Combination Therapies for Treating Abnormal Cell Growth - Patent application

Abstract

The present disclosure relates to methods, compositions, and oral dosage forms of an anti-PD-1 or anti-PD-L1 antibody, and a KRAS G12C inhibitor, and optionally a FAK inhibitor, for treating abnormal cell growth (e.g., cancer). The methods disclosed herein, in some embodiments, include treating cancer in a subject in need thereof by administering an effective amount of a RAF / MEK dual inhibitor (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof), an effective amount of an anti-PD-1 or anti-PD-L1 antibody, and an effective amount of a KRAS G12C inhibitor, thereby treating the subject.

Description

[Technical field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 203,555, filed July 27, 2021, which is incorporated by reference in its entirety herein. [Background technology]

[0002] background Components of the RAS / RAF / MEK / ERK (MAPK) signaling pathway present opportunities for the treatment of abnormal cell growth, such as cancer. For example, RAS and RAF are frequently mutated in human cancers. These mutations result in constitutively active MAPK kinase cascades, leading to tumor cell proliferation, differentiation, survival, and migration. Selective inhibitors of certain components of the RAS / RAF / MEK / ERK signaling pathway (e.g., RAS, RAF, MEK, and ERK) are useful in the treatment of abnormal cell growth, particularly in cancer, in humans.

[0003] Kirsten 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 that cycles between inactive (GDP-bound) and active (GTP-bound) states to transmit upstream cellular signals received from multiple tyrosine kinases to downstream effectors and regulate a wide variety of processes, including cell proliferation (see, e.g., Alamgeer et al., (2013) Current Opin. Pharmcol. 13:394-401). KRAS gene mutations are common in cancers, e.g., pancreatic cancer, lung adenocarcinoma, colorectal cancer (CRC), gallbladder cancer, thyroid cancer, and cholangiocarcinoma (Kodaz et al., EJMO 2017).

[0004] Immune checkpoints refer to a number of inhibitory pathways that help maintain self-tolerance and modulate the duration and amplitude of physiological immune responses in peripheral tissues to minimize secondary tissue damage. Tumors incorporate certain immune checkpoint pathways as a mechanism of immune tolerance, particularly against tumor antigen-specific T cells. For example, the development of checkpoint blocking antibodies, such as inhibitory receptors, that target or are directed against programmed death 1 receptor (PD-1) can facilitate the treatment of abnormal cell growth. PD-1 can function as a negative regulator and have a non-redundant role in modulating immune responses. They are expressed on tumor-specific T cells and can result in compromised activation and suppression of effector functions (e.g., proliferation, cytokine secretion, and tumor cell lysis). PD-1 is involved in modulating T cell activity, for example, through interaction with its ligands (i.e., PD-L1 and PD-L2), for example, in peripheral tissues. Blockade of immune checkpoint pathways may enhance anti-tumor immunity, provide an opportunity to treat abnormal cell growth, and provide more effective treatment for subjects afflicted with cancer.

[0005] Due to the severity and prevalence of diseases and disorders associated with abnormal cell growth (e.g., cancer), effective therapeutic approaches and methods for treatment are needed. The compounds, compound combinations, compositions, and methods described herein are directed to this end. Summary of the Invention [Means for solving the problem]

[0006] Abstract The present disclosure provides, in part, a method of treating abnormal cell growth (e.g., cancer) in a subject in need thereof. The methods disclosed herein, in some embodiments, include treating cancer in a subject in need thereof by administering an effective amount of a RAF / MEK dual inhibitor (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof), an effective amount of an anti-PD-1 antibody or an anti-PD-L1 antibody, and an effective amount of a KRAS G12C inhibitor, thereby treating the subject. The methods disclosed herein, in some embodiments, further include administering an effective amount of a FAK inhibitor (e.g., defactinib or a pharma-ceutically acceptable salt thereof) to the subject.

[0007] In one aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a RAF / MEK dual inhibitor (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof), an effective amount of an anti-PD-1 antibody, and an effective amount of a KRAS G12C inhibitor, thereby treating the subject.

[0008] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a RAF / MEK dual inhibitor (e.g., Compound 1 or a pharma- ceutical acceptable salt thereof), an effective amount of an anti-PD-L1 antibody, and an effective amount of a KRAS G12C inhibitor, thereby treating the subject.

[0009] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a RAF / MEK dual inhibitor (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof), an effective amount of an anti-PD-1 antibody, an effective amount of a KRAS G12C inhibitor, and an effective amount of a FAK inhibitor, thereby treating the subject.

[0010] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a RAF / MEK dual inhibitor (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof), an effective amount of an anti-PD-L1 antibody, an effective amount of a KRAS G12C inhibitor, and an effective amount of a FAK inhibitor, thereby treating the subject.

[0011] In some embodiments, the RAF / MEK dual inhibitor is Compound 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the RAF / MEK dual inhibitor is Compound 1. In some embodiments, the RAF / MEK dual inhibitor is a pharma- ceutically acceptable salt of Compound 1 (e.g., the potassium salt of Compound 1, i.e., VS-6766).

[0012] In some embodiments, the RAF / MEK dual inhibitor is administered at least once a week. In some embodiments, the RAF / MEK dual inhibitor is administered twice a week.

[0013] In some embodiments, the RAF / MEK dual inhibitor is administered as a cycle, where the cycle comprises administering the RAF / MEK dual inhibitor for three weeks, followed by one week of not administering the RAF / MEK dual inhibitor, in some embodiments, the cycle is repeated at least once.

[0014] In some embodiments, the RAF / MEK dual inhibitor is administered as a cycle, where the cycle comprises administering the RAF / MEK dual inhibitor twice a week for three weeks, followed by one week of not administering the RAF / MEK dual inhibitor, in some embodiments, the cycle is repeated at least once.

[0015] In some embodiments, the RAF / MEK dual inhibitor is administered at about 0.8 mg to about 10 mg per dose. In some embodiments, the RAF / MEK dual inhibitor is administered at about 0.8 mg to about 5 mg per dose. In some embodiments, the RAF / MEK dual inhibitor is administered at about 2.4 mg per dose. In some embodiments, the RAF / MEK dual inhibitor is administered at about 3.2 mg per dose. In some embodiments, the RAF / MEK dual inhibitor is administered at about 4 mg per dose.

[0016] In some embodiments, the anti-PD-1 antibody is selected from the group consisting of: balstilimab, budigalimab, kadonilimab, camrelizumab, cemiplimab, cetrelimab, dostallimab, exabenlimab, geptanolimab, nivolumab, pembrolizumab, pemplimab, pidilizumab, pimivalimab, prorugolimab, pucotenlimab, retifanlimab, sasanlimab, serplulimab, serplulimab, sintilimab, spartalizumab, slituzumab, tebotelimab, teripalimab, tislelizumab, toripalimab, toripalimab, zimvelerimab, AK-112 (Akeso Inc), AK-123 (Akeso Inc), ALPN-202 (Alpine Immune Sciences Inc), AMG-404(Amgen), AMP-224(MedImunne), AMP-514(MedImunne), ASKG-915(AskGene Pharma), AT-16201(AIMM Therapeutics BV), AVI-102(AbVision Inc), AZD-7789(Astrazeneca), BAT-1308(Bio-Thera Solutions Ltd), BCD-217(Biocad), BH-2950(Beijing Hanmi Pharmaceutical Co Ltd), BSI-050K01(Biosion Inc), CB-201(Crescendo Biologics Ltd), CB-213(Crescendo Biologics Ltd), CBT-103(Cellective BioTherapy Inc), CBT-107(Cellective BioTherapy Inc), CS-1003(CStone Pharmaceuticals), CYTO-101 (Cytocom Inc), DB-004 (DotBio Pte Ltd), EX-105 (Excelmab Inc), EX-108 (Excelmab Inc), F-520 (Shandong New Time Pharmaceutical), GNR-051 (Generium), GR-1405 (Genrix Biopharmaceutical), HAB-21 (Suzhou Stainwei BiotechInc)、HX-009(Waterstone Hanxbio Pty Ltd)、IBI-319(Innovent Biologics Inc)、IBI-321(Innovent Biologics Inc)、IKT-202(Icell Kealex Therapeutics LLC)、IMU-201(Imugene Ltd)、JS-201(Shanghai Junshi Bioscience Co Ltd)、KD-050(Kadmon)、KJ-101(KisoJi Biotechnology Inc)、KLS-3021(Kolon Life Science Inc)、LBL-006(Leads Biolabs Inc)、LBL-024(Leads Biolabs Inc)、LD-01(Leidos Health Holdings LLC)、LNL-005(L&L Biopharma)、LQ-005(Shanghai Novamab Biopharmaceuticals Co Ltd)、LQ-008(Shanghai Novamab Biopharmaceuticals Co Ltd)、LZM-009(Livzon Pharmaceutical Group)、MEDI-5752(Astrazeneca)、MD-402(MD Biosciences GmbH),mgD-019(MacoGenics)、OT-2(OncoTrap Inc)、OSE-279(OSE Immunotherapeutics)、PE-0105(Shanghai Yunyi Health Technology Development Co Ltd)、PF-07209960(Pfizer Inc)、PH-762(Phio Pharmaceuticals Corp)、PSB-205(Qilu Puget Sound)、QL-1604(Qilu Pharmaceutical Co)、REGN-PD-1 / XX(Regeneron)、RG-6139(Hoffmann La Roche)、RO7216661(Hoffmann La Roche)、RO7284755(Hoffmann La Roche)、SAUG-1(Juvenescence UK Ltd)、SAUG-2(Juvenescence UKLtd), SCTI-10A (Sinocelltech), SG-001 (CSPC Pharmaceutical Group Ltd), SHR-1701 (Jiangsu Hengrui Medicine), SIB-003 (SystImmune), SL-279137 (Shattuck Labs), SOT-201 (Sotio), SSI-361 (Lyvgen Biopharma Ltd), STIA-1015 (Sorrento Therapeutics), STI-A1110 (Servier), STM-418 (Stcube Inc), Sym-021 (Symphogen A / S), T-3011 (Immvira Co Ltd), TSR-075 (GlaxoSmithKline Plc), TY101 (Tayu Huaxia Biotech), Twist-PD-1(Twist XmAb-TGFβR2 (Xencor), XmAb-YYCD28 (Xencor), XmAb20717 (Xencor), XmAb23104 (Xencor), YBL-006 (Y Biologics), YBL-019 (Y Biologics), and mDX-400 (Merck & Co Inc). In some embodiments, the anti-PD-1 antibody is selected from the group consisting of cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, AMP-224, and AMP-514. In some embodiments, the anti-PD-1 antibody is selected from the group consisting of balstilimab, budigalimab, kadonilimab, camrelizumab, cemiplimab, cetrelimab, dostallimab, exabenlimab, geptanolimab, nivolumab, pembrolizumab, pemplimab, pidilizumab, pimivalimab, prorugolimab, pucotenlimab, retifanlimab, sasanlimab, serplulimab, serplulimab, sintilimab, spartalizumab, slituzumab, tebotelimab, teripalimab, tislelizumab, toripalimab, toripalimab, and zimvelerimab.

[0017] In some embodiments, the anti-PD-L1 antibody is selected from the group consisting of atezolizumab, vintrafusp alfa, avelumab, cosibelimab, durvalumab, embafolimab, lazertinib, lodapolimab, pakmilimab, socazolimab, sugemalimab, ABL-501 (ABL Bio), ABM-101 (Abeome Corp), ABP-160 (Abpro Corp), ABM-101 (Abeome Corp), ABSK-043 (Abbisko Therapeutics), ACE-1708 (Acepodia), ADG-104 (Adagene Suzhou Ltd), AP-505 (AP Biosciences Inc), APL-502 (Apollomics, Inc), APL-801 (Apollomics Inc), ASC-61 (Ascletis Pharma), ASC-63(Ascletis Pharma), ATG-101(Antengene Corp Ltd), AVA-004(Avacta Life Sciences), AVA-021(Avacta Life Sciences), AVA-027(Avacta Life Sciences Ltd), AVA-040(Avacta Life Sciences), AUNP12(Aurigene), B-1961(AP Biosciences Inc), BAT-7104 (Bio-Thera), BBI-801 (Sumitomo Dainippon Pharma Oncology, Inc), BH-3012 (Hanmi Pharmaceuticals Co Ltd), BH-3120 (Hanmi Pharmaceuticals Co Ltd), BMS-986189 (Bristol Myers Squibb), BMX-101 (Onward Therapeutics SA), BNT-311 (BioNTech), BPI-9220 (Beta Pharma Inc), BPI-9320 (Beta Pharma Inc), CA-170 (Curis Inc), CCX-559 (ChemoCentryx Inc), CDR-1 (CDR-Life Inc), KJ-CDX-527 (CelldexTherapeutics)、CK-301(コシベリマブ)、CS-17938(Shenzhen Chipscreen Biosciences Co Ltd)、CTX-8371(Compass Therapeutics Inc)、CYTCDR-2(CytImmune Sciences Inc)、DB-002(DotBio Pte Ltd)、DB-003(DotBio Pte Ltd)、DF-002(Suzhou Dingfu Target Biotechnology Co Ltd)、DPDL-1E(Shanghai Hycharm Inc)、DR-30207(Zhejiang Doer Biologics Corp)、DSP-105(KAHR medical Ltd)、DSP-502(KAHR medical Ltd)、EI-011(Elixiron Immunotherapeutics Inc)、EI-014(Elixiron Immunotherapeutics Inc)、EMB-08(EpimAb Biotherapeutics Inc)、ENN-101(Ennovabio)、ENN-102(Ennovabio)、EPIM-001(Elpis Biopharmaceuticals Corp)、FAZ-053(Novartis)、FS-118(F-star Therapeutics Inc)、GB-262(Genor BioPharma Co Ltd)、GB-7003(Shanghai GeneChem Co Ltd)、GR-1405(Genrix(Shanghai) Biopharmaceutical Co Ltd)、GS-19(Gensun Biopharma Inc)、GS-4224(Gilead Sciences)、Gensci-047(GeneScience Pharmaceuticals Co Ltd)、HB-0025(Huabo Biopharm(Shanghai) Co Ltd)、HB-0028(Huabo Biopharm(Shanghai) Co Ltd)、HB-0036(Huabo Biopharm(Shanghai) Co Ltd)、HBM-7015(Harbour BioMed(Guangzhou) CoLtd)、HLX-20(Shanghai Henlius Biotech)、HS-636(Zhejiang Hisun)、IBI-318(Innovent Biologics)、IBI-322(Innovent Biologics)、IBI-323(Innovent Biologics)、IBI-327(Innovent Biologics Inc)、IGM-7354(IGM Biosciences Inc)、IKT-201(Icell Kealex Therapeutics LLC)、IMC-2101(ImmuneOncia Therapeutics LLC)、IMC-2102(ImmuneOncia Therapeutics LLC)、IMGS-002(Immunogenesis Inc)、IMM-2505(ImmuneOnco Biopharmaceuticals(Shanghai) Co Ltd)、IMM-2510(ImmuneOnco Biopharmaceuticals(Shanghai) Co Ltd)、IMM-2520(ImmuneOnco Biopharmaceuticals(Shanghai) Co Ltd)、IMMH-010(Tianjin Chase Sun Pharmaceutical Co Ltd)、INCB-86550(Incyte)、INBRX-105(Elpiscience Biopharmaceutical Ltd)、IO-103(IO Biotech)、JBI-426(Jubilant Therapeutics Inc)、JNB-809(JN Biosciences LLC)、JNB-813(JN Biosciences LLC)、JS-003(Shanghai Junshi Biosciences)、KD-033(Kadmon)、KLA-167(Sichuan Kelun Pharmaceutical)、KN-046(Alphamab Oncology)、KN-052(Alphamab Oncology)、KY-1043(Kymab Ltd)、LP-002(Lepu Biopharma Co Ltd)、LP-008(Lepu Biopharma Co Ltd)、LQ-002(Shanghai NovamabBiopharmaceuticals Co Ltd)、LQ-004(Shanghai Novamab Biopharmaceuticals Co Ltd)、LVGN-1673(Lyvgen Biopharma Ltd)、LY-3434172(Eli Lilly and Co)、LYN-102(LynkCell Inc)、Max-10181(Maxinovel Pharmaceuticals)、MCLA-145(Merus NV)、MEDI-7526(AstraZeneca Plc)、MSB-2311(Transcenta Holding)、ND-021(Numab Therapeutics)、PF-07257876(Pfizer)、PH-790(Phio Pharmaceuticals Corp)、PM-1003(Biotheus Inc)、PM-8001(Biotheus Inc)、PMC-122(PharmAbcine Inc)、PRS-344(Pieris Pharmaceuticals Inc)、Q-1802(QureBio)、QL-301(QLSF Biotherapeutics Inc)、QLS31901(Qilu Pharmaceutical)、RC98(RemeGen)、SHR-1316(Jiangsu Hengrui Medicine Co Ltd)、SHR-1701(Jiangsu Hengrui Medicine Co Ltd)、SIM-236(Jiangsu Simcere Pharmaceutical Co Ltd)、SIM-237(Jiangsu Simcere Pharmaceutical Co Ltd),SL-279252(Shattuck Labs Inc)、SL-279258(Shattuck Labs Inc)、SLSP-03(Salspera LLC)、SNA-02(Oneness Biotech Co Ltd)、SPX-301(Sparx Therapeutics Inc)、STIA-1014(Sorrento Therapeutics)、STIA-1015(Sorrento Therapeutics)、STT-01(Stcube Inc)、TI-1007(Timmune Biotech)、TJL-1C4(I-MabBiopharma), TJL-1D5(I-Mab Biopharma), TJL-1H3(I-Mab Biopharma), TJL-1I7(I-Mab Biopharma), TJL-14B(I-Mab Biopharma), TS1905(Luye Pharma Group), TST-005(Transcenta Holding Ltd), TST-006(Transcenta Holding Ltd), TTXsiPDL-1 (Transcode Therapeutics Inc), TXB-4BC3 (Ossianix Inc), VS-161 (Virogin Biotech), VXM-10 (Vaximm AG), WP-1066 (Moleculin Biotech), Y-111 (Wuhan YZY), YBL-007 (Y-Biologics Inc), YBL-008 (Y-Biologics Inc), YBL-009 (Y-Biologics Inc), YBL-013 (Y-Biologics Inc), YBL-016 (Y-Biologics Inc), and YBL-020 (Y-Biologics Inc). In some embodiments, the anti-PD-L1 antibody is selected from the group consisting of atezolizumab, vintrafusp alfa, avelumab, cosibelimab, durvalumab, embafolimab, lazertinib, lodapolimab, pakmilimab, socazolimab, and sugemalimab.

[0018] In some embodiments, the KRAS G12C inhibitor is selected from the group consisting of ARS-853 (Araxes Pharma), ARS-1620 (Araxes Pharma), ARS-3248 (Araxes Pharma), LY3499446 (Eli Lilly), AMG-510 (sotorasib), MRTX849 (adagrasib), APG-1842 (Ascentage Pharma), AST KRAS G12C inhibitor (Allist Pharmaceuticals), AZ KRAS G12C inhibitor (AstraZeneca), D-1553 (InventisBio), GDC-6036 (Genentech), JAB-21000 (Jacobio Pharmaceuticals), JAB-21822 (Jacobio Pharmaceuticals), JDQ443 (Novartis), JNJ-74699157 (Janssen), LY3537982 (Eli Lilly), MRTX1257 (Mirati Therapeutics), RMC-6291 (Revolution Medicines), SF KRAS G12C inhibitor (Sanofi), X-Chem KRAS (X-Chem Pharmaceuticals), BI 1823911 (Boehringer Ingelheim), MK-1084 (Merck), YL-15293 (Shanghai YingLi Pharmaceutical), GFH925 (GenFleet), GH35 (Genhouse Bio), BPI-421286 (Betta Pharmaceuticals Co.), D3S-001 (D3 Bui), ZG19018 (Zejing Pharmaceuticals), HS-10370(Jiangsu Hansoh Pharmaceutical), G12C inhibitor (Frontier Medicines), and EB160 (Shanghai Euregen Biopharma), or a pharma- ceutically acceptable salt thereof.In some embodiments, the KRAS G12C inhibitor is ARS-853, ARS-1620, ARS-3248, sotorasib, adagrasib, APG-1842, D-1553, GDC-6036, JAB-21822, JDQ443, JNJ-74699157, LY3537982, MRTX1257, RMC-6291, BI 1823911, MK-1084 YL-15293, GFH925, GH35, BPI-421286, D3S-001, ZG19018, HS-10370, or EB160, or a pharma- ceutically acceptable salt thereof. In some embodiments, the KRAS G12C inhibitor is ARS-853, ARS-1620, ARS-3248, sotorasib, adagrasib, GDC-6036, JDQ443, LY3537982, or MRTX1257, or a pharmaceutically acceptable salt thereof.In some embodiments, the KRAS G12C inhibitor is sotorasib or a pharmaceutically acceptable salt thereof.In some embodiments, the KRAS G12C inhibitor is adagrasib or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the cancer is characterized as having a RAS mutation. In some embodiments, the cancer is characterized as having a KRAS mutation. In some embodiments, the cancer is characterized as having a KRAS G12C mutation.

[0020] In some embodiments, the cancer is lung cancer, colorectal cancer, uveal melanoma, ovarian cancer, uterine endometrioid carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, cervical squamous cell carcinoma, cutaneous melanoma, endocervical adenocarcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma, biphasic pleural mesothelioma, renal clear cell carcinoma, renal clear cell carcinoma, gastric adenocarcinoma, tubular gastric adenocarcinoma, uterine carcinosarcoma, or uterine malignant mixed Mullerian tumor.

[0021] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description, examples, and claims. [Brief description of the drawings]

[0022] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] FIG. 1 shows an exemplary combination of a dual RAF / MEK inhibitor and a KRAS G12C inhibitor that creates a favorable immune microenvironment for combination with an anti-PD-1 antibody. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Detailed Description The present disclosure provides, in some embodiments, methods and combinations of compounds useful for treating abnormal cell growth (e.g., cancer) in a subject in need thereof.

[0024] definition "About" and "approximately" are intended to generally mean an acceptable degree of error for the quantity measured, given the nature and precision of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value or range of values.

[0025] As used herein, "pharmaceutically acceptable salts" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and commensurate 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 disclosure include those obtained from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods used in the art (e.g., ion exchange). Other pharma- ceutically acceptable salts include: adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanoate ... and the like.Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N. + (C 1-4 Alkyl) 4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0026] As used herein, "pharmaceutical acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances, For example, phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable 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 copolymers, polyethylene glycol and wool fat.

[0027] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or senior adult)) and / or a non-human animal, e.g., a mammal such as a primate (e.g., cynomolgus monkey, rhesus monkey), cow, pig, horse, sheep, goat, rodent, cat, and / or dog. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0028] Disease, disorder, and condition are used interchangeably herein.

[0029] As used herein, and unless otherwise specified, the terms "treat", "treating" and "treatment" contemplate actions taken while a subject is afflicted with a specified disease, disorder or condition, which reduce the severity of the disease, disorder or condition, or prevent or slow the progression of the disease, disorder or condition (also "therapeutic treatment").

[0030] In general, the "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response.As will be understood by those skilled in the art, the effective amount of the compound of the present disclosure can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health and condition of the subject.

[0031] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a 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 therapeutically effective amount of a compound refers to an amount of a therapeutic agent that alone or in combination with other treatments provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0032] As used herein, "prophylactic treatment" contemplates actions taken before a subject begins to suffer from a particular disease, disorder or condition.

[0033] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with the disease, disorder, or condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent that alone or in combination with other agents provides a prophylactic benefit in the prevention of the disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prevention or enhances the prophylactic effectiveness of another prophylactic agent.

[0034] The term "oral dosage form" as used herein refers to a composition or vehicle used to administer a drug to a subject. Typically, oral dosage forms are administered via the mouth, but "oral dosage form" is intended to cover any substance that is administered to a subject and absorbed across a membrane (e.g., mucosa) of the digestive tract (including, for example, the mouth, esophagus, stomach, small intestine, large intestine, and colon). For example, "oral dosage form" covers a liquid agent that is administered via a feeding tube into the stomach.

[0035] "Cycle," as used herein in the context of a cycle of administration of a drug, refers to the period during which the drug is administered and may further include a rest period during which the drug is not administered to the subject. In some embodiments, a cycle is 4 weeks.

[0036] A "RAS mutation" is a mutation in a RAS gene. For example, a "KRAS mutation" is a mutation in a KRAS gene (i.e., a nucleic acid mutation) or a mutation in a Kras protein (i.e., an amino acid mutation) that results in an abnormal Kras protein function associated with increased activity and / or constitutive activity by favoring an active GTP-bound state of the Kras protein. The mutation may be in a conserved site that favors GTP-bound and constitutively active Kras protein. In some cases, the mutation is in one or more of codons 12, 13, and 16 of the KRAS gene. For example, the KRAS mutation may be in codon 12 of the KRAS gene, and may exist as, for example, a single point substitution mutation (i.e., a KRAS G12X mutation) in codon 12 (e.g., a KRAS G12V mutation results from a single nucleotide change (c.35G>T), resulting in an amino acid substitution of glycine (G) at position 12 with valine (V)).

[0037] Treatment The combinations provided herein, such as the combination of RAF / MEK dual inhibitors, anti-PD-1 and / or anti-PD-L1 antibodies, and KRAS G12C inhibitors, and optionally FAK inhibitors, provide significant anti-tumor effects when compared to monotherapy alone administered at comparable durations and / or dosages. The combinations provided herein provide the opportunity to improve the overall survival of subjects, reduce the risk of developing resistance to monotherapy, and reduce or prevent adverse side effects compared to long-term administration of monotherapy. Thus, the combinations of compounds described herein (e.g., an effective amount of RAF / MEK dual inhibitors, an effective amount of anti-PD-1 and / or anti-PD-L1 antibodies, and an effective amount of KRAS G12C inhibitors, and optionally an effective amount of FAK inhibitors) and pharmaceutical compositions thereof are useful in methods of treating abnormal cell growth (e.g., cancer).

[0038] In one aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a RAF / MEK dual inhibitor, an effective amount of an anti-PD-1 antibody, and an effective amount of a KRAS G12C inhibitor, thereby treating the subject.

[0039] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a dual RAF / MEK inhibitor, an effective amount of an anti-PD-L1 antibody, and an effective amount of a KRAS G12C inhibitor, thereby treating the subject.

[0040] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a RAF / MEK dual inhibitor, an effective amount of an anti-PD-1 antibody, an effective amount of a KRAS G12C inhibitor, and a FAK inhibitor, thereby treating the subject.

[0041] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a RAF / MEK dual inhibitor, an effective amount of an anti-PD-L1 antibody, an effective amount of a KRAS G12C inhibitor, and a FAK inhibitor, thereby treating the subject.

[0042] Dual RAF / MEK inhibitor An exemplary RAF / MEK dual inhibitor described herein is VS-6766 (also referred to as CKI27, CH5126766, or RO5126766).

[0043] In some embodiments, the RAF / MEK dual inhibitor has formula (I): [ka] or a pharma- ceutically acceptable salt thereof.

[0044] In some embodiments, the compound of formula (I) is [ka] which is also referred to herein as Compound 1 or VS-6766 free form.

[0045] In some embodiments, the RAF / MEK dual inhibitor is a pharma- ceutically acceptable salt of a compound of formula (I). In some embodiments, the RAF / MEK dual inhibitor is a potassium salt of a compound of formula (I), also referred to as VS-6766. In some embodiments, VS-6766 has the following structure: [ka] has.

[0046] Other pharma- ceutically acceptable salts of the compounds of formula (I) are contemplated herein.

[0047] In some embodiments, the RAF / MEK dual 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 RAF / MEK dual inhibitor is administered once a week. In some embodiments, the RAF / MEK dual inhibitor is administered twice a week. In some embodiments, the RAF / MEK dual inhibitor is administered three times a week.

[0048] In some embodiments, the RAF / MEK dual inhibitor is administered at about 0.1 mg to about 100 mg per administration, for example, about 0.1 mg to about 50 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5 mg, about 0.1 mg to about 4 mg, about 0.1 mg to about 3 mg, about 0.1 mg to about 2 mg, about 0.1 mg to about 1 mg, about 1 mg to about 10 mg, about 1 mg to about 20 mg, about 1 mg to about 40 mg, about 1 mg to about 60 mg, about 1 mg to about 80 mg, about 1 mg to about 100 mg, about 10 mg to about 100 mg, about 20 mg to about 100 mg, about 40 mg to about 100 mg, about 60 mg to about 100 mg, or about 80 mg to about 100 mg. In some embodiments, the RAF / MEK dual inhibitor is administered at about 0.5 mg to about 10 mg per administration. In some embodiments, the RAF / MEK dual inhibitor is administered at about 0.8 mg to about 10 mg per administration. In some embodiments, the RAF / MEK dual inhibitor is administered at 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 per administration. In some embodiments, the RAF / MEK dual inhibitor is administered at about 0.8 mg to about 10 mg per administration. In some embodiments, the RAF / MEK dual inhibitor is administered at about 0.8 mg to about 5 mg per administration. In some embodiments, the RAF / MEK dual inhibitor is administered at about 1 mg to about 4 mg per administration. In some embodiments, the RAF / MEK dual inhibitor is administered at about 1 mg to about 3 mg per administration. In some embodiments, the RAF / MEK dual inhibitor is administered at about 2 mg to about 5 mg per administration. In some embodiments, the RAF / MEK dual inhibitor is administered at about 2 mg to about 4 mg per administration. In some embodiments, the RAF / MEK dual inhibitor is administered at about 2 mg to about 3 mg per administration. In some embodiments, the RAF / MEK dual inhibitor is administered at about 4 mg per administration.In some embodiments, the RAF / MEK dual inhibitor is administered at about 3.2 mg per administration. In some embodiments, the RAF / MEK dual inhibitor is administered at about 2.4 mg per administration. In some embodiments, the RAF / MEK dual inhibitor is administered orally.

[0049] In some embodiments, the RAF / MEK dual inhibitor is administered as a cycle that includes administering the RAF / MEK dual inhibitor for three weeks, followed by one week without administering the RAF / MEK dual inhibitor. In some embodiments, the RAF / MEK dual inhibitor is administered twice per week. In some embodiments, the RAF / MEK dual inhibitor is administered three times per week. In some embodiments, the RAF / MEK dual inhibitor is administered at about 0.8 mg to about 10 mg (e.g., about 4 mg or about 3.2 mg or about 2.4 mg) per administration.

[0050] In some embodiments, the RAF / MEK dual inhibitor is administered as a cycle that includes administering the RAF / MEK dual inhibitor twice a week at a dose of about 0.8 mg to about 10 mg per dose (e.g., about 4 mg or about 3.2 mg or about 2.4 mg per dose) for three weeks, followed by one week of not administering the RAF / MEK dual inhibitor. In some embodiments, the cycle is repeated at least once.

[0051] In some embodiments, the RAF / MEK dual inhibitor is administered as a cycle that includes administering the RAF / MEK dual inhibitor at a dose of about 0.8 mg to about 10 mg per dose (e.g., about 4 mg or about 3.2 mg or about 2.4 mg per dose) three times per week for three weeks, followed by one week of not administering the RAF / MEK dual inhibitor. In some embodiments, the cycle is repeated at least once.

[0052] In alternative embodiments, the RAF / MEK dual inhibitor is administered consecutively (i.e., without a week without administration of the RAF / MEK dual inhibitor). In some embodiments, the RAF / MEK dual inhibitor is administered twice per week. In some embodiments, the RAF / MEK dual inhibitor is administered three times per week. In some embodiments, the RAF / MEK dual inhibitor is administered at a dose of about 0.8 mg to about 10 mg per administration (e.g., about 4 mg or about 3.2 mg or about 2.4 mg per administration) per administration. In some embodiments, the RAF / MEK dual inhibitor is administered for at least four weeks. In some embodiments, the RAF / MEK dual inhibitor is administered for four weeks.

[0053] In some embodiments, the RAF / MEK dual inhibitor is administered to the subject twice a week at a dose of about 0.8 mg to about 10 mg per dose (e.g., about 4 mg or about 3.2 mg or about 2.4 mg per dose) and then administered periodically (as a cycle comprising administering the RAF / MEK dual inhibitor for three weeks and then not administering the RAF / MEK dual inhibitor for one week), where the cycle is repeated at least once. In some embodiments, the RAF / MEK dual inhibitor, when administered as a cycle, comprises administering the RAF / MEK dual inhibitor twice a week at a dose of about 0.8 mg to about 10 mg per dose (e.g., about 4 mg or about 3.2 mg or about 2.4 mg per dose) for three weeks and then not administering the RAF / MEK dual inhibitor for one week.

[0054] In some embodiments, the RAF / MEK dual inhibitor is administered to the subject at a dose of about 0.8 mg to about 10 mg per dose (e.g., about 4 mg or about 3.2 mg or about 2.4 mg per dose) three times per week, and then administered periodically (as a cycle comprising administering the RAF / MEK dual inhibitor for three weeks, and then not administering the RAF / MEK dual inhibitor for one week), where the cycle is repeated at least once. In some embodiments, the RAF / MEK dual inhibitor, when administered as a cycle, comprises administering the RAF / MEK dual inhibitor three times per week at a dose of about 0.8 mg to about 10 mg per dose (e.g., about 4 mg or about 3.2 mg or about 2.4 mg per dose) for three weeks, and then not administering the RAF / MEK dual inhibitor for one week.

[0055] Anti-PD-1 antibody / anti-PD-L1 antibody Antibody therapeutics are antibody proteins that are produced by the immune system and bind to target antigens on the surface of cells. Antibodies are typically encoded by immunoglobulin genes or fragments thereof. Under normal physiological conditions, antibodies are used by the immune system to fight pathogens. Each antibody is specific for one or several proteins, and those that bind to cancer antigens are used, for example, for the treatment of cancer. An antibody can specifically bind an antigen or epitope (Fundamental Immunology, 3rd ed., We, Paul, et al., Raven Press, NY (1993)). Specific binding occurs to its corresponding antigen or epitope even in the presence of a heterogeneous population of proteins and other organisms. Specific binding of an antibody indicates that the antibody binds to its target antigen or epitope with substantially greater affinity than it binds to an unrelated antigen. The relative difference in affinity is often at least 25% greater, more often at least 50% greater, and most often at least 100% greater. The relative difference can be, for example, at least 2-fold, at least 5-fold, at least 10-fold, at least 25-fold, at least 50-fold, at least 100-fold, or at least 1000-fold.

[0056] Exemplary types of antibodies include, but are not limited to, human, humanized, chimeric, monoclonal, polyclonal, single chain, antibody-binding fragments, and diabodies. Once bound to a cancer antigen, an antibody can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, prevent receptor interaction with its ligand, or deliver a payload of chemotherapy or radiation, all of which can result in cell death.

[0057] In some embodiments, the anti-PD-1 antibody is selected from the group consisting of: balstilimab, budigalimab, kadonilimab, camrelizumab, cemiplimab, cetrelimab, dostallimab, exabenlimab, geptanolimab, nivolumab, pembrolizumab, pemplimab, pidilizumab, pimivalimab, prorugolimab, pucotenlimab, retifanlimab, sasanlimab, serplulimab, serplulimab, sintilimab, spartalizumab, slituzumab, tebotelimab, teripalimab, tislelizumab, toripalimab, toripalimab, zimvelerimab, AK-112 (Akeso Inc), AK-123 (Akeso Inc), ALPN-202 (Alpine Immune Sciences Inc), AMG-404(Amgen), AMP-224(MedImunne), AMP-514(MedImunne), ASKG-915(AskGene Pharma), AT-16201(AIMM Therapeutics BV), AVI-102(AbVision Inc), AZD-7789(Astrazeneca), BAT-1308(Bio-Thera Solutions Ltd), BCD-217(Biocad), BH-2950(Beijing Hanmi Pharmaceutical Co Ltd), BSI-050K01(Biosion Inc), CB-201(Crescendo Biologics Ltd), CB-213(Crescendo Biologics Ltd), CBT-103(Cellective BioTherapy Inc), CBT-107(Cellective BioTherapy Inc), CS-1003(CStone Pharmaceuticals), CYTO-101 (Cytocom Inc), DB-004 (DotBio Pte Ltd), EX-105 (Excelmab Inc), EX-108 (Excelmab Inc), F-520 (Shandong New Time Pharmaceutical), GNR-051 (Generium), GR-1405 (Genrix Biopharmaceutical), HAB-21 (Suzhou Stainwei BiotechInc)、HX-009(Waterstone Hanxbio Pty Ltd)、IBI-319(Innovent Biologics Inc)、IBI-321(Innovent Biologics Inc)、IKT-202(Icell Kealex Therapeutics LLC)、IMU-201(Imugene Ltd)、JS-201(Shanghai Junshi Bioscience Co Ltd)、KD-050(Kadmon)、KJ-101(KisoJi Biotechnology Inc)、KLS-3021(Kolon Life Science Inc)、LBL-006(Leads Biolabs Inc)、LBL-024(Leads Biolabs Inc)、LD-01(Leidos Health Holdings LLC)、LNL-005(L&L Biopharma)、LQ-005(Shanghai Novamab Biopharmaceuticals Co Ltd)、LQ-008(Shanghai Novamab Biopharmaceuticals Co Ltd)、LZM-009(Livzon Pharmaceutical Group)、MEDI-5752(Astrazeneca)、MD-402(MD Biosciences GmbH),mgD-019(MacoGenics)、OT-2(OncoTrap Inc)、OSE-279(OSE Immunotherapeutics)、PE-0105(Shanghai Yunyi Health Technology Development Co Ltd)、PF-07209960(Pfizer Inc)、PH-762(Phio Pharmaceuticals Corp)、PSB-205(Qilu Puget Sound)、QL-1604(Qilu Pharmaceutical Co)、REGN-PD-1 / XX(Regeneron)、RG-6139(Hoffmann La Roche)、RO7216661(Hoffmann La Roche)、RO7284755(Hoffmann La Roche)、SAUG-1(Juvenescence UK Ltd)、SAUG-2(Juvenescence UKLtd., SCTI-10A (Sinocelltech), SG-001 (CSPC Pharmaceutical Group Ltd.), SHR-1701 (Jiangsu Hengrui Medicine), SIB-003 (SystImmune), SL-279137 (Shattuck). Labs, SOT-201 (Sotio), SSI-361 (Lyvgen Biopharma Ltd), STIA-1015 (Sorrento Therapeutics), STI-A1110 (Servier), STM-418 (Stcube Inc), Sym-021 (Symphogen). A / S, T-3011 (Immvira Co Ltd), TSR-075 (GlaxoSmithKline Plc), TY101 (Tayu Huaxia Biotech), Twist-PD-1 (Twist Bioscience, XmAb-TGFβR2 (Xencor), XmAb-YYCD28 (Xencor), XmAb20717 (Xencor), XmAb23104 (Xencor), YBL-006 (Y Biologics), YBL-019 (Y Biologics) and mDX-400(Merck & Co.).In some embodiments, the anti-PD-1 antibody is selected from the group consisting of cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, AMP-224, and AMP-514. In some embodiments, the anti-PD-1 antibody is selected from the group consisting of balstilimab, budigalimab, kadonilimab, camrelizumab, cemiplimab, cetrelimab, dostallimab, exabenlimab, geptanolimab, nivolumab, pembrolizumab, pemplimab, pidilizumab, pimivalimab, prorugolimab, pucotenlimab, retifanlimab, sasanlimab, serplulimab, serplulimab, sintilimab, spartalizumab, slituzumab, tebotelimab, teripalimab, tislelizumab, toripalimab, toripalimab, and zimvelerimab. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0058] In some embodiments, the anti-PD-1 antibody is administered at least once a week. In some embodiments, the anti-PD-1 antibody is administered once a week. In some embodiments, the anti-PD-1 antibody is administered twice a week. In other embodiments, the anti-PD-1 antibody is administered every two weeks. In other embodiments, the anti-PD-1 antibody is administered every three weeks. In other embodiments, the anti-PD-1 antibody is administered every four weeks. In other embodiments, the anti-PD-1 antibody is administered every five weeks. In other embodiments, the anti-PD-1 antibody is administered every six weeks.

[0059] In some embodiments, the anti-PD-1 antibody is administered at about 10 mg to about 5000 mg, about 10 mg to about 4000 mg, about 10 mg to about 3000 mg, about 10 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 2000 mg, about 100 mg to about 1500 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg (e.g., about 200 mg, 240 mg, or about 480 mg) per administration.

[0060] In some embodiments, the anti-PD-1 antibody is administered parenterally (eg, intravenous infusion).

[0061] In some embodiments, the anti-PD-L1 antibody is selected from the group consisting of atezolizumab, vintrafusp alfa, avelumab, cosibelimab, durvalumab, embafolimab, lazertinib, lodapolimab, pakmilimab, socazolimab, sugemalimab, ABL-501 (ABL Bio), ABM-101 (Abeome Corp), ABP-160 (Abpro Corp), ABM-101 (Abeome Corp), ABSK-043 (Abbisko Therapeutics), ACE-1708 (Acepodia), ADG-104 (Adagene Suzhou Ltd), AP-505 (AP Biosciences Inc), APL-502 (Apollomics, Inc), APL-801 (Apollomics Inc), ASC-61 (Ascletis Pharma), ASC-63(Ascletis Pharma), ATG-101(Antengene Corp Ltd), AVA-004(Avacta Life Sciences), AVA-021(Avacta Life Sciences), AVA-027(Avacta Life Sciences Ltd), AVA-040(Avacta Life Sciences), AUNP12(Aurigene), B-1961(AP Biosciences Inc), BAT-7104 (Bio-Thera), BBI-801 (Sumitomo Dainippon Pharma Oncology, Inc), BH-3012 (Hanmi Pharmaceuticals Co Ltd), BH-3120 (Hanmi Pharmaceuticals Co Ltd), BMS-986189 (Bristol Myers Squibb), BMX-101 (Onward Therapeutics SA), BNT-311 (BioNTech), BPI-9220 (Beta Pharma Inc), BPI-9320 (Beta Pharma Inc), CA-170 (Curis Inc), CCX-559 (ChemoCentryx Inc), CDR-1 (CDR-Life Inc), KJ-CDX-527 (CelldexTherapeutics)、CK-301(コシベリマブ)、CS-17938(Shenzhen Chipscreen Biosciences Co Ltd)、CTX-8371(Compass Therapeutics Inc)、CYTCDR-2(CytImmune Sciences Inc)、DB-002(DotBio Pte Ltd)、DB-003(DotBio Pte Ltd)、DF-002(Suzhou Dingfu Target Biotechnology Co Ltd)、DPDL-1E(Shanghai Hycharm Inc)、DR-30207(Zhejiang Doer Biologics Corp)、DSP-105(KAHR medical Ltd)、DSP-502(KAHR medical Ltd)、EI-011(Elixiron Immunotherapeutics Inc)、EI-014(Elixiron Immunotherapeutics Inc)、EMB-08(EpimAb Biotherapeutics Inc)、ENN-101(Ennovabio)、ENN-102(Ennovabio)、EPIM-001(Elpis Biopharmaceuticals Corp)、FAZ-053(Novartis)、FS-118(F-star Therapeutics Inc)、GB-262(Genor BioPharma Co Ltd)、GB-7003(Shanghai GeneChem Co Ltd)、GR-1405(Genrix(Shanghai) Biopharmaceutical Co Ltd)、GS-19(Gensun Biopharma Inc)、GS-4224(Gilead Sciences)、Gensci-047(GeneScience Pharmaceuticals Co Ltd)、HB-0025(Huabo Biopharm(Shanghai) Co Ltd)、HB-0028(Huabo Biopharm(Shanghai) Co Ltd)、HB-0036(Huabo Biopharm(Shanghai) Co Ltd)、HBM-7015(Harbour BioMed(Guangzhou) CoLtd)、HLX-20(Shanghai Henlius Biotech)、HS-636(Zhejiang Hisun)、IBI-318(Innovent Biologics)、IBI-322(Innovent Biologics)、IBI-323(Innovent Biologics)、IBI-327(Innovent Biologics Inc)、IGM-7354(IGM Biosciences Inc)、IKT-201(Icell Kealex Therapeutics LLC)、IMC-2101(ImmuneOncia Therapeutics LLC)、IMC-2102(ImmuneOncia Therapeutics LLC)、IMGS-002(Immunogenesis Inc)、IMM-2505(ImmuneOnco Biopharmaceuticals(Shanghai) Co Ltd)、IMM-2510(ImmuneOnco Biopharmaceuticals(Shanghai) Co Ltd)、IMM-2520(ImmuneOnco Biopharmaceuticals(Shanghai) Co Ltd)、IMMH-010(Tianjin Chase Sun Pharmaceutical Co Ltd)、INCB-86550(Incyte)、INBRX-105(Elpiscience Biopharmaceutical Ltd)、IO-103(IO Biotech)、JBI-426(Jubilant Therapeutics Inc)、JNB-809(JN Biosciences LLC)、JNB-813(JN Biosciences LLC)、JS-003(Shanghai Junshi Biosciences)、KD-033(Kadmon)、KLA-167(Sichuan Kelun Pharmaceutical)、KN-046(Alphamab Oncology)、KN-052(Alphamab Oncology)、KY-1043(Kymab Ltd)、LP-002(Lepu Biopharma Co Ltd)、LP-008(Lepu Biopharma Co Ltd)、LQ-002(Shanghai NovamabBiopharmaceuticals Co Ltd)、LQ-004(Shanghai Novamab Biopharmaceuticals Co Ltd)、LVGN-1673(Lyvgen Biopharma Ltd)、LY-3434172(Eli Lilly and Co)、LYN-102(LynkCell Inc)、Max-10181(Maxinovel Pharmaceuticals)、MCLA-145(Merus NV)、MEDI-7526(AstraZeneca Plc)、MSB-2311(Transcenta Holding)、ND-021(Numab Therapeutics)、PF-07257876(Pfizer)、PH-790(Phio Pharmaceuticals Corp)、PM-1003(Biotheus Inc)、PM-8001(Biotheus Inc)、PMC-122(PharmAbcine Inc)、PRS-344(Pieris Pharmaceuticals Inc)、Q-1802(QureBio)、QL-301(QLSF Biotherapeutics Inc)、QLS31901(Qilu Pharmaceutical)、RC98(RemeGen)、SHR-1316(Jiangsu Hengrui Medicine Co Ltd)、SHR-1701(Jiangsu Hengrui Medicine Co Ltd)、SIM-236(Jiangsu Simcere Pharmaceutical Co Ltd)、SIM-237(Jiangsu Simcere Pharmaceutical Co Ltd),SL-279252(Shattuck Labs Inc)、SL-279258(Shattuck Labs Inc)、SLSP-03(Salspera LLC)、SNA-02(Oneness Biotech Co Ltd)、SPX-301(Sparx Therapeutics Inc)、STIA-1014(Sorrento Therapeutics)、STIA-1015(Sorrento Therapeutics)、STT-01(Stcube Inc)、TI-1007(Timmune Biotech)、TJL-1C4(I-MabBiopharma), TJL-1D5(I-Mab Biopharma), TJL-1H3(I-Mab Biopharma), TJL-1I7(I-Mab Biopharma), TJL-14B(I-Mab Biopharma), TS1905(Luye Pharma Group), TST-005(Transcenta Holding Ltd), TST-006(Transcenta Holding Ltd), TTXsiPDL-1 (Transcode Therapeutics Inc), TXB-4BC3 (Ossianix Inc), VS-161 (Virogin Biotech), VXM-10 (Vaximm AG), WP-1066 (Moleculin Biotech), Y-111 (Wuhan YZY), YBL-007 (Y-Biologics Inc), YBL-008 (Y-Biologics Inc), YBL-009 (Y-Biologics Inc), YBL-013 (Y-Biologics Inc), YBL-016 (Y-Biologics Inc), and YBL-020 (Y-Biologics Inc). In some embodiments, the anti-PD-L1 antibody is selected from the group consisting of atezolizumab, vintrafusp alfa, avelumab, cosibelimab, durvalumab, embafolimab, lazertinib, lodapolimab, pakmilimab, socazolimab, and sugemalimab.

[0062] In some embodiments, the anti-PD-L1 antibody is administered at least once a week. In some embodiments, the anti-PD-L1 antibody is administered once a week. In some embodiments, the anti-PD-L1 antibody is administered twice a week. In other embodiments, the anti-PD-L1 antibody is administered every two weeks. In other embodiments, the anti-PD-L1 antibody is administered every three weeks. In other embodiments, the anti-PD-L1 antibody is administered every four weeks. In other embodiments, the anti-PD-L1 antibody is administered every five weeks. In other embodiments, the anti-PD-L1 antibody is administered every six weeks.

[0063] In some embodiments, the anti-PD-L1 antibody is administered at about 10 mg to about 5000 mg, about 10 mg to about 4000 mg, about 10 mg to about 3000 mg, about 10 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 2000 mg, about 100 mg to about 1500 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg, about 500 mg to about 1500 mg, about 500 mg to about 1200 mg, about 800 mg to about 1200 mg, or about 800 mg to about 1500 mg per administration. For example, in some embodiments, the anti-PD-L1 antibody is administered at about 400 mg, about 800 mg, or about 1200 mg per administration.

[0064] In some embodiments, the anti-PD-L1 antibody is administered parenterally (e.g., by intravenous infusion).

[0065] In some embodiments, the methods described herein contemplate administering to a subject in need thereof an anti-PD-1 and anti-PD-L1 bispecific antibody (e.g., where the bispecific antibody targets both PD-1 and PD-L1). Exemplary anti-PD-1 and anti-PD-L1 bispecific antibodies include, but are not limited to, CTX-8371, LY 3434172, and IBI318.

[0066] In some embodiments, the methods described herein contemplate administering to a subject in need thereof an effective amount of an anti-PD-1 antibody and an effective amount of an anti-PD-L1 antibody. In some embodiments, the anti-PD-1 antibody is administered simultaneously with the anti-PD-L1 antibody. In some embodiments, the anti-PD-1 antibody is administered prior to the anti-PD-L1 antibody. In some embodiments, the anti-PD-1 antibody is administered subsequent to the anti-PD-L1 antibody.

[0067] KRAS G12C inhibitors Exemplary KRAS G12C inhibitors include, but are not limited to, the following: The following structure: [ka] MRTX849 (adagrasib); The following structure: [ka] AMG-510 (Sotorasib); The following structure: [ka] ARS-1620 with; The following structure: [ka] ARS-853 with; The following structure: [ka] GDC-6036 with; The following structure: [ka] ARS-3248 with; The following structure: [ka] JDQ443 with; The following structure: [ka] LY3537982 with; The following structure: [ka] MRTX1257 with; LY3499446 (Eli Lilly); APG-1842 (Ascentage Pharma), AST KRAS G12C inhibitor (Allist Pharmaceuticals), AZ KRAS G12C inhibitor (AstraZeneca), D-1553 (InventisBio), JAB-21000 (Jacobio Pharmaceuticals), JAB-21822 (Jacobio Pharmaceuticals), JNJ-74699157 (Janssen), RMC-6291 (Revolution Medicines), SF KRAS G12C inhibitor (Sanofi), Pharmaceutical), GFH925 (GenFleet), GH35 (Genhouse Bio), BPI-421286 (Betta Pharmaceuticals Co.), D3S-001 (D3 Bio), ZG19018 (Zejing Pharmaceuticals), HS-10370 (Jiangsu Hansoh Pharmaceutical), G12C inhibitor (Frontier Medicines), and EB160 (Shanghai Euregen Biopharma), or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS G12C inhibitor is ARS-853, ARS-1620, ARS-3248, sotorasib, adagrasib, APG-1842, D-1553, GDC-6036, JAB-21822, JDQ443, JNJ-74699157, LY3537982, MRTX1257, RMC-6291, BI 1823911, MK-1084, YL-15293, GFH925, GH35, BPI-421286, D3S-001, ZG19018, HS-10370, or EB160, or a pharma- ceutically acceptable salt thereof.In some embodiments, the KRAS G12C inhibitor is ARS-853, ARS-1620, ARS-3248, sotorasib, adagrasib, GDC-6036, JDQ443, LY3537982, or MRTX1257, or a pharmaceutically acceptable salt thereof.In some embodiments, the KRAS G12C inhibitor is sotorasib or a pharmaceutically acceptable salt thereof.In some embodiments, the KRAS G12C inhibitor is adagrasib or a pharmaceutically acceptable salt thereof.

[0068] 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.

[0069] In some embodiments, the KRAS G12C inhibitor is administered at a dose of about 10 mg to about 2000 mg, for example, about 100 mg to about 2000 mg, about 100 mg to about 1500 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 100 mg to about 200 mg, about 200 mg to about 2000 mg, about 200 mg to about 1500 mg, about 200 mg to about 1000 mg, about 200 mg to about 800 mg, about 200 mg to about 600 mg, about 200 mg to about 400 mg, about 400 mg to about 20 In some embodiments, the KRAS G12C inhibitor is administered at a dose of about 100 mg / administration. In some embodiments, the KRAS G12C inhibitor is administered at about 200 mg / dose. In some embodiments, the KRAS G12C inhibitor is administered at about 300 mg / dose. In some embodiments, the KRAS G12C inhibitor is administered at about 400 mg / dose. In some embodiments, the KRAS G12C inhibitor is administered at about 500 mg / dose. In some embodiments, the KRAS G12C inhibitor is administered at about 600 mg / dose. In some embodiments, the KRAS G12C inhibitor is administered at about 700 mg / dose. In some embodiments, the KRAS G12C inhibitor is administered at about 800 mg / dose. In some embodiments, the KRAS G12C inhibitor is administered at about 900 mg / dose. In some embodiments, the KRAS G12C inhibitor is administered at about 1000 mg / dose.

[0070] FAK inhibitors Potent inhibitors of FAK protein tyrosine kinase may be adapted for therapeutic use in mammals, particularly humans, as antiproliferative (e.g., anticancer), antitumor (e.g., effective against solid tumors), and antiangiogenic (e.g., halt or prevent blood vessel growth). In some embodiments, the methods described herein further contemplate administering to a subject a FAK inhibitor described herein. The FAK inhibitor is useful in preventing and treating non-hematologic malignancies, various human hyperproliferative disorders (e.g., liver, kidney, bladder, breast, stomach, ovarian, colorectal, prostate, pancreatic, lung, vulva, thyroid, hepatoma, sarcoma, glioblastoma, malignant and benign tumors of the head and neck), and other hyperplastic conditions (e.g., benign hyperplasia of the skin (e.g., psoriasis) and benign hyperplasia of the prostate (e.g., BPH)), and in preventing and treating disorders such as mesothelioma. In some embodiments, the compounds described herein, e.g., FAK inhibitors, inhibit protein tyrosine kinase 2 (PYK2).

[0071] Exemplary FAK inhibitors include those having the following structure: [ka] Defactinib includes, but is not limited to, defactinib having the formula: or its pharmaceutically acceptable salt. Defactinib is also known as VS-6063 (e.g., VS-6063 free base) or PF-04554878. VS-6063 and related compounds are also disclosed, for example, in U.S. Patent No. 7,928,109, the contents of which are incorporated herein by reference. In some embodiments, VS-6063 can form pharmaceutically acceptable salt (e.g., VS-6063 hydrochloride).

[0072] In some embodiments, the FAK inhibitor has the following structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0073] In some embodiments, the FAK inhibitor has the following structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0074] In some embodiments, the FAK inhibitor has the following structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0075] In some embodiments, the FAK inhibitor has the following structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0076] In some embodiments, the FAK inhibitor has the following structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0077] In some embodiments, the FAK inhibitor has the following structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0078] In some embodiments, the FAK inhibitor has the following structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0079] 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 its pharmaceutically acceptable salt.For example, in some embodiments, the FAK inhibitor is defactinib or its pharmaceutically acceptable salt.

[0080] In some embodiments, the FAK inhibitor is administered at least once every day. For example, in some embodiments, the FAK inhibitor is administered twice every day. In some embodiments, the FAK inhibitor is administered once every day.

[0081] In some embodiments, the FAK inhibitor is administered at about 100 mg to about 1000 mg per administration, for example, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 100 mg to about 200 mg, about 200 mg to about 1000 mg, about 400 mg to about 1000 mg, about 600 mg to about 1000 mg, about 800 mg to about 1000 mg, about 200 mg to about 800 mg, about 200 mg to about 600 mg, about 200 mg to about 400 mg, about 400 mg to about 800 mg, or about 400 mg to about 600 mg. In some embodiments, the FAK inhibitor is administered at about 200 mg to about 400 mg / administration. In some embodiments, the FAK inhibitor is administered at about 100 mg / administration. In some embodiments, the FAK inhibitor is administered at about 200 mg / dose. In some embodiments, the FAK inhibitor is administered at about 300 mg / dose. In some embodiments, the FAK inhibitor is administered at about 400 mg / dose. In some embodiments, the FAK inhibitor is administered at about 500 mg / dose. In some embodiments, the FAK inhibitor is administered at about 600 mg / dose. In some embodiments, the FAK inhibitor is administered orally.

[0082] In some embodiments, the FAK inhibitor is administered as a cycle that includes administering the FAK inhibitor for three weeks, and then not administering the FAK inhibitor for one week. In some embodiments, the cycle is repeated at least once.

[0083] In alternative embodiments, the FAK inhibitor is administered continuously (i.e., without a week during which the FAK inhibitor is not administered). In some embodiments, the FAK inhibitor is administered for at least four weeks.

[0084] Diseases and Disorders Abnormal cell growth Abnormal cell growth, as used herein and unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors), for example, that proliferate due to expression of mutated tyrosine kinases or overexpression of receptor tyrosine kinases; (2) benign and malignant cells, for example, of other proliferative diseases, where aberrant tyrosine kinase activation occurs; (3) any tumors, for example, that proliferate due to receptor tyrosine kinases; (4) any tumors, for example, that proliferate due to aberrant serine / threonine kinase activation; and (5) benign and malignant cells, for example, of other proliferative diseases, where aberrant serine / threonine kinase activation occurs. Abnormal cell growth may refer to cell growth in epithelial cells (e.g., carcinoma, adenocarcinoma); cell growth in mesenchymal cells (e.g., sarcoma (e.g., leiomyosarcoma, Ewing's sarcoma)); cell growth in hematopoietic cells (e.g., lymphoma, leukemia, myelodysplasia (e.g., precancerous)); or cell growth in other cells (e.g., melanoma, mesothelioma, and other tumors of unknown origin).

[0085] Neoplastic Disorders Abnormal cell growth may refer to a neoplastic disorder. A "neoplastic disorder" is a disease or disorder characterized by cells capable of autonomous growth or replication, e.g., an abnormal state or condition characterized by proliferative cell growth. An abnormal mass of tissue, or "neoplasm," resulting from abnormal cell growth or division, may be benign, precancerous (carcinoma in situ) or malignant (cancer).

[0086] Exemplary neoplastic disorders include carcinomas, sarcomas, metastatic disorders (e.g., tumors arising from prostate, colon, lung, breast, and liver origins), hematopoietic neoplastic disorders, e.g., leukemia, metastatic tumors. Treatment with the compound is in an amount effective to ameliorate at least one symptom of the neoplastic disorder (e.g., reduced cell proliferation, reduction in tumor mass, etc.).

[0087] cancer The methods of the present disclosure are useful in preventing and treating cancer, including, for example, solid tumors, soft tissue tumors, and their metastases. The methods of the present disclosure are also useful in treating non-solid cancers. Exemplary solid tumors include malignant tumors (e.g., sarcomas, adenocarcinomas, and carcinomas) of various organ systems, such as those of the lung, breast, lymphatic, gastrointestinal tract (e.g., colon), and genitourinary system (e.g., kidney, urothelial, or testicular tumors), pharynx, prostate, and ovary. 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 cancer of the small intestine.

[0088] The cancer may include mesothelioma, neurofibromatosis, e.g., 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, schwannoma, meningioma, schwannomatosis, acoustic neuroma, adenoid cystic carcinoma, ependymoma, ependymal tumors, or any other tumors that show reduced merlin expression and / or mutations, and / or deletion and / or promoter hypermethylation of the NF-2 gene. In some embodiments, the cancer is renal cancer.

[0089] The cancer may include cancers characterized as containing cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells. The cancer may include cancers characterized as enriched in cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells (e.g., tumors enriched in cells that have undergone epithelial-mesenchymal transition, or metastatic tumors).

[0090] The cancer may be a primary tumor, i.e., located at the anatomical site where tumor growth begins. The cancer may also be metastatic, i.e., appear at least at a second anatomical site other than the anatomical site where tumor growth begins. The cancer may be a recurrent cancer, i.e., a cancer that returns after treatment and after a period of time during which the cancer was undetectable. The recurrent cancer may be anatomically local to the original tumor, e.g., anatomically proximal to the original tumor: regional to the original tumor, e.g., in a lymph node located proximal to the original tumor; or distal to the original tumor, e.g., regionally remote from the original tumor.

[0091] The cancer may also include, but is not limited to, for example, epithelial cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer (e.g., metastatic colorectal cancer, e.g., metastatic KRAS mutant cancer), prostate cancer, head and neck cancer, melanoma (e.g., NRAS mutant locally advanced or metastatic malignant cutaneous melanoma), acute myeloid leukemia, and glioblastoma.Exemplary breast cancer includes triple-negative breast cancer, basal-like breast cancer, claudin-low type breast cancer, aggressive, inflammatory, metastatic, and treatment-resistant progressive HER-2 positive or ER positive cancer.

[0092] In some embodiments, the cancer includes the cancer characterized as having RAS mutation.The cancer can also include the cancer characterized as having KRAS mutation.In some embodiments, the KRAS mutation is KRAS G12C mutation.

[0093] The cancer may also include lung cancer, colorectal cancer (CRC), pancreatic cancer, uveal melanoma, ovarian cancer, uterine endometrioid cancer, bladder urothelial carcinoma, breast invasive lobular carcinoma, cervical squamous cell carcinoma, cutaneous melanoma, endocervical adenocarcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma, biphasic pleural mesothelioma, renal clear cell carcinoma, renal clear cell carcinoma, gastric adenocarcinoma, tubular gastric adenocarcinoma, uterine carcinosarcoma, or uterine malignant mixed Mullerian tumor. In some embodiments, the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, or ovarian cancer.

[0094] In some embodiments, the cancer is unresectable or metastatic melanoma, melanoma involving lymph nodes or metastatic disease that has undergone complete resection, metastatic non-small cell lung cancer that has progressed during and after platinum-based chemotherapy, metastatic small cell lung cancer that has progressed after platinum-based chemotherapy and at least one other line of therapy, advanced renal cell carcinoma that has previously received anti-angiogenic therapy, advanced renal cell carcinoma, classical Hodgkin's lymphoma, recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression during or after platinum-based therapy, locally advanced or metastatic urothelial carcinoma, microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, or hepatocellular carcinoma.

[0095] In some embodiments, the cancer is melanoma, non-small cell lung cancer, small cell lung cancer, head and neck squamous cell carcinoma, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability high carcinoma, gastric cancer, esophageal cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, or endometrial carcinoma.

[0096] Other cancers include uveal melanoma, brain cancer, abdominal cancer, esophageal cancer, gastrointestinal cancer, glioma, liver cancer, tongue cancer, neuroblastoma, osteosarcoma, ovarian cancer, retinoblastoma, Wilms' tumor, multiple myeloma, skin cancer, lymphoma, blood and bone marrow cancers (e.g., progressive hematologic malignancies, leukemias, e.g., acute myeloid leukemia (e.g., primary or secondary), acute lymphoblastic leukemia, acute lymphocytic leukemia, T-cell leukemia, hematologic malignancies, progressive myeloproliferative disorders, myelodysplastic syndromes, relapsed or refractory multiple myeloma, progressive myeloproliferative disorders, myelodysplastic syndromes, sexual disorder), retinal cancer, bladder cancer, cervical cancer, kidney cancer, endometrial cancer, meningioma, lymphoma, skin cancer, uterine cancer, lung cancer, non-small cell lung cancer, nasopharyngeal carcinoma, neuroblastoma, solid tumors, hematological malignancies, squamous cell carcinoma, testicular cancer, thyroid cancer, mesothelioma, brain cancer, vulvar cancer, sarcoma, intestinal cancer, oral cancer, endocrine cancer, salivary gland cancer, spermatocytic seminoma, sporadic medullary thyroid cancer, non-proliferative testicular cell carcinoma, malignant mast cell associated cancer, non-Hodgkin's lymphoma, and diffuse large B-cell lymphoma.

[0097] In some embodiments, the tumor is a solid tumor. In some embodiments, the solid tumor is locally advanced or metastatic, and in some embodiments, the solid tumor is refractory (e.g., resistant) to standard treatments.

[0098] The methods described herein can reduce, improve or completely eliminate the disorder and / or its associated symptoms, so that the disorder does not get worse, can slow the rate of progression, or can minimize the recurrence rate of the disorder (i.e., avoid recurrence) once the disorder is initially eliminated.Appropriate doses and treatment regimens vary depending on the specific compound, combination, and / or pharmaceutical composition used, and the mode of delivery of the compound, combination, and / or pharmaceutical composition.In some embodiments, the methods increase the average length of survival, increase the average length of progression-free survival, and / or reduce the recurrence rate of subjects treated with the combination described herein in a statistically significant manner.

[0099] In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer (NSCLC), e.g., KRAS mutant NSCLC; metastatic cancer), bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer (e.g., unresectable low-grade ovarian cancer, advanced or metastatic ovarian cancer), rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer (e.g., triple-negative breast cancer (e.g., breast cancer that does not express genes for estrogen receptors, progesterone receptors, and Her2 / neu)), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, In some embodiments, the cancer is selected from the group consisting of cancers of the small intestine, cancers of the endocrine system, thyroid cancer, parathyroid carcinoma, adrenal cancer, sarcoma of soft tissue, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, cancer of the kidney or ureter, renal cell carcinoma, renal pelvis carcinoma, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma), or a combination of one or more of the foregoing cancers. In some embodiments, the cancer is metastatic. In some embodiments, the abnormal cell growth recurs locally (e.g., the subject has a locally recurring disease, e.g., cancer).

[0100] Further treatment In some embodiments, the methods and compositions described herein are administered together with an additional treatment (e.g., a cancer treatment). In one embodiment, a mixture of one or more compounds or pharmaceutical compositions can be administered together with the combinations described herein to a subject in need thereof. In yet another embodiment, one or more compounds or compositions (e.g., pharmaceutical compositions) can be administered together with the combinations described herein to treat or prevent various diseases, including, for example, cancer, diabetes, neurodegenerative diseases, cardiovascular diseases, blood clotting, inflammation, flushing, obesity, aging, stress, and the like. In various embodiments, the combination treatment comprising the compounds or pharmaceutical compositions described herein can refer to (1) a pharmaceutical composition comprising one or more compounds in combination with the combinations described herein; and (2) co-administration of one or more compounds or pharmaceutical compositions described herein with the combinations described herein, where the compounds or pharmaceutical compositions described herein are not formulated in the same composition. In some embodiments, the combinations described herein can be administered together with an additional treatment (e.g., an additional cancer treatment). In some embodiments, the additional treatment (e.g., additional cancer treatment) can be administered simultaneously (e.g., at the same time), in the same or separate compositions, or sequentially. Sequential administration refers to administering one treatment before (e.g., immediately before, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes; 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours or more; 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or more days; 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks or more weeks) administration of the additional (e.g., second) treatment (e.g., compound or treatment). The order of administration of the first and second compound or treatment can also be reversed.

[0101] Exemplary cancer treatments include, for example, chemotherapy, targeted therapy (e.g., antibody therapy, immunotherapy, and hormonal therapy). Examples of each of these treatments are provided below.

[0102] chemotherapy In some embodiments, the combination described herein is administered with chemotherapy. Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. "Chemotherapy" usually refers to cytotoxic drugs that generally affect rapidly dividing cells, as opposed to targeted therapy. Chemotherapy drugs interfere with cell division in various possible ways, for example, with DNA replication or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific to cancer cells, but some degree of specificity may arise from the fact that many cancer cells cannot repair DNA damage, whereas normal cells generally can.

[0103] Examples of chemotherapeutic agents used in cancer treatment include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkylsulfonates, hydrazines, triazenes, aziridines, spindle poisons, cytotoxic agents, topoisomerase inhibitors, etc.). Exemplary agents include: aclarubicin, actinomycin, alitretin, altretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bexarotene, endamustine, bleomycin, bortezomib, busulfan, camptothecin, capesimerin, cefotaxime ... Tabine, carboplatin, carboquin, carmofur, carmustine, celecoxib, chlorambucil, chlormethine, cisplatin, cladribine, clofarabine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, demecolcine, docetaxel, doxorubicin, efaproxiral, elesclomol, elsamitrucin, enocitabine, epirubicin, estramustine, edullopidine, cyclosporine, etoposide, floxuridine, fludarabine, fluorouracil (5FU), fotemustine, gemcitabine, gliadel implant, hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, irinotecan, irofulven, ixabepilone, larotaxel, leucovorin, liposomal doxorubicin, liposomal daunorubicin, lonidamine, lomustine, lucantone, mannosulfan, masoprocol, melphalan, mercapto Brine, mesna, methotrexate, methyl aminolevulinate, mitobronitol, mitoguazone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, oblimersen, omacetaxine, ortataxel, oxaliplatin, paclitaxel, pegaspargase, pemetrexed, pentostatin, pirarubicin, pixantrone, plicamycin, porfimer sodium, prednimustine, procarbazine,Raltitrexed, Ranimustine, Rubitecan, Sapacitabine, Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin, Talaporfm, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide, Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurin, Thioguanine, Tipifarnib, Topotecan, Trabectedin, Triazicon, Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfamide, Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vorinostat, Zorubicin, and other cell growth inhibitory or cytotoxic agents described herein.

[0104] Because some drugs work better together than alone, two or more drugs are often given simultaneously or sequentially. Often, two or more chemotherapeutic agents are used as combination chemotherapy. In some embodiments, the chemotherapeutic agents (including combination chemotherapy) can be used in combination with the combinations described herein.

[0105] targeted therapy In some embodiments, the combination described herein is administered with targeted therapy. Targeted therapy constitutes the use of drugs specific to the disordered proteins of cancer cells. Small molecule targeted therapeutic drugs are generally inhibitors of enzyme domains on mutated, overexpressed, or otherwise important proteins in cancer cells. Notable examples are tyrosine kinase inhibitors (e.g., axitinib, bosutinib, cediranib, desatinib, erolotinib, imatinib, gefitinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, and vandetanib), and cyclin-dependent kinase inhibitors (e.g., alvocidib and seliciclib). Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody that specifically binds to a protein on the surface of cancer cells. Examples include the anti-HER2 / neu antibody trastuzumab (HERCEPTIN®), typically used in breast cancer, and the anti-CD20 antibodies rituximab and tositumomab, typically used in various B-cell malignancies. Other exemplary antibodies include cetuximab (Ctuximab), panitumumab, trastuzumab, alemtuzumab, bevacizumab, edrecolomab, and gemtuzumab. Exemplary fusion proteins include aflibercept and denileukin diftitox. In some embodiments, the targeted therapy may be used in combination with the combinations described herein,

[0106] Targeted therapies may also include small peptides as "homing devices" that bind to cell surface receptors or affected extracellular matrix around the tumor. Radionuclides attached to these peptides (e.g., RGDs) ultimately kill cancer cells when the nuclides decay in the vicinity of the cells. Examples of such therapies include BEXXAR®.

[0107] immunotherapy In some embodiments, the combinations described herein are administered with immunotherapy, which refers to a diverse set of therapeutic strategies designed to induce a patient's own immune system to fight tumors.

[0108] Modern methods for generating immune responses against tumors include intravesicular BCG immunotherapy for superficial bladder cancer, and the use of interferon and other cytokines to induce immune responses in subjects with renal cell carcinoma and melanoma.Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, because donor immune cells often attack tumors in a graft-versus-tumor effect.In some embodiments, the immunotherapeutic agents can be used in combination as described herein.

[0109] Hormone treatment In some embodiments, the described combination is administered together with hormone therapy. 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 cancer and prostate cancer. Removal or blocking of estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists (e.g., progestogens) can be therapeutically beneficial. In some embodiments, the above-mentioned hormone therapy agents can be used in combination with the combinations described herein.

[0110] Radiation therapy The combinations described herein may be used in combination with directed energy or particle, or radioisotope treatment (e.g., radiation therapy, e.g., radiation oncology) for the treatment of proliferative diseases (e.g., cancer, e.g., cancer associated with cancer stem cells). The combinations described herein may be administered to a subject simultaneously or sequentially with directed energy or particle, or radioisotope treatment. For example, the combinations described herein may be administered before, during, or after directed energy or particle, or radioisotope treatment, or combinations thereof. Directed energy or particle therapy may include total body irradiation, local body irradiation, or point irradiation. Directed energy or particles may be generated from accelerators, synchrotrons, nuclear reactions, vacuum tubes, lasers, or from radioisotopes. The treatments may include external beam radiation therapy, teletherapy, brachytherapy, sealed source radiation therapy, total body radioisotope therapy, or unsealed source radiation therapy. The treatment may include the ingestion or proximal placement of radioisotopes, such as radioactive iodine, cobalt, cesium, potassium, bromine, fluorine, carbon. External beam radiation may include exposure to directed alpha particles, electrons (e.g., beta particles), protons, neutrons, positrons, or photons (e.g., radio waves, millimeter waves, microwaves, infrared, visible light, ultraviolet light, X-rays, or gamma ray photons). Radiation may be directed to any part of the subject requiring treatment.

[0111] surgery The combinations described herein can be used in combination with surgery, e.g., surgical exploration, intervention, biopsy, for the treatment of proliferative diseases, e.g., cancer, e.g., cancer associated with cancer stem cells. The combinations described herein can be administered to a subject simultaneously or sequentially with surgery. For example, the combinations described herein can be administered before surgery (pre-op), during surgery, or after surgery (post-op), or a combination thereof. The surgery can be a biopsy in which one or more cells are collected for further analysis. The biopsy can be accomplished, for example, with a scalpel, needle, catheter, endoscope, spatula, or scissors. The biopsy can be an excision biopsy, an incision biopsy, a core biopsy, or a needle biopsy, e.g., a needle aspiration biopsy. The surgery can include the removal of localized tissue suspected or identified as cancerous. For example, the procedure can include the removal of a cancerous lesion, mass, polyp, or nevus. The procedure may include removal of larger amounts of tissue (e.g., breast, bone, skin, fat, or muscle). The procedure may include removal of part or all of an organ or node (e.g., lung, throat, tongue, bladder, cervix, ovaries, testes, lymph nodes, liver, pancreas, brain, eye, kidney, gallbladder, stomach, colon, rectum, or intestine). In one embodiment, the cancer is breast cancer, e.g., triple-negative breast cancer, and the surgery is a mastectomy or lumpectomy.

[0112] Anti-inflammatory agents The combinations described herein may be administered with anti-inflammatory agents. Anti-inflammatory agents may include, but are not limited to, nonsteroidal anti-inflammatory agents (e.g., salicylates (aspirin (acetylsalicylic acid)), diflunisal, salsalate), propionic acid derivatives (ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, loxoprofen), acetic acid derivatives (indomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone), enolic acids (Enolic acid) (oxicam) derivatives (piroxicam, meloxicam, tenoxicam, droxicam, lomoxicam, isoxicam), fenamic acid derivatives (fenamates) (mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (coxibs) (celecoxib), sulphonanilides (nimesulide), steroids (e.g., hydrocortisone (cortisol), cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone).

[0113] Painkillers Analgesics may include, but are not limited to, opiates (e.g., morphine, codeine, oxycodone, hydrocodone, dihydromorphine, pethidine, buprenorphine, tramadol, venlafaxine), paracetomal) and nonsteroidal anti-inflammatory drugs (e.g., salicylates (aspirin (acetylsalicylic acid)), diflunisal, salsalate), propionic acid derivatives (ibuprofen, naproxen, fenoprofen, ketoprofen). , flurbiprofen, oxaprozin, loxoprofen), acetic acid derivatives (indomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone), enolic acid (oxicam) derivatives (piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam), fenamic acid derivatives (fenamates) (mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (coxibs) (celecoxib), sulfonamides (nimesulide).

[0114] Antiemetics The combinations described herein may be administered with antiemetics. Antiemetics may include, but are not limited to, 5-HT3 receptor antagonists (dolasetron (Anzemet), granisetron (Kytril, Thankuso), ondansetron (Zofran), tropisetron (Navoban), palonosetron (Aloxi), mirtazapine (Remeron)), dopamine antagonists (domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide (Reglan), alizapride, prochlorperazine (Compazine, Stemzine, Bucca Stem), stem, stemethyl, Phenotil), NK1 receptor antagonists (aprepitant (Emend), antihistamines (cyclizine, diphenhydramine (Benadryl), dimenhydrinate (Gravol, Dramamine), meclozine (Bonin, Antivert), promethazine (Pentazin, Phenergan, Promacot), hydroxyzine), benzodiazapines (lorazepam, midazolam), anticholinergics (hyoscine), steroids (dexamethasone).

[0115] combination The phrases "in combination with" and the terms "co-administration", "co-administering" or "co-providing", as used herein in the context of administration of a compound described herein or a treatment described herein, mean that two or more different compounds or treatments are delivered to a subject during the course of the subject's suffering from a disease or disorder (e.g., a disease or disorder as described herein, e.g., cancer). For example, two or more different compounds or treatments are delivered to the subject after the subject has been diagnosed with the disease or disorder (e.g., a disease or disorder as described herein, e.g., cancer) and before the disease or disorder is cured or eliminated or treatment is discontinued for other reasons.

[0116] In some embodiments, the delivery of one compound or treatment is still occurring when the delivery of the second or third or fourth compound or treatment begins, so that there is an overlap in terms of administration. This is sometimes referred to herein as "simultaneous" or "concurrent delivery". In other embodiments, the delivery of one compound or treatment ends before the delivery of the other compound or treatment begins. In some embodiments in either case, the treatment (e.g., administration of the compound, composition, or treatment) is more effective due to the combined administration. For example, the second compound or treatment and / or the third compound or treatment and / or the fourth compound or treatment is more effective, e.g., a comparable effect is observed with less of the second compound or treatment, or the second compound or treatment and / or the third compound or treatment and / or the fourth compound or treatment reduces symptoms to a greater extent than is observed when the second compound or treatment and / or the third compound or treatment and / or the fourth compound or treatment is administered in the absence of the first compound or treatment, or a similar situation is observed with the first compound or treatment. In some embodiments, the delivery is performed such that the reduction in symptoms, or other parameters associated with the disorder, is greater than is observed when one compound or treatment is delivered in the absence of the other. The effects of the two or three or four compounds or treatments may be partially additive, wholly additive, or greater than additive (e.g., synergistic). In some embodiments, the effect of the combination disclosed herein is synergistic. The delivery can be performed such that a first compound or treatment delivered is still detectable when a second and / or third and / or fourth compound or treatment is delivered.

[0117] In some embodiments, the first compound or treatment and the second compound or treatment and the third compound or treatment and optionally the fourth compound or treatment can be administered simultaneously (e.g., at the same time), in the same or separate compositions, or sequentially.Sequential administration refers to administering one compound or treatment before the administration of the further, for example, the second compound or treatment and / or the third compound or treatment and / or the fourth compound or treatment (e.g., immediately before, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes; 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours or more; 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or more days; 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks or more weeks). The order of administration of the first and second and third compounds or treatments, and optionally the fourth compound or treatment, can also be reversed or any sequential combination of the above compounds / treatments can be provided.

[0118] The combinations described herein can be a first line treatment for abnormal cell growth, e.g., cancer (i.e., it can be used in patients who have not previously been administered another drug intended to treat the cancer); a second line treatment for the cancer (i.e., it is used in subjects who have previously been administered, and need to be administered, another drug intended to treat the cancer); a third or fourth line treatment for the cancer (i.e., it is used in subjects who have previously been administered two or three other drugs intended to treat the cancer).

[0119] Administration and Dosage The combinations of the present disclosure can be administered orally, parenterally, topically, rectally, or via an implanted reservoir, preferably by oral administration or injection. In some cases, the pH of a composition (e.g., a pharmaceutical composition) can be adjusted with pharma- ceutically acceptable acids, bases, or buffers to enhance the stability or effectiveness of the composition.

[0120] In some embodiments, the subject is administered the composition (e.g., pharmaceutical composition) orally. In some embodiments, the composition (e.g., pharmaceutical composition) is administered orally in any orally acceptable dosage form, including, but not limited to, liqui-gel tablets or capsules, syrups, emulsions, and aqueous suspensions. The liquid-gel may contain gelatin, plasticizers, and / or opacifiers, if needed to achieve the appropriate consistency, and may be coated with an enteric coating approved for use (e.g., shellac). Additional thickening agents (e.g., gums, e.g., xanthan gum), starches (e.g., corn starch), or gluten may be added to achieve the desired consistency of the composition (e.g., pharmaceutical composition) when used as an oral dosage. If desired, certain sweeteners and / or flavorings and / or colorings may be added.

[0121] In some embodiments, the subject is administered the composition (e.g., pharmaceutical composition) in a form suitable for oral administration (e.g., tablet, capsule, pill, powder, sustained release formulation, solution, and suspension). The composition (e.g., pharmaceutical composition) may be in a unit dosage form suitable for single administration of a precise dosage. The pharmaceutical composition may include, in addition to the compound as described herein, a pharma- ceutically acceptable carrier, and may further include one or more pharma- ceutically acceptable excipients, such as, for example, stabilizers, diluents, binders, and lubricants, as needed. In addition, the tablet may include other medicinal or pharmaceutical agents, carriers, and / or adjuvants. Exemplary pharmaceutical compositions include compressed tablets (e.g., direct compressed tablets).

[0122] Tablets containing active or therapeutic ingredients (e.g., compounds as described herein) are also provided. In addition to the active or therapeutic ingredients, tablets may contain many inert substances (e.g., carriers). Pharmaceutically acceptable carriers may be sterile liquids, such as water and oils (including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, sesame oil, and the like). Saline and aqueous dextrose may also be used as liquid earners. Oral dosage forms for use according to the present disclosure may thus be formulated in a conventional manner using one or more pharma- ceutically acceptable carriers, including excipients and auxiliary substances. The excipients and auxiliary substances facilitate the processing of the active ingredients into preparations that can be used as pharmaceuticals. Excipients may impart good powder flow and compression properties for materials to be compressed. Examples of excipients are described, for example, in the Handbook of Pharmaceutical Excipients (5th ed.), edited by Raymond C Rowe, Paul J. Sheskey, and Sian C. Owen; Publisher: Pharmaceutical Press.

[0123] For oral administration, the active ingredient, for example, the compound as described herein, can be easily formulated by combining the active ingredient with a pharma- ceutically acceptable carrier well known in the art. Such carriers allow the active ingredient of the present disclosure to be formulated for oral ingestion by subjects as tablets, pills, capsules, liquids, gels, syrups, slurries, powders or granules, suspensions or solutions in water or non-aqueous media, etc. Pharmaceutical preparations for oral use can be made using solid excipients, and the resulting mixture can be milled as necessary, and after adding suitable auxiliary substances if desired, the granular mixture can be processed to obtain, for example, tablets. Suitable excipients (e.g., diluents, binders or disintegrants) can be desirable.

[0124] Dosage varies depending on the dosage form used and the route of administration utilized. The exact formulation, route of administration and dosage can be selected by the individual physician in view of the patient's condition (see, for example, Fingl et al., 1975, in "Pharmacological Basis of Therapeutics"). Lower or higher doses than those described above may be required. The specific dosage and treatment regimen for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, excretion rate, drug combination, severity and course of the disease, condition or symptom, the subject's predisposition to the disease, condition or symptom, and the judgment of the treating physician. A course of treatment can include one or more separate administrations of the compound as described herein. A course of treatment can include one or more cycles of the compound as described herein.

[0125] In some embodiments, cycle, as used herein in the context of the cycle of administration of a drug, refers to the period during which the drug is administered to a patient.For example, if a drug is administered over a 21-day cycle, its periodic administration (e.g., daily or twice daily) is given over 21 days.The drug can be administered over more than one cycle.A rest period can be inserted between cycles.A rest cycle can be 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or 1 week, 2 weeks, 3 weeks, 4 weeks, or more weeks long.

[0126] The oral dosage forms may be presented in a pack or dispenser device (e.g., an FDA approved kit) that may contain one or more unit dosage forms containing the active ingredient, if desired. The pack may, for example, comprise metal or plastic foil (e.g., a blister pack). The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals. This notice reflects the format of the composition or its approval by the agency for human or veterinary administration. Such notice may, for example, be that of a label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. EXAMPLES

[0127] Working Example Example 1. Tumor mouse test In vivo experiments were performed using transplantable mouse models of KRAS G12C cancer (e.g., KRAS G12C lung cancer). G12C The cells were then subjected to G12D / WT ;Trp53 fl / fl , Rosa26 APOBEC3Bi / WT ; Rag1 KO / KO Obtained from lung tumors and expressing KRAS G12C These cells form immune-inflammatory tumors that are responsive to immunotherapy (Boumelha et al., bioRxiv). Briefly, tumors were prime-edited to express KPAR1.3. G12C The cells were orthotopically implanted in the lungs by tail vein injection. Mice were sorted into 4 groups: vehicle, VS-6766 (0.3 mg / kg orally, once daily), MRTX849 (50 mg / kg orally, once daily), and VS-6766 + MRTX849. Five days after treatment, mice were euthanized and orthotopic KPAR1.3 G12C Lung tumors were harvested.

[0128] qPCR analysis RNA was extracted and converted to cDNA using the High-Capacity cDNA Reverse Transcription kit. To determine the effect on the tumor microenvironment, TaqMan qPCR was performed using CD8, FOXP3, granzyme A, granzyme B and β2-microglobulin probes from Applied Biosystems. Each PCR reaction was performed in triplicate wells. Expression levels were calculated as the difference (ΔCT) between the target gene CT and the normalization gene CT.

[0129] In Figure 1, the orthotopic KPAR1.3 G12C Mice bearing lung tumors were treated with vehicle, VS-6766 (0.3 mg / kg), MRTX849 (50 mg / kg), and VS-6766+MRTX849 for 5 days. Tumors were harvested and mRNA levels were analyzed by qPCR using specific primers for CD8, FOXP3, granzyme A, granzyme B, and β2-microglobulin probes.

[0130] Figure 1 shows that the combination of VS-6766 and KRAS G12C inhibitor makes the immune microenvironment more favorable for combination with anti-PD-1 antibody. Contemplated anti-PD-1 antibodies are disclosed herein (see, e.g., paragraph

[0057] ). Combination with anti-PD-L1 antibody is also contemplated.

[0131] Example 2. Tumor mouse test A KRAS G12C mutant tumor mouse model (e.g., CT26 KRAS G12C mutant colorectal model) is used. Tumor challenge is initiated by subcutaneous inoculation of mice with a tumor cell suspension. Tumor size (mm 3 Once the tumor has grown to an average volume of 50-80 mm 3Once the mice reach 100 mg / kg / day, they are sorted into 8 groups: vehicle; VS-6766; G12C inhibitor (G12Ci); anti-PD-1; VS-6766+G12Ci; VS-6766+anti-PD-1; G12Ci+anti-PD-1; VS-6766+G12Ci+anti-PD-1. Tumors and body weights are measured for the duration of the study. Animals are checked for tumor growth and any effects of treatment on normal behavior, such as motility, food and water consumption (observation only), and weight gain / loss, eye / coat matting, and any other abnormal effects.

[0132] Equivalents and Scope In the claims, the articles "a," "an," and "the" can mean one or more than one, unless indicated to the contrary or otherwise clear from the context. A claim or description containing "or" between one or more members of a group is considered to be satisfied when one, more than one, or all of the group members are present in, used in, or otherwise relevant to a given product or process, unless indicated to the contrary or otherwise clear from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, used in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one or all of the group members are present in, used in, or otherwise relevant to a given product or process.

[0133] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that is dependent on another claim may be modified to include one or more limitations found in any other claim that is dependent on the same base claim. When elements are presented as lists, for example in Markush group format, each subgroup of the elements is also disclosed, and any element(s) may be removed from the group. In general, when the disclosure, or aspects of the disclosure, are referred to when comparing certain elements and / or features, it should be understood that some embodiments of the disclosure and aspects of the disclosure consist of or consist essentially of such elements and / or features. For the sake of simplicity, those embodiments have not been specifically set forth herein in these terms. It is also noted that the terms "comprising" and "containing" are intended to be open-ended and allow for the inclusion of additional elements or steps. When ranges are stated, the endpoints are included. Moreover, unless otherwise indicated or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can, in different embodiments of the disclosure, envisage any specific value or subrange within the stated range, down to one-tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0134] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. Furthermore, any particular embodiment of the present disclosure that falls within the scope of the prior art may be expressly excluded from any one or more of the claims. Since such embodiments are deemed known to those skilled in the art, they may be excluded even if the exclusion is not expressly set forth herein. Any particular embodiment of the present disclosure may be excluded from any claim for any reason, whether or not the existence of prior art is relevant.

[0135] Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above detailed description, but rather as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

Claim 1 A combination for treating cancer in a subject in need of cancer treatment, comprising a RAF / MEK dual inhibitor, an anti-PD-1 antibody, and a KRAS G12C inhibitor, wherein the RAF / MEK dual inhibitor is of formula (I): 【Chemical 21】 The combination, which is a compound of or a pharmaceutically acceptable salt thereof. Claim 2 The combination according to claim 1, wherein the RAF / MEK dual inhibitor is administered twice a week. Claim 3 The combination according to claim 1, wherein the RAF / MEK dual inhibitor is administered in cycles, where the cycle comprises administering the RAF / MEK dual inhibitor twice a week for 3 weeks and then not administering the RAF / MEK dual inhibitor for 1 week. Claim 4 The combination according to claim 1, wherein the RAF / MEK dual inhibitor is administered at a dose of 0.8 mg to 10 mg, 2.4 mg, 3.2 mg, or 4 mg per administration. Claim 5 The combination according to claim 1, wherein the RAF / MEK dual inhibitor is administered orally. Claim 6 The combination according to claim 1, wherein the anti-PD-1 antibody is selected from the group consisting of balstilimab, budigalimab, cadonilimab, camrelizumab, semaprilimab, cetrelimab, dostarlimab, exavernlimab, geptanolimab, nivolumab, pembrolizumab, pemprilimab, pidilizumab, pimivalimab, prorgolimab, pucotenlimab, retifanlimab, sasanelimab, serplulimab, sintilimab, spartalizumab, srituzumab, tebotelimab, teriparlimab, tislelizumab, tripalimumab, and zimberelimab. Claim 7 The combination according to claim 1, wherein the anti-PD-1 antibody is administered every 2 weeks, every 3 weeks, every 4 weeks, or every 6 weeks, and the anti-PD-1 antibody is administered at a dose of 100 mg to 1000 mg per administration. Claim 8 The combination according to claim 1, wherein the anti-PD-1 antibody is administered parenterally. Claim 9 The KRAS G12C inhibitor in the combination according to claim 1 is ARS-853, ARS-1620, ARS-3248, sotorasib, adagrasib, GDC-6036, JDQ443, LY3537982, or MRTX1257, or a pharmaceutically acceptable salt thereof.

10. The combination according to claim 1, wherein the KRAS G12C inhibitor is administered at a dose of 100 mg to 2000 mg per administration.

11. The combination according to claim 1, wherein the KRAS G12C inhibitor is administered once daily or twice daily.

12. The combination according to claim 1, wherein the KRAS G12C inhibitor is administered orally.

13. A combination for treating cancer in a subject in need thereof, comprising a RAF / MEK dual inhibitor, an anti-PD-L1 antibody, and a KRAS G12C inhibitor, wherein the RAF / MEK dual inhibitor is of formula (I): 【Chemical 22】 The combination which is a compound of or a pharmaceutically acceptable salt thereof.

14. The combination according to claim 13, wherein the RAF / MEK dual inhibitor is administered twice a week.

15. The combination according to claim 13, wherein the RAF / MEK dual inhibitor is administered in cycles, wherein the cycle includes administering the RAF / MEK dual inhibitor twice a week for 3 weeks and then not administering the RAF / MEK dual inhibitor for 1 week.

16. The combination according to claim 13, wherein the RAF / MEK dual inhibitor is administered at a dose of 0.8 mg to 10 mg, 2.4 mg, 3.2 mg, or 4 mg per administration.

17. The combination according to claim 13, wherein the RAF / MEK dual inhibitor is administered orally.

18. The combination according to claim 13, wherein the anti-PD-L1 antibody is selected from the group consisting of atezolizumab, vintafolide alpha, avelumab, cosibelimab, durvalumab, enobafolimab, lazertinib, rodaplimab, pacmilimab, socazolimab, and sugemalimab.

19. The combination according to claim 13, wherein the anti-PD-L1 antibody is administered parenterally.

20. The anti-PD-L1 antibody is administered every two weeks, every three weeks, or every four weeks, and the anti-PD-L1 antibody is administered at a dose of 100 mg to 2000 mg / administration. The combination according to claim 13, characterized in that.

21. The KRAS G12C inhibitor is ARS-853, ARS-1620, ARS-3248, sotorasib, adagrasib, GDC-6036, JDQ443, LY3537982, or MRTX1257, or a pharmaceutically acceptable salt thereof. The combination according to claim 13, characterized in that.

22. The KRAS G12C inhibitor is administered once daily or twice daily, and the KRAS G12C inhibitor is administered at a dose of 100 mg to 2000 mg / administration. The combination according to claim 13, characterized in that.

23. The KRAS G12C inhibitor is characterized by being administered orally. The combination according to claim 13, characterized in that.

24. The combination further comprises a FAK inhibitor, and the FAK inhibitor is defactinib or a pharmaceutically acceptable salt thereof. The combination according to claim 1 or 13, characterized in that.

25. The defactinib is administered once daily or twice daily, and the defactinib is administered at a dose of 100 mg to 1000 mg / administration, 200 mg to 400 mg, 200 mg, or 400 mg / administration. The combination according to claim 24, characterized in that.

26. The defactinib is characterized by being administered orally. The combination according to claim 24, characterized in that.

27. The cancer is a cancer characterized by having a RAS mutation, and the RAS mutation is a KRAS mutation. The combination according to claim 1 or 13, characterized in that.

28. The KRAS mutation is a KRAS G12C mutation. The combination according to claim 27, characterized in that.

29. The cancer is lung cancer, colorectal cancer, pancreatic cancer, or ovarian cancer. The combination according to claim 1 or 13, characterized in that.

30. The lung cancer is non-small cell lung cancer. The combination according to claim 29, characterized in that.

31. The ovarian cancer is low-grade serous ovarian cancer. The combination according to claim 29, characterized in that.

32. The cancer is colorectal cancer. The combination according to claim 29, characterized in that. **Claim 33** A composition for treating cancer in a subject in need thereof, comprising a RAF / MEK dual inhibitor, wherein the composition is administered in combination with an anti-PD-1 antibody and a KRAS G12C inhibitor, wherein the RAF / MEK dual inhibitor is of formula (I): 【Chemical 23】 A composition which is a compound of or a pharmaceutically acceptable salt thereof. **Claim 34** A composition for treating cancer in a subject in need thereof, comprising an anti-PD-1 antibody, wherein the composition is administered in combination with a RAF / MEK dual inhibitor and a KRAS G12C inhibitor, wherein the RAF / MEK dual inhibitor is of formula (I): 【Chemical 24】 A composition which is a compound of or a pharmaceutically acceptable salt thereof. **Claim 35** A composition for treating cancer in a subject in need thereof, comprising a KRAS G12C inhibitor, wherein the composition is administered in combination with a RAF / MEK dual inhibitor and an anti-PD-1 antibody, wherein the RAF / MEK dual inhibitor is of formula (I): 【Chemical 25】 A composition which is a compound of or a pharmaceutically acceptable salt thereof. **Claim 36** A composition for treating cancer in a subject in need thereof, comprising a RAF / MEK dual inhibitor, wherein the composition is administered in combination with an anti-PD-L1 antibody and a KRAS G12C inhibitor, wherein the RAF / MEK dual inhibitor is of formula (I): 【Chemical 26】 A composition which is a compound of or a pharmaceutically acceptable salt thereof. **Claim 37** A composition for treating cancer in a subject in need thereof, comprising an anti-PD-L1 antibody, wherein the composition is administered in combination with a RAF / MEK dual inhibitor and a KRAS G12C inhibitor, wherein the RAF / MEK dual inhibitor is of formula (I): 【Chemical 27】 A composition which is a compound of or a pharmaceutically acceptable salt thereof. **Claim 38** A composition for treating cancer in a subject in need thereof, comprising a KRAS G12C inhibitor, wherein the composition is administered in combination with a RAF / MEK dual inhibitor and an anti-PD-L1 antibody, wherein the RAF / MEK dual inhibitor is of formula (I): 【Chemical Formula 28】 A composition which is a compound of or a pharmaceutically acceptable salt thereof.

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