Combination therapies

Abstract

To provide combination therapies for treating KRas G12C cancers.SOLUTION: The present invention relates to methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a Raf family kinase inhibitor and a KRAS G12C inhibitor of Formula (I) or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to combination therapies useful for treating cancer. In particular, the present invention relates to therapeutically effective combinations of Raf family kinase inhibitors and KRas G12C inhibitors, pharmaceutical compositions comprising the inhibitors, kits comprising the compositions, and methods of use thereof. [Background technology]

[0002] 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, cycling between inactive (GDP-bound) and active (GTP-bound) states to transmit upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes, including cell proliferation (see, e.g., Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignancy was observed more than 30 years ago (see, e.g., Santos et al., (1984) Science 223:661-664). Aberrant expression of KRas accounts for up to 20% of all cancers, and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25-30% of lung adenocarcinomas (see, e.g., Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428). Single nucleotide substitutions resulting in missense mutations in codons 12 and 13 of the primary amino acid sequence of KRas constitute approximately 40% of these KRas driver mutations in lung adenocarcinoma, with the G12C transversion being the most common activating mutation (see, e.g., Dogan et al., (2012) Clin Cancer Res. 18(22):6169-6177, doi:10.1158 / 1078-0432. CCR-11-3265, published online September 26, 2012).

[0004] The well-known role of KRas in malignancy and the discovery of these frequent mutations of KRas in various tumor types have made KRas a highly attractive target for the pharmaceutical industry in cancer therapy. Despite 30 years of extensive discovery efforts to develop KRas inhibitors to treat cancer, no KRas inhibitor has demonstrated sufficient safety and / or efficacy to obtain regulatory approval (see, e.g., McCormick (2015) Clin Cancer Res. 21(8):1797-1801).

[0005] Compounds that inhibit KRas activity, including those that interfere with effectors such as guanine nucleotide exchange factors (see, for example, Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25): 6140-6143 doi: 10.1002 / anie201201358), as well as those that target KRas G12C (see, for example, Ostrem et al., (2013) Nature 503: 548-551), remain highly desirable and under investigation. Clearly, there is still ongoing interest and effort in developing inhibitors of KRas, particularly inhibitors of activated KRas mutants, including KRas G12C.

[0006] The KRas G12C inhibitors disclosed herein are potent inhibitors of KRas G12C enzyme activity and exhibit single-agent activity in inhibiting the in vitro proliferation of cell lines with KRas G12C mutations, but the relative potency and / or maximum observed effect of any given KRas G12C inhibitor may vary among KRAS mutant cell lines. The range of potency and the reason(s) for the maximum observed effect are not fully understood, although certain cell lines appear to have different inherent resistance. Thus, there is a need to develop alternative approaches to maximize the potency, efficacy, therapeutic index, and / or clinical benefit of KRas G12C inhibitors in vitro and in vivo.

[0007] In one embodiment, the combination therapy of the present invention synergistically increases the potency of the KRas G12C inhibitor, resulting in improved efficacy of the KRas G12C inhibitors disclosed herein.In another embodiment, the combination therapy of the present invention provides improved clinical benefit to patients compared to treatment with the KRas G12C inhibitors disclosed herein as single agents. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Alamgeer et al.,(2013)Current Opin Pharmcol.13:394-401 [Non-Patent Document 2] Santos et al.,(1984)Science 223:661-664 [Non-Patent Document 3] Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428 [Non-Patent Document 4] Dogan et al.,(2012)Clin Cancer Res.18(22):6169-6177, doi:10.1158 / 1078-0432.CCR-11-3265 [Non-Patent Document 5] McCormick(2015)Clin Cancer Res.21(8):1797-1801 [Non-Patent Document 6] Sun et al.,(2012)Agnew Chem Int Ed Engl.51(25):6140-6143 doi:10.1002 / anie201201358 [Non-Patent Document 7] Ostrem et al.,(2013)Nature 503:548-551 Summary of the Invention

[0009] In one aspect of the invention, there is provided a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Raf family kinase inhibitor and a KRAS G12C inhibitor of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, X is a 4-12 membered saturated or partially saturated monocyclic ring, bridged ring, or spiro ring, and the saturated or partially saturated monocyclic ring is 8 is optionally replaced by Y is a bond, O, S, or NR5 and R 1 but, [ka] or [ka] and R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -Z-NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, and each of Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl is selected from one or more R 9 and optionally substituted with Z is C1-C4 alkylene; Each R 3 is independently C1-C3 alkyl, oxo, or haloalkyl; L is a bond, -C(O)-, or C1-C3 alkylene; R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl, or heteroaryl, each of which is selected from one or more R 6 or R 7 and optionally substituted with Each R 5 is independently hydrogen or C1-C3 alkyl; R 6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, each of which is selected from one or more R 7 and optionally substituted with Each R 7is independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, and Q is O or S; R 8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -C(O)OR 5 , -C(O)N(R 5 )2, -N(R 5 )2, wherein C1-C3 alkyl is cyano, halogen, -OR 5 , -N(R 5 ) 2, or heteroaryl, Each R 9 are independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein C1-C6 alkyl is optionally substituted with cycloalkyl; Each R 10 is independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl, or hydroxyalkyl; R 11 is haloalkyl, R A is absent, hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 )2, or hydroxyalkyl; Each R B are independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR 5 R 11 , -C(O)N(R 5)2, -NHC(O)C1-C3 alkyl, -CH2NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl, where the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy, and C1-C3 alkyl, and the heteroaryl portion of the heteroaryl or heteroarylalkyl is substituted with one or more R 7 is optionally replaced by m is zero or an integer from 1 to 2; p is 1 or 2; [ka] If is a triple bond, R A does not exist and R B exists and p is 1 or or [ka] If is a double bond, R A exists and R B is present and p is 2 or R A , R B and the carbon atom to which they are attached may be one or more R 7 Methods are provided herein that include administering a combination of:

[0010] For use in the methods provided herein, the KRas G12C inhibitor compound of formula I having formula IA is [ka] and pharma- ceutically acceptable salts thereof, 1 , R 3 , R 4 , R 5 , R 10 , R 11 , L, and m are as defined in formula I, and the piperazinyl ring is R 8Optionally substituted with R 8 is as defined in formula I).

[0011] For use in the methods provided herein, a KRas G12C inhibitor compound of formula I having formula IB is [ka] and pharma- ceutically acceptable salts thereof, 1 , R 3 , R 4 , L, and m are as defined in formula I; R 2 But there is one or more R 9 heterocyclylalkyl optionally substituted with R 9 is as defined in formula I, and the piperazinyl ring is R 8 Optionally substituted with R 8 is as defined in formula I).

[0012] In another aspect of the invention, a pharmaceutical composition is provided for use in the method, comprising a therapeutically effective amount of a combination of a Raf family kinase inhibitor and a KRas G12C inhibitor compound of Formula I, Formula IA, or Formula 1-B, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0013] In one aspect of the present invention, provided herein is a method for treating cancer in a subject in need of cancer treatment, comprising administering to the subject a therapeutically effective amount of a Raf family kinase inhibitor, or its pharma- ceutically acceptable salt or pharmaceutical composition, and a KRAS G12C inhibitor of formula (I), formula IA, or formula IB, or its pharma-ceutically acceptable salt or pharmaceutical composition.In one embodiment, the cancer is a KRas G12C-associated cancer.In one embodiment, the KRas G12C-associated cancer is lung cancer.

[0014] In some embodiments of the present invention, the KRas G12C inhibitor compound and the Raf family kinase inhibitor are the only active agents in the combinations and methods provided.

[0015] Examples of Raf family kinase inhibitors suitable for the provided compositions and methods include encorafenib (LGX818): methyl (S)-(1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate; PLX-8394: N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl )-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide;Raf-709: N-(2-methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide;LXH254: N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide;Sorafenib: 4-(4-(3-(4-chloro -3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide;LY3009120:1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea;Lifirafenib (BGB-283);5-(((1R,1aS,6bS)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran) lan-5-yl)methyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;Tak-632: N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide;CEP-32496: 1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea;CCT196969: 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)phenyl)urea; and RO5126766: N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl-sulfamide;

[0016] In yet another aspect, the present invention provides a method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor, comprising contacting the cancer cell with a therapeutically effective amount of a combination of a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a Raf family kinase inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the Raf family kinase inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor. In one embodiment, the contacting is performed in vitro. In one embodiment, the contacting is performed in vivo.

[0017] Also provided herein is a method for treating cancer in a subject in need of such treatment, comprising: (a) determining that the cancer is associated with a KRas G12C mutation (e.g., is a KRas G12C-associated cancer) (e.g., as determined using a regulatory approved, e.g., FDA approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a combination of a Raf family kinase inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, Formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the Raf family kinase inhibitor synergistically increases the sensitivity of the KRAS G12C-associated cancer to the KRAS G12C inhibitor.

[0018] Also provided herein is a kit comprising a Raf family kinase inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRAS G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof. Also provided is a kit comprising a Raf family kinase inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRAS G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in treating KRas G12C cancer.

[0019] In a related aspect, the present invention provides a kit comprising a dose of a Raf family kinase inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB or a pharma- ceutically acceptable salt or pharmaceutical composition thereof in an amount effective to inhibit the proliferation of cancer cells in a subject. The kit optionally includes an insert comprising instructions for administering the Raf family kinase inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof and the KRAS G12C inhibitor compound of formula (I), formula IA, or formula IB or a pharma- ceutically acceptable salt or pharmaceutical composition thereof. The insert may provide a user with a set of instructions for using the Raf family kinase inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof in combination with the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0020] In some embodiments of any of the methods described herein, prior to treatment with a composition or method of the invention, the patient has been treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, and optionally, the previous treatment has failed, and / or the patient has been subjected to surgery, and optionally, the surgery has failed, and / or the patient has been treated with a platinum-based chemotherapy agent, and optionally, the patient has been previously determined to be unresponsive to treatment with a platinum-based chemotherapy agent, and / or the patient has been treated with a kinase inhibitor, and optionally, the previous treatment with the kinase inhibitor has failed, and / or the patient has been treated with one or more other therapeutic agent(s). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] The present invention relates to combination therapy for treating KRas G12C cancer. In particular, the present invention relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a Raf family kinase inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof and a KRAS G12C inhibitor of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, each of which comprises a therapeutically effective amount of the inhibitor separately, a kit comprising the composition, and a method of use thereof.

[0022] Combining a Raf family kinase inhibitor with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt thereof, increases the potency of the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt thereof, against cancer cells expressing KRas G12C, thereby increasing the efficacy of the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt thereof.

[0023] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications referenced herein are incorporated herein by reference.

[0024] As used herein, "KRas G12C" refers to a mutant mammalian KRas protein containing a glycine to cysteine ​​amino acid substitution at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by Uniprot KB / Swissprot P01116: variant p.Gly12Cys.

[0025] As used herein, "KRas G12C inhibitor" refers to the compounds of the present invention represented by formula (I), formula IA, and formula IB described herein, and their pharma- ceutically acceptable salts. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12C. The KRas G12C inhibitors of the present invention interact with KRas G12C and irreversibly bind thereto by forming a covalent adduct with the sulfhydryl side chain of the cysteine ​​residue at position 12, thereby inhibiting the enzymatic activity of KRas G12C. In one embodiment, the KRas G12C inhibitor is a compound selected from compound numbers 1-678 (as numbered in WO2019 / 099524), or a pharma- ceutically acceptable salt thereof (e.g., Example Nos. 234, 359, 478, or 507, or a pharma- ceutically acceptable salt thereof).

[0026] As used herein, "KRas G12C-associated disease or disorder" refers to a disease or disorder that is associated with, mediated by, or has a KRas G12C mutation. A non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12C-associated cancer.

[0027] As used herein, "Raf family kinase" refers to a member of the mammalian serine / threonine kinases that are composed of three isoforms (C-Raf, B-Raf, and A-Raf), including homodimers of each isoform as well as heterodimers between the isoforms, e.g., C-Raf / B-Raf heterodimers.

[0028] As used herein, "Raf family kinase inhibitor" refers to a compound that can negatively regulate or inhibit all or a portion of the enzymatic activity of one or more members of the Raf family kinases, or disrupt the formation of Raf homodimers or heterodimers to inhibit activity.

[0029] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of the disease or disorder being treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a KRas G12C mutation (e.g., as determined using a regulatory approved, e.g., FDA approved, assay or kit). In some embodiments, the subject has a tumor that is positive for the KRas G12C mutation (e.g., as determined using a regulatory approved, e.g., FDA approved, assay or kit). The subject may be a subject with a tumor(s) that is positive for the KRas G12C mutation (e.g., identified as positive using a regulatory approved, e.g., FDA approved, assay or kit). The subject may be one whose tumor has a KRas G12C mutation (e.g., the tumor has been identified as such using a regulatory approved, e.g., FDA approved, kit or assay). In some embodiments, the subject is suspected of having a cancer associated with the KRas G12C gene. In some embodiments, the subject has clinical records indicating that the subject has a tumor with a KRas G12C mutation (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0030] The term "pediatric patient" as used herein refers to a patient who is under 16 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subpopulations, including neonates (birth to 1 month), infants (1 month to 2 years), children (2 to 12 years), and adolescents (12 to 21 years (until their 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

[0031] In some embodiments of any of the methods or uses described herein, the assay used to determine whether a patient (e.g., a patient suspected of having a cancer associated with KRas G12C, a patient having one or more symptoms of a cancer associated with KRas G12C, and / or a patient at high risk of developing a cancer associated with KRas G12C) has a KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample, such as a paraffin-embedded biopsy sample) from the patient may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR, quantitative real-time RT-PCR, allele-specific genotyping, or ddPCR). As is well known in the art, the assay is typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or an antigen-binding fragment thereof.

[0032] The term "regulatory authority" refers to a national agency that approves pharmaceutical products for medical use in a country. For example, a non-limiting example of a regulatory authority is the United States Food and Drug Administration (FDA).

[0033] The term "amino" refers to --NH.sub.2.

[0034] The term "acyl" refers to -C(O)CH3.

[0035] The term "alkyl" as used herein refers to straight- and branched-chain aliphatic groups having 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms, optionally substituted with 1, 2, or 3 substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0036] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by halogen. Examples of haloalkyl are trifluoromethyl, difluoromethyl, and fluoromethyl.

[0037] The term "haloalkyloxy" refers to -O-haloalkyl.

[0038] An "alkylene" group is an alkyl group, as defined above, that is positioned between and serves to link two other chemical groups. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0039] The term "alkoxy" refers to -OC1-C6 alkyl.

[0040] The term "cycloalkyl" as used herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, for example, 3 to 8 carbons, and further examples, 3 to 6 carbons, which cycloalkyl groups are further optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0041] The term "heteroalkyl" refers to an alkyl group, as defined herein, in which one or more carbon atoms in the chain is replaced by a heteroatom selected from the group consisting of O, S and N.

[0042] As used herein, the term "hydroxyalkyl" refers to -alkyl-OH.

[0043] The term "dihydroxyalkyl" refers to an alkyl group, as defined herein, in which two carbon atoms are each substituted with a hydroxyl group.

[0044] The term "alkylaminyl" means -NR x -alkyl, R x is hydrogen. In one embodiment, R x is hydrogen.

[0045] The term “dialkylaminyl” refers to —N(R y )2, each R y is C1-C3 alkyl.

[0046] The term "alkylaminylalkyl" means -alkyl-NR x -alkyl, R x is hydrogen. In one embodiment, R x is hydrogen.

[0047] The term “dialkylaminylalkyl” refers to -alkyl-N(R y)2, each R y is C1-C4 alkyl, -alkyl-N(R y The alkyl in 2 may be optionally substituted with hydroxy or hydroxyalkyl.

[0048] An "aryl" group is a C6-C aryl group containing one to three aromatic rings, which are optionally substituted. 14 In one embodiment, the aryl group is a C6-C 10 Aryl groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl.

[0049] An "aralkyl" or "arylalkyl" group comprises an aryl group covalently linked to an alkyl group, either of which may be independently optionally substituted or unsubstituted. Examples of aralkyl groups include, but are not limited to, (C1-C6)alkyl(C6-C8)alkyl, (C6-C9)alkyl, (C6-C10)alkyl, (C1-C12)alkyl, (C1-C13)alkyl, (C1-C14)alkyl, (C1-C15)alkyl, (C1-C16)alkyl, (C1-C17)alkyl, (C1-C18)alkyl, (C1-C19)alkyl, (C1-C20)alkyl, (C1-C21)alkyl, (C1-C22)alkyl, (C1-C23)alkyl, (C1-C24)alkyl, (C1-C25)alkyl, (C1-C26)alkyl, (C1-C27)alkyl, (C1-C28 10 ) aryl. An example of a substituted aralkyl is one in which an alkyl group is substituted with a hydroxyalkyl.

[0050] A "heterocyclyl" or "heterocycle" group is a ring structure having from about 3 to about 12 atoms, e.g., 4 to 8 atoms, in which one or more atoms are selected from the group consisting of N, O, and S, and the remainder of the ring atoms are carbon. A heterocyclyl may be a monocyclic, bicyclic, spirocyclic or bridged ring system. A heterocycle group has R on a carbon or nitrogen at one or more positions. 7 Optionally substituted with R 7is as defined in formula I. The heterocyclic groups are also independently optionally substituted on the nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or on sulfur with oxo or lower alkyl. Examples of heterocyclic groups include, but are not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, thiomorpholinyl, thiomorpholinyl, 1,1-dioxide, morpholinyl, oxazepanyl, azabicyclohexane, azabicycloheptane, and oxazabicycloheptane. Specifically excluded from the scope of this term are compounds having adjacent cyclic O and / or S atoms.

[0051] The term "heterocyclylalkyl" refers to a heterocyclyl group, as defined herein, linked to the remainder of the molecule via an alkyl linker, wherein the alkyl linker of the heterocyclylalkyl may be optionally substituted with hydroxy or hydroxyalkyl.

[0052] As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms, having 6, 10, or 14 pi electrons shared in a cyclic array, and having, in addition to carbon atoms, 1 to 3 heteroatoms per ring selected from the group consisting of N, O, and S.Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, and the like. phenyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, Phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydro Examples include isoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0053] A "heteroarylalkyl" group includes a heteroaryl group covalently bonded to an alkyl group, the radical being on the alkyl group, both of which are independently optionally substituted or unsubstituted. Examples of heteroarylalkyl groups include heteroaryl groups having 5, 6, 9, or 10 ring atoms bonded to a C1-C6 alkyl group. Examples of heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl, isoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded from the scope of this term are compounds having adjacent cyclic O and / or S atoms.

[0054] As used herein, an "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit the activity of a desired target, i.e., Raf family kinase or KRas G12C. Such an amount can be administered as a single dose or according to a dosing schedule, whereby this amount is effective.

[0055] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to alleviate symptoms, or in some way reduce symptoms, or to halt or stop the progression of a disease state, or to negatively regulate or inhibit the activity of Raf family kinases or KRas G12C. Such an amount can be administered as a single dose or according to a dosing schedule, whereby this amount is effective.

[0056] As used herein, a "therapeutically effective amount" of two compounds is an amount that synergistically increases the activity of the combination, i.e., is not merely additive, compared to the therapeutically effective amount of each compound in the combination. Alternatively, in vivo, a therapeutically effective amount of a Raf family kinase inhibitor or its pharmaceutically acceptable salt or pharmaceutical composition and a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB or its pharmaceutically acceptable salt or pharmaceutical composition results in an increased overall survival ("OS") period in a subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a Raf family kinase inhibitor or its pharmaceutically acceptable salt or pharmaceutical composition and a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB or its pharmaceutically acceptable salt or pharmaceutical composition results in an increased progression-free survival ("PFS") period in a subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of a Raf family kinase inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor regression in a subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of a Raf family kinase inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor growth inhibition in a subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of a Raf family kinase inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof with a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in improved duration of stable disease in a subject compared to treatment with a KRas G12C inhibitor alone.The amount of each compound in the combination may be the same or different than the therapeutically effective amount of each compound when administered alone as monotherapy, so long as the combination obtains the desired anti-tumor effect. Such amounts may be administered as a single dose or may be administered according to a dosing regimen whereby the amounts are effective.

[0057] As used herein, treatment refers to any manner in which the symptoms or pathology of a condition, disorder, or disease are alleviated or beneficially altered. Treatment also includes any pharmaceutical use of the compositions herein.

[0058] As used herein, alleviation of symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, whether permanent or temporary, persistent or transient, that can result from or be associated with administration of the composition.

[0059] As used herein, the term "about" when used to modify a numerically defined parameter (e.g., a dose of a KRAS inhibitor or a Raf family kinase inhibitor or a pharma- ceutically acceptable salt thereof, or a length of treatment time with a combination therapy described herein) means that the parameter may vary above or below the numerical value listed for that parameter by as much as 10%. For example, a dose of about 5 mg / kg may vary between 4.5 mg / kg and 5.5 mg / kg. "About" used at the beginning of a list of parameters means to modify the respective parameter. For example, about 0.5 mg, 0.75 mg, or 1.0 mg means about 0.5 mg, about 0.75 mg, or about 1.0 mg. Similarly, about 5% or more, 10% or more, 15% or more, 20% or more, and 25% or more means about 5% or more, about 10% or more, about 15% or more, about 20% or more, or about 25% or more.

[0060] Inhibitor Compounds In one aspect of the invention, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of a Raf family kinase inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0061] 1.Raf family kinase inhibitors Raf family kinases are serine / threonine kinases composed of three isoforms (C-Raf, B-Raf, and A-Raf). Raf family members share three conserved regions (CRs) with distinct functions. CR1 contains a Ras-binding domain (RBD) required for interaction with Ras and membrane recruitment, and a cysteine-rich domain (CRD) that is a secondary Ras-binding site and is also required for interaction between CR1 and the kinase domain for Raf autoinhibition. CR2 contains an inhibitory phosphorylation site involved in Ras binding and negative regulation of Raf activation. CR3 is characterized by a kinase domain that includes an activation segment whose phosphorylation is essential for kinase activation (see, e.g., Matallanas et al., (2011) Genes Cancer 2(3):232-260).

[0062] Binding of Ras to the CR1 RBD disrupts the binding of CR3 to the CRD, releasing the kinase domain from its autoinhibited state and also promoting changes in Raf phosphorylation, inducing the formation of Raf dimers, now recognized as a necessary step in the Raf activation process. Raf kinases can dimerize with any of the other Raf family members, and although the factors determining dimerization preference are poorly understood, B-Raf / C-Raf heterodimers predominate in Ras-dependent signaling. The Raf kinase domains contact each other via the left and right dimer interfaces, and as a consequence of protomer transactivation, they assume a catalytically active kinase conformation, leading to the phosphorylation and activation of MEK. Similarly, MEK phosphorylates and activates ERK, which plays a key role in forward signaling and contributes to an inhibitory feedback loop that controls the duration and amplitude of pathway signaling (see, for example, Durrant & Morrison (2018) British J Cancer 118:3-8).

[0063] It has been shown that upregulation of receptor tyrosine kinases, such as EGFR, and / or upregulation of N-Ras expression and / or activity overcomes KRas inhibition by restoring downstream Raf / MEK / ERK signaling, resulting in resistance to KRas inhibition.The combination of the KRasG12C inhibitor of the present invention with a Raf family kinase inhibitor effectively blocks upstream signaling from KRas G12C, wild-type KRas, and / or N-Ras, and shuts down further MEK and ERK signaling via RAF, as shown, for example, in Example B herein, thereby blocking this potential resistance mechanism and enhancing overall tumor response. In certain embodiments, the Raf family kinase inhibitor is active against wild-type A-Raf / A-Raf, C-Raf / C-Raf, and B-Raf / B-Raf homodimers, as well as Raf heterodimers, such as the C-Raf / B-Raf heterodimer (see, e.g., Lito et al., (2016) Science 351(6273):604-8. doi:10.1126 / science.aad6204. Epub 2016 Jan 14).

[0064] Exemplary Raf family kinase inhibitors useful in the methods and compositions disclosed herein include encorafenib (LGX818): methyl (S)-(1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate; PLX-8394: N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridine-3-yl) carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide; Raf-709: N-(2-methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide; LXH254: N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide; Sorafenib: 4-(4-(3-(4- Chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide;LY3009120: 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea;Lifirafenib (BGB-283);5-(((1R,1aS,6bS)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzo furan-5-yl)methyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;Tak-632: N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide;CEP-32496: 1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea;CCT196969: 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)phenyl)urea; and RO5126766: N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl-sulfamide. In one embodiment, the Raf family kinase inhibitor is encoratinib (LGX818). In one embodiment, the Raf family kinase inhibitor is sorafenib. In one embodiment, the Raf family kinase inhibitor is lifirafenib (BGB-283).

[0065] Methods for producing Raf family kinase inhibitors are well known to those of skill in the art, and Raf family kinase inhibitors can be obtained from a wide variety of commercial suppliers in forms suitable for both research or human use. In addition, Raf family kinase inhibitors suitable for use in the compositions and methods disclosed herein, as well as methods for preparing such inhibitors, can be found in U.S. Patent Application Publication Nos. US2017 / 0233391, US2016 / 0368914, US2016 / 0199375, US2015 / 0119392, US2015 / 0105367, US2015 / 0080568, US2015 / 0045355, US2014 / 0329866, US2014 / 0221374, US2015 / 02221375 ... Nos. US2014 / 0045868, US2013 / 0224195, US2013 / 0040983, US2012 / 0288501, US2012 / 0214811, US2012 / 0178780, US2011 / 0257207, US2011 / 0118245, US2010 / 0324047, US2010 / 0196368, US2009 / 0163596, US2009 / 0035309, and US2008 / 0108672.

[0066] 2. KRas G12C inhibitors In one embodiment, the KRas G12C inhibitor used in the method is a compound of formula (I) [ka] or a pharma- ceutically acceptable salt thereof, X is a 4-12 membered saturated or partially saturated monocyclic ring, bridged ring, or spiro ring, and the saturated or partially saturated monocyclic ring is 8 is optionally replaced by Y is a bond, O, S, or NR 5 and R 1 but, [ka] or [ka] and R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -Z-NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, and each of Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl is selected from one or more R 9 and optionally substituted with Z is C1-C4 alkylene; Each R 3 is independently C1-C3 alkyl, oxo, or haloalkyl; L is a bond, -C(O)-, or C1-C3 alkylene; R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl, or heteroaryl, each of which is selected from one or more R6 or R 7 and optionally substituted with Each R 5 is independently hydrogen or C1-C3 alkyl; R 6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, each of which is selected from one or more R 7 and optionally substituted with Each R 7 is independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, and Q is O or S; R 8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -C(O)OR 5 , -C(O)N(R 5 )2, -N(R 5 )2, wherein C1-C3 alkyl is cyano, halogen, -OR 5 , -N(R 5 ) 2, or heteroaryl, Each R 9 are independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein C1-C6 alkyl is optionally substituted with cycloalkyl; Each R 10 is independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl, or hydroxyalkyl; R 11 is haloalkyl, R A is absent, hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5)2, or hydroxyalkyl; Each R B are independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR 5 R 11 , -C(O)N(R 5 )2, -NHC(O)C1-C3 alkyl, -CH2NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl, where the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy, and C1-C3 alkyl, and the heteroaryl portion of the heteroaryl or heteroarylalkyl is substituted with one or more R 7 is optionally replaced by m is zero or an integer from 1 to 2; p is 1 or 2; [ka] If is a triple bond, R A does not exist and R B exists and p is 1 or or [ka] If is a double bond, R A exists and R B is present and p is 2 or R A , R B and the carbon atom to which they are attached may be one or more R 7 forming a 5-8 membered partially saturated cycloalkyl optionally substituted with and pharma- ceutically acceptable salts thereof.

[0067] In one embodiment, the KRas G12C inhibitor used in the methods herein is a compound having formula IA [ka] and pharma- ceutically acceptable salts thereof, 1 , R 3 , R 4 , R 5 , R 10 , L, and m are as defined in formula I; R 11 is hydrogen, methyl, or hydroxyalkyl, and the piperidinyl ring is R 8 wherein R 8 is as defined in formula I.

[0068] In one embodiment, the KRas G12C inhibitor used in the methods herein is a compound having formula IB [ka] and pharma- ceutically acceptable salts thereof, 1 , R 3 , R 4 , R 9 , R 11 , L, and m are as defined in formula I.

[0069] Non-limiting examples of KRas G12C inhibitor compounds of formula (I), formula IA, and formula IB useful in the methods disclosed herein are Example Nos. 1-678 disclosed in WO2019 / 099524; [ka] [ka] [ka] [ka] [ka] [ka]

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[0070] In one embodiment, the KRas G12C inhibitor is [ka] and pharma- ceutically acceptable salts thereof.

[0071] In one embodiment, the KRas G12C inhibitor is [ka] (referred to as Example 234) or a pharma- ceutically acceptable salt thereof.

[0072] In one embodiment, the KRas G12C inhibitor is [ka] (referred to as Example 359) or a pharma- ceutically acceptable salt thereof.

[0073] In one embodiment, the KRas G12C inhibitor is [ka] (referred to as Example 478) or a pharma- ceutically acceptable salt thereof.

[0074] In one embodiment, the KRas G12C inhibitor is [ka] (referred to as Example 507) or a pharma- ceutically acceptable salt thereof.

[0075] The KRas G12C inhibitors used in the methods of the present invention may have one or more chiral centers and may be synthesized as stereoisomeric mixtures, isomers that have the same configuration but differ in the spatial arrangement of their atoms. The compounds may be used as mixtures, or individual components / isomers may be separated using commercially available reagents and conventional methods for isolating stereoisomers and enantiomers that are well known to those skilled in the art, such as CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatographic HPLC columns, following the manufacturer's instructions. Alternatively, the compounds of the present invention may be synthesized using optically pure chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise stated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Unless otherwise stated, whenever this specification, including the claims, refers to a compound of the present invention, the term "compound" should be understood to include all chiral (enantiomers and diastereomers) and racemic forms.

[0076] In one embodiment, the KRas G12C inhibitor compound of formula I, formula IA, or formula IB used in the method comprises a trifluoroacetate salt of the compound described above.

[0077] The method for producing the KRas G12C inhibitor disclosed herein is known.For example, co-owned and published international PCT application WO2017 / 201161 and WO2019 / 099524 describe the general reaction scheme for preparing the compound of formula I, formula IA or formula IB, and also provide the detailed synthetic route for preparing each of the KRas G12C inhibitors disclosed herein.

[0078] The Raf family kinase inhibitor and KRas G12C compound of Formula (I), Formula IA, or Formula IB, or a pharma- ceutically acceptable salt thereof, may be formulated into a pharmaceutical composition.

[0079] Pharmaceutical Compositions In another aspect, the present invention provides a pharmaceutical composition comprising the Raf family kinase inhibitor and KRas G12C inhibitor according to the present invention and a pharma- ceutically acceptable carrier, excipient, or diluent that can be used in the method disclosed herein.The Raf family kinase inhibitor and KRas G12C inhibitor can be independently formulated by any method known in the art and prepared for administration by any route, including but not limited to parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.In certain embodiments, the Raf family kinase inhibitor and / or KRas G12C inhibitor is administered intravenously in a hospital environment.In one embodiment, administration can be by oral route.

[0080] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutical acceptable" refers to a non-toxic material that is compatible with a biological system, such as a cell, cell culture, tissue, or organism, and does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, in addition to the inhibitor, the composition may contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials that are well known in the art. The preparation of pharmaceutical acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0081] As used herein, the term pharma-ceutically acceptable salt refers to the salt that retains the desired biological activity of the above-identified compound and shows minimal or no undesired toxic effects.Examples of such salts include, but are not limited to, the acid addition salt formed with inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and the acid formed with organic acid such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds may also be administered as pharma- ceutically acceptable quaternary salts known to those of skill in the art, including, in particular, quaternary ammonium salts of the formula -NR+Z-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandelloate, benzylloate, and diphenylacetate).

[0082] The active compound is contained in a pharma- ceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing serious toxic effects to the patient being treated. In one embodiment, for all the above conditions, the dose of the active compound is in the range of about 0.01 to 300 mg / kg per day, e.g., 0.1 to 100 mg / kg per day, and as a further example, in the range of 0.5 to about 25 mg per kilogram body weight of the recipient per day. Typical topical dosages are in the range of 0.01 to 3% weight / weight in a suitable carrier. The effective dosage range of the pharma- ceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative is active in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.

[0083] A pharmaceutical composition comprising a Raf family kinase inhibitor and a KRas G12C inhibitor may be used in the methods of use described herein.

[0084] Simultaneous administration The Raf family kinase inhibitor and the KRasG12C inhibitor can be formulated into separate or separate dosage forms and can be co-administered one after the other.Another option is that when the administration route is the same (e.g., oral), the two active compounds can be formulated into a single form for co-administration, but both co-administration methods are part of the same therapeutic treatment or regimen.

[0085] The pharmaceutical composition comprising the Raf family kinase inhibitor and / or the KRas G12C inhibitor for use in the method can be for simultaneous, separate, or sequential use.In one embodiment, the Raf family kinase inhibitor is administered before the administration of the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB.In another embodiment, the Raf family kinase inhibitor is administered after the administration of the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB.In another embodiment, the Raf family kinase inhibitor is administered about simultaneously with the administration of the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB.

[0086] Separate administration of each inhibitor at different times and by different routes may be advantageous in some cases.Therefore, the components of combination, i.e., KRas G12C inhibitor compound of formula (I), formula IA or formula IB or its pharmaceutically acceptable salt or pharmaceutical composition and Raf family kinase inhibitor or its pharmaceutically acceptable salt or pharmaceutical composition, do not necessarily have to be administered at essentially the same time or in any order.

[0087] Tumor drugs are usually administered at their maximum tolerated dose ("MTD"), which is the highest dose of drug that does not cause unacceptable side effects. In one embodiment, the KRas G12C inhibitor and the Raf family kinase inhibitor are each administered at their respective MTD. In one embodiment, the KRas G12C inhibitor is administered at its MTD and the Raf family kinase inhibitor is administered at a lower amount than its MTD. In one embodiment, the KRas G12C inhibitor is administered at a lower amount than its MTD and the Raf family kinase inhibitor is administered at its MTD. In one embodiment, the KRas G12C inhibitor and the Raf family kinase inhibitor are each administered at a lower amount than their respective MTD. The administration can also be timed so that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.

[0088] In one embodiment, a single dose of the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof is administered per day (i.e., about 24 hours apart) (i.e., once a day). In another embodiment, two doses of the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof are administered per day (i.e., twice a day). In another embodiment, three doses of the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof are administered per day (i.e., three times a day).

[0089] In one embodiment, the Raf family kinase inhibitor, or its pharma- ceutically acceptable salt or pharmaceutical composition, is administered once a day. In another embodiment, the Raf family kinase inhibitor, or its pharma- ceutically acceptable salt or pharmaceutical composition, is administered twice a day. In another embodiment, the Raf family kinase inhibitor of the present invention, or its pharma- ceutically acceptable salt or pharmaceutical composition, is administered three times a day.

[0090] In one embodiment, a single dose of the KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the Raf family kinase inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are each administered once daily.

[0091] Exemplary Raf family kinase inhibitors useful in the methods disclosed herein include encorafenib (LGX818): methyl (S)-(1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate; PLX-8394: N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl) Raf-709: N-(2-methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide; LXH254: N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide; Sorafenib: 4-(4-(3-(4-chlorophenyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide; Raf-709: N-(2-methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide; LXH254: N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide; Sorafenib: 4-(4-(3-(4-chlorophenyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide -3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide;LY3009120:1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea;Lifirafenib (BGB-283);5-(((1R,1aS,6bS)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran) lan-5-yl)methyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one;Tak-632: N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide;CEP-32496: 1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea;CCT196969: 1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)phenyl)urea; and RO5126766: N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl-sulfamide;

[0092] In one embodiment, the Raf family kinase inhibitor is encoratinib (LGX818). In one embodiment, the Raf family kinase inhibitor is sorafenib. In one embodiment, the Raf family kinase inhibitor is lifirafenib (BGB-283).

[0093] Combination therapy In one aspect of the present invention, provided herein is a method for treating cancer in a subject in need of cancer treatment, comprising administering to the subject a therapeutically effective amount of a combination of a Raf family kinase inhibitor or its pharma- ceutically acceptable salt or pharmaceutical composition and a KRAS G12C inhibitor of formula (I), formula IA, or formula IB or its pharma-ceutically acceptable salt or pharmaceutical composition.In one embodiment, the cancer is a KRas G12C-associated cancer.In one embodiment, the KRas G12C-associated cancer is lung cancer.

[0094] In yet another aspect, the present invention provides a method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor, comprising contacting the cancer cell with an effective amount of a combination of a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a Raf family kinase inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the Raf family kinase inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor. In one embodiment, the contacting is performed in vitro. In one embodiment, the contacting is performed in vivo.

[0095] In one embodiment, the combination therapy comprises a compound having the formula [ka] or its pharmaceutically acceptable salt and a Raf family kinase inhibitor. In one embodiment, the Raf family kinase inhibitor is encoratinib (LGX818). In one embodiment, the Raf family kinase inhibitor is sorafenib. In one embodiment, the Raf family kinase inhibitor is lifirafenib (BGB-283).

[0096] In one embodiment, the combination therapy comprises a compound having the formula [ka] or its pharmaceutically acceptable salt and a Raf family kinase inhibitor. In one embodiment, the Raf family kinase inhibitor is encoratinib (LGX818). In one embodiment, the Raf family kinase inhibitor is sorafenib. In one embodiment, the Raf family kinase inhibitor is lifirafenib (BGB-283).

[0097] In one embodiment, the combination therapy comprises a compound having the formula [ka] or its pharmaceutically acceptable salt and a Raf family kinase inhibitor. In one embodiment, the Raf family kinase inhibitor is encoratinib (LGX818). In one embodiment, the Raf family kinase inhibitor is sorafenib. In one embodiment, the Raf family kinase inhibitor is lifirafenib (BGB-283).

[0098] In one embodiment, the combination therapy comprises a compound having the formula [ka] or its pharmaceutically acceptable salt and a Raf family kinase inhibitor. In one embodiment, the Raf family kinase inhibitor is encoratinib (LGX818). In one embodiment, the Raf family kinase inhibitor is sorafenib. In one embodiment, the Raf family kinase inhibitor is lifirafenib (BGB-283).

[0099] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro or in vivo system. For example, "contacting" a cancer cell includes administering a combination provided herein to an individual or subject, such as a human, having KRas G12C, as well as introducing a combination provided herein into a sample, including, for example, a cell preparation or purified preparation that contains KRas G12C.

[0100] The method described herein is designed to inhibit undesirable cell proliferation caused by enhanced KRas G12C activity in cells by negatively regulating the activity of KRas G12C.The degree of covalent modification of KRas G12C can be monitored in vitro using known methods, including those described in published International PCT applications WO2017 / 201161 and WO2019 / 099524.In addition, the inhibitory activity of the combination in cells can be monitored, for example, by measuring the inhibition of KRas G12C activity of the amount of phosphorylated ERK to evaluate the effectiveness of treatment, and the dosage can be adjusted by the attending physician accordingly.

[0101] The compositions and methods provided herein can be used to treat KRas G12C-associated cancer in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a combination of a Raf family kinase inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof and a KRAS G12C inhibitor compound of formula (I), formula IA, or formula IB or a pharma-ceutically acceptable salt or pharmaceutical composition thereof, wherein the Raf family kinase inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor. In one embodiment, the KRas G12C-associated cancer is lung cancer.

[0102] In one embodiment, a combination of a therapeutically effective amount of a Raf family kinase inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in an increased overall survival ("OS") period in a subject, compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of a Raf family kinase inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in an increased progression-free survival ("PFS") period in a subject, compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of a Raf family kinase inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor regression in a subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of a Raf family kinase inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor growth inhibition in a subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of a Raf family kinase inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof with a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in improved duration of stable disease in a subject compared to treatment with a KRas G12C inhibitor alone.In one embodiment, the KRas G12C inhibitor is a compound selected from compound numbers 1-678 (as numbered in WO2019 / 099524), or a pharma- ceutically acceptable salt thereof (e.g., Example Nos. 234, 359, 478, or 507, or a pharma- ceutically acceptable salt thereof). In one embodiment, the Raf family kinase inhibitor is selected from encoratinib, sorafenib, or lifirafenib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and encoratinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and sorafenib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and lifirafenib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and encoratinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and sorafenib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and lifirafenib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and encoratinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and sorafenib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and lifirafenib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and encoratinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and sorafenib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and lifirafenib. In one embodiment of any of the combination therapies, the combination is useful for treating a cancer associated with KRas G12C. In one embodiment, the cancer associated with KRas G12C is lung cancer.

[0103] In another embodiment, a Raf family kinase inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered in combination with a KRas G12C inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, at a time when disease progression is observed with KRas G12C monotherapy, and the combination therapy provides enhanced clinical benefit or survival time in the patient by increasing OS, PFS, tumor regression, tumor growth inhibition, or duration of stable disease in the patient.

[0104] In one embodiment, the KRas G12C inhibitor is a compound selected from compound numbers 1-678 (as numbered in WO2019 / 099524), or a pharma- ceutically acceptable salt thereof (e.g., Example Nos. 234, 359, 478, or 507, or a pharma- ceutically acceptable salt thereof). In one embodiment, the Raf family kinase inhibitor is selected from encoratinib, sorafenib, or lifirafenib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and encoratinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and sorafenib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and lifirafenib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and encoratinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and sorafenib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and lifirafenib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and encoratinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and sorafenib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and lifirafenib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and encoratinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and sorafenib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and lifirafenib. In one embodiment of any of the combination therapies, the combination is useful for treating a cancer associated with KRas G12C. In one embodiment, the cancer associated with KRas G12C is lung cancer.

[0105] The compositions and methods provided herein may be used to treat a wide variety of cancers, including, for example, tumors such as lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that may be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, and thyroid cancer, as well as sarcoma. More specifically, these compounds are useful in treating heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), Pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), Prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor Chordoma, osteochondroma (osteochondroma exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);Gynecology: Uterus (endometrial carcinoma), Cervix (cervical carcinoma, preneoplastic cervical dysplasia), Ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), Vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), Fallopian tubes (carcinoma); Hematological: Blood (myeloid leukemia (acute and and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer.

[0106] Also provided herein is a method for treating cancer in a subject in need of such treatment, comprising: (a) determining that the cancer is associated with a KRas G12C mutation (e.g., is a KRas G12C-associated cancer) (e.g., as determined using a regulatory approved, e.g., FDA approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a combination of a Raf family inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, Formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the Raf family kinase inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor.

[0107] In one embodiment, the compound of formula I is administered as a capsule for a period of time. In one embodiment, a tablet or capsule formulation of the compound of formula I is administered in a dosage form of about 10 mg to about 100 mg (e.g., about 10 mg to about 95 mg, about 10 mg to about 90 mg, about 10 mg to about 85 mg, about 10 mg to about 80 mg, about 10 mg to about 75 mg, about 10 mg to about 70 mg, about 10 mg to about 65 mg, about 10 mg to about 60 mg, about 10 mg to about 55 mg, about 10 mg to about 50 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 2 ... mg ~ about 15mg, about 15mg - about 100mg, about 15mg - about 95mg, about 15mg - about 90mg, about 15mg - about 85mg, about 15mg - about 80mg, about 15mg - about 75mg, about 15mg - about 70mg, about 15mg - about 65mg, about 15mg - about 60mg, about 1 5mg to about 55mg, about 15mg to about 50mg, about 15mg to about 45mg, about 15mg to about 40mg, about 15mg to about 35mg, about 15mg to about 30mg, about 15mg to about 25mg, about 15mg to about 20mg, about 20mg to about 100mg, about 20mg to about 95mg, about 20mg to approx. 90mg, approx. 20mg to approx. 85mg, approx. 20mg to approx. 80mg, approx. 20mg to approx. 75mg, approx. 20mg to approx. 70mg, approx. 20mg to approx. 65mg, approx. 20mg to about 40mg, about 20mg to about 35mg, about 20mg to about 30mg, about 20mg to about 25mg, about 25mg to about 100mg, about 25mg to about 95mg, about 25mg to about 90mg, about 25mg to about 85mg, about 25mg to about 80mg, about 25mg to about 75mg, Approximately 25mg to approximately 70mg, approximately 25mg to approximately 65mg, approximately 25mg to approximately 60mg, approximately 25mg to approximately 55mg, approximately 25mg to approximately 50mg, approximately 25mg to approximately 45mg, approximately 25mg to approximately 40mg, approximately 25mg to approximately 35mg, approximately 25mg to approximately 30mg, approximately 30mg to approximately 100mg , about 30 mg to about 95 mg, about 30 mg to about 90 mg, about 30 mg to about 85 mg, about 30 mg to about 80 mg, about 30 mg to about 75 mg, about 30 mg to about 70 mg, about 30 mg to about 65 mg, about 30 mg to about 60 mg, about 30 mg to about 55 mg, about 30 mg to about 50 mg,about 30mg to about 45mg, about 30mg to about 40mg, about 30mg to about 35mg, about 35mg to about 100mg, about 35mg to about 95mg, about 35mg to about 90mg, about 35mg to about 85mg, about 35mg to about 80mg, about 35mg to about 75mg, about 35mg to about 70mg, about 35mg to about 65mg, about 35mg to about 60mg, about 35mg to about 55mg, about 35mg to about 50mg, about 35mg to about 45mg, about 35mg to about 40mg, about 40mg to about 100mg, about 40mg to about 95mg, about 40mg to about 90mg, about 40mg to about 85mg, about 40mg to about 80mg, about 40mg to about 75mg, about 40mg to about 70mg, about 40mg to about 65mg, about 40mg to about 60mg, about 40mg to about 55mg, about 40mg to about 50mg, about 40mg to about 45mg, about 45mg to about 100mg, about 45mg to about 95mg, about 45mg to about 90mg, about 45mg to about 85mg, about 45mg to about 80mg, about 45mg to about 75mg, about 45mg to about 70mg, about 45mg to about 65mg, about 45mg to about 60mg, about 45mg to about 55mg, about 45mg to about 50mg, about 50mg to about 100mg, about 50mg to about 95mg, about 50mg to about 90mg, about 50mg to about 85mg, about 50mg to about 80mg, about 50mg to about 75mg, about 50mg to about 70mg, about 50mg to about 65mg, about 50mg to about 60mg, about 50mg to about 55mg, about 55mg to about 100mg, about 55mg to about 95mg, about 55mg to about 90mg, about 55mg to about 85mg, about 55mg to about 80mg, about 55mg to about 75mg, about 55mg to about 70mg, about 55mg to about 65mg, about 55mg to about 60mg, about 60mg to about 100mg, about 60mg to about 95mg, about 60mg to about 90mg, about 60mg to about about 85mg, about 60mg to about 80mg, about 60mg to about 75mg, about 60mg to about 70mg, about 60mg to about 65mg, about 65mg to about 100mg, about 65mg to about 95mg, about 65mg to about 90mg, about 65mg to about 85mg, about 65mg to about 80mg, about 65mg to about 75mg, about 65mg to about 70mg, about 70mg to about 100mg, about 70mg to about 95mg, about 70mg to about 90mg, about 70mg to about 85mg, about 70mg to about 80mg, about 70mg to about 75mg, about 75mg to about 100mg, about 75mg to about 95mg, about 75mg to about 90mg,Approximately 75mg to approximately 85mg, approximately 75mg to approximately 80mg, approximately 80mg to approximately 100mg, approximately 80mg to approximately 95mg, approximately 80mg to approximately 90mg, approximately 80mg to approximately 85mg, approximately 85mg to approximately 10 0mg, about 85mg to about 95mg, about 85mg to about 90mg, about 90mg to about 100mg, about 90mg to about 95mg, about 95mg to about 100mg, about 10mg, about 15mg, about 20mg , about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg) of a compound of formula I (e.g., a compound selected from compound numbers 1-553, e.g., compound numbers 234, 359, 478, or 507). In one embodiment, the compound of formula I is orally administered once daily (QD) every day for a period of time. In one embodiment, the compound of formula I is orally administered twice daily (BID) every day for a period of time. In one embodiment, the compound of formula I is administered at a dose of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg ~ about 100mg, about 20mg to about 80mg, about 20mg to about 60mg, about 20mg to about 40mg, about 40mg to about 500mg, about 40mg to about 480mg, about 40mg to about 460mg, about 40mg to about 440mg, about 40mg to about 420mg, about 40mg to about 400mg, about 40mg to about 380mg, about 40mg to about 360mg mg, about 40mg to about 340mg, about 40mg to about 320mg, about 40mg to about 300mg, about 40mg to about 280mg, about 40mg to about 260mg, about 40mg ~about 240mg, about 40mg to about 220mg, about 40mg to about 200mg, about 40mg to about 180mg, about 40mg to about 160mg, about 40mg to about 140mg,about 40mg to about 120mg, about 40mg to about 100mg, about 40mg to about 80mg, about 40mg to about 60mg, about 60mg to about 500mg, about 60mg to about 480mg, about 60mg to about 460mg, about 60mg to about 440mg, about 60mg to about 420mg, about 60mg to about 400mg, about 60mg to about 380mg, about 60mg to about 360mg, about 60mg to about 340mg, about 60mg to about 320mg, about 60mg to about 300mg, about 60mg to about 280mg, about 60mg to about 260mg, about 60mg to about 240mg, about 60mg to about 220mg, about 60mg to about 200mg, about 6 0mg to about 180mg, about 60mg to about 160mg, about 60mg to about 140mg, about 60mg to about 120mg, about 60mg to about 100mg, about 60mg to about 80mg, about 80mg to about 500mg, about 80mg to about 480mg, about 80mg to about 460mg, about 80mg to about 440mg, about 80mg to about 420mg, about 80mg to about 400mg, about 80mg to about 380mg, about 80mg to about 360mg, about 80mg to about 340mg, about 80mg to about 320mg, about 80mg to about 300mg, about 80mg to about 280mg, about 80mg g to about 260 mg, about 80 mg to about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg to about 480 mg, about 100 mg to about 460 mg, about 100 mg to about 440 mg, about 100 mg to about 420 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 mg g to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 500 mg, about 120 mg to about 480 mg, about 120 mg to about 460 mg, about 120 mg to about 440 mg, about 120 mg to about 420 mg, about 120 mg to about 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg,about 120mg to about 340mg, about 120mg to about 320mg, about 120mg to about 300mg, about 120mg to about 280mg, about 120mg to about 260mg, about 120mg to about 240mg, about 120mg to about 220mg, about 120mg to about 200mg, about 120mg to about 180mg, about 120mg to about 160mg, about 120mg to about 140mg, about 140mg to about 500mg, about 140mg to about 480mg, about 140mg to about 460mg, about 140mg to about 440mg, about 140mg to about 420mg, about 140mg to about 400mg, about 140mg to about 38 0mg, about 140mg to about 360mg, about 140mg to about 340mg, about 140mg to about 320mg, about 140mg to about 300mg, about 140mg to about 280mg, about 140mg to about 260mg, about 140mg to about 240mg, about 140mg to about 220mg, about 140mg to about 200mg, about 140mg to about 180mg, about 140mg to about 160mg, about 160mg to about 500mg, about 160mg to about 480mg, about 160mg to about 460mg, about 160mg to about 440mg, about 160mg to about 420mg, about 160mg to about 400mg, about 160mg to about about 380mg, about 160mg to about 360mg, about 160mg to about 340mg, about 160mg to about 320mg, about 160mg to about 300mg, about 160mg to about 280mg, about 160mg to about 260mg, about 160mg to about 240mg, about 160mg to about 220mg, about 160mg to about 200mg, about 160mg to about 180mg, about 180mg to about 500mg, about 180mg to about 480mg, about 180mg to about 460mg, about 180mg to about 440mg, about 180mg to about 420mg, about 180mg to about 400mg, about 180mg to about 380mg, about 18 0mg to about 360mg, about 180mg to about 340mg, about 180mg to about 320mg, about 180mg to about 300mg, about 180mg to about 280mg, about 180mg to about 260mg, about 180mg to about 240mg, about 180mg to about 220mg, about 180mg to about 200mg, about 200mg to about 500mg, about 200mg to about 480mg, about 200mg to about 460mg, about 200mg to about 440mg, about 200mg to about 420mg, about 200mg to about 400mg, about 200mg to about 380mg, about 200mg to about 360mg, about 200mg to about 340mg,about 200mg to about 320mg, about 200mg to about 300mg, about 200mg to about 280mg, about 200mg to about 260mg, about 200mg to about 240mg, about 200mg to about 220mg, about 220mg to about 500mg, about 220mg to about 480mg, about 220mg to about 460mg, about 220mg to about 440mg, about 22, 0mg to about 420mg, about 220mg to about 400mg, about 220mg to about 380mg, about 220mg to about 360mg, about 220mg to about 340mg, about 220mg to about 320mg, about 220mg to about 300mg, about 220mg to about 280mg, about 220mg to about 260mg, about 220mg to about 240mg, about 240mg to about 500mg, about 240mg to about 480mg, about 240mg to about 460mg, about 240mg to about 440mg, about 240mg to about 420mg, about 240mg to about 400mg, about 240mg to about 380mg, about 240mg to about 360mg g, about 240mg to about 340mg, about 240mg to about 320mg, about 240mg to about 300mg, about 240mg to about 280mg, about 240mg to about 260mg, about 260mg to about 500mg, about 260mg to about 480mg, about 260mg to about 460mg, about 260mg to about 440mg, about 260mg to about 420mg, about 260mg to about 400mg, about 260mg to about 380mg, about 260mg to about 360mg, about 260mg to about 340mg, about 260mg to about 320mg, about 260mg to about 300mg, about 260mg to about 280mg, about 280mg to about 500mg, about 280mg to about 480mg, about 280mg to about 460mg, about 280mg to about 440mg, about 280mg to about 420mg, about 280mg to about 400mg, about 280mg to about 380mg, about 280mg to about 360mg, about 280mg to about 340mg, about 280mg to about 320mg, about 280mg to about 300mg, about 300mg to about 500mg, about 300mg to about 480mg, about 300mg to about 460mg, about 300mg to about 440mg, about 300mg to about 420mg, about 300mg to about 400mg, about 300mg to about 380mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 500 mg, about 320 mg to about 480 mg, about 320 mg to about 460 mg, about 320 mg to about 440 mg, about 320 mg to about 420 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 320 mg to about 340 mg, about 340 mg to about 500 mg, about 340 mg to about 480 mg, about 340 mg to about 460 mg, about 340 mg to about 440 mg, about 340 mg to about 420 mg, about 340 mg to about 400 mg,Approximately 340mg to approximately 380mg, approximately 340mg to approximately 360mg, approximately 360mg to approximately 500mg, approximately 360mg to approximately 480mg, approximately 360mg to approximately 460mg, approximately 360mg to approximately 440mg, approximately 360mg to approximately 420mg, approximately 360mg to approximately 400mg, approximately 360mg to approximately 380 mg, approx. 380 mg ~ approx. 500 mg, approx. 380 mg ~ approx. 480 mg, approx. 380 mg ~ approx. 460 mg, approx. 380 mg ~ approx. 440 mg, approx. 380 mg ~ approx. 460 mg, about 400 mg to about 440 mg, about 400 mg to about 420 mg, about 420 mg to about 500 mg, about 420 mg to about 480 mg, about 420 mg to about 460 mg, about 420 mg to about 440 mg, about 440 mg to about 500 mg, about 440 mg to about 480 mg, about 440 mg to about 460 mg, about 460 mg to about 500 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg.

[0108] In one embodiment, the combination therapy is administered daily (over a period of time) once or twice daily, for example, at a dose of about 10 mg to about 400 mg (e.g., about 10 mg to about 380 mg, about 10 mg to about 360 mg, about 10 mg to about 340 mg, about 10 mg to about 320 mg, about 10 mg to about 300 mg, about 10 mg to about 280 mg, about 10 mg to about 260 mg, about 10 mg to about 240 mg, about 10 mg to about 220 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, about 10 mg to about 100 mg, mg, approx. 10 mg ~ approx. 80 mg, approx. 10 mg ~ approx. 60 mg, approx. 10 mg ~ approx. 40 mg, approx. 10 mg ~ approx. 20 mg, approx. 20 mg ~ approx. 400 mg, approx. 00mg, about 20mg to about 280mg, about 20mg to about 260mg, about 20mg to about 240mg, about 20mg to about 220mg, about 20mg to about 200mg, about 20mg to about 180mg, about 20mg to about 160mg, about 20mg to about 140mg, about 20mg to about 120mg, about 20 mg ~ about 100mg, about 20mg - about 80mg, about 20mg - about 60mg, about 20mg - about 40mg, about 40mg - about 400mg, about 40mg - about 380mg, about 40mg - about 360mg, about 40mg - about 340mg, about 40mg - about 320mg, about 40mg - about 300mg, About 40mg to about 280mg, about 40mg to about 260mg, about 40mg to about 240mg, about 40mg to about 220mg, about 40mg to about 200mg, about 40mg to about 180mg, about 40mg to about 160mg, about 40mg to about 140mg, about 40mg to about 120mg, about 40mg to about 1 00mg, about 40mg to about 80mg, about 40mg to about 60mg, about 60mg to about 400mg, about 60mg to about 380mg, about 60mg to about 360mg, about 60mg to about 340mg, about 60mg to about 320mg, about 60mg to about 300mg, about 60mg to about 280mg, about 60m g ~ about 260mg, about 60mg - about 240mg, about 60mg - about 220mg, about 60mg - about 200mg, about 60mg - about 180mg, about 60mg - about 160mg, about 60mg - about 140mg, about 60mg - about 120mg, about 60mg - about 100mg, about 60mg - about 80mg,About 80mg to about 400mg, about 80mg to about 380mg, about 80mg to about 360mg, about 80mg to about 340mg, about 80mg to about 320mg, about 80mg to about 300mg, about 80mg to about 280mg, about 80mg to about 260mg, about 80mg to about 240mg, about 80mg to about 220mg, about 80mg to about 200mg, about 80mg to about 180mg, about 80mg to about 160mg, about 80mg to about 140mg, about 80mg to about 120mg, about 80mg to about 100mg, about 100mg to about 400mg, about 10 0mg to about 380mg, about 100mg to about 360mg, about 100mg to about 340mg, about 100mg to about 320mg, about 100mg to about 300mg, about 100mg to about 280mg, about 100mg to about 260mg, about 100mg to about 240mg, about 100mg to about 220mg, about 100mg to about 200mg, about 100mg to about 180mg, about 100mg to about 160mg, about 100mg to about 140mg, about 100mg to about 120mg, about 120mg to about 400mg, about 120mg to about 380mg, about 120mg to about 360mg, about 120mg to about 340mg, about 120mg to about 320mg, about 120mg to about 300mg, about 120mg to about 280mg, about 120mg to about 260mg, about 120mg to about 240mg, about 120mg to about 220mg, about 120mg to about 200mg, about 120mg to about 180mg, about 120mg to about 160mg, about 120mg to about 140mg, about 140mg to about 400mg, about 140mg to about 380mg, about 140mg to about 360mg, about 140mg to about 340mg, about 140mg to about 320mg, about 140mg to about 300mg, about 140mg to about 280mg, about 140mg to about 260mg, about 140mg to about 24 0mg, about 140mg to about 220mg, about 140mg to about 200mg, about 140mg to about 180mg, about 140mg to about 160mg, about 160mg to about 400mg, about 160mg to about 380mg, about 160mg to about 360mg, about 160mg to about 360mg, about 160mg to about 340mg, about 160mg to about 320mg, about 160mg to about 300mg, about 160mg to about 280mg, about 160mg to about 260mg, about 160mg to about 240mg, about 160mg to about 220mg, about 160mg to about 200mg, about 160mg to about 180mg, about 180mg to about 400mg,Approx. 180mg to approx. 380mg, approx. 180mg to approx. 360mg, approx. 180mg to approx. 340mg, approx. 180mg to approx. 320mg, approx. 180mg to approx. 300mg, approx. 220mg, about 180mg to about 200mg, about 200mg to about 400mg, about 200mg to about 380mg, about 200mg to about 360mg, about 200mg to about 340mg, about 200mg to about 320mg, about 200mg to about 300mg, about 200mg to about 280mg, about 20 0mg to about 260mg, about 200mg to about 240mg, about 200mg to about 220mg, about 220mg to about 400mg, about 220mg to about 380mg, about 220mg to about 360mg, about 220mg to about 340mg, about 220mg to about 320mg, about 220mg to about 300 mg, approx. 220 mg ~ approx. 280 mg, approx. 220 mg ~ approx. 260 mg, approx. 220 mg ~ approx. 240 mg, approx. 240 mg ~ approx. 400 mg, approx. 240 mg ~ approx. 380 mg, approx. ~ about 300mg, about 240mg to about 280mg, about 240mg to about 260mg, about 260mg to about 400mg, about 260mg to about 380mg, about 260mg to about 360mg, about 260mg to about 340mg, about 260mg to about 320mg, about 260mg to about 300mg, Approximately 260mg to approximately 280mg, approximately 280mg to approximately 400mg, approximately 280mg to approximately 380mg, approximately 280mg to approximately 360mg, approximately 280mg to approximately 340mg, approximately 280mg to approximately 320mg, approximately 280mg to approximately 300mg, approximately 300mg to approximately 400mg, approximately 300mg to approximately 3 Oral administration of a compound of formula I in an amount of about 80 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 340 mg to about 360 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 400 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg,This includes oral administration of a Raf family kinase inhibitor administered once daily for a period of time. In one embodiment, the KRAS inhibitor is administered orally once daily. In one embodiment, the KRAS inhibitor is administered orally twice daily.

[0109] Those skilled in the art will appreciate that both in vivo and in vitro testing using suitable known and generally accepted cellular and / or animal models will predict the ability of a test compound or combination to treat or prevent a given disorder.

[0110] One of ordinary skill in the art will further appreciate that human clinical trials, including first-in-human studies, dose ranging studies and efficacy studies in healthy patients and / or patients afflicted with a given disorder, may be completed according to methods well known in the clinical and medical arts.

[0111] Synergy In one embodiment, the addition of a Raf family kinase inhibitor synergistically increases the activity of the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB against a cancer or cancer cell line expressing KRas G12C. Any method for determining whether two compounds exhibit synergistic effects can be used to determine the synergistic effect of the combination.

[0112] Several mathematical models have been developed to determine whether two compounds act synergistically, i.e., beyond merely additive effects. For example, Loewe additivity (Loewe (1928) Physiol. 27: 47-187), Bliss independence (Bliss (1939) Ann. Appl. Biol. 26: 585-615), best single agent, ZIP (Yadav et al (2015) Comput Struct Biotech J 13: 504-513), as well as other models (Chou & Talalay (1984) Adv Enzyme Regul 22: 27-55. #6382953, and Greco et al. (1995) Pharmacol Rev 47 (2): 331-85. #7568331) are well-known models in the pharmaceutical industry and can be used to calculate a "synergy score" that indicates whether synergy is detected and the magnitude of such synergy. These synergy scores are combined to generate a composite synergy score that can be used to evaluate and characterize KRas G12C inhibitor compounds of Formula (I), Formula IA, or Formula IB in combination with a Raf family kinase inhibitor.

[0113] Generally, the mathematical model uses data from the single agent values ​​to determine the predicted additive effect of the combination and compares it to the observed effect of the combination. If the observed effect is greater than the predicted effect, the combination is considered to be synergistic. For example, the Bliss independence model uses the observed combination response (Y O ) to the predicted combination response (Y P ) and Y O Y P If it is greater, then the combined effect typically indicates synergy.

[0114] In some embodiments, "synergistic effect" as used herein refers to a combination of a KRAS inhibitor, or a pharma- ceutically acceptable salt thereof, and a Raf family kinase inhibitor, or a pharma- ceutically acceptable salt thereof, that produces an effect that is greater than the sum of the effects observed when the compound of Formula I, or a pharma- ceutically acceptable salt thereof, and the Raf family kinase inhibitor, or a pharma- ceutically acceptable salt thereof, are administered alone, including, for example, any of the beneficial or desired results, including clinical outcomes or endpoints described herein.

[0115] In some embodiments, the methods provided herein provide a method for administering a medicament for a period of 1 day to 2 years (e.g., 1 day to 22 months, 1 day to 20 months, 1 day to 18 months, 1 day to 16 months, 1 day to 14 months, 1 day to 12 months, 1 day to 10 months, 1 day to 9 months, 1 day to 8 months, 1 day to 7 months, 1 day to 6 months, 1 day to 5 months, 1 day to 4 months, 1 day to 3 months, 1 day to 2 months, 1 day to 1 month, 1 week to 2 years, 1 week to 22 months, 1 week to 20 months, 1 week to 18 months, 1 week to 16 months, 1 week to 14 months, 1 week to 12 months, 1 week to 10 months, 1 week to 9 months, 1 week to 8 months , 1 week to 7 months, 1 week to 6 months, 1 week to 5 months, 1 week to 4 months, 1 week to 3 months, 1 week to 2 months, 1 week to 1 month, 2 weeks to 2 years, 2 weeks to 22 months, 2 weeks to 20 months, 2 weeks to 18 months, 2 weeks to 16 months, 2 weeks to 14 months, 2 weeks to 12 months, 2 weeks to 10 months, 2 weeks to 9 months, 2 weeks to 8 months, 2 weeks to 7 months, 2 weeks to 6 months, 2 weeks to 5 months, 2 weeks to 4 months, 2 weeks to 3 months, 2 weeks to 2 months, 2 weeks to 1 month, 1 month to 2 years, 1 month to 22 months, 1 month to 20 months, 1 month to 18 months, 1 month to 16 months months, 1 month to 14 months, 1 month to 12 months, 1 month to 10 months, 1 month to 9 months, 1 month to 8 months, 1 month to 7 months, 1 month to 6 months, 1 month to 6 months, 1 month to 5 months, 1 month to 4 months, 1 month to 3 months, 1 month to 2 months, 2 months to 2 years, 2 months to 22 months, 2 months to 20 months, 2 months to 18 months, 2 months to 16 months, 2 months to 14 months, 2 months to 12 months, 2 months to 10 months, 2 months to 9 months, 2 months to 8 months, 2 months to 7 months, 2 months to 6 months, or 2 months to 5 months, 2 months to 4 months, 3 months to 2 years, 3 months to 2 ... months, 3 months to 2 months, 3 months to 2 years, 3 months to 2 months, 3 months to 2 months, 3 months to 2 months, 3 months to 2 months, 3 months to 2 months, 3 months to 2 months, months to 20 months, 3 months to 18 months, 3 months to 16 months, 3 months to 14 months, 3 months to 12 months, 3 months to 10 months, 3 months to 8 months, 3 months to 6 months, 4 months to 2 years, 4 months to 22 months, 4 months to 20 months, 4 months to 18 months, 4 months to 16 months, 4 months to 14 months, 4 months to 12 months, 4 months to 10 months, 4 months to 8 months, 4 months to 6 months, 6 months to 2 years, 6 months to 22 months, 6 months to 20 months, 6 months to 18 months, 6 months to 16 months, 6 months to 14 months, 6 months to 12 months, 6 months to 10 months, or 6 months to 8 months)1%-99% (e.g., 1%-98%, 1%-95%, 1%-90%, 1%-85%, 1%-80%, 1%-75%, 1%-70%, 1%-65%, 1%-60%, 1%-55%, 1%-50%, 1%-45%, 1%-40%, 1%-35%, 1%-30%, 1%-25%, 1%-20%, 1%-15%, 1%-10%, 1%-5%, 2%-99%, 2%-90%, 2%-85%, 2%-80%, 2%-75%, 2%-70%, 2%-65%, 2%-60%, 2%-55%, 2%-50%) of the volume of one or more solid tumors in a patient after treatment with the combination therapy , 2%~45%, 2%~40%, 2%~35%, 2%~30%, 2%~25%, 2%~20%, 2%~15%, 2%~10%, 2%~5%, 4%~99%, 4%~95%, 4%~90%, 4%~85%, 4%~80%, 4%~75%, 4%~70%, 4%~65%, 4%~60% , 4%~55%, 4%~50%, 4%~45%, 4%~40%, 4%~35%, 4%~30%, 4%~25%, 4%~20%, 4%~15%, 4%~10%, 6%~99%, 6%~95%, 6%~90%, 6%~85%, 6%~80%, 6%~75%, 6%~70%, 6%~65 %, 6%~60%, 6%~55%, 6%~50%, 6%~45%, 6%~40%, 6%~35%, 6%~30%, 6%~25%, 6%~20%, 6%~15%, 6%~10%, 8%~99%, 8%~95%, 8%~90%, 8%~85%, 8%~80%, 8%~75%, 8%~7 0%, 8%~65%, 8%~60%, 8%~55%, 8%~50%, 8%~45%, 8%~40%, 8%~35%, 8%~30%, 8%~25%, 8%~20%, 8%~15%, 10%~99%, 10%~95%, 10%~90%, 10%~85%, 10%~80%, 10%~7 5%, 10%~70%, 10%~65%, 10%~60%, 10%~55%, 10%~50%, 10%~45%, 10%~40%, 10%~35%, 10%~30%, 10%~25%, 10%~20%, 10%~15%, 15%~99%, 15%~95%, 15%~90%, 15 %~85%, 15%~80%, 15%~75%, 15%~70%, 15%~65%, 15%~60%, 15%~55%, 15%~50%, 15%~55%, 15%~50%, 15%~45%, 15%~40%, 15%~35%, 15%~30%, 15%~25%, 15%~20%,20%~99%、20%~95%、20%~90%、20%~85%、20%~80%、20%~75%、20%~70%、20%~65%、20%~60%、20%~55%、20%~50%、20%~45%、20%~40%、20%~35%、20%~30%、20%~25%、25%~99%、25%~95%、25%~90%、25%~85%、25%~80%、25%~75%、25%~70%、25%~65%、25%~60%、25%~55%、25%~50%、25%~45%、25%~40%、25%~35%、25%~30%、30%~99%、30%~95%、30%~90%、30%~85%、30%~80%、30%~75%、30%~70%、30%~65%、30%~60%、30%~55%、30%~50%、30%~45%、30%~40%、30%~35%、35%~99%、35%~95%、35%~90%、35%~85%、35%~80%、35%~75%、35%~70%、35%~65%、35%~60%、35%~55%、35%~50%、35%~45%、35%~40%、40%~99%、40%~95%、40%~90%、40%~85%、40%~80%、40%~75%、40%~70%、40%~65%、40%~60%、40%~55%、40%~60%、40%~55%、40%~50%、40%~45%、45%~99%、45%~95%、45%~95%、45%~90%、45%~85%、45%~80%、45%~75%、45%~70%、45%~65%、45%~60%、45%~55%、45%~50%、50%~99%、50%~95%、50%~90%、50%~85%、50%~80%、50%~75%、50%~70%、50%~65%、50%~60%、50%~55%、55%~99%、55%~95%、55%~90%、55%~85%、55%~80%、55%~75%、55%~70%、55%~65%、55%~60%、60%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、65%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、70%~99%、70%~95%、70%~90%、70%~85%、70%~80%、70%~75%、may result in a 75%-99%, 75%-95%, 75%-90%, 75%-85%, 75%-80%, 80%-99%, 80%-95%, 80%-90%, 80%-85%, 85%-99%, 85%-95%, 85%-90%, 90%-99%, 90%-95%, or 95%-100% reduction (e.g., compared to the size of one or more solid tumors in the patient prior to treatment).

[0116] The phrase "survival time" refers to the length of time from identification or diagnosis of cancer (e.g., any of the cancers described herein) in a mammal by a medical professional to the time of death (caused by the cancer) of the mammal. Methods of increasing the survival time of a mammal with cancer are described herein.

[0117] In some embodiments, any of the methods described herein provide a method for determining whether or not a patient has a decreased survival rate (e.g., 1%-400%, 1%-380%, 1%-360%, 1%-340%, 1%-320%, 1%-300%, 1%-280%, 1%-260%, 1%-240%, 1%-220%, 1%-200%, 1%-180%, 1%-160%, 1%-140%, 1%-120%, 1%-100%, 1%-95%, 1%-90%, 1%-85%, 1%-80%, 1%-75%, 1%-70%, 1%-65%, 1%-60%, 1%-55%, 1%-50%, 1%-40%, 1%-55%, 1%-60%, 1%-75%, 1%-80%, 1%-95%, 1%-90%, 1%-85%, 1%-80%, 1%-95%, 1%-90%, 1%-85%, 1%-80%, 1%-95%, 1%-70%, 1%-65%, 1%-60%, 1%-55%, 1%-50%, 1%-40%, 1%-50%, 1%-50%, 1%-60%, 1%-75%, 1%-80%, 1%-95 ... 5%, 1%~40%, 1%~35%, 1%~30%, 1%~25%, 1%~20%, 1%~15%, 1%~10%, 1%~5%, 5%~400%, 5%~380%, 5%~360%, 5%~340%, 5%~320%, 5%~300%, 5%~280%, 5%~260%, 5% ~240%, 5%~220%, 5%~200%, 5%~180%, 5%~160%, 5%~140%, 5%~120%, 5%~100%, 5%~90%, 5%~80%, 5%~70%, 5%~60%, 5%~50%, 5%~40%, 5%~30%, 5%~20%, 5%~10%, 10%~400%, 10%~380%, 10%~360%, 10%~340%, 10%~320%, 10%~300%, 10%~280%, 10%~260%, 10%~240%, 10%~220%, 10%~200%, 10%~180%, 10%~160%, 10%~140 %, 10%~120%, 10%~100%, 10%~90%, 10%~80%, 10%~70%, 10%~60%, 10%~50%, 10%~40%, 10%~30%, 10%~20%, 20%~400%, 20%~380%, 20%~360%, 20%~340%, 20%~3 20%, 20%~300%, 20%~280%, 20%~260%, 20%~240%, 20%~220%, 20%~200%, 20%~180%, 20%~160%, 20%~140%, 20%~120%, 20%~100%, 20%~90%, 20%~80%, 20%~7 0%, 20%~60%, 20%~50%, 20%~40%, 20%~30%, 30%~400%, 30%~380%, 30%~360%, 30%~340%, 30%~320%, 30%~300%, 30%~280%, 30%~260%, 30%~240%, 30%~220%,30%~200%、30%~180%、30%~160%、30%~140%、30%~120%、30%~100%、30%~90%、30%~80%、30%~70%、30%~60%、30%~50%、30%~40%、40%~400%、40%~380%、40%~360%、40%~340%、40%~320%、40%~300%、40%~280%、40%~260%、40%~240%、40%~220%、40%~200%、40%~180%、40%~160%、40%~140%、40%~120%、40%~100%、40%~90%、40%~80%、40%~70%、40%~60%、40%~50%、50%~400%、50%~380%、50%~360%、50%~340%、50%~320%、50%~300%、50%~280%、50%~260%、50%~240%、50%~220%、50%~200%、50%~180%、50%~160%、50%~140%、50%~140%、50%~120%、50%~100%、50%~90%、50%~80%、50%~70%、50%~60%、60%~400%、60%~380%、60%~360%、60%~340%、60%~320%、60%~300%、60%~280%、60%~260%、60%~240%、60%~220%、60%~200%、60%~180%、60%~160%、60%~140%、60%~120%、60%~100%、60%~90%、60%~80%、60%~70%、70%~400%、70%~380%、70%~360%、70%~340%、70%~320%、70%~300%、70%~280%、70%~260%、70%~240%、70%~220%、70%~200%、70%~180%、70%~160%、70%~140%、70%~120%、70%~100%、70%~90%、70%~80%、80%~400%、80%~380%、80%~360%、80%~340%、80%~320%、80%~300%、80%~280%、80%~260%、80%~240%、80%~220%、80%~200%、80%~180%、80%~160%、80%~140%、80%~120%、80%~100%、80%~90%、90%~400%、90%~380%、90%~360%、90%~340%、90%~320%、90%~300%、90%~280%、90%~260%、90%~240%、90%~220%、90%~200%、90%~180%、90%~160%、90%~140%、90%~120%、90%~100%、100%~400%、100%~380%、100%~360%、100%~340%、100%~320%、100%~300%、100%~280%、100%~260%、100%~240%、100%~220%、100%~200%、100%~180%、100%~160%、100%~140%、100%~120%、120%~400%、120%~380%、120%~360%、120%~340%、120%~320%、120%~300%、120%~280%、120%~260%、120%~240%、120%~220%、120%~200%、120%~180%、120%~160%、120%~140%、140%~400%、140%~380%、140%~360%、140%~340%、140%~320%、140%~300%、140%~280%、140%~260%、140%~240%、140%~220%、140%~200%、140%~180%、140%~160%、160%~400%、160%~380%、160%~360%、160%~340%、160%~320%、160%~300%、160%~280%、160%~260%、160%~240%、160%~220%、160%~200%、160%~180%、180%~400%、180%~380%、180%~360%、180%~340%、180%~320%、180%~300%、180%~280%、180%~260%、180%~240%、180%~220%、180%~200%、200%~400%、200%~380%、200%~360%、200%~340%、200%~320%、200%~300%、200%~280%、200%~260%、200%~240%、200%~220%、220%~400%、220%~380%、220%~360%、220%~340%、220%~320%、220%~300%、220%~280%、220%~260%、220%~240%、240%~400%、240%~380%、240%~360%、240%~340%、240%~320%、240%~300%、240%-280%, 240%-260%, 260%-400%, 260%-380%, 260%-360%, 260%-340%, 260%-320%, 260%-300%, 260%-280%, 280%-400%, 280%-380%, 280%-360%, 280%-340%, 280%-320%, 280%-300%, 300%-400%, 300%-380%, 300%-360%, 300%-340%, or 300%-320%) increase (e.g., compared to a patient with a similar cancer who has been treated differently or who has not been treated).

[0118] In some embodiments of any of the methods described herein, prior to treatment with a composition or method of the invention, the patient has been treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, and optionally, the previous treatment has failed, and / or the patient has been subjected to surgery, and optionally, the surgery has failed, and / or the patient has been treated with a platinum-based chemotherapy agent, and optionally, the patient has been previously determined to be unresponsive to treatment with a platinum-based chemotherapy agent, and / or the patient has been treated with a kinase inhibitor, and optionally, the previous treatment with the kinase inhibitor has failed, and / or the patient has been treated with one or more other therapeutic agent(s).

[0119] kit The present invention also relates to a kit comprising a Raf family kinase inhibitor and a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB. Kits comprising a Raf family kinase inhibitor, or a pharma- ceutically acceptable salt thereof, and a KRAS G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt thereof, are also provided for use in treating hematological cancers.

[0120] In a related aspect, the present invention provides a kit comprising a dose of a Raf family kinase inhibitor or a pharma- ceutically acceptable salt thereof and a dose of a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt thereof, in an amount effective to inhibit the proliferation of cancer cells, particularly cancer cells expressing KRas G12C, in a subject. The kit optionally includes an insert comprising instructions for administering the Raf family kinase inhibitor or a pharma- ceutically acceptable salt thereof and the KRAS G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt thereof. The insert may provide a user with a set of instructions for using the Raf family kinase inhibitor, or a pharma- ceutically acceptable salt thereof, in combination with the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt thereof.

[0121] Example A Raf family kinase inhibitors synergistically increase the activity of KRas G12C inhibitors against cell lines expressing KRas G12C. This example can be used to show that a combination of an exemplary KRas G12C inhibitor compound of Formula I, Formula IA, and Formula 1-B, or a pharma- ceutically acceptable salt thereof (e.g., a compound selected from Compound Example Nos. 1-678, or a pharma- ceutically acceptable salt thereof, e.g., Example Nos. 234, 359, 478, or 507, or a pharma- ceutically acceptable salt thereof) with a Raf family kinase inhibitor, or a pharma- ceutically acceptable salt thereof, synergistically inhibits the growth of a tumor cell line expressing KRas G12C.

[0122] To determine whether combining Raf family kinase inhibitors with the exemplary KRas G12C inhibitors disclosed herein results in synergistic activity, a panel of eight lung cancer and one colorectal cell line carrying KRas G12C mutation is collected. The collection may include NCI-H1373 (ATCC CRL-5866), NCI-H1792 (ATCC CRL-5895), NCI-H2030 (ATCC CRL-5985), NCI-H2122 (ATCC CRL-5985), HCC1171 (KCLB 71171), HCC44 (DSMZ ACC-534), LU99 (RCB1900), SW1573 (ATCC CRL-2170), and SW837 (ATCC CCL-235).

[0123] Assays to determine synergy scores for each cell line pairwise combination are performed in triplicate. Three 96-well plates for determining baseline luminescence and four additional wells of a separate 96-well control plate are seeded with 2000 cells / well of a particular cell line in a total volume of 90 μl of the appropriate growth medium for that cell line, e.g., RPMI 1640 medium supplemented with 10% FBS, plus any cell line-specific reagents required for growth. Plates are incubated overnight at 37° C. in a 5% CO2 atmosphere.

[0124] For each of the designated baseline wells, 30 μl of Cell-Titer Glo reagent (CTG; Promega Corporation) is added to each well and the plate is incubated for 20 minutes at room temperature with shaking. Baseline luminescence is quantified using a BMG ClarioStar multimode plate reader according to the manufacturer's instructions.

[0125] Prepare a series of working stock 1000X drug dilutions in 100% DMSO, including an 8-point single agent dilution of an exemplary KRas G12C inhibitor of formula (I) and a 5-point single agent dilution of a Raf family kinase inhibitor. The dilutions used for the KRas G12C inhibitor and the Raf family kinase inhibitor will vary for each individual compound, but typically range from 3-6 fold / serial dilution.

[0126] Exemplary KRasG12C inhibitors for testing in this example include the following: [Table 1]

[0127] A 10X intermediate dose plate is prepared in serum-free RPMI medium containing an array of single agent dilutions of an exemplary KRas G12C inhibitor of formula (I) or a Raf family kinase inhibitor. In addition, 40 matrix dilution combinations of an exemplary KRas G12C inhibitor of formula (I), formula IA, or formula IB and a Raf family kinase inhibitor are prepared as test samples.

[0128] To each corresponding well of three 96-well plates seeded with the appropriate cell line above, 10 μl of each 10X single agent and dose matrix 40 combination is added and the plates are incubated for 72 hours at 37C, 5% CO2 atmosphere. A 30 μl aliquot of Cell-Titer Glo reagent (CTG) is added to each test well and the plates are incubated for 20 minutes with shaking at room temperature and luminescence is quantified using a BMG ClarioStar multimode plate reader according to the manufacturer's instructions.

[0129] Using the raw data and metadata files as input files, effect rates for each treatment condition can be calculated and analyzed using four independent mathematical reference models (Loewe additivity, Bliss independence, best single agent, and ZIP) designed to determine whether two test compounds exhibit synergistic effects. The data output from each mathematical model is the assignment of a relative synergy score ("composite synergy score"), such as Loewe additivity, Bliss independence, best single agent, and a grand total of ZIP scores.

[0130] Example B In vivo model to investigate the combination of KRas G12C inhibitors with Raf family kinase inhibitors Immunodeficient nude / nude mice were inoculated into the right hind limb with cells carrying the KRas G12C mutation or tumor samples from patients. 3 When the tumors reached a size of 100 mm, the mice were divided into four groups of 5-12 mice each. The first group received vehicle only. The second group received a single-agent dose of a KRas G12C inhibitor at a concentration that results in a maximal or submaximal biological effect, depending on the cell line and single-agent activity, but does not result in complete tumor regression. The third group received a single-agent dose of a Raf family kinase inhibitor at a concentration that results in a maximal or submaximal biological effect, depending on the cell line and single-agent activity, but does not result in complete tumor regression. The fourth group received a single-agent dose of a KRas G12C inhibitor in combination with a single-agent dose of a Raf family kinase inhibitor. The duration of treatment varied for each cell line but was usually 21-35 days. Tumor volumes were measured using calipers every 2-3 days and tumor volume was calculated using the formula: 0.5 × (length × width) 2 The greater degree of tumor growth inhibition of the combination in this model indicated that the combination therapy is more likely to provide clinically meaningful benefit to treated subjects compared with treatment with either a KRas G12C inhibitor alone or a Raf family kinase inhibitor alone.

[0131] For example, on day 1, 20 nude / nude mice were inoculated with 5 × 10 6 NCI-H2122 cells were inoculated into the right hind leg. The tumor volume was approximately 300 mm 3At the time of reaching 10 days (study day 0), five mice in each of the four groups were administered vehicle alone (10% Captisol), 100 mg / kg of the KRAS G12C inhibitor Compound 478 (10% Captisol in 50 mM citrate buffer, pH 5.0) (once daily), 10 mg / kg of the Raf family kinase inhibitor BGB-283 (0.5% methylcellulose / 0.4% Tween-80) (twice daily), or 100 mg / kg of the KRas G12C inhibitor Compound 478 (once a day) and 10 mg / kg BGB-283 (twice a day) were orally administered daily for 21 days. In addition, 5 mice were administered 100 mg / kg KRasG12C inhibitor Compound 478 (once a day) for 15 days. On study day 16, these mice were administered 100 mg / kg KRasG12C inhibitor Compound 478 (once a day) in combination with 10 mg / kg BGB-283 (twice a day) for an additional 9 days. Tumor volumes were measured on the pre-specified days shown below. Tumor volumes of 5 mice per group were averaged and reported in Table 1. ND=not measured. [Table 2]

[0132] As shown in Table 1, administration of compound 478 or BGB-283 as single agents resulted in 82.8% and 48.9% tumor growth inhibition, respectively, on study day 9. The combination of the Raf family kinase inhibitor BGB-283 with compound 478 resulted in 34.6% tumor regression after 9 days of simultaneous combination treatment. In addition, combination therapy with BGB-283 for 9 days, followed by administration of compound 478 for 15 days, resulted in 73.8% tumor growth regression after only 9 days of combination therapy. These results indicate that in contrast to the single-agent administration of either agent alone, which resulted in tumor growth inhibition, the combination therapy resulted in potent tumor regression, whether administered for 25 days or in a combination of only 9 days of treatment. These results indicate the enhanced in vivo antitumor efficacy of the combination against cancers expressing KRas G12C.

[0133] While the invention has been described in relation to particular embodiments thereof, which are capable of further modification, it will be understood that this application is generally intended to cover any variation, use, or alteration of the invention in accordance with the principles of the invention, including departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and that may apply to the essential features set forth above and that fall within the scope of the following appended claims.

Claims

1. 1. A pharmaceutical composition for use in a method of treating cancer in a subject in need thereof, comprising: The method comprises administering to the subject a therapeutically effective amount of a Raf family kinase inhibitor selected from the group consisting of encorafenib (LGX818), PLX-8394, Raf-709, LXH254, sorafenib, LY3009120, lifirafenib (BGB-283), Tak-632, CEP-32496, CCT196969, and RO5126766, and a KRAS G12C inhibitor of the formula: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, The pharmaceutical composition, wherein the cancer is a KRas G12C associated cancer.

2. 2. The pharmaceutical composition of claim 1, wherein the Raf family kinase inhibitor is encorafenib (LGX818), sorafenib, or lifirafenib (BGB-283).

3. 3. The pharmaceutical composition of claim 2, wherein the Raf family kinase inhibitor is encorafenib (LGX818).

4. The pharmaceutical composition of claim 2 , wherein the Raf family kinase inhibitor is sorafenib.

5. The pharmaceutical composition of claim 2, wherein the Raf family kinase inhibitor is lifirafenib (BGB-283).

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the Raf family kinase inhibitor and the KRAS G12C inhibitor are administered on the same day.

7. The pharmaceutical composition of any one of claims 1 to 5, wherein the Raf family kinase inhibitor and the KRAS G12C inhibitor are administered on different days.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the KRas G12C inhibitor is administered at a maximum tolerated dose.

9. The pharmaceutical composition of any one of claims 1 to 7, wherein the Raf family kinase inhibitor and the KRAS G12C inhibitor are each administered at a maximum tolerated dose.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the therapeutically effective amount of the combination of the Raf family kinase inhibitor and the KRAS G12C inhibitor results in increased overall survival, increased progression free survival, increased tumor growth regression, increased tumor growth inhibition, or increased duration of stable disease in the subject compared to treatment with the KRAS G12C inhibitor alone.

11. 1. A pharmaceutical composition for treating cancer in a subject, comprising: a therapeutically effective amount of a Raf family kinase inhibitor selected from the group consisting of encorafenib (LGX818), PLX-8394, Raf-709, LXH254, sorafenib, LY3009120, lifirafenib (BGB-283), Tak-632, CEP-32496, CCT196969, and RO5126766; and a KRas G12C inhibitor of the formula 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

12. 1. A pharmaceutical composition for use in a method for inhibiting KRas G12C activity in a cell, comprising: The method comprises treating the cells in which inhibition of KRas G12C activity is desired with an effective amount of a Raf family kinase inhibitor selected from the group consisting of encorafenib (LGX818), PLX-8394, Raf-709, LXH254, sorafenib, LY3009120, lifirafenib (BGB-283), Tak-632, CEP-32496, CCT196969, and RO5126766, and a KRas G12C inhibitor of the formula: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof; the pharmaceutical composition comprises the Raf family kinase inhibitor and / or the KRas G12C inhibitor compound or a pharma- ceutically acceptable salt thereof; A pharmaceutical composition, wherein the Raf family kinase inhibitor synergistically increases the sensitivity of a cancer cell to the KRas G12C inhibitor.

13. The pharmaceutical composition of any one of claims 1 to 12, wherein the Raf family kinase inhibitor synergistically increases the sensitivity of cancer cells to the KRas G12C inhibitor.

14. A KRas G12C inhibitor compound of the formula 【Chemistry 4】 or a pharma- ceutical acceptable salt thereof, comprising: The method comprises administering to a patient a compound of the formula: 【Chemistry 5】 or a pharma- ceutical acceptable salt thereof, administering to a subject undergoing KRas G12C therapy a therapeutically effective amount of a Raf family kinase inhibitor selected from the group consisting of encorafenib (LGX818), PLX-8394, Raf-709, LXH254, sorafenib, LY3009120, lifirafenib (BGB-283), Tak-632, CEP-32496, CCT196969, and RO5126766; the pharmaceutical composition comprises the Raf family kinase inhibitor, A pharmaceutical composition, wherein the Raf family kinase inhibitor synergistically increases the sensitivity of a cancer cell to the KRas G12C inhibitor.

15. The pharmaceutical composition of any one of claims 1 to 14, wherein the therapeutically effective amount of the KRas G12C inhibitor in the combination is about 0.01 to 100 mg / kg / day.

16. 16. The pharmaceutical composition of claim 15, wherein the therapeutically effective amount of the KRas G12C inhibitor in the combination is about 0.1 to 50 mg / kg / day.

17. The pharmaceutical composition of any one of claims 1 to 16, wherein the therapeutically effective amount of the Raf family kinase inhibitor in the combination is about 0.01 to 100 mg / kg / day.

18. 18. The pharmaceutical composition of claim 17, wherein the therapeutically effective amount of the Raf family kinase inhibitor in the combination is about 0.1 to 50 mg / kg / day.

19. The cancer is cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrotic hamartoma, mesothelioma; Gastrointestinal: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroid exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid, and giant cell tumor; Nervous system: skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans) , meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell 19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the therapeutic agent is selected from the group consisting of: anterior (abdominal) tumor, sertoli-leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematological: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

20. 20. The pharmaceutical composition of claim 19, wherein the cancer is non-small cell lung cancer.

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