments, the delivery is such that the reduction in symptoms or other parameters related to the disorder is greater than that would be observed with one compound or treatment delivered in the absence of the other. The effects of two compounds or treatments may be partially additive, entirely additive, or more than additive (e.g., synergistic). Their delivery may be such that the first compound or treatment being delivered is still detectable when the second is delivered.

[0105] In some embodiments, the first compound or treatment and the second compound or treatment may be administered simultaneously (e.g., at the same time) or sequentially in the same or separate compositions. Sequential administration refers to administering one compound or treatment before an additional administration, for example, the second compound or treatment (e.g., immediately before, less than 5, 10, 15, 30, 45, 60 minutes before, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 hours before or earlier, 4, 5, 6, 7, 8, 9 days before or earlier, 1, 2, 3, 4, 5, 6, 7, 8 weeks before or earlier). The order of administration of the first and second compounds or treatments may also be reversed.

[0106] The combinations described herein may be for abnormal cell growth, for example, first-line treatment of cancer (i.e., used in patients who have not previously received another drug intended to treat cancer); second-line treatment of cancer (i.e., used in subjects who have previously received another drug intended to treat cancer and require it); or third or fourth treatment of cancer (i.e., used in subjects who have previously received two or three other drugs intended to treat cancer).

[0107] In some embodiments, FAK inhibitors and KRAS G12C inhibitors are administered in amounts (e.g., doses) that produce a synergistic (e.g., therapeutic) effect.

[0108] In some embodiments, the FAK inhibitor is administered before the KRAS G12C inhibitor. In some embodiments, the FAK inhibitor is administered after the KRAS G12C inhibitor. In some embodiments, the FAK inhibitor is administered concurrently with the KRAS G12C inhibitor.

[0109] In some embodiments, KRAS G12C inhibitors and MEK inhibitors are administered in amounts (e.g., doses) that produce a synergistic (e.g., therapeutic) effect.

[0110] In some embodiments, the MEK inhibitor is administered before the KRAS G12C inhibitor. In some embodiments, the MEK inhibitor is administered after the KRAS G12C inhibitor. In some embodiments, the MEK inhibitor is administered concurrently with the KRAS G12C inhibitor.

[0111] In some embodiments, FAK inhibitors, KRAS G12C inhibitors, and MEK inhibitors are administered in amounts (e.g., doses) that produce a synergistic (e.g., therapeutic) effect. In some embodiments, MEK inhibitors and FAK inhibitors are administered concurrently with KRAS G12C inhibitors.

[0112] Dosage and administration The combinations of the present invention can be administered orally, parenterally, topically, rectally, or via an implantable laser bar, preferably by oral or injectable administration. In some cases, the pH of the composition (e.g., a pharmaceutical composition) can be adjusted with a pharmaceutically acceptable acid, base, or buffer to enhance the stability or efficacy of the composition.

[0113] In some embodiments, the subject is administered the composition (e.g., the pharmaceutical composition) orally. In some embodiments, the composition (e.g., the pharmaceutical composition) is administered orally in any orally acceptable dosage form, including, but not limited to, liquid gel tablets or capsules, syrups, emulsions, and aqueous suspensions. The liquid gel may contain gelatin, plasticizers, and / or opacifiers, if necessary to achieve a suitable viscosity, and may be coated with an enteric coating approved for use, such as shellac. When used for oral administration, additional thickeners, such as gum, e.g., xanthan gum, starch, e.g., corn starch, or gluten, may be added to achieve the desired viscosity of the composition (e.g., the pharmaceutical composition). If desired, certain sweeteners and / or flavoring agents and / or colorants may be added.

[0114] In some embodiments, subjects are administered a composition (e.g., a pharmaceutical composition) in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, solutions, and suspensions. The composition (e.g., a pharmaceutical composition) may also be in a unit dosage form suitable for a single dose of a precise amount. In addition to the compounds described herein, the pharmaceutical composition may contain pharmaceutically acceptable carriers, such as stabilizers, excipients, binders, and lubricants. Furthermore, the tablet may contain other medical or pharmaceutical agents, carriers, and / or adjuvants. An exemplary pharmaceutical composition includes a compressed tablet (e.g., a directly compressed tablet).

[0115] Tablets containing an active or therapeutic ingredient (e.g., compounds described herein) are also provided. In addition to the active or therapeutic ingredient, the tablets may contain several inactive substances, such as carriers. Pharmaceutically acceptable carriers can be sterile liquids such as water and oil, including those of petroleum, animal, plant, or synthetic origin (e.g., peanut oil, sesame oil). Salt solutions and aqueous dextrose can also be used as liquid carriers. Thus, oral dosage forms for use according to the present invention can be formulated in the conventional manner using one or more pharmaceutically acceptable carriers, including additives and auxiliaries, which facilitate the processing of the active ingredient into a pharmaceutically usable preparation.

[0116] Additives can impart good powder flow and compressibility characteristics to materials being compressed. Examples of additives are described, for example, in the Handbook of Pharmaceutical Excipients (5th edition), edited by Raymond C Rowe, Paul J. Sheskey, and Sian C. Owen; published by Pharmaceutical Press.

[0117] For oral administration, the active ingredient, for example, the compounds described herein, can be readily formulated by combining the active ingredient with a pharmaceutically acceptable carrier well known in the art. Such carriers enable the formulation of the active ingredient of the present invention for oral administration by a subject as tablets, pills, capsules, liquids, gels, syrups, slurries, powders or granules, suspensions or solutions in aqueous or non-aqueous media, etc. Pharmacological preparations for oral use can be obtained, for example, by using solid additives, optionally grinding the resulting mixture, processing the granular mixture, and adding suitable adjuvants if desired, to obtain tablets. Appropriate additives such as excipients, binders or disintegrants may be desirable.

[0118] Dosage can vary depending on the dosage form used and the route of administration utilized. The exact formulation, route of administration, and dosage may be selected by the individual physician, taking into account the patient's condition (for example, Fingl et al., 1975, "The Pharmacological See "Basis of Therapeutics"). Lower or higher doses than those listed above may be required. The specific dosage and treatment regimen for any particular subject depends on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, administration time, elimination rate, drug combinations, severity and course of the disease, condition or symptom, the subject's susceptibility to the disease, condition or symptom, and the judgment of the treating physician. A course of treatment may include one or more separate administrations of the compounds described herein. A course of treatment may include one or more cycles of the compounds described herein.

[0119] In some embodiments, a cycle, as used herein in the context of a cycle of drug administration, refers to the period over which a drug is administered to a patient. For example, if a drug is administered over a 21-day cycle, this cyclical administration would be, for example, administered daily or twice daily for 21 days. A drug may be administered over more than one cycle. Rest periods may be provided between each cycle. Rest cycles can be of a length of 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 1, 2, 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks or longer.

[0120] Oral dosage forms may, if desired, be presented in packs or dispenser devices such as FDA-approved kits, which may contain one or more unit dosage forms containing the active ingredient. These packs may include, for example, metal or plastic foil, such as blister packs. The packs or dispenser devices may be accompanied by instructions for administration. The packs or dispensers may also be accompanied by cautionary notes in a form prescribed by the government agency regulating the manufacture, use, or sale of the drug, which reflect the agency's approval of the composition in form or for human or veterinary administration. Such cautionary notes may, for example, be labeling approved by the U.S. Food and Drug Administration for prescription drugs, or approved product inserts. [Examples]

[0121] Examples are provided below to allow for a more complete understanding of the inventions described herein. The examples described herein are presented to illustrate the pharmaceutical compositions and methods provided herein and should not be construed as limiting their scope.

[0122] The following abbreviations may be used in the following examples: DMSO: dimethyl sulfoxide; HPCD: 2-hydroxypropyl-beta-cyclodextrin; HPMC: hydroxypropyl methylcellulose; PO: oral; QD: once daily; BID: twice daily; G12Ci: G12C inhibitor; FAKi: FAK inhibitor

[0123] (Example 1) Synergistic antitumor efficacy of the dual RAF / MEK inhibitor VS-6766 and the KRAS G12C inhibitor in a preclinical solid tumor model. This study investigates whether vertical pharmacological blockade of RAS, RAF, and MEK by a G12C inhibitor combined with a dual RAF / MEK inhibitor (e.g., VS-6766) + / -FAK inhibitor, as intended by the inventors, results in superior pathway blockade and antitumor efficacy.

[0124] material and method In vitro 3D proliferation assay KRAS G12C mutant NSCLC (H2122, H358, H2030, H1373) and colorectal cancer (CRC; SW837 and SW1463) were used. Briefly, 96-well plates were coated with 50 μL of Matrigel (100%) and incubated at 37°C and 5% CO2 for 30 minutes to solidify the Matrigel. Cells were seeded in 100 μL of medium containing 2% Matrigel. After incubating the cells overnight (17-22 hours), they were treated with VS-6766+ / -G12C inhibitor + / - defactinib for 7 days. Cell viability was measured using the CellTiter-Glo 3D assay. Combination effects were evaluated by comparing the mean viability / inhibition against two different null reference models derived from the activity of the single agent. Bliss, Loewe, and Highest Single Agent synergy analyses were performed to determine synergy scores.

[0125] Western blot KRAS G12C mutant NSCLC cells (H2122, H358, H1373, and SW1573) were seeded in 10 cm dishes. After incubation overnight (17–22 hours), the cells were treated with 100 nM VS-6766 + / - 100 nM G12C inhibitor. Cells were harvested 4 hours and 48 hours after treatment with the compound, and cell lysates were prepared using RIPA buffer containing a protease inhibitor. Western blot assays were performed using antibodies against pMEK, MEK, pERK, ERK, p-p90RSK, p90RSK, and actin.

[0126] Xenograft tumor mouse study KRAS G12C mutant NSCLC H2122 and H358 tumor cells, as well as Balb / c nude mice, were used. 1 × 10⁶ cells were placed in the right flank of the recipient mice. 7 Tumor challenge was initiated by subcutaneous inoculation of a suspension of tumor cells. Tumor size (mm) 3 Body weight and weight were measured three times a week during the duration of this study. During routine monitoring, animals were observed for any effects of tumor growth and treatment on normal behavior, including mobility, food and water intake (visual only), and weight gain / loss, eye / hair matting, and any other abnormal behavior.

[0127] For pharmacodynamic studies, the tumor was initially 200-300 mm in size. 3 Upon reaching the average volume, the mice were divided into four groups (n=5): Vehicle 1 (5% DMSO, 10% HPCD in sterile water) + Vehicle 2 (2% HPMC, 1% Tween® 80 in sterile water), VS-6766 (0.3 mg / kg PO QD, 5 days) in Vehicle 1 + Vehicle 2, AMG-510 (30 mg / kg PO QD, 5 days) in Vehicle 2 + Vehicle 1, and VS-6766 + AMG-510.

[0128] For efficacy studies, the tumor was initially 150-200 mm in size. 3Upon reaching the average volume, the mice were classified into 10 groups (n=10): Vehicle 1 (5% DMSO, 10% HPCD in sterile water) + Vehicle 2 (2% HPMC, 1% Tween® 80 in sterile water), VS-6766 in Vehicle 1 (0.3 mg / kg PO QD, 28 days) + Vehicle 2, AMG-510 in Vehicle 2 (30 mg / kg PO QD, 28 days) + Vehicle 1, VS-6766 + AMG-510, VS-4718 (0.5% CMC-Na, 0.1% Tween® 80 in sterile water) (50 mg / kg PO BID (28 days) + Vehicle 2, VS-4718 + VS-6766, VS-4718 + AMG-510, VS-4718 + AMG-510 + VS-6766, Trametinib (0.3 mg / kg PO QD, 28 days) (0.5% hydroxypropyl methylcellulose and 0.2% Tween®-80 (pH 8.0) in distilled water) + Vehicle 2, and Trametinib + AMG-510. Mice were used in a study with tumor volume > 2,000 mm². 3 When that happened, they euthanized it.

[0129] result In in vitro 3D proliferation assays, VS-6766 was synergistic with both sotrasib and adagrasib in reducing the survival of a panel of KRAS G12C mt NSCLC and colorectal cancer cell lines (Figures 1 and 2). In Figure 1B, the effects of the drugs were analyzed using the Loewe additive model to determine whether the combined effect reflected an addition of individual drug responses (blue line (middle line): expected cancer growth inhibition, or synergistic effect if the drugs are simply additive; red line (lower line): deviation from the blue line (middle line) and indicating synergy). In Figure 2, defactinib also showed synergistic effects with both sotrasib and adagrasib in reducing the survival of a panel of KRAS G12C mt NSCLC and colorectal cancer cell lines.

[0130] Therefore, VS-6766 effectively suppresses RAS pathway signaling (pMEK, pERK, p-p90RSK) as a monotherapy across the entire KRAS-G12C NSCLC cell line, and the VS-6766 + G12Ci combination improved the depth and duration of RAS pathway signaling compared to G12Ci alone (Figures 3 and 4). Figure 3 shows that pERK inhibition with VS-6766 + G12C inhibitor is superior to MRTX849 or AMG-510 alone across the entire panel of KRAS G12C mt NSCLC cell lines. Figure 4 shows that the addition of VS-6766 to AMG-510 or MRTX849 increases the depth and duration of MEK / ERK signaling inhibition compared to the G12C inhibitor alone across the entire panel of KRAS G12C mt NSCLC cell lines. Similarly, in the H2122 KRAS G12C NSCLC xenograft model, VS-6766, when combined with sotrasib, improved pMEK and pERK inhibition in tumors compared to sotrasib alone (Figure 5). 0.3 mg / kg of VS-6766, 30 mg / kg of AMG-510, or a combination thereof, was administered daily for 5 days via oral gastric tube feeding to mice (n=5 / group) carrying H21222 cell line xenografts. Tumors were collected 2, 8, and 24 hours after the final dose.

[0131] In H2122 KRAS G12C mutant NSCLC, VS-6766 and FAKi activate the efficacy of AMG-510 in vivo (Figure 6). In the H2122 KRAS G12C mt NSCLC xenograft model, the combination of VS-6766 (0.3 mg / kg QD) and sotrasib (30 mg / kg QD) enhanced tumor growth inhibition, while trametinib (0.3 mg / kg QD) was far less effective in enhancing the efficacy of sotrasib. Sotrasib monotherapy induced >20% tumor regression in 0 / 10 mice, while combinations of VS-6766, trametinib, or FAK inhibitors with sotrasib induced tumor regression in 5 / 10, 1 / 10, and 4 / 10 mice, respectively, after 10 days of treatment. Notably, the triple combination of VS-6766, sotracib, and a FAK inhibitor resulted in ≥35% tumor reduction in 10 / 10 mice. Similar results were observed in the H358 KRAS G12C mt NSCLC model (Figure 7).

[0132] conclusion VS-6766, as monotherapy, provides vertical blockade of the RAS pathway. A synergistic effect of VS-6766 + G12Ci was observed across KRAS-G12C mt NSCLC and CRC cell lines. The VS-6766 combination provides superior ERK pathway blockade in vitro and in vivo compared to G12Ci alone. Both VS-6766 and FAKi enhance the efficacy of G12Ci in H2122 and H358 xenograft models. The triple combination of G12Ci + VS-6766 + FAKi resulted in tumor regression in all mice. These results support the clinical evaluation of dual RAF / MEK inhibitors (e.g., VS-6766) ± FAK inhibitors (e.g., defactinib) combined with a G12C inhibitor for the treatment of KRAS G12C mt NSCLC and CRC.

[0133] Equivalents and range In the claims, articles such as “a,” “an,” and “the” can mean one or more unless otherwise stated or the context makes it obvious. A claim or statement containing “or” between one or more components of a group is considered satisfied unless otherwise stated or the context makes it obvious that one, more or all components of that group are present in, used in, or otherwise related to a given product or process. The present invention includes embodiments in which exactly one component of that group is present in, used in, or otherwise related to a given product or process. The present invention includes embodiments in which more than one or all of the components of that group are present in, used in, or otherwise related to a given product or process.

[0134] Furthermore, the present invention encompasses all variations, combinations, and modifications, in which case one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims may be derived into another claim. For example, any claim that depends on another claim may be modified to include one or more limitations found in any other claim that depends on the same basic claim. Where elements are presented as a list, for example in the form of a group of marks, each of the subgroups of these elements is also disclosed, and any element may be removed from this group. In general, where the present invention or an aspect of the present invention is referred to as including certain elements and / or features, it should be understood that certain embodiments of the present invention or aspects of the present invention consist of, or are essentially derived from, such elements and / or features. For the sake of simplicity, such embodiments are not specifically described in precise terms herein. It should also be noted that the terms “including” and “containing” are intended to be open and allow for the inclusion of further elements or steps. Where a scope is indicated, it includes the endpoints. Furthermore, unless otherwise indicated or is obvious from the context and the understanding of those skilled in the art, values ​​expressed as ranges may refer to any specific value or subrange within the ranges specified in the various embodiments of the present invention, up to one-tenth of the lower limit of that range, unless the context clearly specifies otherwise.

[0135] This application references various granted patents, published patent applications, academic papers, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any of the incorporated references and this specification, this specification shall prevail. Furthermore, any particular embodiment of the Invention that falls within the scope of the prior art may be expressly excluded from any one or more of the claims. Such embodiments are considered to be known to those skilled in the art, and therefore may be excluded even if this exclusion is not expressly described herein. Any particular embodiment of the Invention may be excluded from any claim for any reason, whether or not it relates to the existence of the prior art.

[0136] Those skilled in the art will be able to identify or elucidate many equivalents to the specific embodiments described herein by conventional experimentation alone. The scope of the embodiments of the present invention described herein is not intended to be limited to the foregoing description, but rather as described in the appended claims. Those skilled in the art will understand that various changes and modifications to this description can be made without departing from the spirit or scope of the invention, as defined in the following claims. The present invention provides, for example, the following items: (Item 1) A method for treating cancer in a subject requiring cancer treatment, and KRAS A method comprising the step of administering to a subject a G12C inhibitor or a pharmaceutically acceptable salt thereof in combination with a FAK inhibitor or a pharmaceutically acceptable salt thereof, thereby treating the subject. (Item 2) The method according to item 1, wherein the FAK inhibitor is selected from the group consisting of defactinib, TAE226, BI-853520 (IN10018), GSK2256098, PF-03814735, BI-4464, VS-4718, and APG-2449 or pharmaceutically acceptable salts thereof. (Item 3) The method according to item 1 or 2, wherein the FAK inhibitor is defactinib or a pharmaceutically acceptable salt thereof. (Item 4) The method according to any one of items 1 to 3, wherein the KRAS G12C inhibitor is selected from the group consisting of ARS-853, ARS-1620, ARS-3248, LY3499446, AMG-510, and MRTX849 or pharmaceutically acceptable salts thereof. (Item 5) The method according to any one of items 1 to 4, wherein the KRAS G12C inhibitor is AMG-510 or a pharmaceutically acceptable salt thereof. (Item 6) The method according to any one of items 1 to 4, wherein the KRAS G12C inhibitor is MRTX849 or a pharmaceutically acceptable salt thereof. (Item 7) The method according to any one of items 1 to 6, further comprising the step of administering a MEK inhibitor. (Item 8) The method according to item 7, wherein the MEK inhibitor is selected from the group consisting of trametinib, cobimetinib, binimetinib, selumetinib, PD-325901, CI-1040, CH5126766, MEK162, AZD8330, GDC-0623, refametinib, pimacertib, WX-554, HL-085, CH4987655, TAK-733, CInQ-03, G-573, PD184161, PD318088, PD98059, RO5068760, U0126, and SL327 or pharmaceutically acceptable salts thereof. (Item 9) The method according to item 7, wherein the MEK inhibitor is a dual RAF / MEK inhibitor. (Item 10) The method according to any one of items 7 to 9, wherein the MEK inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof. (Item 11) The method according to any one of items 1 to 10, wherein the FAK inhibitor (e.g., defactinib) is administered twice daily. (Item 12) The method according to any one of items 1 to 10, wherein the FAK inhibitor (e.g., defactinib) is administered once daily. (Item 13) The method according to any one of items 1 to 12, wherein the FAK inhibitor (e.g., defactinib) is administered in a dose of approximately 100 mg to approximately 1000 mg. (Item 14) The method according to any one of items 1 to 13, wherein the FAK inhibitor (e.g., defactinib) is administered in a dose of approximately 200 mg to approximately 400 mg. (Item 15) The method according to any one of items 1 to 14, wherein the FAK inhibitor (e.g., defactinib) is administered orally. (Item 16) The method according to any one of items 1 to 15, wherein the KRAS G12C inhibitor is administered in a dose of approximately 100 mg to approximately 2000 mg. (Item 17) The method according to any one of items 1 to 16, wherein the KRAS G12C inhibitor is administered once daily. (Item 18) The method according to any one of items 1 to 16, wherein the KRAS G12C inhibitor is administered twice daily. (Item 19) The method according to any one of items 1 to 18, wherein the KRAS G12C inhibitor is administered orally. (Item 20) The method according to any one of items 1 to 19, wherein the FAK inhibitor is administered before the KRAS G12C inhibitor is administered. (Item 21) The method according to any one of items 1 to 19, wherein the FAK inhibitor is administered after the KRAS G12C inhibitor is administered. (Item 22) The method according to any one of items 1 to 19, wherein the FAK inhibitor is administered concurrently with the KRAS G12C inhibitor. (Item 23) The method according to any one of items 7 to 22, wherein the MEK inhibitor is administered at least once a week (for example, once a week, twice a week, three times a week, four times a week, five times a week, or six times a week). (Item 24) The method according to any one of items 7 to 23, wherein the MEK inhibitor is administered once a week. (Item 25) The method according to any one of items 7 to 23, wherein the MEK inhibitor is administered twice a week. (Item 26) The method according to any one of items 7 to 22, wherein the MEK inhibitor is administered once daily. (Item 27) The method according to any one of items 7 to 22, wherein the MEK inhibitor is administered twice daily. (Item 28) The method according to any one of items 7 to 27, wherein the MEK inhibitor is administered in an amount of approximately 0.1 mg to approximately 100 mg. (Item 29) The method according to any one of items 7 to 28, wherein the MEK inhibitor is administered orally. (Item 30) The method according to any one of items 7 to 29, wherein the FAK inhibitor is defactinib or a pharmaceutically acceptable salt thereof, the KRAS G12C inhibitor is MRTX849 or a pharmaceutically acceptable salt thereof, and the MEK inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof. (Item 31) The method according to any one of items 7 to 29, wherein the FAK inhibitor is defactinib or a pharmaceutically acceptable salt thereof, the KRAS G12C inhibitor is AMG-510 or a pharmaceutically acceptable salt thereof, and the MEK inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof. (Item 32) A method for treating cancer in a subject requiring cancer treatment, and KRAS A method comprising the step of administering to a subject a G12C inhibitor or a pharmaceutically acceptable salt thereof in combination with a dual RAF / MEK inhibitor or a pharmaceutically acceptable salt thereof, thereby treating the subject. (Item 33) The method according to item 32, wherein the KRAS G12C inhibitor is selected from the group consisting of ARS-853, ARS-1620, ARS-3248, LY3499446, AMG-510, and MRTX849 or pharmaceutically acceptable salts thereof. (Item 34) The method according to item 32 or 33, wherein the KRAS G12C inhibitor is AMG-510 or a pharmaceutically acceptable salt thereof. (Item 35) The method according to item 32 or 33, wherein the KRAS G12C inhibitor is MRTX849 or a pharmaceutically acceptable salt thereof. (Item 36) The method according to any one of items 32 to 35, wherein the dual RAF / MEK inhibitor is CH5126766 or a pharmaceutically acceptable salt thereof. (Item 37) The method according to any one of items 32 to 36, wherein the KRAS G12C inhibitor is administered in a dose of approximately 100 mg to approximately 2000 mg. (Item 38) The method according to any one of items 32 to 37, wherein the KRAS G12C inhibitor is administered once daily. (Item 39) The method according to any one of items 32 to 37, wherein the KRAS G12C inhibitor is administered twice daily. (Item 40) The method according to any one of items 32 to 39, wherein the KRAS G12C inhibitor is administered orally. (Item 41) The method according to any one of items 32 to 40, wherein the dual RAF / MEK inhibitor is administered at least once a week (for example, once a week, twice a week, three times a week, four times a week, five times a week, or six times a week). (Item 42) The method according to any one of items 32 to 41, wherein the dual RAF / MEK inhibitor is administered once a week. (Item 43) The method according to any one of items 32 to 41, wherein the dual RAF / MEK inhibitor is administered twice a week. (Item 44) The method according to any one of items 32 to 41, wherein the dual RAF / MEK inhibitor is administered once daily. (Item 45) The method according to any one of items 32 to 41, wherein the dual RAF / MEK inhibitor is administered twice daily. (Item 46) The method according to any one of items 32 to 45, wherein the dual RAF / MEK inhibitor is administered in a dose of approximately 0.1 mg to approximately 100 mg. (Item 47) The method according to any one of items 32 to 46, wherein the dual RAF / MEK inhibitor is administered orally. (Item 48) The method according to any one of items 32 to 47, wherein the dual RAF / MEK inhibitor is administered before the KRAS G12C inhibitor is administered. (Item 49) The method according to any one of items 32 to 47, wherein the dual RAF / MEK inhibitor is administered after the KRAS G12C inhibitor is administered. (Item 50) The method according to any one of items 32 to 47, wherein the dual RAF / MEK inhibitor is administered concurrently with the KRAS G12C inhibitor. (Item 51) The method according to any one of items 1 to 50, wherein the cancer is a cancer having a KRAS G12C mutation. (Item 52) The method according to any one of items 1 to 51, wherein the cancer is lung adenocarcinoma, non-small cell lung cancer, colorectal cancer (CRC), endometrioid carcinoma of the uterus, urothelial carcinoma of the bladder, invasive lobular carcinoma of the breast, squamous cell carcinoma of the cervix, cutaneous melanoma, intracervical adenocarcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma, biphasic pleural mesothelioma, clear cell carcinoma of the kidney, clear cell carcinoma of the kidney, gastric adenocarcinoma, tubular gastric adenocarcinoma, uterine carcinosarcoma, or mixed Müller tumor of the uterus.

Claims

1. A pharmaceutical for use in the treatment of cancer in a subject requiring treatment for cancer, comprising a combination of a KRAS G12C inhibitor and a FAK inhibitor, wherein the cancer is a cancer having a KRAS G12C mutation, the FAK inhibitor is defactinib or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is AMG-510 or a pharmaceutically acceptable salt thereof, or MRTX849 or a pharmaceutically acceptable salt thereof.

2. The combination further comprises a dual RAF / MEK inhibitor, and the dual RAF / MEK inhibitor is The pharmaceutical product according to claim 1, which is CH5126766 having the structure or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical product according to claim 1 or claim 2, wherein the defactinib or a pharmaceutically acceptable salt thereof is administered twice daily or once daily.

4. The pharmaceutical product according to claim 3, wherein the defactinib is administered at a dose of 200 mg with each administration.

5. The pharmaceutical product according to claim 3, wherein the defactinib is administered at a dose of 400 mg with each administration.

6. The pharmaceutical product according to any one of claims 1 to 5, wherein the KRAS G12C inhibitor is administered once or twice daily.

7. The pharmaceutical product according to claim 6, wherein the KRAS G12C inhibitor is administered in doses of 100 mg to 2000 mg, 400 mg to 1500 mg, 600 mg to 1000 mg, 800 mg to 1000 mg, 200 mg to 1000 mg, or 400 mg to 800 mg per dose.

8. The defactinib or a pharmaceutically acceptable salt thereof is administered before the administration of the KRAS G12C inhibitor, or The defactinib or a pharmaceutically acceptable salt thereof is administered after the administration of the KRAS G12C inhibitor, or The defactinib or a pharmaceutically acceptable salt thereof is administered concurrently with the KRAS G12C inhibitor. A pharmaceutical product according to any one of claims 1 to 7.

9. The pharmaceutical product according to claim 2, wherein CH5126766 or a pharmaceutically acceptable salt thereof is administered at least once a week, once a week, or twice a week.

10. The pharmaceutical product according to claim 9, wherein CH5126766 or a pharmaceutically acceptable salt thereof is administered in doses of 0.1 mg to 100 mg, 0.1 mg to 10 mg, or 0.1 mg to 5 mg per dose.

11. In a subject requiring treatment for cancer, a pharmaceutical for treating cancer comprising a combination of a KRAS G12C inhibitor and a dual RAF / MEK inhibitor, wherein the cancer is a cancer having a KRAS G12C mutation, and the dual RAF / MEK inhibitor is A pharmaceutical product having the structure CH5126766 or a pharmaceutically acceptable salt thereof, wherein the KRAS G12C inhibitor is AMG-510 or a pharmaceutically acceptable salt thereof, or MRTX849 or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical product according to claim 11, wherein the KRAS G12C inhibitor is administered in doses of 100 mg to 2000 mg, 400 mg to 1500 mg, 600 mg to 1000 mg, 800 mg to 1000 mg, 200 mg to 1000 mg, or 400 mg to 800 mg per dose.

13. The pharmacopoeia according to claim 11 or claim 12, wherein CH5126766 or a pharmaceutically acceptable salt thereof is administered at least once a week, once a week, or twice a week.

14. The pharmaceutical product according to claim 13, wherein CH5126766 or a pharmaceutically acceptable salt thereof is administered in doses of 0.1 mg to 100 mg, 0.1 mg to 10 mg, or 0.1 mg to 5 mg per dose.

15. The CH5126766 or a pharmaceutically acceptable salt thereof is administered before the administration of the KRAS G12C inhibitor, or The CH5126766 or a pharmaceutically acceptable salt thereof is administered after the administration of the KRAS G12C inhibitor, or The aforementioned CH5126766 or a pharmaceutically acceptable salt thereof is administered concurrently with the KRAS G12C inhibitor. The pharmaceutical product according to any one of claims 11 to 14.

16. The pharmaceutical product according to any one of claims 1 to 15, wherein the cancer is lung cancer, non-small cell lung cancer, colorectal cancer, endometrioid carcinoma of the uterus, urothelial carcinoma of the bladder, invasive lobular carcinoma of the breast, squamous cell carcinoma of the cervix, cutaneous melanoma, intracervical adenocarcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma, biphasic pleural mesothelioma, clear cell carcinoma of the kidney, clear cell carcinoma of the kidney, gastric adenocarcinoma, tubular gastric adenocarcinoma, uterine carcinosarcoma or malignant mixed Müller tumor of the uterus, ovarian cancer, lymphoma or multiple myeloma.

17. The pharmaceutical product according to claim 16, wherein the cancer is non-small cell lung cancer.

18. The pharmaceutical product according to claim 16, wherein the cancer is colorectal cancer.

19. The pharmaceutical product according to claim 16, wherein the cancer is pancreatic adenocarcinoma.

20. A pharmaceutical product according to any one of claims 1 to 19, further comprising additional treatment.

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