Combination therapy

Abstract

The present invention relates to combination therapies for treating KRas G12C cancer. Specifically, the present invention relates to methods for treating cancer in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a pan-ErbB family inhibitor in combination with a KRAS G12C inhibitor of Formula (I), Formula I-A or Formula I-B; pharmaceutical compositions comprising a therapeutically effective amount of the inhibitor, kits comprising the composition, and methods of use thereof.

Description

Technical Field

[0001] The present invention relates to combination therapies that can be used to treat cancer. Specifically, the present invention relates to therapeutically effective combinations of pan-ErbB family inhibitors and KRas G12C inhibitors, pharmaceutical compositions comprising the inhibitors, kits comprising the compositions, and methods of use thereof. Background Art

[0002] Kirsten Rat Sarcoma 2 viral oncogene homolog ("KRas") is a member of the small GTPase and Ras oncogene family. KRas acts as a molecular switch cycling between an inactive (GDP-bound) state and an active (GTP-bound) state to convert upstream cellular signals received from multiple tyrosine kinases into downstream effectors that 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 malignant diseases was observed more than three decades 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 at codons 12 and 13 of the KRas primary amino acid sequence account for approximately 40% of these KRas driver gene mutations in lung adenocarcinoma, with the G12C transversion being the most common activating mutation (e.g., see Dogan et al. (2012) Clin Cancer Res. 18(22):6169-6177, published online Sept. 26, 2012. doi:10.1158 / 1078-0432.CCR-11-3265).

[0004] The well-known role of KRas in malignant diseases and the discovery of these frequent mutations of KRas in various tumor types make KRas a highly attractive target for cancer therapy by the pharmaceutical industry. Despite three decades of extensive discovery efforts to develop KRas inhibitors for the treatment of cancer, KRas inhibitors do not exhibit safety and / or efficacy sufficient to obtain regulatory approval (e.g., see McCormick (2015) Clinical Cancer Research 21(8): 1797-1801).

[0005] Compounds that inhibit KRas activity remain highly desirable and under investigation, including compounds that disrupt effectors such as guanine nucleotide exchange factors (see, e.g., Sun et al., (2012) AgnewChem Int Ed Engl. 51(25):6140-6143 doi:10.1002 / anie201201358) and compounds that target KRasG12C (see, e.g., Ostrem et al., (2013) Nature 503:548-551). Clearly, there remains a continued interest and effort in developing KRas inhibitors, particularly inhibitors of activated KRas mutants including KRas G12C.

[0006] Although the KRas G12C inhibitors disclosed herein are potent inhibitors of KRas G12C enzymatic activity and exhibit single agent activity that inhibits in vitro proliferation of cell lines with KRas G12C mutations, the relative potency and / or maximum observed effect of any given KRas G12C inhibitor may vary between KRAS mutant cell lines. One or more reasons for the range of potency and maximum observed effect are not fully understood, but specific cell lines appear to have different intrinsic tolerances. Therefore, 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 aspect, the combination therapy of the invention synergistically increases the potency of the KRas G12C inhibitor, resulting in improved efficacy of the KRas G12C inhibitor disclosed herein. In another aspect, the combination therapy of the invention provides improved clinical benefit to patients compared to treatment with the KRas G12C inhibitor disclosed herein as a single agent. Summary of the invention

[0008] In one aspect of the present invention, provided herein is a method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a pan-ErbB family inhibitor and a KRAS G12C inhibitor of formula (I):

[0009]

[0010] or a combination of pharmaceutically acceptable salts thereof, wherein:

[0011] X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted by one or more R 8 replace;

[0012] Y is a bond, O, S or NR 5 ;

[0013] R 1 -C(O)C(R A ) C(R B ) p or -SO2C(R A ) C(R B ) p ;

[0014] R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, -Z-NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaromatic or heteroaromaticalkyl, wherein each of Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaromatic and heteroaromaticalkyl may be optionally replaced by one or more R 9 replace;

[0015] Z is C1-C4 alkylene;

[0016] Each R 3 are independently C1-C3 alkyl, oxo or haloalkyl;

[0017] L is a bond, -C(O)- or C1-C3 alkylene;

[0018] R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaromatic, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaromatic may be optionally replaced by one or more R 6 or R 7 replace;

[0019] Each R 5 are independently hydrogen or C1-C3 alkyl;

[0020] R 6is a cycloalkyl, a heterocyclyl, a heterocyclylalkyl, an aryl or a heteroaromatic group, wherein each of the cycloalkyl, heterocyclyl, aryl or heteroaromatic group may be optionally replaced by one or more R 7 replace;

[0021] Each R 7 are independently halogen, hydroxy, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;

[0022] R 8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -C(O)OR 5 、-C(O)N(R 5 )2、-N(R 5 ) 2, wherein the C1-C3 alkyl group may be optionally substituted by cyano, halogen, -OR 5 、-N(R 5 )2 or heteroaromatic substituted

[0023] Each R 9 are independently hydrogen, oxo, acyl, hydroxy, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylamino, dialkylamidoalkyl or dialkylaminoalkyl, wherein the C1-C6 alkyl may be optionally substituted with cycloalkyl;

[0024] Each R 10 are independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl or hydroxyalkyl;

[0025] R 11 is a haloalkyl group;

[0026] R A does not exist, is hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 )2 or hydroxyalkyl;

[0027] Each R B are independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR 5 R 11 、-C(O)N(R 5)2, -NHC(O)C1-C3 alkyl, -CH2NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminoalkyl or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxy, alkoxy and C1-C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R 7 replace;

[0028] m is zero or an integer between 1 and 2;

[0029] p is one or two; and wherein,

[0030] when When it is a triple bond, R A Does not exist, R B exists and p is equal to one,

[0031] or when When it is a double bond, R A Existence, R B exists and p is equal to two, or R A , R B and the carbon atom to which it is attached form a 7 Substituted 5-8 membered partially saturated cycloalkyl.

[0032] Also included are KRas G12C inhibitor compounds of Formula I having Formula IA for use in the methods provided herein:

[0033]

[0034] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , R 4 , R 5 , R 10 , R 11 , L and m are as defined for Formula I, and the piperazinyl ring is optionally replaced by R 8 Substitution, where R 8 As defined for Formula I.

[0035] Also included are KRas G12C inhibitor compounds of Formula IB for use in the methods provided herein:

[0036]

[0037] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , R 4 , L and m are as defined for Formula I, R2 is optionally represented by one or more R 9 Substituted heterocyclylalkyl, wherein R 9 As defined for formula I, and the piperazinyl ring is optionally replaced by R 8 Substitution, where R 8 As defined for Formula I.

[0038] In another aspect of the present invention, a pharmaceutical composition for use in the method is provided, comprising a therapeutically effective amount of a pan-ErbB family inhibitor in combination with a KRas G12C inhibitor compound of Formula I, Formula IA or Formula 1-B or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0039] In one aspect of the invention, provided herein is a method for treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a pan-ErbB family inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRAS G12C inhibitor of Formula (I), Formula IA or Formula IB or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In one embodiment, the cancer is a KRas G12C-related cancer. In one embodiment, the KRas G12C-related cancer is lung cancer.

[0040] In some aspects of the invention, the KRas G12C inhibitor compound and the pan-ErbB family inhibitor are the only active agents in the provided compositions and methods.

[0041] In one embodiment, the pan-ErbB family inhibitor is an irreversible inhibitor. Examples of irreversible pan-ErbB family inhibitors suitable for use in the provided compositions and methods include, but are not limited to, Afatinib; Dacomitinib; Canertinib; Poziotinib, AV 412; PF 6274484 and HKI 357.

[0042] In one embodiment, the pan-ErbB family inhibitor is a reversible inhibitor. Examples of reversible pan-ErbB family inhibitors suitable for use in the provided compositions and methods include, but are not limited to, erlotinib, gefitinib, sapitinib; varlitinib; TAK-285 (N-[2-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]phenylamino]-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-3-hydroxy-3-methylbutanamide); AEE788 (6-[4-(4-ethylpiperazin-1-ylmethyl)phenyl]-N-[1(R)-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine); tarloxotinib (3-[N-[4-(3-bromo-4-chlorophenylamino)pyrido[3,4-d]pyrimidin-6-yl]carbamoyl]-N,N-dimethyl-N-(1-methyl-4-nitro-1H-imidazol-5-ylmethyl)-2(E)-propen-1-aminium bromide); BMS 599626 / AC-480 (morpholin-3(S)-ylmethyl N-[4-[1-(3-fluorobenzyl)-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamate hydrochloride); and GW 583340 HCl (N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[2-[2-(methylsulfonyl)ethylaminomethyl]thiazol-4-yl]quinazolin-4-amine).

[0043] In one embodiment, the pan-ErbB family inhibitor is a combination of an EGFR inhibitor and a HER2 inhibitor, wherein the EGFR inhibitor and the HER2 inhibitor are a combination of two of the following: AG 1478 (N-(3-chlorophenyl)-6-methoxy-7-[11C]methoxyquinazolin-4-amine); AG 555 (2-cyano-3-(3,4-dihydroxyphenyl)-N-(3-phenylpropyl)-2(E)-acrylamide); AG 556 ((E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-(4-phenylbutyl)acrylamide); AG 825 (3-[3-(benzothiazol-2-ylsulfanylmethyl)-4-hydroxy-5-methoxyphenyl]-2-cyano-2-acrylamide); CP 724714 (2-methoxy-N-[3-[4-[3-methyl-4-(6-methylpyridin-3-yloxy)phenylamino]quinazolin-6-yl]-2(E)-propenyl]acetamide); BIBU 1361 (N-(3-chloro-4-fluorophenyl)-6-[4-(diethylaminomethyl)piperidin-1-yl]pyrimido[5,4-d]pyrimidin-4-amine); BIBU 1382; JNJ 28871063 ((E)-4-amino-6-[4-(benzyloxy)-3-chlorophenylamino]pyrimidine-5-carbaldehyde O-[2-(4-morpholinyl)ethyl]oxime); PD 153035 (4-(3-bromophenylamino)-6,7-dimethoxyquinazoline); and PD 158780 (N 4 -(3-Bromophenyl)-N 6 -methyl-pyrido[3,4-d]pyrimidine-4,6-diamine).

[0044] In one embodiment, the pan-ErbB family inhibitor is an anti-EGFR antibody, an anti-HER2 antibody, or a combination of an anti-EGFR antibody and an anti-HER2 antibody. Antibodies, including monoclonal antibodies, antibody conjugates, and bispecific antibodies targeting EGFR and / or HER2 are well known, and a variety of antibodies are commercially available for research and human clinical use.

[0045] Examples of anti-EGFR antibodies suitable for use in the compositions and methods provided include necitumumab, panitumumab, and cetuximab. Examples of anti-HER2 antibodies suitable for use in the compositions and methods provided include pertuzumab, trastuzumab, and trastuzumab emtansine.

[0046] In yet another aspect, the present invention provides a method for increasing the sensitivity of cancer cells to KRas G12C inhibitors, the method comprising contacting cancer cells with a therapeutically effective amount of a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a combination of a pan-ErbB family inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the pan-ErbB family inhibitor synergistically increases the sensitivity of cancer cells to the KRas G12C inhibitor. In one embodiment, the contact is performed in vitro. In one embodiment, the contact is performed in vivo.

[0047] Also provided herein are methods of treating cancer in an individual in need thereof, the methods comprising (a) determining that the cancer is associated with a KRasG12C mutation (e.g., a KRas G12C-associated cancer) (e.g., determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit); and (b) administering to the patient a therapeutically effective amount of a pan-ErbB family inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in combination with a KRas G12C inhibitor compound of Formula I, Formula IA, or Formula 1-B, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the pan-ErbB family inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor.

[0048] Also provided herein are kits comprising a pan-ErbB inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula IA or formula IB or a pharmaceutically acceptable salt or pharmaceutical composition thereof. Also provided are kits comprising a pan-ErbB family inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula IA or formula IB or a pharmaceutically acceptable salt or pharmaceutical composition thereof for treating KRas G12C cancer.

[0049] In a related aspect, the present invention provides a kit containing a certain dose of a pan-ErbB inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula IA or formula IB or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the dose is an amount effective to inhibit the proliferation of cancer cells in an individual. In some cases, the kit includes instructions for administering a pan-ErbB family inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula IA or formula IB or a pharmaceutically acceptable salt or pharmaceutical composition thereof. The instructions can provide a user with a set of instructions for using a combination of a pan-ErbB family inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula IA or formula IB or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0050] In some embodiments of any of the methods described herein, prior to treatment with a composition or method of the invention, the patient was treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, and optionally, the previous treatment was unsuccessful; and / or surgery has been administered to the patient, and optionally, the surgery was unsuccessful; and / or the patient has been treated with a platinum-based chemotherapeutic agent, and optionally, the patient has been previously determined to be non-responsive to treatment with the platinum-based chemotherapeutic agent; and / or the patient has been treated with a kinase inhibitor, and optionally, the previous treatment with the kinase inhibitor was unsuccessful; and / or the patient is treated with one or more other therapeutic agents. DETAILED DESCRIPTION

[0051] The present invention relates to a combination therapy for treating KRas G12C cancer. Specifically, the present invention relates to a method for treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a pan-ErbB family inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRAS G12C inhibitor of Formula (I), Formula IA or Formula IB or a pharmaceutically acceptable salt or pharmaceutical composition thereof; each individually comprising a therapeutically effective amount of the inhibitor, a kit comprising the composition, and a method of using the same.

[0052] The combination of a pan-ErbB family inhibitor and a KRasG12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, synergistically increases the potency of the KRasG12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, against cancer cells expressing KRasG12C, thereby increasing the efficacy and therapeutic index of the KRasG12C inhibitor compound of Formula (I), Formula IA or Formula IB and a pharmaceutically acceptable salt thereof.

[0053] definition

[0054] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. All patents, patent applications and publications cited herein are incorporated by reference.

[0055] As used herein, "KRas G12C" refers to a mutant form of the mammalian KRas protein containing an amino acid substitution of cysteine ​​for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Gly12Cys.

[0056] As used herein, "KRas G12C inhibitor" refers to compounds of the present invention represented by formula (I), formula IA and formula IB as described herein and pharmaceutically acceptable salts thereof. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12C. The KRas G12C inhibitor of the present invention interacts with KRas G12C and irreversibly binds thereto by forming a covalent adduct with the sulfhydryl side chain of the cysteine ​​residue at position 12, causing inhibition of the enzymatic activity of KRasG12C. In one embodiment, the KRas G12C inhibitor is a compound selected from compounds Nos. 1-678 (numbered in WO2019099524) or a pharmaceutically acceptable salt thereof (e.g., Examples No. 234, 359, 478 or 507 or pharmaceutically acceptable salts thereof).

[0057] As used herein, "KRas G12C-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12C mutation. A non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12C-associated cancer.

[0058] As used herein, "ErbB family" or "ErbB family member" refers to members of the mammalian transmembrane protein tyrosine kinase family including: EGFR, ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4).

[0059] As used herein, "pan-ErbB family inhibitor" refers to an agent, such as a compound or antibody, that is capable of negatively regulating or inhibiting all or a portion of the activity of at least one member of the ErbB family. Regulation or inhibition of one or more ErbB family members can occur by regulating or inhibiting the kinase enzyme activity of one or more ErbB family members or by blocking homodimerization or heterodimerization of ErbB family members. In some embodiments of the methods herein, the term "pan-ErbB inhibitor" refers to the use of a single pan-ErbB inhibitor. In some embodiments of the methods herein, the term "pan-ErbB inhibitor" refers to the use of two pan-ErbB inhibitors.

[0060] As used herein, the terms "subject" or "patient" used interchangeably refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the individual has experienced and / or exhibits at least one symptom of a disease or condition to be treated and / or prevented. In some embodiments, the individual has been identified or diagnosed as having a cancer with a KRas G12C mutation (e.g., using an assay or kit approved by a regulatory agency, such as FDA-approved). In some embodiments, the individual has a tumor that is positive for a KRas G12C mutation (e.g., using an assay or kit approved by a regulatory agency, such as FDA-approved). The individual can be an individual with one or more tumors that are positive for a KRas G12C mutation (e.g., using an assay or kit approved by a regulatory agency, such as FDA-approved to identify positive). The individual can be an individual whose tumor has a KRas G12C mutation (e.g., wherein a tumor is identified as having a KRas G12C mutation using a kit or assay approved by a regulatory agency, such as FDA-approved). In some embodiments, the individual is suspected of having a KRas G12C gene-related cancer. In some embodiments, the individual has a clinical record indicating that the individual has a tumor with a KRas G12C mutation (and optionally, the clinical record indicates that the individual should be treated with any of the compositions provided herein).

[0061] As used herein, the term "pediatric patient" refers to a patient under the age of 16 at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups, including: neonates (from birth to the first month of life); infants (1 month to two years); children (two years to 12 years); and adolescents (12 years to 21 years (up to but not including the twenty-second 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.

[0062] In some embodiments of any of the methods or uses described herein, an assay for determining whether a patient has a KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample)) from a patient (e.g., a patient suspected of having a KRas G12C-related cancer, a patient having one or more symptoms of a KRas G12C-related cancer, and / or a patient with an increased risk of developing a KRas G12C-related cancer) is used, which 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, for example, with at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0063] The term "regulatory agency" is a national agency that approves the medical use of a pharmaceutical agent in a country. For example, a non-limiting example of a regulatory agency is the US Food and Drug Administration (FDA).

[0064] The term "amino" refers to -NH2;

[0065] The term "acyl" refers to -C(O)CH3.

[0066] As used herein, the term "alkyl" refers to a straight chain and branched aliphatic group 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 one, two or three substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

[0067] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by a halogen. Examples of haloalkyl are trifluoromethyl, difluoromethyl and fluoromethyl.

[0068] The term "haloalkoxy" refers to an -O-haloalkyl group.

[0069] "Alkylene" is an alkyl group as defined above that is located between and serves to connect two other chemical groups. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0070] The term "alkoxy" refers to an -OC1-C6 alkyl group.

[0071] The term "cycloalkyl" as used herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, such as 3 to 8 carbons and further such as 3 to 6 carbons, wherein the cycloalkyl is additionally optionally substituted. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0072] The term "heteroalkyl" refers to an alkyl group as defined above wherein one or more carbon atoms in the chain are replaced by a heteroatom selected from the group consisting of O, S and N.

[0073] The term "hydroxyalkyl" as used herein refers to an -alkyl-OH group.

[0074] The term "dihydroxyalkyl" refers to an alkyl group as defined herein wherein two carbon atoms are each substituted with hydroxy groups.

[0075] The term "alkylamino" refers to -NR x -alkyl, where R x In one embodiment, R x For hydrogen.

[0076] The term "dialkylamino" refers to -N(R y )2, where each R y It is a C1-C3 alkyl group.

[0077] The term "alkylaminoalkyl" refers to an -alkyl-NR x -alkyl, where R x In one embodiment, Rx For hydrogen.

[0078] The term "dialkylaminoalkyl" refers to an -alkyl-N(R y )2, where each R y is a C1-C4 alkyl group, wherein --alkyl-N(R y The alkyl group of )2 may be optionally substituted with a hydroxyl group or a hydroxyalkyl group.

[0079] "Aryl" is an optionally substituted C6-C 14 As an example, the aromatic group is C6-C 10 Aryl. Examples of aromatic groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl.

[0080] "Aralkyl" or "arylalkyl" comprises an aromatic group covalently linked to an alkyl group, either of which may independently be optionally substituted or unsubstituted. Examples of aralkyl groups are (C1-C6)alkyl (C6-C 10 ) aryl groups, including but not limited to benzyl, phenethyl and naphthylmethyl. An example of a substituted aralkyl group is one in which the alkyl group is substituted with a hydroxyalkyl group.

[0081] "Heterocyclyl" or "heterocyclic group" is a ring structure having about 3 to about 12 atoms, for example 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O and S, and the rest of the ring atoms are carbon. The heterocyclyl can be a monocyclic, bicyclic, spirocyclic or bridged ring system. The heterocyclyl is optionally substituted by R on one or more carbon or nitrogen positions. 7 Substitution, where R 7 As defined for formula I. Heterocyclic radical is also independently optionally replaced by alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkyloxycarbonyl, or replaced by oxo or low carbon alkyl on sulfur. Examples of heterocyclic radicals include but are not limited to epoxy, azetidinyl, aziridine, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolane, oxazolidinyl, oxazolidinone, decahydroquinolinyl, piperidone, 4-piperidone, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, oxazepanyl, azabicyclohexane, azabicycloheptane and oxazepane. Specifically excluded from the scope of this term are compounds having adjacent ring-shaped O atoms and / or S atoms.

[0082] The term "heterocyclylalkyl" refers to a heterocyclyl group as defined herein attached 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.

[0083] 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 common π electrons in a cyclic array; and each ring having, in addition to carbon atoms, one to three heteroatoms selected from the group consisting of N, O and S. Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, benzopyranyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolene, indolinyl, indolizinyl , indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazine yl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolyl, 4H-quinolizinyl, quinoxalinyl, quinuclidine, Tetrahydroisoquinolyl, tetrahydroquinolyl, 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, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthrenyl.

[0084] " Heteroaromatic alkyl " comprises the heteroaromatic group that is covalently connected with alkyl, wherein said group is on alkyl, and any one of them is optionally substituted or unsubstituted independently.The example of heteroaromatic alkyl comprises the heteroaromatic group with 5,6,9 or 10 ring atoms of C1-C6 alkyl bonding.The example of heteroaralkyl comprises pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethylquinazolinylmethyl, quinolylmethyl, quinolylethyl, benzofuranylmethyl, indolinylethyl isoquinolylmethyl, isoindolylmethyl, cinnolinylmethyl and benzothienylethyl.The scope of this term specifically excludes the compound with adjacent annular O atom and / or S atom.

[0085] 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., an ErbB family member or KRas G12C. The amount can be administered, for example, in a single dose form or can be administered according to a regimen such that it is effective.

[0086] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to improve or alleviate symptoms in some way, or to stop or reverse the progression of a condition, or to negatively regulate or inhibit the activity of one or more ErbB family members or KRas G12C. The amount can be administered, for example, in a single dose form or can be administered according to a regimen, whereby it is effective.

[0087] As used herein, a "combined therapeutically effective amount" of two compounds is an amount that together synergistically increases the activity of the combination (i.e., not merely additive) compared to the therapeutically effective amount of each compound in the combination. Alternatively, in vivo, a therapeutically effective amount of a pan-ErbB inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in the duration of overall survival ("OS") of an individual relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a pan-ErbB inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in the duration of progression-free survival ("PFS") of an individual relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a pan-ErbB inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, combined with a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, causes an increase in tumor regression in an individual relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a pan-ErbB inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, combined with a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, causes an increase in tumor growth inhibition in an individual relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a pan-ErbB inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, combined with a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, causes an increase in the duration of disease stabilization in an individual relative to treatment with a KRas G12C inhibitor alone. The amount can be administered, for example, in a single dose form or can be administered according to a regimen, whereby it is effective.

[0088] As used herein, treatment means any manner in which the symptoms or pathology of a condition, disorder, or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.

[0089] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, whether permanent or temporary, sustained or transient, attributable to or associated with administration of the composition.

[0090] As used herein, the term "about" when used to modify a numerically defined parameter (e.g., the dose of a KRAS inhibitor or a pan-ErbB family inhibitor or a pharmaceutically acceptable salt thereof, or the duration of treatment with the combination therapy described herein) means that the degree of change in the parameter may be up to 10% lower or higher than the stated value of the parameter. For example, a dose of about 5 mg / kg can vary between 4.5 mg / kg and 5.5 mg / kg. "About" is intended to modify each parameter when used at the beginning of a parameter list. 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, and about 25% or more.

[0091] Inhibitor compounds

[0092] In one aspect of the invention, provided herein is a method for treating cancer, e.g., a KRas G12C-related cancer, in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a pan-ErbB family inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in combination with a KRAS G12C inhibitor of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0093] 1.ErbB family

[0094] Epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase of the ErbB receptor family. In conjunction with epidermal growth factor (EGF), the EGFR receptor can homodimerize with another EGFR molecule or heterodimerize with another family member such as ErbB2 (HER2), ErbB3 (HER3) or ErbB4 (HER4). The homodimerization of ErbB receptors and / or heterodimerization causes phosphorylation of key tyrosine residues in the intracellular domain and causes stimulation of many intracellular signal transduction pathways involved in cell proliferation and survival.

[0095] Overexpression of the EGFR gene has been identified in various cancers, including bladder cancer, brain cancer, head and neck cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, prostate cancer, and kidney cancer. In addition to overexpression, EGFR activating mutations have been detected in a subset of non-small cell lung cancer (NSCLC) tumors. These mutations tend to occur within EGFR exons 18-21, which encode a portion of the EGFR kinase domain. About 90% of these mutations are exon 19 deletions or exon 21 L858R point mutations (Ladanyi and Pao (2008) "Modern Pathology (Mod Path.)" May; 21 Supplement 2: S16-22.doi: 10.1038 / modpathol.3801018). These mutations increase the kinase activity of EGFR, leading to overactivation of downstream pro-survival signaling pathways.

[0096] The overexpression and / or frequency of activating mutations of EGFR make it a desirable target for anticancer therapy, and several EGFR inhibitors have been developed and are clinically available.

[0097] The first generation of erlotinib and gefitinib inhibits EGFR activity by competitively binding to the ATP binding site of the EGFR kinase domain; however, additional mutations in the EGFR gene, such as the T790M mutation, produce mutant EGFR proteins to which drugs such as erlotinib and gefitinib bind less effectively. Those mutations are associated with drug resistance and relapse in cancer patients carrying them, leading to the development of second-generation EGFR inhibitors targeting the T790M mutation.

[0098] Furthermore, inhibition of the pathway-associated enzyme MEK leads to increased expression of ErbB family members, particularly EGFR, which may lead to adaptation and acquired resistance to ErbB family inhibitors (Sun et al., (2014) Cell Reports 7:86-93).

[0099] 2. Pan-ErbB family inhibitors

[0100] The pan-ErbB family inhibitor used in the method of the present invention can be a reversible or irreversible ErbB family inhibitor. In one embodiment, the pan-ErbB family inhibitor inhibits the activity of more than one ErbB family member.

[0101] In one embodiment, the pan-ErbB family inhibitor is an irreversible inhibitor. The irreversible pan-ErbB family inhibitor forms a covalent bond with the sulfhydryl groups of cysteine ​​797 and cysteine ​​773, respectively, blocking the binding of ATP to the intracellular catalytic domain, thereby inhibiting the activity of EGFR and HER2. Therefore, these inhibitors are active against cell lines with, for example, EGFR exon 19 deletions / insertions and L858R and T790M tolerance mutations.

[0102] Exemplary irreversible pan-ErbB family inhibitors for use in the methods include afatinib ((E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide); dacomitinib ((2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl}-4-(1-piperidinyl)-2-butenamide); canertinib (N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide); Pocitinib (1-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one); AV412 (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butyn-1-yl]-6-quinazolinyl]-2-acrylamide); PF 6274484 (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-acrylamide) and HKI 357 ((2E)-N-[[4-[[(3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) and pharmaceutically acceptable salts or pharmaceutical compositions thereof. In one embodiment, the irreversible pan-ErbB family inhibitor is afatinib. In one embodiment, the irreversible pan-ErbB family inhibitor is dacomitinib.

[0103] In one embodiment, the pan-ErbB family inhibitor is a reversible inhibitor. Exemplary reversible pan-EGFR family inhibitors include erlotinib ([6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine)), gefitinib (4-(3'-chloro-4'-fluorophenylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, sabitinib (2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-methylacetamide); vanitinib ((R)-N4-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)-N6-(4-methyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine); TAK-2 85 (N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide); AEE788 ((S)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine); Tarotinib (3-[N-[4-(3-bromo-4-chlorophenylamino)pyrido[3,4-d]pyrimidin-6-yl]carbamoyl]-N,N-dimethyl-N-(1-methyl-4-nitro-1H-imidazol-5-ylmethyl)-2(E)-propen-1-aminium bromide); BMS 599626 ((3S)-3-morpholinylmethyl-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-yl]-carbamate dihydrochloride); and GW 583340HCl (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[[[2-(methylsulfonyl)ethyl]amino]methyl]-4-thiazolyl]-4-quinazolinamine dihydrochloride) and pharmaceutically acceptable salts or pharmaceutical compositions thereof. In one embodiment, the reversible pan-ErbB family inhibitor is sabitinib. In one embodiment, the reversible pan-ErbB family inhibitor is tarotinib.

[0104] In one embodiment, the pan-ErbB family inhibitor is a combination of an EGFR inhibitor and a HER2 inhibitor, wherein the EGFR inhibitor and the HER2 inhibitor are a combination of two of the following: AG 1478 HCl (N-(3-chlorophenyl)-6,7-dimethoxy-4-quinazolinamine hydrochloride); AG 494 ((E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-phenyl-2-acrylamide); AG555 ((E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-(3-phenylpropyl)-2-acrylamide); AG 556 ((E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-(4-phenylbutyl)-2-acrylamide); AG 825 ((E)-3-[3-[2-benzothiazolylthio)methyl]-4-hydroxy-5-methoxyphenyl]-2-cyano-2-acrylamide); CP 724714 (2-methoxy-N-[(2E)-3-[4-[[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]phenyl]amino]-6-quinazolinyl]-2-propen-1-yl]acetamide); BIBU 1361 diHCl (N-(3-chloro-4-fluorophenyl)-6-[4-[(diethylamino)methyl]-1-piperidinyl]-pyrimido[5,4-d]pyrimidin-4-amine dihydrochloride); BIBU 1382 (N 8 -(3-Chloro-4-fluorophenyl)-N 2 -(1-methyl-4-piperidinyl)-pyrimido[5,4-d]pyrimidine-2,8-diamine dihydrochloride); JNJ 28871063 HCl(5E-4-amino-6-(4-benzyloxy-3-chlorophenylamino)pyrimidine-5-carboxaldehyde N-(2-morpholin-4-ylethyl)oxime hydrochloride); PD 153035(4-[(3-bromophenyl)amino]-6,7-dimethoxyquinazoline hydrochloride); PD 158780(N 4 -(3-Bromophenyl)-N 6 -methyl-pyrido[3,4-d]pyrimidine-4,6-diamine) and a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0105] Methods for making reversible and irreversible pan-ErbB family inhibitors that target wild-type and mutant ErbB family members are well known to those of skill in the art, and pan-ErbB family inhibitors are available from a wide variety of commercial suppliers in forms suitable for both research or human use.In addition, reversible and irreversible pan-ErbB family inhibitors suitable for use in the compositions and methods disclosed herein and methods for preparing the same are disclosed in U.S. Patent Application Publication Nos. US20180050993; US20180016268; US20180008607; US20170362204; US20170362203; US20170355683; US20170342055; US20170267671; US20170183330; US20170174697; 20170008856; US20160375148; US20160332994; US20160257682; US No. US 20160244469; No. US 20160137610; No. US20160102076; No. US20160016948; No. US20150284340; No. US20150274678; No. US20150250778; No. US 20150246047; No. US20150126508; No. US20150025055; No. US20140221403; No. US No. 20140178412; No. US20140161722; No. US20140155606; No. US20140038981; No. US20140038940; No. US20140005391; No. US 20130296348; No. US20130209461; No. US20130137709; No. US 20120316135L; No. US 20120094999; No. US20110295004; No. US 20110033453; No. US No. 20100196365; No. 20100143295; No. 20100120678; No. US 20100034689; No. US 20090209758; No. US 20090111772; No. US20090029968; No. US20080194578; No. US 20080139590; No. US 2000125448; No. US20080051395; No. US 20070232607; No. US 20060235046 and No. US20040023957.

[0106] In one embodiment, the pan-ErbB family inhibitor is an anti-EGFR antibody, an anti-HER2 antibody, or a combination of an anti-EGFR antibody and an anti-HER2 antibody or a pharmaceutical composition thereof. Antibodies, antibody-drug conjugates and bispecific antibodies including monoclonal antibodies targeting EGFR and / or HER2 are well known, and a variety of antibodies are commercially available for research and human clinical use.

[0107] Exemplary anti-EGFR monoclonal antibodies approved for clinical use in humans include, but are not limited to, necituzumab (Eli Lilly), panitumumab (Amgen), and cetuximab (ImClone). Other anti-EGFR antibodies suitable for use in the methods include EP384, H11, 11.6, 225 and 199.12 (Thermo Fisher), GT133 (GeneTex), and those disclosed in U.S. Patent Application Publication Nos. US 20080274114; US 20100166755; US 20100117110; US 20120034211; US ​​20120308576; US 20130273033; US 20130344093; US 20140286969; US 20150337042; US 20170218073; US 20170267765; US The anti-EGFR antibodies in US Pat. No. 20180036405; US Pat. No. 20180066066; US Pat. No. 20180094062; US Pat. No. 20180155433; US Pat. No. 20180306049; US Pat. No. 20180362443; US Pat. No. 20190040143; US Pat. No. 20190151328; US Pat. No. 20190194347; US Pat. No. 20190194350; US Pat. No. 20190209704; US Pat. No. 20190216924 and US Pat. No. 20190263930.

[0108] In one embodiment, the anti-EGFR monoclonal antibody is cetuximab.

[0109] Exemplary anti-HER-2 monoclonal antibodies approved for clinical use in humans include, but are not limited to, pertuzumab (Roche), trastuzumab (Roche), and trastuzumab-emtansine (Roche). Other anti-HER2 antibodies, antibody drug conjugates and bispecific antibodies suitable for use in the method include those disclosed in U.S. Patent Application Publication Nos. US20030228663; US 20060018899; US 20090187007; US 20090285837; US20110159014; US 20110177095; US 20110313137; US 20120309942; US20150166664; US 20150352225; US 20160051695; US 20160096893; US20180022816; US Anti-HER2 antibodies in US Patent No. 20180022820; US Patent No. 20180057608; US Patent No. 20180118837; US Patent No. 20180258173; US Patent No. 20190177428 and US Patent No. 20190248918.

[0110] 2. KRas G12C inhibitors

[0111] In one embodiment, the KRas G12C inhibitor used in the method is a compound of formula (I):

[0112]

[0113] or a pharmaceutically acceptable salt thereof, wherein:

[0114] X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted by one or more R 8 replace;

[0115] Y is a bond, O, S or NR 5 ;

[0116] R 1 -C(O)C(R A ) C(R B ) p or -SO2C(R A ) C(R B ) p ;

[0117] R 2is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, -Z-NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaromatic or heteroaromaticalkyl, wherein each of Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaromatic and heteroaromaticalkyl may be optionally replaced by one or more R 9 replace;

[0118] Z is C1-C4 alkylene;

[0119] Each R 3 are independently C1-C3 alkyl, oxo or haloalkyl;

[0120] L is a bond, -C(O)- or C1-C3 alkylene;

[0121] R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaromatic, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaromatic may be optionally replaced by one or more R 6 or R 7 replace;

[0122] Each R 5 are independently hydrogen or C1-C3 alkyl;

[0123] R 6 is a cycloalkyl, a heterocyclyl, a heterocyclylalkyl, an aryl or a heteroaromatic group, wherein each of the cycloalkyl, heterocyclyl, aryl or heteroaromatic group may be optionally replaced by one or more R 7 replace;

[0124] Each R 7 are independently halogen, hydroxy, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;

[0125] R 8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -C(O)OR 5 、-C(O)N(R 5 )2、-N(R 5 ) 2, wherein the C1-C3 alkyl group may be optionally substituted by cyano, halogen, -OR 5 、-N(R 5 )2 or heteroaromatic substitution;

[0126] Each R 9are independently hydrogen, oxo, acyl, hydroxy, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylamino, dialkylamidoalkyl or dialkylaminoalkyl, wherein the C1-C6 alkyl may be optionally substituted with cycloalkyl;

[0127] Each R 10 are independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl or hydroxyalkyl;

[0128] R 11 is a haloalkyl group;

[0129] R A does not exist, is hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 )2 or hydroxyalkyl;

[0130] Each R B are independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR 5 R 11 、-C(O)N(R 5 )2, -NHC(O)C1-C3 alkyl, -CH2NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminoalkyl or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxy, alkoxy and C1-C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R 7 replace;

[0131] m is zero or an integer between 1 and 2;

[0132] p is one or two; and wherein,

[0133] when When it is a triple bond, R A Does not exist, R B exists and p is equal to one;

[0134] or when When it is a double bond, R A Existence, R B exists and p is equal to two, or R A , R B and the carbon atom to which it is attached form a 7 Substituted 5-8 membered partially saturated cycloalkyl.

[0135] In one embodiment, the KRas G12C inhibitor used in the methods herein includes a compound having Formula IA:

[0136]

[0137] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , R 4 , R 5 , R 10 , L and m are as defined for Formula I, R 11 is hydrogen, methyl or hydroxyalkyl, and the piperidinyl ring is optionally replaced by R 8 Substitution, where R 8 As defined for Formula I.

[0138] In one embodiment, the KRas G12C inhibitor used in the methods herein includes a compound having Formula IB:

[0139]

[0140] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , R 4 , R 9 , R 11 , L and m are as defined for Formula I.

[0141] Non-limiting examples of KRas G12C inhibitor compounds of Formula (I), Formula IA, and Formula IB that can be used in the methods disclosed herein are selected from the group consisting of Examples Nos. 1-678 including the following structures:

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187] and pharmaceutically acceptable salts thereof.

[0188] In one embodiment, the KRas G12C inhibitor is selected from:

[0189]

[0190] and pharmaceutically acceptable salts thereof.

[0191] In one embodiment, the KRas G12C inhibitor is:

[0192]

[0193] (also known as Example 234) or a pharmaceutically acceptable salt thereof.

[0194] In one embodiment, the KRas G12C inhibitor is:

[0195]

[0196] (also known as Example 359) or a pharmaceutically acceptable salt thereof.

[0197] In one embodiment, the KRas G12C inhibitor is:

[0198]

[0199] (also known as Example 478) or a pharmaceutically acceptable salt thereof.

[0200] In one embodiment, the KRas G12C inhibitor is:

[0201]

[0202] (also known as Example 507) or a pharmaceutically acceptable salt thereof.

[0203] 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, i.e., isomers of identical structure but different atomic arrangements in space. The compounds may be used as mixtures, or the individual components / isomers may be separated according to the manufacturer's instructions using commercially available reagents and conventional methods known to those skilled in the art for separation of stereoisomers and enantiomers, such as using (Sigma-Aldrich) or (Diacel Corp) chiral chromatography HPLC column for separation. Alternatively, the compounds of the present invention can be synthesized using optically pure chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomers and diastereoisomers) and racemic forms are within the scope of the present invention. Unless otherwise indicated, whenever the specification including the claims refers to the compounds of the present invention, the term "compound" is understood to cover all chiral (enantiomers and diastereoisomers) and racemic forms.

[0204] 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 above compound.

[0205] Methods for making the KRas G12C inhibitors disclosed herein are known. For example, co-owned published International PCT Application Nos. WO2017201161 and WO2019099524 describe general reaction schemes for preparing compounds of Formula I, Formula IA or Formula IB and pharmaceutically acceptable salts thereof, and also provide detailed synthetic routes for preparing each KRas G12C inhibitor disclosed herein.

[0206] The pan-ErbB inhibitor and the KRas G12C compound of Formula (I), Formula IA or Formula IB or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition.

[0207] Pharmaceutical composition

[0208] In another aspect, the present invention provides a pharmaceutical composition comprising a pan-ErbB family inhibitor and a KRas G12C inhibitor of the present invention and a pharmaceutically acceptable carrier, excipient or diluent that can be used in the methods disclosed herein. The pan-ErbB family inhibitor and the KRas G12C inhibitor can be independently formulated by any method known in the art and can be prepared for administration by any route including but not limited to parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal or rectal. In certain embodiments, the pan-ErbB family inhibitor and the KRas G12C inhibitor are administered intravenously in a hospital setting. In one embodiment, administration can be performed by an oral route.

[0209] The carrier characteristics will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system such as a cell, a cell culture, a tissue or a biocompatibility and does not interfere with the biological activity effectiveness of one or more active ingredients. Therefore, in addition to the inhibitor, the composition can also contain diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials known in the art. The preparation of pharmaceutically acceptable formulations is described in, for example, "Remington's Pharmaceutical Sciences", the 18th edition, editor A. Gennaro, Mack Publishing Co., Easton, Pa., Easton, Pennsylvania, in 1990.

[0210] The term pharmaceutically acceptable salt as used herein refers to a salt that retains the desired biological activity of the compound identified above and exhibits minimal or no undesirable toxicological effects. Examples of the salt include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and salts formed with organic acids (e.g., acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, and polygalacturonic acid). The compounds can also be administered in the form of pharmaceutically acceptable quaternary salts known to those skilled in the art, which specifically include quaternary ammonium salts of the formula --NR+Z-, wherein R is hydrogen, alkyl or benzyl, and Z is a counterion including chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methanesulfonate, sulfonate, phosphate or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzoate and diphenylacetate).

[0211] The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing severe toxic effects in the treated patient. In one embodiment, for all the above-mentioned conditions, the dosage range of the active compound is about 0.01 to 300 mg / kg recipient body weight / day, such as 0.1 to 100 mg / kg recipient body weight / day, and for example 0.5 to about 25 mg / kg recipient body weight / day. The typical local dose range in a suitable carrier will be 0.01-3% wt / wt. The effective dose range of a pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound to be delivered. If the derivative itself exhibits activity, then the effective dose can be estimated as above using the weight of the derivative or by other means known to those skilled in the art.

[0212] Pharmaceutical compositions comprising a pan-ErbB family inhibitor and a KRas G12C inhibitor can be used in the methods of use described herein.

[0213] Co-administration

[0214] The pan-ErbB family inhibitor and the KRas G12C inhibitor can be formulated into separate or individual dosage forms that can be co-administered one after the other. Another option is that if the route of administration is the same (e.g. oral), the two active compounds can be formulated into a single form for co-administration, however, the two co-administration methods are part of the same therapeutic treatment or regimen.

[0215] The pharmaceutical composition comprising a pan-ErbB family inhibitor and / or a KRas G12C inhibitor used in the method can be used simultaneously, separately or sequentially. In one embodiment, the pan-ErbB family inhibitor is administered before administering a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB. In another embodiment, the pan-ErbB family inhibitor is administered after administering a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula I-B. In another embodiment, the pan-ErbB family inhibitor is administered at about the same time as the KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB is administered.

[0216] In some cases, it will be advantageous to administer each inhibitor separately at different times and by different routes. Thus, the components of the combination, i.e., the KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, and the pan-ErbB family inhibitor, or a pharmaceutically acceptable salt thereof, need not necessarily be administered at substantially the same time or in any order.

[0217] Tumor drugs are usually administered at a maximum tolerated dose ("MTD"), which is the highest drug dose that does not cause unacceptable side effects. In one embodiment, a KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a pan-ErbB family inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof are each administered at their corresponding MTD. In one embodiment, a KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered at its MTD, and a pan-ErbB family inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered in an amount less than its MTD. In one embodiment, a KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered in an amount less than its MTD, and a pan-ErbB family inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered at its MTD. In one embodiment, a KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a pan-ErbB family inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof are each administered at less than their corresponding MTD. Administration can be timed so that the peak pharmacokinetic effect of one compound is consistent with the peak pharmacokinetic effect of another compound.

[0218] In one embodiment, the KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is administered daily (i.e., at about 24 hour intervals) (i.e., QD). In another embodiment, the KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is administered daily (i.e., BID). In another embodiment, the KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is administered daily (i.e., TID).

[0219] In one embodiment, the pan-ErbB family inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition is administered QD. In another embodiment, the pan-ErbB family inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition is administered BID. In another embodiment, the pan-ErbB family inhibitor of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition is administered TID.

[0220] In one embodiment, a single dose of a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a pan-ErbB family inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, are each administered once a day.

[0221] In one embodiment, the pan-ErbB family inhibitor is an irreversible inhibitor. Exemplary irreversible pan-ErbB family inhibitors for use in the methods herein include afatinib ((E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide); dacomitinib ((2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl)-}-4-(1-piperidinyl)-2-butenamide); canertinib (N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-morpholinopropoxy)quinazolin-6-yl)acrylamide); pocitinib (1-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one); AV PF 6274484 (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-acrylamide) and HKI 357 ((2E)-N-[[4-[[(3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0222] In one embodiment, the pan-ErbB family inhibitor is a reversible inhibitor. Exemplary reversible pan-EGFR family inhibitors include erlotinib ([6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine)), gefitinib ((4-(3'-chloro-4'-fluorophenylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline), sabitinib (2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-methylacetamide); vanitinib ((R)-N4-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)-N6-(4-methyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine); TAK-285 (N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide); AEE788 ((S)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine); Tarotinib ([(E)-4-[[4-(3-bromo-4-chlorophenylamino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazole-4-yl)methyl]ammonium); BMS 599626 ((3S)-3-morpholinylmethyl-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamate dihydrochloride); and GW 583340HCl (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[[[2-(methylsulfonyl)ethyl]amino]methyl]-4-thiazolyl]-4-quinazolinamine dihydrochloride) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0223] In one embodiment, the pan-ErbB family inhibitor is an anti-EGFR antibody, an anti-HER2 antibody, or a combination of an anti-EGFR antibody and an anti-HER2 antibody or a pharmaceutical composition thereof. In one embodiment, the anti-EGFR antibody is naxituzumab, panitumumab or cetuximab. In one embodiment, the anti-EGFR antibody is cetuximab. In one embodiment, the anti-HER2 antibody suitable for use in the method herein is pertuzumab, trastuzumab or trastuzumab-emtansine.

[0224] In one embodiment, the pan-ErbB family inhibitor is an EGFR inhibitor and a HER2 inhibitor, wherein the EGFR inhibitor and the HER2 inhibitor are independently selected from two agents selected from the group consisting of: AG 1478 HCl (N-(3-chlorophenyl)-6,7-dimethoxy-4-quinazolinamine hydrochloride); AG 494 ((E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-phenyl-2-acrylamide); AG 555 ((E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-(3-phenylpropyl)-2-acrylamide); AG 556 ((E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-(4-phenylbutyl)-2-acrylamide); AG 825 ((E)-3-[3-[2-benzothiazolylthio)methyl]-4-hydroxy-5-methoxyphenyl]-2-cyano-2-acrylamide); CP 724714 (2-methoxy-N-[(2E)-3-[4-[[3-methyl-4-[(6-methyl-3-pyridyl)oxy]phenyl]amino]-6-quinazolinyl]-2-propen-1-yl]acetamide); BIBU 1361 diHCl (N-(3-chloro-4-fluorophenyl)-6-[4-[(diethylamino)methyl]-1-piperidinyl]-pyrimido[5,4-d]pyrimidin-4-amine dihydrochloride); BIBU 1382 (N 8 -(3-Chloro-4-fluorophenyl)-N 2 -(1-methyl-4-piperidinyl)-pyrimido[5,4-d]pyrimidine-2,8-diamine dihydrochloride); JNJ 28871063 HCl(5E-4-amino-6-(4-benzyloxy-3-chlorophenylamino)pyrimidine-5-carboxaldehyde N-(2-morpholin-4-ylethyl)oxime hydrochloride); PD 153035(4-[(3-bromophenyl)amino]-6,7-dimethoxyquinazoline hydrochloride); PD 158780(N 4 -(3-Bromophenyl)-N 6 -methyl-pyrido[3,4-d]pyrimidine-4,6-diamine) or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0225] Combination therapy

[0226] In one aspect of the invention, provided herein is a method for treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a pan-ErbB family inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRAS G12C inhibitor of Formula (I), Formula IA or Formula IB or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In one embodiment, the cancer is a KRas G12C-related cancer. In one embodiment, the KRas G12C-related cancer is lung cancer.

[0227] In yet another aspect, the present invention provides a method for increasing the sensitivity of cancer cells to KRas G12C inhibitors, the method comprising contacting cancer cells with an effective amount of a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a combination of a pan-ErbB family inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the pan-ErbB family inhibitor synergistically increases the sensitivity of cancer cells to the KRas G12C inhibitor. In one embodiment, the contact is performed in vitro. In one embodiment, the contact is performed in vivo.

[0228] In one embodiment, the combination therapy comprises a compound having the formula:

[0229]

[0230] Or a combination of a pharmaceutically acceptable salt thereof and a pan-ErbB family inhibitor. In one embodiment, the pan-ErbB family inhibitor is afatinib. In one embodiment, the pan-ErbB family inhibitor is dacomitinib. In one embodiment, the pan-ErbB family inhibitor is pocitinib. In one embodiment, the pan-ErbB family inhibitor is erlotinib. In one embodiment, the pan-ErbB family inhibitor is gefitinib. In one embodiment, the pan-ErbB family inhibitor is sabitinib. In one embodiment, the pan-ErbB family inhibitor is tarotinib. In one embodiment, the pan-ErbB family inhibitor is an anti-EGFR antibody, wherein the anti-EGFR antibody is cetuximab.

[0231] In one embodiment, the combination therapy comprises a compound having the formula:

[0232]

[0233] Or a combination of a pharmaceutically acceptable salt thereof and a pan-ErbB family inhibitor. In one embodiment, the pan-ErbB family inhibitor is afatinib. In one embodiment, the pan-ErbB family inhibitor is dacomitinib. In one embodiment, the pan-ErbB family inhibitor is pocitinib. In one embodiment, the pan-ErbB family inhibitor is erlotinib. In one embodiment, the pan-ErbB family inhibitor is gefitinib. In one embodiment, the pan-ErbB family inhibitor is sabitinib. In one embodiment, the pan-ErbB family inhibitor is tarotinib. In one embodiment, the pan-ErbB family inhibitor is an anti-EGFR antibody, wherein the anti-EGFR antibody is cetuximab.

[0234] In one embodiment, the combination therapy comprises a compound having the formula:

[0235]

[0236] Or a combination of a pharmaceutically acceptable salt thereof and a pan-ErbB family inhibitor. In one embodiment, the pan-ErbB family inhibitor is afatinib. In one embodiment, the pan-ErbB family inhibitor is dacomitinib. In one embodiment, the pan-ErbB family inhibitor is pocitinib. In one embodiment, the pan-ErbB family inhibitor is erlotinib. In one embodiment, the pan-ErbB family inhibitor is gefitinib. In one embodiment, the pan-ErbB family inhibitor is sabitinib. In one embodiment, the pan-ErbB family inhibitor is tarotinib. In one embodiment, the pan-ErbB family inhibitor is an anti-EGFR antibody, wherein the anti-EGFR antibody is cetuximab.

[0237] In one embodiment, the combination therapy comprises a compound having the formula:

[0238]

[0239] Or a combination of a pharmaceutically acceptable salt thereof and a pan-ErbB family inhibitor. In one embodiment, the pan-ErbB family inhibitor is afatinib. In one embodiment, the pan-ErbB family inhibitor is dacomitinib. In one embodiment, the pan-ErbB family inhibitor is pocitinib. In one embodiment, the pan-ErbB family inhibitor is erlotinib. In one embodiment, the pan-ErbB family inhibitor is gefitinib. In one embodiment, the pan-ErbB family inhibitor is sabitinib. In one embodiment, the pan-ErbB family inhibitor is tarotinib. In one embodiment, the pan-ErbB family inhibitor is an anti-EGFR antibody, wherein the anti-EGFR antibody is cetuximab.

[0240] As used herein, the term "contacting" refers to bringing together specified parts in an in vitro system or an in vivo system. For example, "contacting" a cancer cell includes administering a combination provided herein to an individual, such as a human, having KRas G12C, and, for example, introducing a combination provided herein into a sample containing cells or purified preparations containing KRas G12C.

[0241] By negatively regulating the activity of KRas G12C, the methods described herein are designed to inhibit the undesired cell proliferation caused by the enhanced KRas G12C activity in the cell. The degree of covalent modification of KRas G12C can be monitored in vitro using well-known methods, including the methods described in the published international PCT applications No. WO2017201161 and No. WO2019099524. In addition, the inhibitory activity of the combination in the cell can be monitored, for example, by measuring the inhibition of KRas G12C activity by a certain amount of phosphorylated ERK to assess the effectiveness of the treatment, and thus the dosage can be adjusted by the attending physician.

[0242] The compositions and methods provided herein can be used to treat KRas G12C-related cancers in individuals in need thereof, comprising administering to the individual a therapeutically effective amount of a pan-ErbB family inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a combination of a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the pan-ErbB family inhibitor synergistically increases the sensitivity of the KRas G12C-related cancer to the KRas G12C inhibitor. In one embodiment, the KRas G12C-related cancer is lung cancer.

[0243] In one embodiment, the combination of a therapeutically effective amount of a pan-ErbB family inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in the duration of overall survival ("OS") of the individual relative to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of a pan-ErbB family inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in the duration of progression-free survival ("PFS") of the individual relative to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of a pan-ErbB family inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of Formula (I), Formula IA, or Formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increase in tumor growth inhibition of the individual relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a pan-ErbB family inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition and a KRasG12C inhibitor compound of formula (I), formula IA or formula IB or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof causes an individual to have a prolonged duration of disease stability compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the KRas G12C inhibitor is a compound selected from compounds No. 1-678 (numbered in WO2019099524) or a pharmaceutically acceptable salt thereof (e.g., No. 234, 359, 478 or 507 examples or pharmaceutically acceptable salts thereof). In one embodiment, the pan-ErbB family inhibitor is selected from afatinib, dacomitinib, pocitinib, erlotinib, gefitinib, sabitinib and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of example No. 234 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of example No. 234 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of example No. 234 and pocitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and erlotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and talotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and the anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and dacomitinib.In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and Pocitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and erlotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and the anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and Pocitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and erlotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and the anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and pocitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and erlotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and anti-EGFR antibody cetuximab. In one embodiment of any of the combination therapies, the combination can be used to treat KRas G12C-related cancers. In one embodiment, the KRas G12C-related cancer is lung cancer.

[0244] In another embodiment, for KRas G12C monotherapy, once disease progression has been observed, a pan-ErbB family inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered in combination with a KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the combination therapy causes an enhancement of clinical benefit or a prolonged survival time in the patient by prolonging OS, prolonging PFS, increasing tumor regression, increasing tumor growth inhibition, or prolonging the duration of disease stabilization in the patient. In one embodiment, the KRas G12C inhibitor is a compound selected from No. 1-678 (numbered in WO2019099524) compounds or a pharmaceutically acceptable salt thereof (e.g., No. 234, 359, 478 or No. 507 examples or pharmaceutically acceptable salts thereof). In one embodiment, the pan-ErbB family inhibitor is selected from afatinib, dacomitinib, pocitinib, erlotinib, gefitinib, shabitinib, and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of No. 234 examples and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and pocitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and erlotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and pocitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and erlotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and the anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and pocitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and erlotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and tarotinib.In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and the anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and pocitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and erlotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and the anti-EGFR antibody cetuximab. In one embodiment of any of the combination therapies, the combination can be used to treat KRas G12C-related cancers. In one embodiment, the KRas G12C-related cancer is lung cancer.

[0245] In one embodiment of any of the methods herein, the pan-ErbB family inhibitor and the KRAS G12C inhibitor are administered on the same day.

[0246] In one embodiment of any of the methods herein, the pan-ErbB family inhibitor and the KRAS G12C inhibitor are administered on different days.

[0247] The compositions and methods provided herein can be used to treat a wide variety of cancers, including tumors, such as lung tumors, prostate tumors, breast tumors, brain tumors, skin tumors, cervical cancer, testicular cancer, etc. More specifically, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, sarcoma), leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder cancer, ampullary carcinoma, bile duct cancer; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant Lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondrofibroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, blastomas (pinealomas), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);Gynecology: Uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical atypical hyperplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecoma cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (carcinoma); Hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer. ;

[0248] Also provided herein are methods for treating cancer in an individual in need thereof, the methods comprising (a) determining that the cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer) (e.g., using an assay or kit approved by a regulatory agency, such as FDA-approved); and (b) administering to the patient a therapeutically effective amount of a pan-ErbB family inhibitor and a KRas G12C inhibitor compound of Formula I, Formula IA, Formula 1-B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the pan-ErbB inhibitor synergistically increases the sensitivity of KRas G12C-associated cancer to the KRas G12C inhibitor. In one embodiment, the KRas G12C inhibitor is a compound selected from compounds Nos. 1-678 (numbered in WO2019099524) or a pharmaceutically acceptable salt thereof (e.g., Examples No. 234, 359, 478, or 507, or a pharmaceutically acceptable salt thereof). In one embodiment, the pan-ErbB family inhibitor is selected from afatinib, dacomitinib, pocitinib, erlotinib, gefitinib, sabitinib and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and pocitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and erlotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and pocitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and erlotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and talotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and the anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and pocitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and erlotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and gefitinib.In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and the anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and pocitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and erlotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and the anti-EGFR antibody cetuximab. In one embodiment of any of the combination therapies, the combination can be used to treat a KRas G12C-related cancer. In one embodiment, the KRas G12C-related cancer is lung cancer.

[0249] In another embodiment, for KRas G12C monotherapy, once disease progression has been observed, a pan-ErbB family inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered in combination with a KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the combination therapy causes an enhancement of clinical benefit or a prolonged survival time in the patient by prolonging OS, prolonging PFS, increasing tumor regression, increasing tumor growth inhibition, or prolonging the duration of disease stabilization in the patient. In one embodiment, the KRas G12C inhibitor is a compound selected from No. 1-678 (numbered in WO2019099524) compounds or a pharmaceutically acceptable salt thereof (e.g., No. 234, 359, 478 or No. 507 examples or pharmaceutically acceptable salts thereof). In one embodiment, the pan-ErbB family inhibitor is selected from afatinib, dacomitinib, pocitinib, erlotinib, gefitinib, shabitinib, and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of No. 234 examples and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and pocitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and erlotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and pocitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and erlotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and the anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and pocitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and erlotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and tarotinib.In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and the anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and pocitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and erlotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and the anti-EGFR antibody cetuximab. In one embodiment of any of the combination therapies, the combination can be used to treat KRas G12C-related cancers. In one embodiment, the KRas G12C-related cancer is lung cancer.

[0250] In one embodiment, the compound of Formula I or its pharmaceutically acceptable salt or pharmaceutical composition is administered in capsule form during a certain period of time. In one embodiment, the tablet or capsule formulation of the compound of Formula I contains 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 20 mg, about 10 mg to about 15 mg, about 15 mg to about 100 mg, about 15 mg to about 95 mg, about 15 mg to about 90 mg, about 15 mg to about 85 mg, about 15 mg to about 80 mg, about 15 mg to about 75 mg, about 15 mg to about 70 mg, about 15 mg to about 65 mg, about 15 mg to about 60 mg, about 15 mg to about 55 mg, about 15 mg to about 50 mg, about 15 mg to about 45 mg, about 15 mg to about 40 mg, about 15 mg to about 35 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg, about 15 mg to about 20 mg, about 20 mg to about 100 mg, about 20 mg to about 95 mg, about 20 mg g to about 90 mg, about 20 mg to about 85 mg, about 20 mg to about 80 mg, about 20 mg to about 75 mg, about 20 mg to about 70 mg, about 20 mg to about 65 mg, about 20 mg to about 60 mg, about 20 mg to about 55 mg, about 20 mg to about 50 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 25 mg to about 100 mg, about 25 mg to about 95 mg, about 25 mg to about 90 mg, about 25 mg to about 85 mg, about 25 mg to about 80 mg, about 25 mg to about 75 mg, about 2 about 25 mg to about 65 mg, about 25 mg to about 60 mg, about 25 mg to about 55 mg, about 25 mg to about 50 mg, about 25 mg to about 45 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 30 mg to about 100 mg, about 30 mg to about 95 mg, about 30 mg to about 90 mg, about 30 mg to about 85 mg, about 30 mg to about 80 mg, about 30 mg to about 75 mg, about 30 mg to about 70 mg, about 30 mg to about 65 mg, about 30 mg to about 60 mg, about 30 mg to about 55 mg, about 30 mg to about 50 mg,about 30 mg to about 45 mg, about 30 mg to about 40 mg, about 30 mg to about 35 mg, about 35 mg to about 100 mg, about 35 mg to about 95 mg, about 35 mg to about 90 mg, about 35 mg to about 85 mg, about 35 mg to about 80 mg, about 35 mg to about 75 mg, about 35 mg to about 70 mg, about 35 mg to about 65 mg, about 35 mg to about 60 mg, about 35 mg to about 55 mg, about 35 mg to about 50 mg, about 35 mg to about 45 mg, about 35 mg to about 40 mg, about 40 mg to about 100 mg, about 40 mg to about 95 mg, about 40 mg to about 90 mg, about 40 mg to about 85 mg, about 40 mg to about about 80 mg, about 40 mg to about 75 mg, about 40 mg to about 70 mg, about 40 mg to about 65 mg, about 40 mg to about 60 mg, about 40 mg to about 55 mg, about 40 mg to about 50 mg, about 40 mg to about 45 mg, about 45 mg to about 100 mg, about 45 mg to about 95 mg, about 45 mg to about 90 mg, about 45 mg to about 85 mg, about 45 mg to about 80 mg, about 45 mg to about 75 mg, about 45 mg to about 70 mg, about 45 mg to about 65 mg, about 45 mg to about 60 mg, about 45 mg to about 55 mg, about 45 mg to about 50 mg, about 50 mg to about 100 mg, about 50 mg to about 95 mg, about 50 mg to about 90 mg, about 50 mg to about 85 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg, about 50 mg to about 70 mg, about 50 mg to about 65 mg, about 50 mg to about 60 mg, about 50 mg to about 55 mg, about 55 mg to about 100 mg, about 55 mg to about 95 mg, about 55 mg to about 90 mg, about 55 mg to about 85 mg, about 55 mg to about 80 mg, about 55 mg to about 75 mg, about 55 mg to about 70 mg, about 55 mg to about 65 mg, about 55 mg to about 60 mg, about 60 mg to about 100 mg, about 60 mg to about 95 mg, about 60 mg to about 90 mg, about 60 mg to about about 85 mg, about 60 mg to about 80 mg, about 60 mg to about 75 mg, about 60 mg to about 70 mg, about 60 mg to about 65 mg, about 65 mg to about 100 mg, about 65 mg to about 95 mg, about 65 mg to about 90 mg, about 65 mg to about 85 mg, about 65 mg to about 80 mg, about 65 mg to about 75 mg, about 65 mg to about 70 mg, about 70 mg to about 100 mg, about 70 mg to about 95 mg, about 70 mg to about 90 mg, about 70 mg to about 85 mg, about 70 mg to about 80 mg, about 70 mg to about 75 mg, about 75 mg to about 100 mg, about 75 mg to about 95 mg, about 75 mg to about 90 mg,about 75 mg to about 85 mg, about 75 mg to about 80 mg, about 80 mg to about 100 mg, about 80 mg to about 95 mg, about 80 mg to about 90 mg, about 80 mg to about 85 mg, about 85 mg to about 100 mg, about 85 mg to about 95 mg, about 85 mg to about 90 mg, about 90 mg to about 100 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 3 0mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg or about 100mg) of a compound of formula I (e.g., a compound selected from Nos. 1-678 (numbered in WO2019099524) compounds) or a pharmaceutically acceptable salt thereof (e.g., No. 234, 359, 478 or 507 examples or pharmaceutically acceptable salts thereof). In one embodiment, the compound of formula I is orally administered once a day (QD) on a daily basis during a certain period of time. In one embodiment, the compound of formula I is orally administered twice a day (BID) on a daily basis during a certain period of time. In one embodiment, the compound of Formula I is administered at a dosage of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg) over a period of time. , about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 500 mg, about 40 mg to about 480 mg, about 40 mg to about 460 mg, about 40 mg to about 440 mg, about 40 mg to about 420 mg, about 40 mg to about 400 mg, about 40 mg to about 380 mg, about 40 mg to about 360 mg, about 40 mg to about 340 mg, about 40 mg to about 320 mg, about 40 mg to about 300 mg, about 40 mg to about 280 mg, about 40 mg to about 260 mg, about 40 mg to about 240 mg, about 40 mg to about 220 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, 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 g 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 2 80 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 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 1 100mg to about 320mg, about 100mg to about 300mg, about 100mg to about 280mg, about 100mg to about 260mg, about 100mg to about 240mg, about 100mg to about 220mg, about 100mg to about 200mg, about 100mg to about 180mg, about 100mg to about 160mg, about 100mg to about 140mg, about 100mg to about 120mg, about 120mg to about 500mg, about 120mg to about 480mg, about 120mg to about 460mg, about 120mg to about 440mg, about 120mg to about 420mg, about 120mg to about 400mg, about 120mg to about 380mg,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 500 mg, about 140 mg to about 480 mg, about 140 mg to about 460 mg, about 140 mg to about 440 mg, about 140 mg to about 420 mg, about 140 mg to about 40 0mg, about 140mg to about 380mg, about 140mg to about 360mg, about 140mg to about 340mg, about 140mg to about 320mg, about 140mg to about 300mg, about 140mg to about 280mg, about 140mg to about 260mg, about 140mg to about 240mg, about 140mg to about 220mg, about 140mg to about 200mg, about 140mg to about 180mg, about 140mg to about 160mg, about 160mg to about 500mg, about 160mg to about 480mg, about 160mg to about 460mg, about 160mg to about 440mg, about 160mg to about 420mg, about 160mg to about about 400 mg, about 160 mg to about 380 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 500 mg, about 180 mg to about 480 mg, about 180 mg to about 460 mg, about 180 mg to about 440 mg, about 180 mg to about 420 mg, about 180 mg to about 400 mg, about 180 mg to about 480 mg 0mg to about 380mg, about 180mg to about 360mg, about 180mg to about 340mg, about 180mg to about 320mg, about 180mg to about 300mg, about 180mg to about 280mg, about 180mg to about 260mg, about 180mg to about 240mg, about 180mg to about 220mg, about 180mg to about 200mg, about 200mg to about 500mg, about 200mg to about 480mg, about 200mg to about 460mg, about 200mg to about 440mg, about 200mg to about 420mg, about 200mg to about 400mg, about 200mg to about 380mg, about 200mg to about 360mg,about 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 mg to 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 30 0mg, about 220mg to about 280mg, about 220mg to about 260mg, about 220mg to about 240mg, about 240mg to about 500mg, about 240mg to about 480mg, about 240mg to about 460mg, about 240mg to about 440mg, about 240mg to about 420mg, about 240mg to about 400mg, about 240mg to about 380mg, about 240mg to about 360mg, about 240mg to about 340mg, about 240mg to about 320mg, about 240mg to about 300mg, about 240mg to about 280mg, about 240mg to about 260mg, about 260mg to about 500mg, about 260mg to about 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 38 ... 0mg to about 360mg, about 280mg to about 340mg, about 280mg to about 320mg, about 280mg to about 300mg, about 300mg to about 500mg, about 300mg to about 480mg, about 300mg to about 460mg, about 300mg to about 440mg, about 300mg to about 420mg, about 300mg to about 400mg, about 300mg to about 380mg, about 300mg to about 360mg, about 300mg to about 340mg, about 300mg to about 320mg, about 320mg to about 500mg, about 320mg to about 480mg, about 320mg to about 460mg, about 320mg to about 440mg,about 320 mg to about 420 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 320 mg to about 340 mg, about 340 mg to about 500 mg, about 340 mg to about 480 mg, about 340 mg to about 460 mg, about 340 mg to about 440 mg, about 340 mg to about 420 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 500 mg, about 360 mg to about 480 mg, about 360 mg to about 460 mg, about 360 mg to about 440 mg, about 360 mg to about 420 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 500 mg, about 380 mg to about 480 mg, about 380 mg to about 460 mg g, about 380 mg to about 440 mg, about 380 mg to about 420 mg, about 380 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to 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) can be administered orally.

[0251] In one embodiment, the combination therapy comprises administering 10 mg to about 400 mg of the drug on a daily basis (during a certain period of time), for example, at 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, about 10 mg to about 80mg, about 10mg to about 60mg, about 10mg to about 40mg, about 10mg to about 20mg, about 20mg to about 400mg, about 20mg to about 380mg, about 20mg to about 360mg, about 20mg to about 340mg, about 20mg to about 320mg, about 20mg to about 300mg, 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 20mg to about 100mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 400 mg, about 40 mg to about 380 mg, about 40 mg to about 360 mg, about 40 mg to about 340 mg, about 40 mg to about 320 mg, about 40 mg to about 300 mg, about 40 mg to about 280 mg, about 40 mg to about 260 mg, about 40 mg to about 240 mg, about 40 mg to about 220 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, 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 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 60mg to about 260mg, about 60mg to about 240mg, about 60mg to about 220mg, about 60mg to about 200mg, about 60mg to about 180mg, about 60mg to about 160mg, about 60mg to about 140mg, about 60mg to about 120mg, about 60mg to about 100mg, about 60mg to about 80mg, about 80mg to about 400mg,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 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 2 0mg to about 200mg, about 140mg to about 180mg, about 140mg to about 160mg, about 160mg to about 400mg, about 160mg to about 380mg, about 160mg to about 360mg, about 160mg to about 360mg, about 160mg to about 340mg, about 160mg to about 320mg, about 160mg to about 300mg, about 160mg to about 280mg, about 160mg to about 260mg, about 160mg to about 240mg, about 160mg to about 220mg, about 160mg to about 200mg, about 160mg to about 180mg, about 180mg to about 400mg, about 180mg to about 380mg,about 180 mg to about 360 mg, about 180 mg to about 340 mg, about 180 mg to about 320 mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about 260 mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about 200 mg, about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 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 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 300mg, about 220mg to about 280mg, about 220mg to about 260mg, about 220mg to about 240mg, about 240mg to about 400mg, about 240mg to about 380mg, about 240mg to about 360mg, about 240mg to about 340mg, about 240mg to about 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 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 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 30 0mg, about 300mg to about 400mg, about 300mg to about 380mg, about 300mg to about 360mg, about 300mg to about 340mg, about 300mg to about 320mg, about 320mg to about 400mg, about 320mg to about 380mg, about 320mg to about 360mg, about 340mg to about 360mg, about 340mg to about 400mg, about 340mg to about 380mg, about 340mg to about 360mg, about 360mg to about 400mg, about 360mg to about 380mg, about 380mg to about 400mg, about 100mg, about 200mg,The compound of Formula I is orally administered once or twice a day in an amount of about 300 mg or about 400 mg), and the pan-ErbB inhibitor is orally administered, for example, once a day on a daily basis (during a certain period of time). In one embodiment, the KRASG12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is orally administered once a day. In one embodiment, the KRAS G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is orally administered twice a day.

[0252] Those skilled in the art will recognize that both in vivo and in vitro assays performed using appropriate, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0253] Those skilled in the art will further recognize that human clinical trials, including first-in-human trials, dose-ranging and efficacy trials, can be accomplished in healthy patients and / or patients with established conditions according to methods well known in the clinical and medical arts.

[0254] Synergy

[0255] In one embodiment, the addition of a pan-ErbB family inhibitor synergistically increases the activity of a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB against a cancer cell line expressing KRas G12C. Any method for determining whether two compounds exhibit synergy can be used to determine the synergy of the combination.

[0256] Several mathematical models have been developed to determine whether two compounds act synergistically, i.e., not just additively. For example, the Loewe additive model (Loewe (1928) Physiol. 27:47-187), the Bliss independence model (Bliss (1939) Ann. Appl. Biol. 26:585-615), the Highest Single Agent model, the ZIP model (Yadav et al. (2015) Comput Struct Biotech J 13:504-513), and other models (Chou and Talalay (1984) Adv Enzyme Regul 22:27-55.#6382953; and Greco et al. (1995) Pharmacol Rev. Rev)》47(2):331-85.#7568331) is a well-known model in the pharmaceutical industry and can be used to calculate a "synergy score" indicating whether synergy is detected and the magnitude of the synergy. Combining these synergy scores generates a comprehensive synergy score that can be used to evaluate and characterize the combination of a KRas G12C inhibitor compound of Formula (I), Formula IA or Formula IB and a pan-ErbB inhibitor.

[0257] In general, mathematical models use data obtained from single agent values ​​to determine the predicted additive effect of the combination compared to the observed effect of the combination. If the observed effect is greater than the predicted effect, the combination is considered synergistic. For example, the Bliss independence model compares the observed combination response (Y O ) and the predicted combined reaction (Y P ), the predicted combined response is obtained based on the assumption that drug-drug interactions do not exist. Generally speaking, if Y O Greater than Y P , it indicates that the combination effect is synergistic.

[0258] In some embodiments, "synergistic effect" as used herein refers to the combination of a KRAS inhibitor or a pharmaceutically acceptable salt thereof and a pan-ErbB family inhibitor or a pharmaceutically acceptable salt thereof, for example, any of the beneficial or desired results, including clinical results or endpoints as described herein, which is greater than the sum of the effects observed when a compound of Formula I, Formula IA or Formula IB or a pharmaceutically acceptable salt thereof (e.g., 1-678 (numbered in WO2019099524) or a pharmaceutically acceptable salt thereof (e.g., Examples No. 234, 359, 478 or 507 or a pharmaceutically acceptable salt thereof)) and a pan-ErbB family inhibitor or a pharmaceutically acceptable salt thereof are administered alone. In one embodiment, the KRas G12C inhibitor is a compound selected from Compound Nos. 1-678 (numbered in WO2019099524) or a pharmaceutically acceptable salt thereof (e.g., Examples No. 234, 359, 478 or 507 or a pharmaceutically acceptable salt thereof). In one embodiment, the pan-ErbB family inhibitor is selected from afatinib, dacomitinib, gefitinib, sabitinib, tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 234 and anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 359 and anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and gefitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and tarotinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 478 and the anti-EGFR antibody cetuximab. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and afatinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and dacomitinib. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and gefitinib.In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and tarotinibi. In one embodiment, the therapeutic combination comprises a therapeutically effective amount of Example 507 and the anti-EGFR antibody cetuximab. In one embodiment of any of the combination therapies, the combination can be used to treat a KRas G12C-related cancer. In one embodiment, the KRas G12C-related cancer is lung cancer.

[0259] In some embodiments, the methods provided herein can be used in patients who have been treated with the combination therapy for between 1 day and 2 years (e.g., between 1 day and 22 months, between 1 day and 20 months, between 1 day and 18 months, between 1 day and 16 months, between 1 day and 14 months, between 1 day and 12 months, between 1 day and 10 months, between 1 day and 9 months, between 1 day and 8 months, between 1 day and 7 months, between 1 day and 6 months, between 1 day and 5 months, between 1 day and 4 months, between 1 day and 3 months, between 1 day and 2 months, between 1 day and 1 month, between one week and 2 years, between 1 week and 22 months, between 1 week and 20 months, between 1 week and 18 months, between 1 day and 7 months, between 1 day and 6 months, between 1 day and 5 months, between 1 day and 4 months, between 1 day and 3 months, between 1 day and 2 months, between 1 day and 1 month, between one week and 2 years, between 1 week and 22 months, between 1 week and 20 months, between 1 week and 18 months, between 1 day and 12 months, between 1 day and 12 months, between 1 day and 12 months, between 1 day and 12 months, between 1 day and 1 Between 1 week and 16 months, Between 1 week and 14 months, Between 1 week and 12 months, Between 1 week and 10 months, Between 1 week and 9 months, Between 1 week and 8 months, Between 1 week and 7 months, Between 1 week and 6 months, Between 1 week and 5 months, Between 1 week and 4 months, Between 1 week and 3 months, Between 1 week and 2 months, Between 1 week and 1 month, Between 2 weeks and 2 years, Between 2 weeks and 22 months, Between 2 weeks and 20 months, Between 2 weeks and 18 months, Between 2 weeks and 16 months, Between 2 weeks and 14 months, Between 2 weeks and 12 months, Between 2 weeks and 10 months, Between 2 weeks and 9 months, Between 2 weeks and 8 months, Between 2 weeks and 7 months , between 2 weeks and 6 months, between 2 weeks and 5 months, between 2 weeks and 4 months, between 2 weeks and 3 months, between 2 weeks and 2 months, between 2 weeks and 1 month, between 1 month and 2 years, between 1 month and 22 months, between 1 month and 20 months, between 1 month and 18 months, between 1 month and 16 months, between 1 month and 14 months, between 1 month and 12 months, between 1 month and 10 months, between 1 month and 9 months, between 1 month and 8 months, between 1 month and 7 months, between 1 month and 6 months, between 1 month and 6 months, between 1 month and 5 months, between 1 month and 4 months, between 1 month and 3 months, between 1 month and between 2 months, between 2 months and 2 years, between 2 months and 22 months, between 2 months and 20 months, between 2 months and 18 months, between 2 months and 16 months, between 2 months and 14 months, between 2 months and 12 months, between 2 months and 10 months, between 2 months and 9 months, between 2 months and 8 months, between 2 months and 7 months, between 2 months and 6 months or between 2 months and 5 months, between 2 months and 4 months, between 3 months and 2 years, between 3 months and 22 months, between 3 months and 20 months, between 3 months and 18 months, between 3 months and 16 months, between 3 months and 14 months, between 3 months and 12 months,between 3 months and 10 months, between 3 months and 8 months, between 3 months and 6 months, between 4 months and 2 years, between 4 months and 22 months, between 4 months and 20 months, between 4 months and 18 months, between 4 months and 16 months, between 4 months and 14 months, between 4 months and 12 months, between 4 months and 10 months, between 4 months and 8 months, between 4 months and 6 months, between 6 months and 2 years, between 6 months and 22 months, between 6 months and 20 months, between 6 months and 18 months, between 6 months and 16 months, between 6 months and 14 months, between 6 months and 12 months, between 6 months and 10 months, or between 6 months and to 8 months) after a period of time (e.g., 1% to 98%, 1% to 95%, 1% to 90%, 1 to 85%, 1 to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 2% to 99%, 2% to 90%, 2% to 85%, 2% to 80%, 2% to 75%, 2% to 70%, 2% to 65%, 2% to 60%, 2% to 55%, 2% to 50%, 2% to 45%, 2% to 40%, 2% to 35%, 2% to 30%, 2% to 25%, 2% to 20%, 2% to 15%, 2% to 10%, 2% to 5%, 4% to 99%, 4% to 95%, 4% to 90%, 4% to 85%, 4% to 80%, 4% to 75%, 4% to 70%, 4% to 65%, 4% to 60%, 4% to 55%, 4% to 50%, 4% to 45%, 4% to 40%, 4% to 35%, 4% to 30%, 4% to 25%, 4% to 20%, 4% to 15%, 4% to 10%, 6% to 99%, 6% to 95%, 6% to 90%, 6% to 85%, 6% to 80%, 6% to 75%, 6% to 70%, 6% to 65 ...6 % to 60%, 6% to 55%, 6% to 50%, 6% to 45%, 6% to 40%, 6% to 35%, 6% to 30%, 6% to 25%, 6% to 20%, 6% to 15%, 6% to 10%, 8% to 99%, 8% to 95%, 8% to 90%, 8% to 85%, 8% to 80%, 8% to 75%, 8% to 70%, 8% to 65%, 8% to 60%, 8% to 55%, 8% to 50%, 8% to 45%, 8% to 40%, 8% to 35%, 8% to 30%, 8% to 25%, 8% to 20%, 8% to 15%, 10% to 99%, 10% to 95%, 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%,10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 10% to 15%, 15% to 99%, 15% to 95%, 15% to 90%, 15% to 8 5%, 15% to 80%, 15% to 75%, 15% to 70%, 15% to 65%, 15% to 60%, 15% to 55%, 15% to 50%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 15% to 20%, 20 ... % to 99%, 20% to 95%, 20% to 90%, 20% to 85%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 35%, 20% to 30%, 20% to 25% , 25% to 99%, 25% to 95%, 25% to 90%, 25% to 85%, 25% to 80%, 25% to 75%, 25% to 70%, 25% to 65%, 25% to 60%, 25% to 55%, 25% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 25% to 30%, 30% to 99%, 30% to 95%, 30% to 90%, 30% to 85%, 30% to 80%, 30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 30% to 45%, 30% to 40%, 30% to 35%, 35% to 99%, 35% to 95%, 35% to 99% 5% to 90%, 35% to 85%, 35% to 80%, 35% to 75%, 35% to 70%, 35% to 65%, 35% to 60%, 35% to 55%, 35% to 50%, 35% to 45%, 35% to 40%, 40% to 99%, 40% to 95%, 40% to 90%, 40% to 85%, 40% to 80% %, 40% to 75%, 40% to 70%, 40% to 65%, 40% to 60%, 40% to 55%, 40% to 60%, 40% to 55%, 40% to 50%, 40% to 45%, 45% to 99%, 45% to 95%, 45% to 95%, 45% to 90%, 45% to 85%, 45% to 80%, 45% to 75%, 45% to 70%, 45% to 65%, 45% to 60%, 45% to 55%, 45% to 50%, 50% to 99%, 50% to 95%, 50% to 90%, 50% to 85%, 50% to 80%, 50% to 75%, 50% to 70%, 50% to 65%, 50% to 60%, 50% to 55%,55% to 99%, 55% to 95%, 55% to 90%, 55% to 85%, 55% to 80%, 55% to 75%, 55% to 70%, 55% to 65%, 55% to 60%, 60% to 99%, 60% to 95%, 60% to 90%, 60% to 85%, 60% to 80%, 60% to 75%, 60% to 70%, 60% to 65%, 65% to 99%, 60% to 95%, 60% to 90%, 60% to 85%, 60% to 80%, 60% to 75%, 60% to 70%, 60% to 65% , 70% to 99%, 70% to 95%, 70% to 90%, 70% to 85%, 70% to 80%, 70% to 75%, 75% to 99%, 75% to 95%, 75% to 90%, 75% to 85%, 75% to 80%, 80% to 99%, 80% to 95%, 80% to 90%, 80% to 85%, 85% to 99%, 85% to 95%, 85% to 90%, 90% to 99%, 90% to 95%, or 95% to 100%) (e.g., compared to the size of one or more solid tumors in the patient prior to treatment).

[0260] In some embodiments of any of the methods described herein, prior to treatment with a composition or method of the invention, the patient was treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, and optionally, the previous treatment was unsuccessful; and / or surgery has been administered to the patient, and optionally, the surgery was unsuccessful; and / or the patient has been treated with a platinum-based chemotherapeutic agent, and optionally, the patient has been previously determined to be non-responsive to treatment with the platinum-based chemotherapeutic agent; and / or the patient has been treated with a kinase inhibitor, and optionally, the previous treatment with the kinase inhibitor was unsuccessful; and / or the patient is treated with one or more other therapeutic agents.

[0261] Reagent test kit

[0262] The present invention also relates to a kit comprising a pan-ErbB family inhibitor or a pharmaceutically acceptable salt thereof and a KRas G12C inhibitor compound of formula (I), formula IA or formula IB or a pharmaceutically acceptable salt thereof. Also provided is a kit comprising a pan-ErbB family inhibitor or a pharmaceutically acceptable salt thereof and a KRas G12C inhibitor compound of formula (I), formula IA or formula IB or a pharmaceutically acceptable salt thereof for treating KRas G12C-related cancers.

[0263] In a related aspect, the present invention provides a kit containing a certain dose of a pan-ErbB family inhibitor and a certain dose of a KRas G12C inhibitor compound of formula (I), formula IA or formula IB, or a pharmaceutically acceptable salt thereof, wherein the dose is an amount effective to inhibit the proliferation of cancer cells in an individual, particularly cancer cells expressing KRas G12C. In some cases, the kit includes instructions for administering the pan-ErbB family inhibitor and the KRas G12C inhibitor compound of formula (I), formula IA or formula IB. The instructions can provide a user with a set of instructions for using the combination of a pan-ErbB family inhibitor and a KRas G12C inhibitor compound of formula (I), formula IA or formula I-B.

[0264] Example A

[0265] Pan-ErbB family inhibitors synergistically increase the activity of KRas G12C inhibitors against KRas G12C-expressing cell lines

[0266] This example illustrates that the combination of exemplary Formula I, Formula IA and Formula 1-B KRas G12C inhibitor compounds or pharmaceutically acceptable salts thereof (e.g., a compound selected from Compound Examples Nos. 1-678 or pharmaceutically acceptable salts thereof, such as Examples Nos. 234, 359, 478 or 507 or pharmaceutically acceptable salts thereof) and a pan-ErbB family inhibitor or pharmaceutically acceptable salts thereof or pharmaceutical compositions synergistically inhibits the growth of tumor cell lines expressing KRas G12C.

[0267] A panel of 9 lung cancer and 1 colorectal cell lines with KRas G12C mutations was assembled to determine whether combining the pan-ErbB family inhibitors disclosed herein with exemplary KRas G12C inhibitors results in synergistic activity. The panel includes NCI-H1373 (ATCC CRL-5866); NCI-H1792 (ATCC CRL-5895); NCI-H2030 (ATCC CRL-5985); NCI-H2122 (ATCC CRL-5985); HCC1171 (KCLB 71171); HCC44 (DSMZ ACC-534); LU99 (RCB1900); SW1573 (ATCC CRL-2170), SW837 (ATCC CCL-235), and KYSE-410 (ECACC 94072023).

[0268] The analysis for determining the synergy score of the pairwise combinations for each cell line was performed in triplicate. Three 96-well plates plus an additional 4 wells of a separate 96-well control plate for determining baseline luminescence were seeded with 2000 cells / well of the specific cell line in a total volume of 90 μl of growth medium appropriate for the cell line, such as RPMI 1640 medium supplemented with 10% FBS and any cell line-specific reagents required for growth. The plates were incubated overnight at 37° C. in a 5% CO2 atmosphere.

[0269] To each designated baseline well, 30 μl of Cell-Titer Glo reagent (CTG; Promega Corporation) was added to each well and the plate was incubated at room temperature with shaking for 20 minutes. Baseline luminescence was quantified using a BMG ClarioStar multi-template reader according to the manufacturer's instructions.

[0270] A series of working stock 1000× drug dilutions in 100% DMSO was prepared, including 8-point single-agent dilutions of an exemplary KRas G12C inhibitor of Formula (I) and 5-point single-agent dilutions of a pan-ErbB family inhibitor. The dilutions used for the KRas G12C inhibitor and the pan-ErbB family inhibitor varied for each individual compound, but were within a 3- to 6-fold / serial dilution range.

[0271] Exemplary KRas G12C inhibitors tested in this example include:

[0272]

[0273]

[0274] *Example number refers to the example number of each compound disclosed in published international PCT application WO2019099524.

[0275] Prepare 10× midi-dose plates containing arrayed single-agent dilutions of exemplary Formula (I) KRas G12C inhibitors or pan-ErbB inhibitors in serum-free RPMI medium. In addition, prepare a matrix of 40 dilution combinations of exemplary Formula (I), Formula IA or Formula IB KRas G12C inhibitors and pan-ErbB family inhibitors as test samples.

[0276] 10 μl of each 10× single agent and 40 dose matrix combination was added to each corresponding well of three 96-well plates seeded with the appropriate cell lines above, and the plates were incubated at 37° C. in a 5% CO atmosphere for 72 hours. A 30 μl aliquot of Cell-Titer Glo reagent (CTG) was added to each test well, the plates were incubated at room temperature with shaking for 20 minutes, and luminescence was quantified using a BMG ClarioStar multi-template reader according to the manufacturer's instructions.

[0277] The raw data and metadata files were used as input files to calculate the percent effect for each treatment condition and analyzed using the following four independent mathematical reference models designed to determine whether two test compounds exhibit synergy: Loewe Additive, Bliss Independent, Highest Single Agent, and ZIP.

[0278] The data output from each mathematical model is the assignment of a relative synergy score. The data reported in Table 3 is the sum of the Loewe summed, Bliss independent, highest single agent and ZIP scores (the "combined synergy score").

[0279] Table 3

[0280] Comprehensive synergy scores for combinations of exemplary pan-ErbB family inhibitors and exemplary KRas G12C inhibitors of Formula (I) against KRas G12C cell lines

[0281]

[0282] Composite scores greater than or equal to 27 are interpreted as synergistic hits, while composite scores between 17 and 26 indicate potential synergy. These results indicate that synergy of the combination of various pan-ErbB family inhibitors and exemplary KRas G12C inhibitor compounds of Formula (I) is observed in most cell lines with KRas G12C mutations listed in Table 1 that are less sensitive to KRas G12C single agent treatment, thereby increasing the sensitivity of KRas G12C cell lines to KRas G12C inhibitors.

[0283] Example B

[0284] In vivo model for testing the combination of KRas G12C inhibitor plus pan-ErbB family inhibitor

[0285] Immunocompromised nude / nude mice were inoculated with cells harboring the KRas G12C mutation or patient-derived tumor samples in the right flank. 3When the size was between 10 and 20 mm, the mice were divided into four groups of 5-12 mice per group. The first group was administered only the vehicle. Depending on the cell line and the activity of the single agent, the second group was administered a single-agent dose of a KRas G12C inhibitor at a concentration that produced the maximum biological effect or less than the maximum biological effect, which did not cause complete tumor regression. Depending on the cell line and the activity of the single agent, the third group was administered a single-agent dose of a pan-ErbB inhibitor at a concentration that produced the maximum biological effect or less than the maximum biological effect, which also did not cause complete tumor regression. The fourth group was administered a single-agent dose of a KRas G12C inhibitor in combination with a single-agent dose of a pan-ErbB family inhibitor. The treatment period varies depending on the cell line, but is generally between 21-35 days. Tumor volume was measured every two to three days using a caliper, and tumor volume was calculated by the following formula: 0.5×(length×width) 2 The higher degree of tumor regression with the combination in this model suggests that combination therapy may have clinically meaningful benefit to treated individuals relative to treatment with a KRas G12C inhibitor alone.

[0286] For example, on day 1, three groups of 20 nude mice were inoculated in the right hind limbs with 5 × 10 6 H2122 cells, KYSE-410 cells, or LU6405 cells (PDX models). When the tumor volume reaches ∼300 mm 3 At 14:00 (Day 11), five mice in each of four groups were administered po daily for 21 days: vehicle alone (10% Captisol), 100 mg / kg KRas G12C inhibitor compound 478 (10% Captisol in 50 mM citrate buffer, pH 5.0), 12.5 mg / kg pan-ErbB family inhibitor afatinib (0.5% methylcellulose / 0.4% Tween-80), or 100 mg / kg KRas G12C inhibitor compound 478 and 12.5 mg / kg afatinib. Tumor volumes were measured on the scheduled days described below. Tumor volumes of five mice / group were averaged and reported in Table 4a (H2122 cell line), Table 4b (KYSE-410 cell line), and Table 4c (LU6405 cells).

[0287] Table 4a

[0288] Mean tumor volume (mm) of H2122 tumor-bearing mice treated with single agents and combination agents 3 )

[0289] Days after implantation Medium Compound 478 Afatinib Compound 478 + afatinib 11 324.86 325.05 324.86 329.49 13 519.62 339.80 429.76 257.56 15 688.80 337.58 573.36 186.03 18 954.95 381.78 694.70 170.99 20 1126.81 462.40 850.85 174.29 22 1350.85 479.48 931.53 194.99 25 1504.56 492.76 1153.42 220.34 27 1574.31 541.06 1307.50 246.90 29 1343.95 537.14 1137.09 246.42 32 1491.71 547.06 1403.33 219.49 34 1559.70 546.96 1830.13 208.05

[0290] Table 4b

[0291] Mean tumor volume (mm) of KYSE-410 tumor-bearing mice treated with single agents and combination agents 3 )

[0292] Days after implantation Medium Compound 478 Afatinib Compound 478 + afatinib 11 308.24 307.30 311.84 313.08 14 333.98 274.64 199.20 137.64 16 388.62 311.34 135.30 77.84 18 418.14 297.62 114.40 49.02 21 420.80 338.18 114.08 34.60 23 494.66 320.42 132.92 33.40 25 519.48 358.68 141.90 27.22 28 577.98 459.20 144.36 24.60 30 673.74 441.60 166.46 21.12 32 738.70 480.62 163.92 21.92 35 889.72 543.02 181.68 18.12 37 905.00 525.86 198.34 18.57

[0293] Table 4c

[0294] Mean tumor volume (mm) of mice bearing LU6405 tumors treated with single agents and combination agents 3 )

[0295] Days after implantation Medium Compound 478 Afatinib Compound 478 + afatinib 11 256.45 256.06 257.48 253.48 14 447.44 308.98 371.98 273.28 18 877.95 324.46 585.54 264.33 21 1215.89 329.09 775.75 199.62 25 1727.56 310.21 1056.23 168.34 28 1950.09 290.88 1197.31 144.99 32 2074.33 257.34 1540.74 82.99 34 2074.33 249.19 1655.49 53.55

[0296] As shown in Table 4a, administration of Compound 478 or afatinib as single agents to H2122 tumor-bearing mice exhibited 85% and 41% tumor growth inhibition, respectively, at day 22 (treatment day 10). The combination of the pan-ErbB family inhibitor afatinib and Compound 478 caused 41% tumor regression at day 22.

[0297] As shown in Table 4b, administration of compound 478 as a single agent to mice bearing KYSE-410 tumors resulted in 64% tumor growth inhibition on day 37 (treatment day 27), while the combination of the pan-ErbB family inhibitor afatinib and compound 478 resulted in 93% tumor regression on day 37 compared to administration of compound 478 as a single agent.

[0298] As shown in Table 4c, administration of compound 478 as a single agent to LU6405-implanted mice resulted in 96% tumor growth inhibition on day 34 (treatment day 24), while the combination of the pan-ErbB family inhibitor afatinib and compound 478 resulted in 67% tumor regression on day 37 compared to administration of compound 478 as a single agent.

[0299] In related experiments, on day 1, the right hind limbs of two groups of 20 nude mice were inoculated with 5 × 10 6 CR6256 cells or CR2528 cells (PDX model). When the tumor volume reaches 200-300mm 3At 11 days (day 11), five mice in each of the first two groups were administered po daily for 21 days: vehicle only (10% cabodisol) or 100 mg / kg KRas G12C inhibitor compound 478 (50 mM citrate buffer containing 10% cabodisol, pH 5.0). The third group of mice was administered 0.25 mg / kg pan-ErbB family inhibitor antibody cetuximab (PBS, pH 7.2) ip every two days, or 100 mg / kg KRas G12C inhibitor compound 478 and 0.25 mg / kg cetuximab ip every three days. Tumor volume was measured on the scheduled days described below. The tumor volume of five mice / group was averaged and reported in Table 5a (CR6256 cell line) and Table 5b (CR2528 cell line).

[0300] Table 5a

[0301] Mean tumor volume (mm) of CR6258 tumor-bearing mice treated with single agents and combination agents 3 )

[0302] Days after implantation Medium Compound 478 Cetuximab Compound 478 + cetuximab 11 187.38 190.54 187.77 192.96 14 330.09 253.11 258.50 270.22 18 510.20 256.91 321.93 277.94 21 773.12 252.05 390.52 257.98 25 1135.07 201.00 503.75 90.49 28 1473.99 128.77 571.30 40.33 32 1638.23 77.44 652.14 26.89 35 1775.29 56.15 678.49 0.00 39 1740.94 44.24 768.49 0.00 42 1965.90 41.80 890.83 0.00 46 1995.68 29.92 975.10 0.00 49 2469.47 19.79 1233.04 0

[0303] Table 5b

[0304] Mean tumor volume (mm) of CR2528 tumor-bearing mice treated with single agents and combination agents 3 )

[0305] Days after implantation Medium Compound 478 Cetuximab Compound 478 + cetuximab 11 264.96 265.11 266.03 265.85 14 449.44 350.48 450.64 313.82 17 671.85 434.64 616.52 347.80 20 1407.65 656.73 1208.84 352.92 24 1796.07 950.91 1924.82 353.44 27 1776.55 1252.80 2424.63 330.12 31 2215.54 1713.13 2741.36 237.44 34 2757.63 222.67 38 220.78 40 184.11

[0306] As shown in Table 5a, administration of Compound 478 as a single agent to CR6258-implanted mice resulted in 71% tumor regression on day 37 (treatment day 27), while the combination of the pan-ErbB family inhibitor cetuximab and Compound 478 resulted in a complete response or 100% tumor regression on day 37 compared to administration of Compound 478 as a single agent.

[0307] As shown in Table 5b, administration of Compound 478 as a single agent to CR2528-implanted mice did not result in single agent anti-tumor activity on day 34 (treatment day 24), whereas the combination of the pan-ErbB family inhibitor cetuximab and Compound 478 resulted in 31% tumor regression on day 37 compared to administration of Compound 478 as a single agent.

[0308] In yet another experiment, on day 1, two groups of 20 nude mice were inoculated in the right hind limbs with 5×10 6 When the tumor volume reached 300 mm 3At 11 days (day 11), five mice in each of four groups were administered po daily for 21 days: vehicle alone (10% cabodisol) or 100 mg / kg KRas G12C inhibitor compound 478 (50 mM citrate buffer containing 10% cabodisol, pH 5.0). A third group of five mice were administered ip every seven days 48 mg / kg pan-ErbB family inhibitor taromab (10 mg / kg β-cyclodextrin), or 100 mg / kg KRas G12C inhibitor compound 478 and ip 48 mg / kg taromab. Tumor volumes were measured on the scheduled days described below. The tumor volumes of five mice / group were averaged and reported in Table 6a (KYSE-410 cell line) and Table 6b (H2122 cell line).

[0309] Table 6a

[0310] Mean tumor volume (mm) of KYSE-410 tumor-bearing mice treated with single agents and combination agents 3 )

[0311] Days after implantation Medium Compound 478 Tacrolimab Compound 478 + Taromumab 11 225.71 231.53 233.57 237.74 19 310.33 237.61 40.90 32.96 26 367.27 273.90 28.99 23.87 33 456.50 306.12 20.30 14.08 40 579.80 334.72 20.81 10.12 47 646.54 354.97 14.67 10.67 54 854.31 431.28 19.20 7.87 61 1129.53 488.08 15.55 7.73

[0312] Table 6b

[0313] Mean tumor volume (mm) of H2122 tumor-bearing mice treated with single agents and combination agents 3 )

[0314] Days after implantation Medium Compound 478 Tacrolimab Compound 478 + Taromumab 11 313.60 314.62 305.56 296.06 14 395.56 281.54 287.64 163.54 18 494.74 233.12 380.02 101.60 21 650.72 277.28 374.78 91.42 26 749.66 252.14 443.76 72.12 28 887.98 277.48 450.62 50.80 32 1027.62 269.90 466.00 66.14 35 1151.30 254.30 471.26 56.78 39 1202.5 276 544.78 63.38 43 1232.14 286.56 507.6 53.46 46 1243.74 304.9 640.975 62.34

[0315] As shown in Table 6a, administration of Compound 478 as a single agent to KYSE-410-implanted mice resulted in 71% tumor growth inhibition on day 61 (treatment day 50), while the combination of the pan-ErbB family inhibitor cetuximab and Compound 478 resulted in 97% tumor regression on day 61 compared to administration of Compound 478 as a single agent.

[0316] As shown in Table 6b, administration of Compound 478 as a single agent to H2122-implanted mice resulted in 3% tumor regression on day 46 (treatment day 35), while the combination of the pan-ErbB family inhibitor cetuximab and Compound 478 resulted in 79% tumor regression on day 37 compared to administration of Compound 478 as a single agent.

[0317] These results indicate that each combination therapy caused a higher amount of tumor growth inhibition than either single agent alone, suggesting enhanced in vivo antitumor efficacy of the combination.

[0318] Although the invention has been described in conjunction with particular embodiments thereof, it will be understood that it is capable of further modifications, and this application is intended to cover any variations, uses, or adaptations of the invention generally following the principles of the invention and including such departures from the present disclosure as come within known or customary practice in the art to which the invention pertains and as may be applied to the basic features set forth above and as fall within the scope of the appended claims.

Claims

1. A use of a pharmaceutical composition for preparing a medicament for treating lung cancer or colorectal cancer in an individual in need thereof, the composition comprising cetuximab and a KRas G12C inhibitor of the following formula: or a combination of pharmaceutically acceptable salts thereof.

2. The use according to claim 1, wherein cetuximab and the KRas G12C inhibitor are administered on the same day.

3. The use according to claim 1, wherein cetuximab and the KRas G12C inhibitor are administered on different days.

4. The use according to claim 1, wherein cetuximab is administered at a maximum tolerated dose.

5. The use according to claim 1, wherein cetuximab and the KRas G12C inhibitor are each administered at a maximum tolerated dose.

6. The use according to claim 1, wherein the composition causes a prolonged duration of overall survival, a prolonged duration of progression-free survival, an increase in tumor growth regression, or a prolonged duration of disease stabilization in the subject.

7. A pharmaceutical composition for use in the preparation of a KRas G12C inhibitor compound of the following formula: or a pharmaceutically acceptable salt thereof, The pharmaceutical composition comprises a therapeutically effective amount of cetuximab and a KRas G12C inhibitor of the following formula: and wherein cetuximab synergistically increases the sensitivity of the cancer cells to the KRas G12C inhibitor.

8. The use according to any one of claims 1 to 7, wherein the therapeutically effective amount of the KRas G12C inhibitor is between 0.01 mg / kg / day and 100 mg / kg / day.

9. The use according to claim 8, wherein the therapeutically effective amount of the KRas G12C inhibitor is between 0.1 mg / kg / day and 50 mg / kg / day.

10. The use according to any one of claims 1 to 7, wherein the therapeutically effective amount of cetuximab is between 0.01 mg / kg / day and 100 mg / kg / day.

11. The use according to claim 10, wherein the therapeutically effective amount of cetuximab is between 0.1 mg / kg / day and 50 mg / kg / day.

12. The use according to any one of claims 1 to 7, wherein the lung cancer is non-small cell lung cancer.

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