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 CDK 4 / 6 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 cyclin-dependent kinase 4 and / or 6 ("CDK4 / 6") 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 [Non-Patent Document 4] Dogan et al.,(2012)Clin Cancer Res.18(22):6169-6177 [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 [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 therapeutically effective amounts of a CDK4 / 6 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 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 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 7 is independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, and Q is O or S; R8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -C(O)OR 5 , -C(O)N(R 5 ) 2 , -N(R 5 ) 2 and 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, -CH 2NHC(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] or a pharma- ceutically acceptable salt 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 8 Optionally substituted with R 8is 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] or a pharma- ceutically acceptable salt 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 9 is as defined in formula I, and the piperazinyl ring is R 8 wherein 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 CDK4 / 6 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 CDK4 / 6 inhibitor or its pharmacologic acceptable salt or pharmaceutical composition and a KRAS G12C inhibitor of formula (I), formula IA, or formula IB or its pharmacologic 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 invention, the KRas G12C inhibitor compound and the CDK4 / 6 inhibitor are the only active agents in the combinations and methods provided.

[0015] Examples of CDK4 / 6 inhibitors suitable for the provided compositions and methods include, but are not limited to, palbociclib, abemaciclib, ribociclib, trilaciclib, and PF-06873600.

[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 CDK4 / 6 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the CDK4 / 6 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 CDK4 / 6 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 CDK4 / 6 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 CDK4 / 6 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 CDK4 / 6 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 CDK4 / 6 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 CDK4 / 6 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 the user with a set of instructions for using the CDK4 / 6 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 for treating cancer in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a CDK4 / 6 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, a pharmaceutical composition comprising a therapeutically effective amount of the inhibitor, a kit comprising the composition, and a method of use thereof.

[0022] The combination of a CDK4 / 6 inhibitor with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt thereof, synergistically increases the potency of the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB against cancer cells expressing KRas G12C, thereby increasing the efficacy and therapeutic index 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. 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.

[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, "CDK4 / 6" refers to members of the mammalian serine / threonine protein kinases CDK4 and CDK6, which play an important role in the G1 to S phase transition of the cell cycle.

[0028] As used herein, "CDK4 / 6 inhibitor" refers to a compound capable of negatively regulating or inhibiting all or part of the enzymatic activity of CDK4 and / or 6.

[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" means -NH 2 Refers to...

[0034] The term "acyl" means -C(O)CH 3 Refers to...

[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(Ry ) 2 Each R y is C1-C4 alkyl, -alkyl-N(R y ) 2 The alkyl may be optionally substituted with hydroxy or hydroxyalkyl.

[0048] An "aryl" group is a C aryl group containing 1 to 3 aromatic rings, which are optionally substituted. 6 -C 14 In one embodiment, the aryl group is 6 -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 independently be optionally substituted or unsubstituted. Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl, and naphthylmethyl (C 1 -C 6 )Alkyl(C 6 -C 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., CDK4 / 6 or KRas G12C. Such an amount can be administered as a single dose or according to a dosing regimen, 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 CDK4 / 6 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 CDK4 / 6 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 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 CDK4 / 6 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 results in an increased progression-free survival ("PFS") 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 CDK4 / 6 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, a combination of a therapeutically effective amount of a CDK4 / 6 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 therapeutically effective amount of a CDK4 / 6 inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof in combination 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 a monotherapy, so long as the combination is synergistic. 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 CDK4 / 6 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 up or down by as much as 10% from the numerical value listed for that parameter. 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, comprising administering to the subject a therapeutically effective amount of a combination of a CDK4 / 6 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.CDK4 / 6 Inhibitors Cyclin-dependent kinases ("CDK") 4 and 6 are serine / threonine protein kinases that play a key role in the transition from the G1 to the S phase of the cell cycle. Both CDK4 and CDK6 regulate this transition by phosphorylating the tumor suppressor retinoblastoma ("Rb"), which, in conjunction with their cognate cyclin partners, regulates cell cycle progression. Phosphorylation of Rb disrupts the association between Rb and E2F transcription factors, promoting the expression of E2F-regulated genes whose products are required for DNA replication during the S phase (for review, see, e.g., de Groot et al., Cancer Treat Rev. 2017 Nov;60:130-138.doi:10.1016 / j.ctrv.2017.09.003Epub 2017 Sep 20).

[0062] Amplification of CDK4 and / or CDK6 has been reported in many tumor types, including breast cancer, sarcoma, glioma, and non-small cell lung cancer. For example, overexpression of CDK6 leads to resistance to temozolomide treatment and hormonal therapy treatments, such as fulvestrant, in breast cancer patients.

[0063] In addition, CDK4 and CDK6 activity is negatively regulated by the cyclin-dependent kinase inhibitor p16, encoded by the CDKN2A gene. CDKN2A normally functions to inhibit CDK4 / 6 kinase activity, thereby preventing phosphorylation of Rb. As a result, Rb remains complexed with E2F transcription factors and represses the expression of E2F-regulated gene products, blocking the G1 to S phase transition and inhibiting cell proliferation. Inactivating mutations, particularly homozygous deletions, of CDKN2A result in enhanced CDK4 / 6 activity and unchecked cell cycle progression. Such inactivating mutations and deletions have been reported in several cancer types, including bladder cancer, melanoma, glioma, pancreatic cancer, colorectal cancer, and non-small cell lung cancer. Therefore, CDK4 / 6 inhibition has attracted interest as an approach for anticancer therapy beyond the current FDA-approved indications for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer.

[0064] Several inhibitors with activity against CDK4 / 6 family kinases have been developed, and many have received marketing approval. For example, approved CDK4 / 6 inhibitors include abemaciclib (N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine); palbociclib (6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-1); and ribociclib (6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-1). These include trilaciclib (7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide), while the CDK4 / 6 inhibitor trilaciclib (2'-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one) is in late-stage clinical trials. Another CDK4 / 6 inhibitor useful in the methods herein is the CDK2 / 4 / 6 inhibitor PF-06873600 (pyrido[2,3-d]pyrimidin-7(8H)-one, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1-(methylsulfonyl)-4-piperidinyl]amino]).

[0065] Methods for producing CDK4 / 6 inhibitors are well known to those of skill in the art, and CDK4 / 6 inhibitors can be obtained from a wide variety of commercial suppliers in forms suitable for both research or human use. In addition, CDK4 / 6 inhibitors suitable for use in the compositions and methods disclosed herein, as well as methods for preparing such inhibitors, are described in U.S. Patent Application Publication Nos. US2018 / 0201619, US2018 / 0201618, US2018 / 0148431, US2017 / 0218018, US2017 / 0157212, US2017 / 0157213, US2017 / 0157214, US2017 / 0157215, US2017 / 0157216, US2017 / 0157217, US2017 / 0157218, US2017 / 0157219 ... US2017 / 0057971, US2015 / 0246926, US2015 / 0246925, US2015 / 0031880, US2015 / 0011730, US2014 / 0296484, US2014 / 0227222, US2014 / 0142306, US2014 / 0142299, US2 US2013 / 0289240, US2013 / 0237544, US2013 / 0237534, US2013 / 0237533, US2013 / 0237495, US2013 / 0184288, US2013 / 0045993, US2012 / 0295948, US2012 / 0165335, US2011 and US2008 / 0081811.

[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 R 6 or R 7 and optionally substituted with Each R 5 is independently hydrogen or C1-C3 alkyl; R 6is 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 and 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 Bare 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, -CH 2 NHC(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

[0067] In one embodiment, the KRas G12C inhibitor used in the methods herein is a compound having formula IA [ka] or a pharma- ceutically acceptable salt thereof, 1 , R3 , 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] or a pharma- ceutically acceptable salt 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 selected from Example Nos. 1-678 of International Patent Application Publication No. WO2019099524; and [ka] [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) and pharma- ceutically acceptable salts thereof.

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

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

[0074] In one embodiment, the KRas G12C inhibitor is [ka] (referred to as Example 507) and pharma- ceutically acceptable salts 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 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 CDK4 / 6 inhibitor, or a pharma- ceutically acceptable salt thereof, and the 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 CDK4 / 6 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 methods disclosed herein. The CDK4 / 6 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 CDK4 / 6 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 CDK4 / 6 inhibitor and a KRas G12C inhibitor may be used in the methods of use described herein.

[0084] Simultaneous administration The CDK4 / 6 inhibitor, or its pharmaceutically acceptable salt or pharmaceutical composition, and the KRas G12C inhibitor, or its pharmaceutically acceptable salt or pharmaceutical composition, can be formulated separately or into separate dosage forms that can be administered simultaneously in sequence.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 simultaneous administration, but both simultaneous administration methods are part of the same therapeutic treatment or regimen.

[0085] For use in this method, the pharmaceutical composition comprising CDK4 / 6 inhibitor or its pharmaceutically acceptable salt or pharmaceutical composition and / or KRAS G12C inhibitor or its pharmaceutically acceptable salt or pharmaceutical composition can be for simultaneous, separate or sequential use.In one embodiment, the CDK4 / 6 inhibitor or its pharmaceutically acceptable salt or pharmaceutical composition is administered before the administration of the KRas G12C inhibitor compound of formula (I), formula IA or formula IB or its pharmaceutically acceptable salt or pharmaceutical composition.In another embodiment, the CDK4 / 6 inhibitor or its pharmaceutically acceptable salt or pharmaceutical composition is administered after the administration of the KRas G12C inhibitor compound of formula (I), formula IA or formula IB or its pharmaceutically acceptable salt or pharmaceutical composition. In another embodiment, the CDK4 / 6 inhibitor, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered approximately simultaneously with the administration of the KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[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 CDK4 / 6 inhibitor, or its pharmaceutically acceptable salt or pharmaceutical composition, do not necessarily have to be administered essentially at the same time or in any order.In one embodiment, CDK4 / 6 inhibitor and KRAS G12C inhibitor are administered on the same day.In one embodiment, CDK4 / 6 inhibitor and KRAS G12C inhibitor are administered on different days.

[0087] Tumor drugs are usually administered at the 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 or its pharma- ceutically acceptable salt or pharmaceutical composition and the CDK4 / 6 inhibitor or its pharma- ceutically acceptable salt or pharmaceutical composition are each administered at their respective MTD. In one embodiment, the KRas G12C inhibitor or its pharma- ceutically acceptable salt or pharmaceutical composition is administered at its MTD, and the CDK4 / 6 inhibitor or its pharma- ceutically acceptable salt or pharmaceutical composition is administered at an amount less than its MTD. In one embodiment, the KRas G12C inhibitor or its pharma- ceutically acceptable salt or pharmaceutical composition is administered at an amount less than its MTD, and the CDK4 / 6 inhibitor or its pharma- ceutically acceptable salt or pharmaceutical composition is administered at its MTD. In one embodiment, the KRas G12C inhibitor or its pharmaceutically acceptable salt or pharmaceutical composition and the CDK4 / 6 inhibitor or its pharmaceutically acceptable salt or pharmaceutical composition are each administered at an amount less 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 compound.

[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 CDK4 / 6 inhibitor, or its pharma- ceutically acceptable salt or pharmaceutical composition, is administered once a day. In another embodiment, the CDK4 / 6 inhibitor, or its pharma- ceutically acceptable salt or pharmaceutical composition, is administered twice a day. In another embodiment, the CDK4 / 6 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 CDK4 / 6 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are each administered once daily.

[0091] Exemplary CDK4 / 6 inhibitors useful in the compositions and methods disclosed herein include abemaciclib (N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine); palbociclib (6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one) and ribociclib (7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1 These include 2'-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide), trilaciclib (2'-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one), and PF-06873600 (pyrido[2,3-d]pyrimidin-7(8H)-one, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1-(methylsulfonyl)-4-piperidinyl]amino]).

[0092] 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 CDK4 / 6 inhibitor or its pharmacologic acceptable salt or pharmaceutical composition and a KRAS G12C inhibitor of formula (I), formula IA, or formula IB or its pharmacologic 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.

[0093] 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 and a CDK4 / 6 inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the CDK4 / 6 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.

[0094] In one embodiment, the combination therapy comprises a compound having the formula [ka] or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor. In one embodiment, the CDK4 / 6 inhibitor is palbociclib. In one embodiment, the CDK4 / 6 inhibitor is abemaciclib.

[0095] In one embodiment, the combination therapy comprises a compound having the formula [ka] or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor. In one embodiment, the CDK4 / 6 inhibitor is palbociclib. In one embodiment, the CDK4 / 6 inhibitor is abemaciclib.

[0096] In one embodiment, the combination therapy comprises a compound having the formula [ka] or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor. In one embodiment, the CDK4 / 6 inhibitor is palbociclib. In one embodiment, the CDK4 / 6 inhibitor is abemaciclib.

[0097] In one embodiment, the combination therapy comprises a compound having the formula [ka] or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor. In one embodiment, the CDK4 / 6 inhibitor is palbociclib. In one embodiment, the CDK4 / 6 inhibitor is abemaciclib.

[0098] 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.

[0099] 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.

[0100] 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 CDK4 / 6 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 CDK4 / 6 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.

[0101] In one embodiment, a therapeutically effective amount of a CDK4 / 6 inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof in combination 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 therapeutically effective amount of a CDK4 / 6 inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof in combination 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, a combination of a therapeutically effective amount of a CDK4 / 6 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, a combination of a therapeutically effective amount of a CDK4 / 6 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 therapeutically effective amount of a CDK4 / 6 inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof in combination 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 CDK4 / 6 inhibitor is selected from palbociclib or abemaciclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and palbociclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and abemaciclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and palbociclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and abemaciclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and palbociclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and abemaciclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and palbociclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and abemaciclib.

[0102] In another embodiment, a CDK4 / 6 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 an enhanced clinical benefit in the patient by increasing OS, PFS, tumor regression, tumor growth inhibition, or duration of stable disease in the patient. 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 CDK4 / 6 inhibitor is selected from palbociclib or abemaciclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and palbociclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and abemaciclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and palbociclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and abemaciclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and palbociclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and abemaciclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and palbociclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and abemaciclib.

[0103] 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), anterior 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 osteoma, 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);Gynaecological: 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 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.;

[0104] 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 CDK4 / 6 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 CDK4 / 6 inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor. 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 CDK4 / 6 inhibitor is selected from palbociclib or abemaciclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and palbociclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and abemaciclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and palbociclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and abemaciclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and palbociclib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 478 and abemaciclib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and palbociclib. In one embodiment, the therapeutic combination comprises therapeutically effective amounts of Example No. 507 and abemaciclib.

[0105] 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,From about 30 mg to about 45 mg, from about 30 mg to about 40 mg, from about 30 mg to about 35 mg, from about 35 mg to about 100 mg, from about 35 mg to about 95 mg, from about 35 mg to about 90 mg, from about 35 mg to about 85 mg, from about 35 mg to about 80 mg, from about 35 mg to about 75 mg, from about 35 mg to about 70 mg, from about 35 mg to about 65 mg, from about 35 mg to about 60 mg, from about 35 mg to about 55 mg, from about 35 mg to about 50 mg, from about 35 mg to about 45 mg, from about 35 mg to about 40 mg, from about 40 mg to about 100 mg, from about 40 mg to about 95 mg, from about 40 mg to about 90 mg, from about 40 mg to about 85 mg, from about 40 mg to about 80 mg, from about 40 mg to about 75 mg, from about 40 mg to about 70 mg, from about 40 mg to about 65 mg, from about 40 mg to about 60 mg, from about 40 mg to about 55 mg, from about 40 mg to about 50 mg, from about 40 mg to about 45 mg, from about 45 mg to about 100 mg, from about 45 mg to about 95 mg, from about 45 mg to about 90 mg, from about 45 mg to about 85 mg, from about 45 mg to about 80 mg, from about 45 mg to about 75 mg, from about 45 mg to about 70 mg, from about 45 mg to about 65 mg, from about 45 mg to about 60 mg, from about 45 mg to about 55 mg, from about 45 mg to about 50 mg, from about 50 mg to about 100 mg, from about 50 mg to about 95 mg, from about 50 mg to about 90 mg, from about 50 mg to about 85 mg, from about 50 mg to about 80 mg, from about 50 mg to about 75 mg, from about 50 mg to about 70 mg, from about 50 mg to about 65 mg, from about 50 mg to about 60 mg, from about 50 mg to about 55 mg, from about 55 mg to about 100 mg, from about 55 mg to about 95 mg, from about 55 mg to about 90 mg, from about 55 mg to about 85 mg, from about 55 mg to about 80 mg, from about 55 mg to about 75 mg, from about 55 mg to about 70 mg, from about 55 mg to about 65 mg, from about 55 mg to about 60 mg, from about 60 mg to about 100 mg, from about 60 mg to about 95 mg, from about 60 mg to about 90 mg, from about 60 mg to about 85 mg, from about 60 mg to about 80 mg, from about 60 mg to about 75 mg, from about 60 mg to about 70 mg, from about 60 mg to about 65 mg, from about 65 mg to about 100 mg, from about 65 mg to about 95 mg, from about 65 mg to about 90 mg, from about 65 mg to about 85 mg, from about 65 mg to about 80 mg, from about 65 mg to about 75 mg, from about 65 mg to about 70 mg, from about 70 mg to about 100 mg, from about 70 mg to about 95 mg, from about 70 mg to about 90 mg, from about 70 mg to about 85 mg, from about 70 mg to about 80 mg, from about 70 mg to about 75 mg, from about 75 mg to about 100 mg, from about 75 mg to about 95 mg, from about 75 mg to about 90 mgApproximately 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 100mg, approximately 85 mg ~ about 95mg, about 85mg - about 90mg, about 90mg - about 100mg, about 90mg - about 95mg, about 95mg - about 100mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, The compound of formula I (e.g., a compound selected from compound numbers 1-678, e.g., compound numbers 234, 359, 478, or 507, as numbered in WO2019099524) of 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 the compound of formula I. 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 ~120mg, 20mg~100mg, 20mg~80mg, 20mg~60mg, 20mg~40mg, 40mg~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 40m g ~ about 380mg, about 40mg - about 360mg, about 40mg - about 340mg, about 40mg - about 320mg, about 40mg - about 300mg, about 40mg - about 2 80mg, 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 40 mg to about 160 mg, about 40 mg to about 140 mg, about 40 mg to about 120 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 500 mg, about 60 mg to about 480 mg, about 60 mg to about 460 mg, about 60 mg to about 440 mg, about 60 mg to about 420 mg, about 60 mg to about 400 mg, about 60 mg to about 380 mg, about 60 mg to about 360 mg, about 60 mg to about 340 mg, about 60 mg to about 320 mg, about 60 mg to about 300 mg, about 60 mg to about 280 mg, about 60 mg to about 260 mg, about 60 mg to about 240 mg, about 60 mg to about 220 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 500 mg, about 80 mg to about 480 mg, about 80 mg to about 460 mg, about 80 mg to about 440 mg, about 80 mg to about 420 mg, about 80 mg to about 400 mg, about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg 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 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 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,From about 120 mg to about 380 mg, from about 120 mg to about 360 mg, from about 120 mg to about 340 mg, from about 120 mg to about 320 mg, from about 120 mg to about 300 mg, from about 120 mg to about 280 mg, from about 120 mg to about 260 mg, from about 120 mg to about 240 mg, from about 120 mg to about 220 mg, from about 120 mg to about 200 mg, from about 120 mg to about 180 mg, from about 120 mg to about 160 mg, from about 120 mg to about 140 mg, from about 140 mg to about 500 mg, from about 140 mg to about 480 mg, from about 140 mg to about 460 mg, from about 140 mg to about 440 mg, from about 140 mg to about 420 mg, from about 140 mg to about 400 mg, from about 140 mg to about 380 mg, from about 140 mg to about 360 mg, from about 140 mg to about 340 mg, from about 140 mg to about 320 mg, from about 140 mg to about 300 mg, from about 140 mg to about 280 mg, from about 140 mg to about 260 mg, from about 140 mg to about 240 mg, from about 140 mg to about 220 mg, from about 140 mg to about 200 mg, from about 140 mg to about 180 mg, from about 140 mg to about 160 mg, from about 160 mg to about 500 mg, from about 160 mg to about 480 mg, from about 160 mg to about 460 mg, from about 160 mg to about 440 mg, from about 160 mg to about 420 mg, from about 160 mg to about 400 mg, from about 160 mg to about 380 mg, from about 160 mg to about 360 mg, from about 160 mg to about 340 mg, from about 160 mg to about 320 mg, from about 160 mg to about 300 mg, from about 160 mg to about 280 mg, from about 160 mg to about 260 mg, from about 160 mg to about 240 mg, from about 160 mg to about 220 mg, from about 160 mg to about 200 mg, from about 160 mg to about 180 mg, from about 180 mg to about 500 mg, from about 180 mg to about 480 mg, from about 180 mg to about 460 mg, from about 180 mg to about 440 mg, from about 180 mg to about 420 mg, from about 180 mg to about 400 mg, from about 180 mg to about 380 mg, from about 180 mg to about 360 mg, from about 180 mg to about 340 mg, from about 180 mg to about 320 mg, from about 180 mg to about 300 mg, from about 180 mg to about 280 mg, from about 180 mg to about 260 mg, from about 180 mg to about 240 mg, from about 180 mg to about 220 mg, from about 180 mg to about 200 mg, from about 200 mg to about 500 mg, from about 200 mg to about 480 mg, from about 200 mg to about 460 mg, from about 200 mg to about 440 mg, from about 200 mg to about 420 mg, from about 200 mg to about 400 mg, from about 200 mg to about 380 mgAbout 200 mg to about 360 mg, about 200 mg to about 340 mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about 200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about 220 mg, about 220 mg to about 500 mg, about 220 mg to about 480 mg, about 220 m g ~ about 460 mg, about 220 mg to about 440 mg, about 220 mg to about 420 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about 280 mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about 500 mg, about 240 mg to about 480 mg, about 240 mg to about 460 mg, about 240 mg to about 440 mg, about 240 mg to about 420 mg, about 240 mg to about 400 mg, about 240 mg to about 380 mg, about 240 mg to about 360 mg, about 240 mg to about 340 mg, about 240 mg to about 320 mg, about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 500 mg, about 260 mg to about 480 mg, about 260 mg to about 460 mg, about 260 mg to about 440 mg, about 260 mg to about 420 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 500 mg, about 280 mg to about 480 mg, about 280 mg to about 460 mg, about 280 mg to about 440 mg, about 280 mg to about 420 mg, about 280 mg to about 400 mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about 340 mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg, about 300 mg to about 500 mg, about 300 mg to about 480 mg, about 300 mg to about 460 mg, about 300 mg to about 440 mg, about 300 mg to about 420 mg, about 300 mg to about 400 mg, about 300 mg to about 380 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 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,Approximately 340mg to approximately 420mg, approximately 340mg to approximately 400mg, 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 360 mg ~ about 400mg, about 360mg - about 380mg, about 380mg - about 500mg, about 380mg - about 480mg, about 380mg - about 460mg, about 380mg - about 440mg, about 380mg - about 420mg, about 380mg - about 400mg, about 400mg - about 500mg, about 400mg - about 480 mg, about 400 mg to about 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.

[0106] 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 80 mg to about 400 mg, about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg 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 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 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 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 400 mg,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 CDK4 / 6 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.

[0107] 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.

[0108] 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, can be completed according to methods well known in the clinical and medical arts.

[0109] Synergy In one embodiment, the addition of a CDK4 / 6 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, synergistically increases the activity of the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, 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.

[0110] 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 CDK4 / 6 inhibitor.

[0111] 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.

[0112] In some embodiments, "synergy" as used herein refers to a combination of a KRAS inhibitor or a pharma- ceutically acceptable salt thereof with a CDK4 / 6 inhibitor or a pharma- ceutically acceptable salt thereof that produces a beneficial or desired result, including, for example, any of the clinical outcomes or endpoints described herein, that is greater than the sum of the effects observed when the compound of formula I or a pharma- ceutically acceptable salt thereof (e.g., a compound selected from compound numbers 1-678 (as numbered in WO2019 / 099524), or a pharma- ceutically acceptable salt thereof) and the CDK4 / 6 inhibitor or a pharma- ceutically acceptable salt thereof are administered 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 CDK4 / 6 inhibitor is selected from palbociclib or abemaciclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and palbociclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 234 and abemaciclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and palbociclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 359 and abemaciclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and palbociclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 478 and abemaciclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and palbociclib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example No. 507 and abemaciclib.

[0113] 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).

[0114] 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.

[0115] 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).

[0116] 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).

[0117] kit The present invention also relates to a kit comprising a CDK4 / 6 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 (e.g., a compound selected from Example Nos. 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). A kit comprising a CDK4 / 6 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, is also provided for use in treating hematological cancers.

[0118] In a related aspect, the invention provides a kit comprising a dose of a CDK4 / 6 inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof and a dose of a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB (e.g., a compound selected from Example Nos. 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 an amount effective to inhibit proliferation of cancer cells, particularly cancer cells expressing KRas G12C, in a subject. The kit optionally includes an insert comprising instructions for administration of the CDK4 / 6 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 include a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharma- ceutically acceptable salt thereof. The user may be provided with a set of instructions for using the CDK4 / 6 inhibitor in combination with the G12C inhibitor compound.

[0119] Example A CDK4 / 6 inhibitors synergistically increase the activity of KRas G12C inhibitors against cell lines expressing KRas G12C. This example shows that the combination of exemplary KRas G12C inhibitor compounds of Formula I, Formula IA, and Formula IB with CDK4 / 6 inhibitors synergistically inhibits the growth of tumor cell lines expressing KRas G12C.

[0120] To determine whether combining a CDK4 / 6 inhibitor with an exemplary KRas G12C inhibitor disclosed herein results in synergistic activity, a panel of eight lung cancer and one colorectal cell line harboring the KRas G12C mutation was assembled. The collection included NCI-H1373 (ATCC CRL-5866; CDKN2A C72 mutation); NCI-H1792 (ATCC CRL-5895; CDK4 amplification); NCI-H2030 (ATCC CRL-5985); NCI-H2122 (ATCC CRL-5985; CDKN2A deletion; CDK6 amplification); HCC1171 (KCLB 71171; CDKN2A deletion); HCC44 (DSMZ ACC-534); LU99 (RCB1900; CDKN2A deletion); SW1573 (ATCC CRL-2170; CDKN2A deletion), and SW837 (ATCC CCL-235).

[0121] Assays to determine synergy scores for each cell line pairwise combination were performed in triplicate. Three 96-well plates for determining baseline luminescence and an additional four wells of a separate 96-well control plate were 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 were incubated at 4°C for 30 min at 5% CO 2 The mixture was incubated overnight at 37°C in air.

[0122] For each of the designated baseline wells, 30 μl of Cell-Titer Glo reagent (CTG; Promega Corporation) was added to each well and the plate was incubated for 20 min with shaking at room temperature. Baseline luminescence was quantified using a BMG ClarioStar multimode plate reader according to the manufacturer's instructions.

[0123] A series of working stock 1000X drug dilutions in 100% DMSO were prepared, including 8-point single agent dilutions of exemplary KRas G12C inhibitors of Formula (I), Formula IA, and Formula IB, and 5-point single agent dilutions of CDK4 / 6 inhibitors. The dilutions used for the KRas G12C inhibitors and CDK4 / 6 inhibitors varied for each individual compound, but ranged from 3-6 fold / serial dilution.

[0124] Exemplary KRasG12C inhibitors tested in this example include the following: [Table 1]

[0125] A 10X intermediate dose plate was prepared in serum-free RPMI medium containing an array of single agent dilutions of an exemplary KRas G12C inhibitor of formula (I) or a CDK4 / 6 inhibitor. In addition, 40 matrix dilution combinations of an exemplary KRas G12C inhibitor of formula (I), formula IA, or formula IB and a CDK4 / 6 inhibitor were prepared as test samples.

[0126] Add 10 μl of each 10X single agent and dose matrix combination to each corresponding well of three 96-well plates seeded with the appropriate cell line above and incubate the plates at 37°C, 5% CO. 2 The plates were incubated at room temperature for 72 hours at room temperature for 30 minutes and incubated at room temperature for 30 minutes at room temperature for 30 minutes. The plates were incubated at room temperature for 20 minutes at room temperature for 30 minutes and incubated at room temperature for 30 minutes ...

[0127] Using the raw data and metadata files as input files, effect rates for each treatment condition were 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.

[0128] The data output from each mathematical model is the assignment of a relative synergy score. The data reported in Table 1 are the sum of Loewe additivity, Bliss independence, best single agent, and ZIP score ("composite synergy score"). [Table 2]

[0129] A combined score of 27 or greater was interpreted as a synergistic hit, whereas a combined score of 17-26 indicates potential synergy. These results indicate that synergy was observed in combination with various CDK4 / 6 family inhibitors and the exemplary KRas G12C inhibitor compounds of Formula (I), Formula IA, and Formula IB in the majority of cell lines harboring the KRas G12C mutation in Table 1 that were less sensitive to treatment with KRas G12C alone, thereby increasing the sensitivity of the KRas G12C cell lines to the combination of KRas G12C inhibitors.

[0130] Example B In vivo model to investigate the combination of KRas G12C and CDK4 / 6 inhibitors Immunodeficient nude / nude mice were inoculated into the right hind limb with cells carrying the KRas G12C mutation or tumor samples from patients. 3When 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 CDK4 / 6 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 CDK4 / 6 inhibitor. The duration of treatment varied for each cell line, but was typically 21-35 days. Tumor volumes were measured using calipers every 2-3 days and tumor volume was calculated using the formula: 0.5 x (length x width) 2 The greater degree of tumor growth inhibition of the combination in this model indicated that the combination therapy is likely to provide clinically meaningful benefit to treated subjects compared with treatment with a KRas G12C inhibitor alone.

[0131] For example, 5 × 10 6 SW1573 cells were inoculated into the right hind leg. The tumor volume was approximately 350 mm 3 When tumor volume reached 0 (study day 0), seven mice in each of the four groups were orally administered vehicle alone (10% Captisol in 50 mM citrate buffer, pH 5.0), 100 mg / kg of the KRAS G12C inhibitor Compound 478 (10% Captisol in 50 mM citrate buffer, pH 5.0), 130 mg / kg of the CDK4 / 6 inhibitor Palbociclib (saline), or 100 mg / kg of the KRas G12C inhibitor Compound 478 and 130 mg / kg of Palbociclib daily for 28 days. Tumor volumes measured at pre-specified days for the seven mice per group were averaged and are reported in Table 2. [Table 3]

[0132] As shown in Table 2, administration of compound 478 or palbociclib as single agents showed 71% and 40% tumor growth inhibition, respectively, at day 28. The combination of the CDK4 / 6 inhibitor palbociclib with compound 478 resulted in 58% tumor regression at day 28.

[0133] Similarly, 20 nude / nude mice were inoculated with 5 × 10 6 H2122 cells were inoculated into the right hind leg. The tumor volume was approximately 325 mm 3 When tumor volume reached 0 (study day 0), five mice in each of the four groups were orally administered vehicle alone (10% Captisol in 50 mM citrate buffer, pH 5.0), 100 mg / kg of the KRAS G12C inhibitor Compound 478 (10% Captisol in 50 mM citrate buffer, pH 5.0), 130 mg / kg of the CDK4 / 6 inhibitor Palbociclib (saline), or 100 mg / kg of the KRas G12C inhibitor Compound 478 and 130 mg / kg of Palbociclib daily for 21 days. Tumor volumes measured at prespecified days for five mice per group were averaged and are reported in Table 3. [Table 4]

[0134] As shown in Table 3, administration of compound 478 or palbociclib as single agents showed 85% and 65% tumor growth inhibition, respectively, at day 23. The combination of the CDK4 / 6 inhibitor palbociclib with compound 478 resulted in 56% tumor regression at day 23.

[0135] In a separate experiment, on day 0, 20 nude / nude mice were inoculated with 5 × 10 6 LU6405 cells were inoculated into the right hind leg. The tumor volume was approximately 350 mm 3When tumor volume reached 100 mg / kg (study day 1), five mice in each of the four groups were orally administered vehicle alone (10% Captisol in 50 mM citrate buffer, pH 5.0), 100 mg / kg of the KRAS G12C inhibitor Compound 478 (10% Captisol in 50 mM citrate buffer, pH 5.0), 130 mg / kg of the CDK4 / 6 inhibitor Palbociclib (saline), or 100 mg / kg of the KRas G12C inhibitor Compound 478 and 130 mg / kg of Palbociclib daily for 21 days. Tumor volumes measured on prespecified days for five mice per group were averaged and are reported in Table 4. [Table 5]

[0136] As shown in Table 4, administration of compound 478 resulted in 96% tumor growth inhibition at day 24. Combination of the CDK4 / 6 inhibitor palbociclib with compound 478 resulted in 77% tumor regression at day 24.

[0137] These results show that the combination therapy resulted in a greater amount of tumor growth inhibition compared to either single agent alone, indicating an enhanced in vivo antitumor effect of the combination against KRas G12C-expressing cancers.

[0138] 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) a CDK4 / 6 inhibitor selected from the group consisting of abemaciclib, palbociclib, ribociclib, trilaciclib, and PF-06873600; and b) 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 CDK4 / 6 inhibitor is abemaciclib.

3. 2. The pharmaceutical composition of claim 1, wherein the CDK4 / 6 inhibitor is palbociclib.

4. 2. The pharmaceutical composition of claim 1, wherein the CDK4 / 6 inhibitor is ribociclib.

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the CDK4 / 6 inhibitor and the KRAS G12C inhibitor are administered on the same day.

6. The pharmaceutical composition of any one of claims 1 to 4, wherein the CDK4 / 6 inhibitor and the KRAS G12C inhibitor are administered on different days.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the KRas G12C inhibitor is administered at a maximum tolerated dose.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the CDK4 / 6 inhibitor and the KRAS G12C inhibitor are each administered at their maximum tolerated doses.

9. 9. The pharmaceutical composition of any one of claims 1 to 8, wherein a therapeutically effective amount of a combination of said CDK4 / 6 inhibitor and said 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 said subject compared to treatment with said KRas G12C inhibitor alone.

10. 1. A pharmaceutical composition for treating cancer in a subject, comprising: a therapeutically effective amount of: a) a CDK4 / 6 inhibitor selected from the group consisting of abemaciclib, palbociclib, ribociclib, trilaciclib, and PF-06873600; and b) a KRas G12C inhibitor of the formula: 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

11. 1. A pharmaceutical composition for use in a method for inhibiting KRas G12C activity in a cell, comprising: The method comprises treating the cell in which inhibition of KRas G12C activity is desired with an effective amount of a) a CDK4 / 6 inhibitor selected from the group consisting of abemaciclib, palbociclib, ribociclib, trilaciclib, and PF-06873600, and b) a KRas G12C inhibitor compound of the formula: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof, the pharmaceutical composition comprises the CDK4 / 6 inhibitor and / or the KRas G12C inhibitor compound, or a pharma- ceutically acceptable salt thereof; A pharmaceutical composition, wherein said CDK4 / 6 inhibitor synergistically increases the sensitivity of a cancer cell to said KRas G12C inhibitor.

12. The pharmaceutical composition of any one of claims 1 to 11, wherein the CDK4 / 6 inhibitor synergistically increases the sensitivity of cancer cells to the KRas G12C inhibitor.

13. 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 pharmaceutically acceptable salt thereof, administering to a subject undergoing KRas G12C therapy a therapeutically effective amount of a CDK4 / 6 inhibitor selected from the group consisting of abemaciclib, palbociclib, ribociclib, trilaciclib, and PF-06873600; the pharmaceutical composition comprises the CDK4 / 6 inhibitor, A pharmaceutical composition, wherein said CDK4 / 6 inhibitor synergistically increases the sensitivity of a cancer cell to said KRas G12C inhibitor.

14. The pharmaceutical composition of any one of claims 1 to 13, wherein the therapeutically effective amount of the KRas G12C inhibitor in the combination is about 0.01 to 100 mg / kg / day.

15. 15. The pharmaceutical composition of claim 14, wherein the therapeutically effective amount of the KRas G12C inhibitor in the combination is about 0.1 to 50 mg / kg / day.

16. 16. The pharmaceutical composition of any one of claims 1 to 15, wherein the therapeutically effective amount of the CDK4 / 6 inhibitor in the combination is about 0.01 to 100 mg / kg / day.

17. 17. The pharmaceutical composition of claim 16, wherein the therapeutically effective amount of the CDK4 / 6 inhibitor in the combination is about 0.1 to 50 mg / kg / day.

18. 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 (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), marrow Membranes (meningiomas, meningeal sarcomas, 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 tumor, cell 18. The pharmaceutical composition according to any one of claims 1 to 9 and 11 to 17, wherein the therapeutic agent is selected from the group consisting of: tri-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.

19. 19. The pharmaceutical composition of claim 18, wherein the cancer is non-small cell lung cancer.

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