EA044829B1 - METHODS OF COMBINATION THERAPY - Google Patents

Description

Field of technology

The invention relates to methods of combination therapy suitable for the treatment of cancer. In particular, the invention relates to therapeutically effective combinations of an inhibitor of Src homology domain 2 (SH2), (SHP-2) and a KRas G12C inhibitor, to pharmaceutical compositions containing these inhibitors, to kits containing the compositions, and to methods for their applications.

State of the art

Kirsten's rat sarcoma viral oncogene homolog 2 (KRas) is a small GTPase and is a member of the Ras oncogene family. KRas serves as a molecular switch that cycles between inactive (GDP-bound) and active (GTP-bound) states to transmit upstream cellular signals from multiple tyrosine kinases to downstream cascade effectors that regulate a variety of processes, including cell proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

The effect of activated KRas on malignancies was noted more than thirty years ago (eg, see Der et al., (1982) Proc. Natl Acad. Sci. USA 79(11):3637-3640). Abnormal KRas expression occurs in approximately 20% of all cancers, and oncogenic KRas mutations, which stabilize GTP binding and lead to constitutive activation of KRas and subsequent signaling, are reported in approximately 25–30% of lung adenocarcinomas (e.g., see below). Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12): 928-942 doi: 10.1038/nrd428). Single nucleotide substitutions that cause missense mutations in codons 12 and 13 of the primary amino acid sequence of KRas account for approximately 40% of the reported KRas driver mutations in lung adenocarcinoma, with the G12C transversion being the most common activating mutation (for example, see Dogan et al., ( 2012) Clin Cancer Res 18(22):6169-6177, published online September 26, 2012, doi: 10.1158/1078-0432.CCR-11-3265).

The well-studied role of KRas in malignancies and the discovery of these common KRas mutations in different tumor types have made KRas an extremely attractive target for cancer therapy in the pharmaceutical industry. Despite thirty years of large-scale research efforts to develop KRas inhibitors for the treatment of cancer, no KRas inhibitor has demonstrated sufficient safety and/or efficacy to warrant regulatory approval (e.g., see McCormick (2015) Clin Cancer Res. 21 (8 ):1797-1801).

Compounds that inhibit KRas activity remain highly desirable and are the subject of research, including compounds that disrupt effectors such as guanine nucleotide exchange factors (for example, see Sun et al., (2012) Agnew Chem Int Ed Engl. 51 (25):6140-6143 doi: 10.1002/anie201201358), and also target KRas G12C (for example, see Ostrem et al., (2013) Nature 503:548-551). It is clear that there is ongoing interest and efforts to develop KRas inhibitors, in particular inhibitors of activating KRas mutants, including KRas G12C.

Although the KRas G12C inhibitors described herein are highly potent inhibitors of KRas G12C enzymatic activity and, when used as a single agent, exhibit activity that inhibits the proliferation of KRas G12C mutant cell lines in vitro, the relative activity and/or observed The maximum effect for any given KRas G12C inhibitor may be different for different KRAS mutant cell lines. The reason or reasons for the observed spectrum of activity and maximum effect are not fully understood, but certain cell lines appear to have different intrinsic resistance than others. Thus, there is a need to develop alternative approaches to maximize the potency, efficacy, therapeutic index, and/or clinical benefit of KRas G12C inhibitors in vitro and in vivo.

The combination therapy of the present invention, in one aspect, synergistically increases the activity of KRas G12C inhibitors, resulting in increased effectiveness of the KRas G12C inhibitors described herein. The combination therapy of the present invention, in another aspect, provides improved clinical benefit in patients compared to treatment with the KRas G12C inhibitors described herein as a single agent.

Brief description of the invention

According to one aspect of the invention, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SHP-2 inhibitor and a KRAS G12C inhibitor, wherein said KRas G12C inhibitor is

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or a pharmaceutically acceptable salt thereof.

In one embodiment, said SHP-2 inhibitor is SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine dihydrochloride); RMC-4550 (3-(((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(2,3-dichlorophenyl)-5 -methylpyrazin-2yl)methanol), RMC-4360 or TNO155 (Novartis).

In one embodiment, said SHP-2 inhibitor is SHP-099.

In one embodiment, said SHP-2 inhibitor is RMC-4550.

In one embodiment, said SHP-2 inhibitor is RMC4360 or TNO155.

In one embodiment, a therapeutically effective amount of said combination of an SHP-2 inhibitor and a KRAS G12C inhibitor provides increased duration of overall survival, increased duration of progression-free survival, increased regression of tumor growth, increased suppression of tumor growth, or increased duration of stable disease in subjects compared to treatment only KRas G12C inhibitor.

Another aspect of the present invention relates to a pharmaceutical composition for the treatment of cancer expressing KRas G12C, containing a therapeutically effective amount of a combination of an SHP-2 inhibitor and a KRas G12C inhibitor, as defined above, and a pharmaceutically acceptable excipient. Another aspect of the present invention relates to a method of inhibiting KRas G12C activity in a cell, comprising contacting the cell in which it is desired to inhibit KRas G12C activity with an effective amount of an SHP-2 inhibitor and a KRas G12C inhibitor compound as defined above, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions containing them.

Another aspect of the present invention relates to a method of increasing the susceptibility of a cancer cell expressing KRas G12C to a KRas G12C inhibitor compound, comprising administering to a subject undergoing treatment targeting KRas G12C the compound or a pharmaceutically acceptable salt thereof, as defined above, alone or in combinations with pharmaceutically acceptable carriers, excipients or diluents, and a therapeutically effective amount of an SHP-2 inhibitor.

In one embodiment, the said therapeutically effective amount of the KRas G12C inhibitor in combination is from 0.01 to 100 mg/kg per day.

In one embodiment, said cancer is a cancer expressing KRas G12C selected from the group consisting of heart diseases: sarcomas (angiosarcomas, fibrosarcomas, rhabdomyosarcomas, liposarcomas), myxomas, rhabdomyomas, fibromas, lipomas and teratomas; lungs: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, VIPoma), small intestine (adenocarcinoma, lymphoma, carcinoma) cinoid tumors, Kaposi's sarcoma, leiomyomas, hemangiomas, lipomas, neurofibromas, fibromas), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary system: kidneys (adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate gland (adenocarcinoma, sarcoma), testicles (seminoma, teratoma, embryonal carcinoma, teratocarcinomas, choriocarcinomas, sarcomas, interstitial cell carcinomas, fibromas, fibroadenomas, adenomatoid tumors, lipomas); liver: hematomas (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, renal cell adenoma, hemangioma; biliary tract: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; bone: osteogenic sarcoma (osteosarcoma)

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In one embodiment, said cancer is non-small cell lung cancer.

Another aspect of the present invention relates to a kit for the treatment of cancer expressing KRas G12C in a subject, containing the pharmaceutical composition described above, and an insert with instructions for the administration of the composition.

Another aspect of the present invention relates to a kit for the treatment of cancer expressing KRas G12C in a subject, comprising: a) a pharmaceutical composition containing an SHP2 inhibitor, and b) a pharmaceutical composition containing a KRas G12C inhibitor representing

or a pharmaceutically acceptable salt thereof, and an insert with instructions for administering said compositions.

Detailed Description of the Invention

The present invention relates to methods of combination therapy for the treatment of cancers associated with KRas G12C. In particular, the present invention relates to methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same and a KRAS G12C inhibitor of formula (I), formula I-A or formula IB or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing it, to pharmaceutical compositions containing therapeutically effective amounts of inhibitors, to kits containing the compositions, and to methods of using them.

Combinations of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, with a KRas G12C inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, synergistically enhance the activity of the KRas G12C inhibitor compounds of formula (I), formula I-A or formula I-B against cancer cells expressing KRas G12C, and thereby increase the effectiveness and therapeutic index of the KRas G12C inhibitor compounds of formula (I), formula I-A or formula I-B or pharmaceutically acceptable salts thereof.

Definitions

Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which this invention relates. The contents of all patents, patent applications and publications referenced herein are incorporated by reference.

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As used herein, KRas G12C refers to a mutant form of the mammalian KRas protein that contains the amino acid substitution of cysteine instead of glycine as the amino acid at position 12. The definition of amino acid codons and residue positions in human KRas is based on the amino acid sequence identified in UniProtKB/Swiss-Prot P01116: Variant

p.Gly12Cys.

As used herein, KRas G12C inhibitor refers to the compounds of the present invention which are represented by Formula (I), Formula I-A and Formula I-B, such as those described herein. These compounds may negatively modulate or inhibit, in whole or in part, the enzymatic activity of KRas G12C. The KRas G12C inhibitors of the present invention react with and irreversibly bind KRas G12C to form a covalent adduct with the sulfhydryl side chain of the cysteine residue at position 12, resulting in inhibition of the enzymatic activity of KRas G12C. In one embodiment, the KRas G12C inhibitor is a compound selected from Compound Nos. 1-678 (as numbered in WO2019099524) or pharmaceutically acceptable salts thereof (e.g., Examples No. 234, 359, 478, or 507, or pharmaceutically acceptable salts thereof ).

Disease or disorder associated with KRas G12C as used herein refers to diseases or disorders associated with, mediated by, or having a mutation in KRas G12C. A non-limiting example of a KRas G12C-associated disease or disorder is KRas G12C-associated cancer.

As used herein, SHP-2 or SHP2 refers to a mammalian non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, which is involved in signal transduction through the Rasmitogen-activated protein kinase, JAK-STAT or phosphoinositol 3-kinase-AKT pathways.

As used herein, an SHP-2 inhibitor or SHP2 inhibitor refers to a compound that can negatively modulate or inhibit, in whole or in part, the enzymatic activity of SHP-2 phosphatase.

As used herein, the terms subject, individual, or patient are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and/or experienced at least one symptom of the disease or disorder being treated and/or prevented. In some embodiments, a subject is identified or diagnosed with a cancer that has a KRas G12C mutation (e.g., as determined using a regulatory agency approved, e.g., FDA-approved, study or kit). In some embodiments, the subject suffers from a tumor that is KRas G12C mutation positive (eg, as determined using a regulatory agency approved assay or kit). The subject may be a subject with tumor(s) that are KRas G12C mutation positive (eg, where positive status is determined using a regulatory agency approved, e.g., FDA approved, study or kit). The subject may be a subject whose tumors have a KRas G12C mutation (eg, where the tumor entity is identified using a regulatory agency approved, eg, FDA approved, kit or study). In some embodiments, the subject is believed to be suffering from cancer associated with the KRas G12C gene. In some embodiments, the subject has a medical record indicating that the subject is suffering from a tumor that has a KRas G12C mutation (and, optionally, the medical record indicates that the subject should be treated with any of the compositions provided herein).

The term pediatric patient as used herein refers to a patient under 16 years of age at the time of diagnosis or treatment. The term childhood can be further divided into different subpopulations, including: newborns (from birth to the first month of life); infants (from 1 month to two years); children (from two years to 12 years); and adolescents (from 12 years to 21 years (up to and including the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21e ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd ed. Baltimore: Williams &Wilkins; 1994.

In some embodiments of any of the methods or uses described herein, the test is used to determine whether a patient may have the KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample (such as a paraffin-embedded biopsy sample) taken in a patient (eg, 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 at increased risk of developing a KRas G12C-related cancer), and may include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, Break-apart probe FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR amplification (e.g., RT-PCR, quantitative RT-PCR real-time, allele-specific genotyping or qPCR) It is well known in the art that assays are typically conducted, for example, using at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

The term regulatory authority is a government body that approves the medical use of pharmaceutical agents in a given state. For example, a non-limiting example of a regulatory agency is the US Food and Drug Administration (FDA).

The term amino refers to -NH2;

The term acyl refers to -C(O)CH ₃ .

The term alkyl as used herein refers to linear or branched aliphatic groups containing 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms, which are 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, t-butyl, pentyl and hexyl.

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

The term haloalkyloxy refers to -O-haloalkyl.

An alkylene group is an alkyl group, as defined above, that is located between two other chemical groups and serves to connect them. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene and butylene.

The term alkoxy refers to -OC ₁ -C ₆ alkyl.

The term cycloalkyl as used herein includes saturated and partially unsaturated cyclic hydrocarbon groups containing from 3 to 12 carbon atoms, such as 3 to 8 carbon atoms, for example 3 to 6 carbon atoms, wherein the cycloalkyl group is further optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

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

As used herein, the term hydroxyalkyl refers to -alkyl-OH.

The term dihydroxyalkyl refers to an alkyl group, as defined herein, where each of the two carbon atoms is replaced by a hydroxyl group.

The term alkylaminyl refers to -TC ^x -alkyl, where R ^x represents hydrogen. In one embodiment, R ^x is hydrogen.

The term dialkylaminyl refers to -N(R ^y )2, where each R ^y represents C1-C ₃ alkyl.

The term alkylaminylalkyl refers to -alkyl-NR ^x -alkyl, where R ^x represents hydrogen. In one embodiment, R ^x is hydrogen.

The term dialkylaminyl-alkyl refers to -alkyl-N(R ^y )2, where each R ^y represents Ο1-Ο4 alkyl, and the alkyl in -alkyl-N(R ^y ) ₂ may be optionally substituted with hydroxy or hydroxyalkyl.

An aryl group is a C ₆ -C ₁₄ aromatic moiety containing one to three aromatic rings, which is optionally substituted. In one embodiment, the aryl group is a C ₆ -C1o aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl.

An aralkyl or arylalkyl group contains an aryl group covalently bonded to an alkyl group, each of which independently may be optionally substituted or unsubstituted. An example of an aralkyl group is (C1- _C6 )alkyl( _C6 - _C10 )aryl, including but not limited to benzyl, phenethyl and naphthylmethyl. An example of a substituted aralkyl is aralkyl, in which the alkyl group is replaced by hydroxyalkyl.

A heterocyclyl or heterocyclic group is a ring structure containing from about 3 to about 12 atoms, for example from 4 to 8 atoms, where one or more atoms are selected from the group consisting of N, O and S, the remaining atoms in the ring being carbon. The heterocyclyl may be a monocyclic, bicyclic, spirocyclic or bridged ring system. The heterocyclic group is optionally substituted with R ⁷ at a carbon or nitrogen atom in one or more positions, where R ⁷ is as defined for Formula I. The heterocyclic group is also independently and optionally substituted at the nitrogen atom with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl , alkoxycarbonyl, aralkoxycarbonyl or at the sulfur atom oxo or lower alkyl. Examples of heterocyclic groups include, but are not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piper idonyl, 4piperidinonyl, thiomorpholinyl, thiomorpholinyl-1, 1-dioxide, morpholinyl, oxazepanil, azabicyclohexanes, azabicycloheptanes and oxa-azabicycloheptanes. Compounds containing adjacent O and/or S atoms in the ring are specifically excluded from the scope of this term.

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

As used herein, the term heteroaryl refers to groups containing from 5 to 14 ring atoms, preferably 5, 6, 9 or 10 ring atoms; containing 6, 10 or 14 tm electrons combined into a common cyclic system; and containing, in addition to carbon atoms, from one to three heteroatoms in the ring selected from the group consisting of N, O and S. Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl , benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanil, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3Nindolyl, iso benzofuranyl, isochromanil, isoindazolyl, isoindolinyl , isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl . , pyridothiazole, pyridinyl, pyridyl, pyrimidinyl , pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4Hquinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadi azolyl , 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1 ,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

A heteroarylalkyl group contains a heteroaryl group covalently bonded to an alkyl group, where the site of radical attachment is at the alkyl group, each of which is independently optionally substituted or unsubstituted. Examples of heteroarylalkyl groups include a heteroaryl group containing 5, 6, 9 or 10 ring atoms bonded to a C1-C6 alkyl group. Examples of heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl, quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl, isoquinolinylmethyl, isoindolylmethyl, cinnolinylmethyl and benzothiophenylethyl. Compounds containing adjacent O and/or S atoms in the ring are specifically excluded from the scope of this term.

As used herein, an effective amount of a compound is an amount sufficient to negatively modulate or inhibit the activity of the target target, i.e. SHP-2 or KRas G12C. The amount may be administered as a single dose, or may be administered according to a regimen in which it is effective.

As used herein, a therapeutically effective amount of a compound is an amount sufficient to attenuate or alleviate in some way a symptom, or stop or reverse the progression of a condition, or negatively modulate or inhibit the activity of SHP-2 or KRas G12C. The amount may be administered as a single dose, or may be administered according to a regimen in which it is effective.

As used herein, a therapeutically effective amount of a combination of two compounds is an amount that, when used together, synergistically increases the activity of the combination compared to the therapeutically effective amount of each compound in the combination, i.e. provides more than just an additive effect. Alternatively, a therapeutically effective amount in vivo of a combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing thereof, and a KRas G12C inhibitor compound of formula (I), formula I-A or formula I-B or a pharmaceutically acceptable salt thereof, or containing its pharmaceutical composition, provides increased duration of overall survival (OS) in subjects compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount in vivo of a combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, and a KRas G12C inhibitor compound of formula (I), formula I-A or formula I-B or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it provides increased progression-free survival (PFS) in subjects compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount in vivo of a combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, and a KRas G12C inhibitor compound of formula (I), formula I-A or formula I-B or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it provides increased tumor regression in subjects compared to treatment with the KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount in vivo of a combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, and a KRas G12C inhibitor compound of formula (I), formula I-A or formula I-B or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it provides increased suppression of tumor growth in subjects compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount in vivo of a combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, and a KRas G12C inhibitor compound of formula (I), formula I-A or formula I-B or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, provides an increase in the duration of disease stabilization in subjects compared to treatment with a KRas G12C inhibitor alone. The amount of each compound in the combination may be the same as or different from the therapeutically effective amount of each compound when administered separately as monotherapy, provided that the combination is synergistic. Said amounts may be administered as a single dose, or may be administered according to a regimen in which they are effective. As used herein, treatment refers to any method that reduces or otherwise beneficially modifies the symptoms or pathological signs of a condition, disorder or disease. Treatment also includes any pharmaceutical use of the compositions described herein.

As used herein, alleviation of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, which may be permanent or temporary, long-term or short-term, that can be attributed to or associated with the administration of the composition.

As used herein, the term approximately, when used to modify a numerically defined parameter (eg, the dose of a KRAS inhibitor or an SHP-2 inhibitor, or pharmaceutically acceptable salts thereof, or the duration of treatment in a combination therapy method described herein), means that the specified parameter can vary within 10% below or above the specified numerical value of this parameter. For example, a dose of approximately 5 mg/kg per day may range from 4.5 mg/kg to 5.5 mg/kg. The implication is that approximately, if used at the beginning of a list of parameters, modifies each parameter. For example, about 0.5 mg, 0.75 mg, or 1.0 mg means about 0.5 mg, about 0.75 mg, or about 1.0 mg. Likewise, 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 approximately 25% or more.

Inhibitor compounds

In accordance with one aspect of the invention, methods are provided herein for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same and a KRAS G12C inhibitor of formula (I), formula I-A or formula IB or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same.

1. SHP-2 inhibitors.

Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2) is a mammalian non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that is involved in signal transduction through the Ras-mitogen-activated protein kinase, JAK-STAT, or phosphoinositol 3-kinase pathways. (PI3K)-AKT-mTOR. The SHP-2 polypeptide contains two Src homology 2 (SH2) domains (NSH2 and C-SH2) located in the N-terminal region and two possible Grb2 SH2 domain binding sites located in the C-terminal region. SHP-2 has been shown to trigger a mechanism of non-mutational drug resistance in response to tyrosine kinase inhibitors (TKIs). For example, increased SHP-2 phosphatase activity has been shown to confer resistance to the TKI inhibitor imatinib (e.g., see Li et al., (2018) Toxicol. Appl. Pharmacol. 360-249-256). The addition of an SHP-2 inhibitor has been shown to overcome resistance by blocking both the RAF/MEK/ERK and PI3K/AKT/mTOR pathways. In addition, adaptive resistance to direct KRas G12C inhibition via reactivation of the MAPK pathway and failure to inactivate the PI3K/AKT/mTOR pathway were rescued by dual inhibition using PI3K inhibition (e.g., see Misale et al., Clin. Cancer Res., pub. online doi: 10.1158/1078-0432.CCR 18-0368). Given that SHP-2 can modulate the PI3K/AKT/mTOR pathway, dual inhibition using SHP-2 may overcome different mechanisms of cell-intrinsic adaptive and/or acquired resistance to direct KRas G12C inhibition.

Several inhibitors have been developed that have activity against SHP-2. Examples of SHP-2 inhibitors include, but are not limited to, SHP-099 (6-(4-amino4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine dihydrochloride); RMC-4550 (3-((3S,4S)-4-amino-3-methyl2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin- 2-yl)methanol), RMC-4630 (Revo- 7 044829 lution Medicine) and TNO155 (Novartis). RMC-4630 and TNO155 are in phase 1 clinical trials in adults with specific advanced solid tumors.

Methods for preparing SHP-2 inhibitors are well known to those skilled in the art, and SHP-2 inhibitors can be obtained from a variety of commercial suppliers in forms suitable for both research and human use. In addition, SHP-2 inhibitors suitable for use in the compositions and methods described herein, and methods for preparing said inhibitors, are described in published US patent applications No.: US20190127378; US20180251471; US 20180201623; US 20180186770; US20180170862; US 20180065949; US20170204080; US20170166510; US20170011975; US201200334186; US20120257184; US20110190315; US20090042788; US20080194563; US20080058431; US20080058431; US20040121384; US20040043434; and US20040110800.

2. KRas G12C inhibitors.

In one embodiment, the KRas G12C inhibitors used in the methods are compounds of formula (I)

R ¹

or pharmaceutically acceptable salts thereof, wherein X represents a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R ⁸ ;

Y represents a bond, O, S or NR ⁵ ;

R ¹ represents -C(O)C(R ^A )

C(R ^B )p or -SO2C(R ^a )

C(R ^b )p;

R ² is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -Z-NR ⁵ R ¹⁰ , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl or heteroarylalkyl, and each of Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl and heteroarylalkyl can be optionally substituted with one or more R ⁹ ;

Z represents C ₁ -C ₄ alkylene;

each R ³ independently represents C ₁ -C ₃ alkyl, oxo or haloalkyl;

L represents a bond, -C(O)- or C ₁ -C ₃ alkylene;

R ⁴ represents hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, and each of cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted by one or more R ⁶ or R ⁷ ;

each R ⁵ independently represents hydrogen or C1-C3 alkyl;

R ⁶ represents cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl or heteroaryl, and each of cycloalkyl, heterocyclyl, aryl or heteroaryl may be optionally substituted by one or more R ⁷ ;

each R ⁷ independently represents halogen, hydroxyl, C ₁ -C ₆ alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;

R ⁸ represents oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -C(O) ^OR5 , -C(O)N( ^R5 )2, -N( ^R5 ) ₂ , and C ₁ -C ₃ alkyl may be optionally substituted with cyano, halogen, -OR ⁵ , -N(R ⁵ )2 or heteroaryl;

each R ⁹ independently represents hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, di-alkylaminyl, dialkylamidoalkyl or dialkylaminylalkyl, wherein C1- C6 alkyl may be optionally substituted with cycloalkyl;

each R ¹⁰ independently represents hydrogen, acyl, C ₁ -C ₃ alkyl, heteroalkyl or hydroxyalkyl;

R ¹¹ represents haloalkyl;

R ^a is absent or represents hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R ⁵ )2 or hydroxyalkyl;

each R ^B is independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR5R ¹¹ , -C(O)N(R ⁵ )2, -NHC(O )C ₁ -C ₃ alkyl, -CH ₂ NHC(O)C ₁ -C ₃ alkyl, heteroaryl, heteroarylalkyl, dialkylaminyl alkyl or heterocyclyl alkyl, wherein the heterocyclyl moiety is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and C ₁ -C ₃ alkyl, wherein the heteroaryl or heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R ⁷ ;

m is zero or an integer from 1 to 2;

p is equal to one or two; and if it is a triple bond, then R ^A is absent, R ^B is present and p is equal to one; or if a double bond, then R ^A is present, R ^B is present and p is two, or R ^A , R ^B and the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl, optionally substituted by one or more ^R7 .

In one embodiment, the KRas G12C inhibitors used in the methods described herein include compounds having Formula I-A

of Formula I, R ¹¹ is hydrogen, methyl or hydroxyalkyl, and the piperidinyl ring is optionally substituted with R ⁸ , R ⁸ being as defined for Formula I.

In one embodiment, the KRas G12C inhibitors used in the methods described herein include compounds having Formula I-B

R ¹

R

R ²

Formula 1-B or pharmaceutically acceptable salts thereof, wherein ^R1 , ^R3 , ^R4 , ^R9 , ^R11 , L and m are as defined for Formula I.

Non-limiting examples of KRas G12C inhibitor compounds of formula (I), formula I-A and formula I-B suitable for the methods described herein are selected from the group consisting of examples No. 1-678 (as numbered in WO 2019099524), including the following structures:

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or pharmaceutically acceptable salts of these compounds.

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In one embodiment, the KRas G12C inhibitor is selected from

or pharmaceutically acceptable salts of these compounds.

In one embodiment, the KRas G12C inhibitor is

(also described as Example 234) or a pharmaceutically acceptable salt thereof.

In one embodiment, the KRas G12C inhibitor is

(also described as Example 359) or a pharmaceutically acceptable salt thereof.

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In one embodiment, the KRas G12C inhibitor is

(also described as Example 478) or a pharmaceutically acceptable salt thereof.

In one embodiment, the KRas G12C inhibitor is

(also described as Example 507) or a pharmaceutically acceptable salt thereof. The KRas G12C inhibitors used in the methods of the present invention may have one or more chiral centers and can be synthesized as mixtures of stereoisomers, isomers of the same composition, differing in the arrangement of atoms in space. The compounds can be used as mixtures, or the individual components/isomers can be separated using commercially available reagents and traditional methods for isolating stereoisomers and enantiomers known to those skilled in the art, for example, using CHIRALPAK® (SigmaAldrich) or CHIRALCEL® chiral HPLC columns (Diacel Corp) according to the manufacturer's instructions. Alternatively, the compounds of the present invention can be synthesized using optically pure chiral reagents and intermediates to obtain individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included within the scope of the invention. It should be understood that, unless otherwise indicated, whenever compounds of the invention are mentioned in the specification, including the claims, the term compound includes all chiral (enantiomeric and diastereomeric) and racemic forms.

In one embodiment, the KRas G12C inhibitor compounds of Formula I, Formula I-A, or Formula I-B used in the methods include trifluoroacetic acid salts of the above compounds.

Methods for preparing the KRas G12C inhibitors described herein are known. For example, jointly applicant published international PCT applications No. W02017201161 and WO 2019099524 describe general reaction schemes for the preparation of compounds of formula I, formula I-A or formula I-B, and also propose detailed synthetic methods for the preparation of each KRas G12C inhibitor described in this document.

SHP-2 inhibitors and KRas G12C inhibitor compounds of formula (I), formula I-A or formula I-B or pharmaceutically acceptable salts thereof can be included in pharmaceutical compositions.

Pharmaceutical compositions.

According to another aspect, the invention provides pharmaceutical compositions comprising an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof and a KRas G12C inhibitor or a pharmaceutically acceptable salt thereof according to the invention and a pharmaceutically acceptable carrier, excipient or diluent, which can be used in the methods described in this document. The SHP-2 inhibitor or a pharmaceutically acceptable salt thereof and the KRas G12C inhibitor or a pharmaceutically acceptable salt thereof may be independently formulated in any manner, well

-70044829 is known in the art, and can be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal or intrarectal. In certain embodiments, the SHP-2 inhibitor or a pharmaceutically acceptable salt thereof and the KRas G12C inhibitor or a pharmaceutically acceptable salt thereof are administered intravenously in a hospital setting. In one embodiment, administration may be done orally.

The characteristics of the carrier 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, cell culture, tissue, or organism, and that does not adversely affect the effectiveness of the biological activity of the active ingredient(s). Thus, the compositions may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubility enhancers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

As used herein, the term pharmaceutically acceptable salt refers to salts that retain the desired biological activity of the above compounds and have minimal or no adverse toxicological effects. Examples of these salts include, but are not limited to, acid addition salts made with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and salts made with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic 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 in particular include a salt of the formula -NR+Z, where R is hydrogen, alkyl or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzylate and diphenylacetate).

The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to a patient without causing serious toxic effects to the patient being treated. In one embodiment, the dosage of the active compound for all of the above conditions is from about 0.01 to about 300 mg/kg, such as from 0.1 to 100 mg/kg per day, and as a further example from 0.5 to about 25 mg per kilogram of consumer body weight per day. Typical topical dosage is 0.01-3% (w/w) in a suitable vehicle. The effective dosage range for pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound delivered. If the derivative is active as such, then the effective dosage can be assessed as described above, taking into account the weight of the derivative or other means known to those skilled in the art.

Pharmaceutical compositions containing an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, and a KRas G12C inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, can be used in the methods of use described herein.

Joint introduction

The SHP-2 inhibitor or a pharmaceutically acceptable salt thereof and the KRas G12C inhibitor or a pharmaceutically acceptable salt thereof may be included in different or separate dosage forms that may be co-administered one after the other. If the modes of administration are the same (eg, oral), then another option may be to include the two active compounds in a single form for co-administration, however, both modes of co-administration are part of the same method or therapeutic regimen.

Pharmaceutical compositions containing an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof and/or a KRas G12C inhibitor or a pharmaceutically acceptable salt thereof for use in the methods may be intended for simultaneous, separate or sequential use. In one embodiment, the SHP-2 inhibitor or a pharmaceutically acceptable salt thereof is administered prior to administration of the KRas G12C inhibitor compound of formula (I), formula I-A or formula I-B or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP-2 inhibitor or a pharmaceutically acceptable salt thereof is administered after administration of a KRas G12C inhibitor compound of formula (I), formula I-A or formula I-B or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP-2 inhibitor or a pharmaceutically acceptable salt thereof is administered at approximately the same time as the KRas G12C inhibitor compound of formula (I), formula I-A or formula I-B, or a pharmaceutically acceptable salt thereof.

In some cases, separate administration of each inhibitor at different times by different routes may be preferable. Thus, the components of the combination, i.e. compound - 71 044829 KRas G12C inhibitor of formula (I), formula I-A or formula I-B or a pharmaceutically acceptable salt thereof and the SHP-2 inhibitor or a pharmaceutically acceptable salt thereof need not be administered at substantially the same time or in any particular order.

Drugs used in oncology are typically administered at the maximum tolerated dose (MTD), which is the highest dose of the drug that will not cause unacceptable side effects. In one embodiment, each of the KRas G12C inhibitor or a pharmaceutically acceptable salt thereof, or a composition containing it, and the SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a composition containing it, are administered in respective IVDs. In one embodiment, the KRas G12C inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, is administered to the IVD, and the SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, is administered in a lower amount compared to the IVD . In one embodiment, the KRas G12C inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, is administered in a lower amount compared to the IVD, and the SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, is administered to the IVD . In one embodiment, each of the KRas G12C inhibitor or a pharmaceutically acceptable salt thereof, or a composition containing thereof, and the SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a composition containing thereof, is administered in lower amounts than the corresponding MTDs. The timing of administration can be adjusted so that the maximum pharmacokinetic effect of one compound coincides with the maximum pharmacokinetic effect of the other compound.

In one embodiment, one dose of a KRas G12C inhibitor compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, is administered daily (i.e., at approximately 24-hour intervals) (or QD). In another embodiment, two doses of a KRas G12C inhibitor compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, are administered daily (ie, BID). In another embodiment, three doses of a KRas G12C inhibitor compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, are administered daily (ie, TID).

In one embodiment, the SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, is administered to the QD. In another embodiment, the SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, is administered to the BID. In another embodiment, the SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, according to the invention is administered by TID.

In one embodiment, each of one dose of a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing thereof, and an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or containing the same pharmaceutical composition, administered once a day. Examples of SHP-2 inhibitors suitable for the proposed compositions and methods include, but are not limited to, SHP099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazine-dihydrochloride 2-amine); RMC4550 (3-(((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine -2-yl)methanol), RMC-4630 and TNO155 (Novartis).

Combination therapy methods

In accordance with one aspect of the invention, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same and a KRAS G12C inhibitor of formula (I), formula I-A or formula IB or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same. In one embodiment, the cancer is a KRas G12C-associated cancer. In one embodiment, the cancer associated with KRas G12C is lung cancer.

In yet another aspect, the invention provides methods for increasing the susceptibility of a cancer cell to a KRas G12C inhibitor, comprising contacting the cancer cell with an effective amount of a combination of a KRas G12C inhibitor compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt thereof, or containing a pharmaceutical composition thereof, and an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, wherein the SHP-2 inhibitor synergistically increases the susceptibility of the cancer cell to the KRas G12C inhibitor. In one embodiment, contacting occurs in vitro. In one embodiment, contacting occurs in vivo.

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In one embodiment, the combination therapy includes a combination of a compound having the formula

or a pharmaceutically acceptable salt thereof and an SHP-2 inhibitor. In one embodiment, the SHP-2 inhibitor is SHP-099. In one embodiment, the SHP-2 inhibitor is RMC-4550. In one embodiment, the SHP-2 inhibitor is RMC4360. In one embodiment, the SHP-2 inhibitor is TNO155. In one embodiment, the combination therapy includes a combination of a compound having the formula

or a pharmaceutically acceptable salt thereof and an SHP-2 inhibitor. In one embodiment, the SHP-2 inhibitor is SHP-099. In one embodiment, the SHP-2 inhibitor is RMC-4550. In one embodiment, the SHP-2 inhibitor is RMC4360. In one embodiment, the SHP-2 inhibitor is TNO155. In one embodiment, the combination therapy includes a combination of a compound having the formula

or a pharmaceutically acceptable salt thereof and an SHP-2 inhibitor. In one embodiment, the SHP-2 inhibitor is SHP-099. In one embodiment, the SHP-2 inhibitor is RMC-4550. In one embodiment, the SHP-2 inhibitor is RMC4360. In one embodiment, the SHP-2 inhibitor is TNO155. In one embodiment, the combination therapy includes a combination of a compound having the formula

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or a pharmaceutically acceptable salt thereof and an SHP-2 inhibitor. In one embodiment, the SHP-2 inhibitor is SHP-099. In one embodiment, the SHP-2 inhibitor is RMC-4550. In one embodiment, the SHP-2 inhibitor is RMC4360. In one embodiment, the SHP-2 inhibitor is TNO155. As used herein, the term contacting refers to the bringing together of said moieties in an in vitro system or in an in vivo system. For example, contacting a cancer cell includes administering a combination provided herein to an individual or subject, such as a human, having KRas G12C, and also, for example, administering a combination provided herein to a sample containing a cell or purified preparation, containing KRas G12C.

By negatively modulating KRas G12C activity, the methods described herein are designed to inhibit unwanted cell proliferation caused by increased KRas G12C activity in a cell. The degree of covalent modification of KRas G12C can be monitored in vitro by well known methods, including those described in published international patent applications PCTWO2017201161 and WO2019099524. In addition, the inhibitory activity of the combination in cells can be monitored, for example by measuring the level of inhibition of KRas G12C activity by the amount of phosphorylated ERK to assess the effectiveness of the treatment, and the treating physician can adjust dosages accordingly.

The compositions and methods provided herein can be used to treat KRas G12C associated cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing thereof , and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, wherein the SHP-2 inhibitor synergistically increases the susceptibility of a KRas G12C-associated cancer to the KRas G12C inhibitor. In one embodiment, the cancer associated with KRas G12C is lung cancer.

In one embodiment, a therapeutically effective amount of a combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing thereof, and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt thereof, or containing the same pharmaceutical composition, provides increased duration of overall survival (OS) in subjects compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing thereof, and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt thereof, or containing the same pharmaceutical composition, provides increased progression-free survival (PFS) in subjects compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing thereof, and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt thereof, or containing the same pharmaceutical composition, provides increased tumor regression in subjects compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing thereof, and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt thereof, or containing the same pharmaceutical composition, provides increased suppression of tumor growth in subjects compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a therapeutically effective amount of a combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing thereof, and a KRas G12C inhibitor compound of formula (I), formula I-A, or formula I-B or a pharmaceutically acceptable salt thereof, or containing the same pharmaceutical composition, provides an increase in the duration of disease stabilization in subjects compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the KRas G12C inhibitor is a compound selected from Compound Nos. 1-678 (as numbered in WO2019099524) or pharmaceutically acceptable salts thereof (e.g., Examples No. 234, 359, 478, or 507, or pharmaceutically acceptable salts thereof ). In one embodiment, the SHP-2 inhibitor is selected from SHP-099, RMC-4550, RMC-4360, and TNO155. In one embodiment, the therapeutic combination contains therapeutically effective amounts of a compound according to Example No. 234 and SHP-099. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 234 and RMC-4550. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 234 and RMC-4360. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 234 and TNO155. In one embodiment, the therapeutic combination contains therapeutically effective amounts of a compound according to Example No. 359 and SHP-099. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 359 and RMC-4550. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 359 and RMC-4360. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 359 and TNO155. In one embodiment, the therapeutic combination contains therapeutically effective amounts of a compound according to Example No. 478 and SHP-099. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 478 and RMC-4550. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 478 and RMC-4360. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 478 and TNO155. In one embodiment, the therapeutic combination contains therapeutically effective amounts of a compound according to Example No. 507 and SHP-099. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 507 and RMC-4550. In one embodiment, the therapeutic combination contains therapeutically effective amounts of a compound according to Example No. 507 and RMC-4360. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 507 and TNO155.

In another embodiment, an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, is administered in combination with a KRas G12C inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, if disease progression is observed during KRas G12C monotherapy, with In this case, combination therapy provides improved clinical benefit to the patient by improving OS, PFS, tumor regression, suppression of tumor growth, or duration of stable disease in the patient. In one embodiment, the KRas G12C inhibitor is a compound selected from Compound Nos. 1-678 (as numbered in WO2019099524) or pharmaceutically acceptable salts thereof (e.g., Examples No. 234, 359, 478, or 507, or pharmaceutically acceptable salts thereof ). In one embodiment, the SHP-2 inhibitor is selected from SHP-099, RMC-4550, RMC-4360, and TNO155. In one embodiment, the therapeutic combination contains therapeutically effective amounts of a compound according to Example No. 234 and SHP-099. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 234 and RMC-4550. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 234 and RMC-4360. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 234 and TNO155. In one embodiment, the therapeutic combination contains therapeutically effective amounts of a compound according to Example No. 359 and SHP-099. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 359 and RMC-4550. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 359 and RMC-4360. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 359 and TNO155. In one embodiment, the therapeutic combination contains therapeutically effective amounts of a compound according to Example No. 478 and SHP-099. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 478 and RMC-4550. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 478 and RMC-4360. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 478 and TNO155. In one embodiment, therapeutic

- 75 044829 combination contains therapeutically effective amounts of the compound according to example No. 507 and SHP-099. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 507 and RMC-4550. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 234 and RMC-4360. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 507 and TNO155. The compositions and methods provided herein can be used to treat a variety of cancers, including tumors such as lung cancer, colorectal cancer, pancreatic, prostate, breast, brain, skin, cervical carcinoma, testicular carcinoma, etc. .d. More specifically, cancers that can be treated with the compositions and methods of the invention include, but are not limited to, tumor types such as astrocytic tumors, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck cancers. , hepatocellular carcinoma, laryngeal, lung, oral cavity, ovarian, prostate and thyroid carcinoma, and sarcoma. More specifically, these compounds can be used for the treatment of heart diseases: sarcomas (angiosarcomas, fibrosarcomas, rhabdomyosarcomas, liposarcomas), myxomas, rhabdomyomas, fibromas, lipomas and teratomas; lungs: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; The gastrointestinal tract: esophagus (plane cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinomas, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinomas, gastrinomas, carcinoid tumors, viopolum), vijah), viopolum), vija), viopolum), vija) small intestine (adenocarcinoma, lymphoma , carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary system: kidneys (adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate gland (adenocarcinoma, sarcoma), testicles (seminoma, teratoma, embryonal carcinoma, teratocarcinomas, choriocarcinomas, sarcomas, interstitial cell carcinomas, fibromas, fibroadenomas, adenomatoid tumors, lipomas); liver: hematomas (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, renal cell adenoma, hemangioma; biliary tract: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; bone: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulocellular sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteocartilaginous exostosis), benign chondroma, chondrobe lastomas, chondromyxofibromas, osteoid osteoma and giant cell tumors; nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), soft shell of the brain (meningiomas, meningiosarcoma, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); gynecological diseases: uterus (endometrial carcinoma), cervix (cervical carcinoma, precancerous cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumors, Sertoli-Leydig cell tumors , dysgerminoma, malignant teratoma), external genitalia (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (carcinoma); hematological diseases: blood ( myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma intracellular carcinoma, Kaposi's sarcoma, syndrome of dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and adrenal glands: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer.

Also provided herein is a method of treating cancer in a subject in need thereof, comprising (a) determining that the cancer is associated with a KRas G12C mutation (e.g., is a KRas G12C-associated cancer) (e.g., using a regulatory agency approved, such as an FDA-approved study or recruitment); and (b) administering to the patient a therapeutically effective amount of a combination of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing thereof, and a KRas G12C inhibitor compound of formula I, formula I-A, formula 1-B or a pharmaceutically acceptable salt thereof, or containing its pharmaceutical composition, wherein the SHP-2 inhibitor synergistically increases the susceptibility of cancer associated with

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KRas G12C, to KRas G12C inhibitor. In one embodiment, the KRas G12C inhibitor is a compound selected from Compound Nos. 1-678 (as numbered in WO2019099524) or pharmaceutically acceptable salts thereof (e.g., Examples No. 234, 359, 478, or 507, or pharmaceutically acceptable salts thereof ). In one embodiment, the SHP-2 inhibitor is selected from SHP-099, RMC-4550, RMC-4360, and TNO155. In one embodiment, the therapeutic combination contains therapeutically effective amounts of a compound according to Example No. 234 and SHP-099. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 234 and RMC-4550. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 234 and RMC-4360. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 234 and TNO155. In one embodiment, the therapeutic combination contains therapeutically effective amounts of a compound according to Example No. 359 and SHP-099. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 359 and RMC-4550. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 359 and RMC-4360. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 359 and TNO155. In one embodiment, the therapeutic combination contains therapeutically effective amounts of a compound according to Example No. 478 and SHP-099. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 478 and RMC-4550. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 478 and RMC-4360. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 478 and TNO155. In one embodiment, the therapeutic combination contains therapeutically effective amounts of a compound according to Example No. 507 and SHP-099. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 507 and RMC-4550. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 234 and RMC-4360. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 507 and TNO155.

In one embodiment, a compound of Formula I is administered in capsule form over a period of time. In one embodiment, a tablet or capsule formulation of a compound of Formula I contains from about 10 mg to about 100 mg (e.g., from about 10 mg to about 95 mg, from about 10 mg to about 90 mg, from about 10 mg to about 85 mg, from about 10 mg to about 80 mg, from about 10 mg to about 75 mg, from about 10 mg to about 70 mg, from about 10 mg to about 65 mg, from about 10 mg to about 60 mg, from 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, from about 10 mg to about 25 mg, from about 10 mg to about 20 mg, from about 10 mg to about 15 mg, from about 15 mg to about 100 mg, from about 15 mg to about 95 mg, from 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 , from about 15 mg to about 60 mg, from about 15 mg to about 55 mg, from about 15 mg to about 50 mg, from about 15 mg to about 45 mg, from about 15 mg to about 40 mg, from about 15 mg to about 35 mg, from about 15 mg to about 30 mg, from about 15 mg to about 25 mg, from about 15 mg to about 20 mg, from about 20 mg to about 100 mg, from about 20 mg to about 95 mg, from about 20 mg to about 90 mg, from about 20 mg to about 85 mg, from about 20 mg to about 80 mg, from about 20 mg to about 75 mg, from about 20 mg to about 70 mg, from about 20 mg to about 65 mg, from about 20 mg to about 60 mg, from about 20 mg to about 55 mg, from about 20 mg to about 50 mg, from about 20 mg to about 45 mg, from about 20 mg to about 40 mg, from 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, from about 25 mg to about 85 mg, from about 25 mg to about 80 mg, from about 25 mg to about 75 mg, from about 25 mg to about 70 mg, from about 25 mg to about 65 mg, from 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, from about 25 mg to about 30 mg, from about 30 mg to about 100 mg, from about 30 mg to about 95 mg, from about 30 mg to about 90 mg, from about 30 mg to about 85 mg, from 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 , from about 30 mg to about

- 77 044829 mg, from about 30 mg to about 45 mg, from about 30 mg to about 40 mg, from about 30 mg to about 35 mg, from about 35 mg to about 100 mg, from about 35 mg to about 95 mg, from about 35 mg to about 90 mg, from about 35 mg to about 85 mg, from about 35 mg to about 80 mg, from about 35 mg to about 75 mg, from about 35 mg to about 70 mg, from about 35 mg to about 65 mg, from about 35 mg to about 60 mg, from about 35 mg to about 55 mg, from about 35 mg to about 50 mg, from about 35 mg to about 45 mg, from about 35 mg to about 40 mg, from about 40 mg to about 100 mg, 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 80 mg, about 40 mg to about 75 mg, from about 40 mg to about 70 mg, from about 40 mg to about 65 mg, from about 40 mg to about 60 mg, from about 40 mg to about 55 mg, from about 40 mg to about 50 mg, from about 40 mg to about 45 mg, 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, from about 45 mg to about 75 mg, from about 45 mg to about 70 mg, from about 45 mg to about 65 mg, from about 45 mg to about 60 mg, from about 45 mg to about 55 mg, from about 45 mg to about 50 mg, 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 , from about 50 mg to about 75 mg, from about 50 mg to about 70 mg, from about 50 mg to about 65 mg, from about 50 mg to about 60 mg, from about 50 mg to about 55 mg, from about 55 mg to about 100 mg, from about 55 mg to about 95 mg, from about 55 mg to about 90 mg, from about 55 mg to about 85 mg, from about 55 mg to about 80 mg, from about 55 mg to about 75 mg, from about 55 mg to about 70 mg, from about 55 mg to about 65 mg, from about 55 mg to about 60 mg, from about 60 mg to about 100 mg, from about 60 mg to about 95 mg, from about 60 mg to about 90 mg, from about 60 mg to about 85 mg, from about 60 mg to about 80 mg, from about 60 mg to about 75 mg, from about 60 mg to about 70 mg, from about 60 mg to about 65 mg, from about 65 mg to about 100 mg, 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, from about 65 mg to about 70 mg, from about 70 mg to about 100 mg, from about 70 mg to about 95 mg, from about 70 mg to about 90 mg, from about 70 mg to about 85 mg, from about 70 mg to about 80 mg, 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, from about 75 mg to about 80 mg, from about 80 mg to about 100 mg, from about 80 mg to about 95 mg, from about 80 mg to about 90 mg, from about 80 mg to about 85 mg, from 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 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about mg, about 60 mg, about 65 mg, about 70 mg , about 75 mg, about 80 mg, about mg, about 90 mg, about 95 mg, or about 100 mg) of a compound of Formula I (e.g., a compound selected from Compounds Nos. 1-553, e.g., Compounds Nos. 234, 359, 478, or 507). In one embodiment, a compound of Formula I is administered orally once daily (QD) daily for a period of time. In one embodiment, a compound of Formula I is administered orally twice daily (BID) daily for a period of time. In one embodiment, a compound of Formula I is administered orally in an amount 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, from about 20 mg to about 420 mg, from about 20 mg to about 400 mg, from about 20 mg to about 380 mg, from about 20 mg to about 360 mg, from about 20 mg to about 340 mg, from about 20 mg to about 320 mg, from about 20 mg to about 300 mg, from about 20 mg to about 280 mg, from about 20 mg to about 260 mg, from about 20 mg to about 240 mg, from about 20 mg to about 220 mg, from about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, from about 20 mg to about 80 mg, from about 20 mg to about 60 mg, from about 20 mg to about 40 mg, from about 40 mg to about 500 mg, from about 40 mg to about 480 mg, from 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, from about 40 mg to about 340 mg, from about 40 mg to about 320 mg, from about 40 mg to about 300 mg, from about 40 mg to about 280 mg, from about 40 mg to about 260 mg, from 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 , from about 40 mg to about 120 mg, from about 40 mg to about 100 mg, from about 40 mg to about 80 mg, from about 40 mg to about 60 mg,

- 78 044829 from about 60 mg to about 500 mg, from about 60 mg to about 480 mg, from about 60 mg to about 460 mg, from about 60 mg to about 440 mg, from about 60 mg to about 420 mg, from 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, from about 60 mg to about 280 mg, from about 60 mg to about 260 mg, from about 60 mg to about 240 mg, from about 60 mg to about 220 mg, from about 60 mg to about 200 mg, from 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 , from about 80 mg to about 500 mg, from about 80 mg to about 480 mg, from about 80 mg to about 460 mg, from about 80 mg to about 440 mg, from about 80 mg to about 420 mg, from about 80 mg to about 400 mg, from about 80 mg to about 380 mg, from about 80 mg to about 360 mg, from about 80 mg to about 340 mg, from about 80 mg to about 320 mg, from about 80 mg to about 300 mg, from about 80 mg to about 280 mg, from about 80 mg to about 260 mg, from about 80 mg to about 240 mg, from about 80 mg to about 220 mg, from about 80 mg to about 200 mg, from about 160 mg , from about 80 mg to about 80 mg to about 100 mg, from about 480 mg, from about 100 mg to about 100 mg to about 420 mg, from about 380 mg, from about 100 mg to about 100 mg to about 320 mg, from about 280 mg, from about 100 mg to about 100 mg to about 220 mg, from about 180 mg, from about 100 mg to about 100 mg to about 120 mg, from about 480 mg , from about 120 mg to about 120 mg to about 420 mg, from about 380 mg, from about 120 mg to about 120 mg to about 320 mg, from about 280 mg, from about 120 mg to about 120 mg to about 220 mg, from about 180 mg, from about 120 mg to about 140 mg to about 500 mg, from about 460 mg, from about 140 mg to about 140 mg to about 400 mg, from about 360 mg , from about 140 mg to about 140 mg to about 300 mg, from about 260 mg, from about 140 mg to about 140 mg to about 200 mg, from about 160 mg, from about 160 mg to about 160 mg to about 460 mg, from about 420 mg, from about 160 mg to about 160 mg to about 360 mg, from about 320 mg, from about 160 mg to about 160 mg to about 260 mg, from about 220 mg , from about 160 mg to about 180 mg to about 500 mg, from about 460 mg, from about 180 mg to about 180 mg to about 400 mg, from about 360 mg, from about 180 mg to about 180 mg to about 300 mg, from about 260 mg, from about 180 mg to about 180 mg to about 200 mg, from about 480 mg, from about 200 mg to about 200 mg to about 420 mg, from about 380 mg , from about 200 mg to about 200 mg to about 320 mg, from about 280 mg, from about 200 mg to about 200 mg to about 220 mg, from about 480 mg, from about 220 mg to about 220 mg to about 420 mg, from about 380 mg, from about 220 mg to about mg to about 180 mg, from about 80 mg to 140 mg, from about 80 mg to about 120 mg, from 100 mg to about 500 mg, from about 100 mg to 460 mg, from about 100 mg to about 440 mg, from 100 mg to about 400 mg, from about 100 mg to 360 mg, from about 100 mg to about 340 mg, from 100 mg to about 300 mg, from about 100 mg to 260 mg, from about 100 mg to about 240 mg, from 100 mg to about 200 mg, from about 100 mg to 160 mg, from about 100 mg to about 140 mg, from 120 mg to about 500 mg, from about 120 mg to 460 mg, from about 120 mg to about 440 mg, from 120 mg to about 400 mg, from about 120 mg to 360 mg, from about 120 mg to about 340 mg, from 120 mg to about 300 mg, from about 120 mg to 260 mg, from about 120 mg to about 240 mg, from 120 mg to about 200 mg, from about 120 mg to 160 mg, from about 120 mg to about 140 mg, from 140 mg to about 480 mg, from about 140 mg to 440 mg, from about 140 mg to about 420 mg, from 140 mg to about 380 mg, from about 140 mg to 340 mg, from about 140 mg to about 320 mg, from 140 mg to about 280 mg, from about 140 mg to 240 mg, from about 140 mg to about 220 mg, from 140 mg to about 180 mg, from about 140 mg to 500 mg, from about 160 mg to about 480 mg, from 160 mg to about 440 mg, from about 160 mg to 400 mg, from about 160 mg to about 380 mg, from 160 mg to about 340 mg, from about 160 mg to 300 mg, from about 160 mg to about 280 mg, from 160 mg to about 240 mg, from about 160 mg to 200 mg, from about 160 mg to about 180 mg, from 180 mg to about 480 mg, from about 180 mg to 440 mg, from about 180 mg to about 420 mg, from 180 mg to about 380 mg, from about 180 mg to 340 mg, from about 180 mg to about 320 mg, from 180 mg to about 280 mg, from about 180 mg to 240 mg, from about 180 mg to about 220 mg, from 200 mg to about 500 mg, from about 200 mg to 460 mg, from about 200 mg to about 440 mg, from 200 mg to about 400 mg, from about 200 mg to 360 mg, from about 200 mg to about 340 mg, from 200 mg to about 300 mg, from about 200 mg to 260 mg, from about 200 mg to about 240 mg, from 220 mg to about 500 mg, from about 220 mg to 460 mg, from about 220 mg to about 440 mg, from 220 mg to about 400 mg, from about 220 mg up to

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360 mg, from about 220 mg to about 340 mg, from about 220 mg to about 320 mg, from about 220 mg to about 300 mg, from about 220 mg to about 280 mg, from about 220 mg to about 260 mg, from about 220 mg to about 240 mg, about 240 mg to about 500 mg, about 240 mg to about 480 mg, about 240 mg to about 460 mg, about 240 mg to about 440 mg, about 240 mg to about 420 mg, from about 240 mg to about 400 mg, from about 240 mg to about 380 mg, from about 240 mg to about 360 mg, from about 240 mg to about 340 mg, from about 240 mg to about 320 mg, from about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 500 mg, about 260 mg to about 480 mg, about 260 mg to about 460 mg , from about 260 mg to about 440 mg, from about 260 mg to about 420 mg, from about 260 mg to about 400 mg, from about 260 mg to about 380 mg, from about 260 mg to about 360 mg, from about 260 mg to about 340 mg, from about 260 mg to about 320 mg, from about 260 mg to about 300 mg, from about 260 mg to about 280 mg, from about 280 mg to about 500 mg, from about 280 mg to about 480 mg, from about 280 mg to about 460 mg, from about 280 mg to about 440 mg, from about 280 mg to about 420 mg, from about 280 mg to about 400 mg, from about 280 mg to about 380 mg, from about 280 mg to about 360 mg, from about 280 mg to about 340 mg, from about 280 mg to about 320 mg, from about 280 mg to about 300 mg, from about 300 mg to about 500 mg, from about 300 mg to about 480 mg, from about 300 mg to about 460 mg, about 300 mg to about 440 mg, about 300 mg to about 420 mg, about 300 mg to about 400 mg, about 300 mg to about 380 mg, about 300 mg to about 360 mg, from about 300 mg to about 340 mg, from about 300 mg to about 320 mg, from about 320 mg to about 500 mg, from about 320 mg to about 480 mg, from about 320 mg to about 460 mg, from about 320 mg to about 440 mg, about 320 mg to about 420 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 320 mg to about 340 mg, from about 340 mg to about 500 mg, from about 340 mg to about 480 mg, from about 340 mg to about 460 mg, from about 340 mg to about 440 mg, from about 340 mg to about 420 mg, from 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 , from about 360 mg to about 440 mg, from about 360 mg to about 420 mg, from about 360 mg to about 400 mg, from about 360 mg to about 380 mg, from about 380 mg to about 500 mg, from about 380 mg to about 480 mg, from about 380 mg to about 460 mg, from about 380 mg to about 440 mg, from about 380 mg to about 420 mg, from about 380 mg to about 400 mg, from about 400 mg to about 500 mg, from about 400 mg to about 480 mg, from about 400 mg to about 460 mg, from about 400 mg to about 440 mg, from about 400 mg to about 420 mg, from about 420 mg to about 500 mg, from 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, from 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) over a period of time. In one embodiment, the combination therapy comprises orally administering a compound of Formula I once or twice daily daily (for a period of time), for example, in an amount of from about 10 mg to about 400 mg (for example, from about 10 mg to about 380 mg , from about 10 mg to about 360 mg, from about 10 mg to about 340 mg, from about 10 mg to about 320 mg, from about 10 mg to about 300 mg, from about 10 mg to about 280 mg, from about 10 mg to about 260 mg, from about 10 mg to about 240 mg, from about 10 mg to about 220 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 140 mg, from about 10 mg to about 120 mg, from about 10 mg to about 100 mg, from about 10 mg to about 80 mg, from about 10 mg to about 60 mg, from about 10 mg to about 40 mg, from about 10 mg to about 20 mg, from about 20 mg to about 400 mg, from about 20 mg to about 380 mg, from about 20 mg to about 360 mg, from about 20 mg to about 340 mg, from 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, from about 20 mg to about 200 mg, from about 20 mg to about 180 mg, from about 20 mg to about 160 mg, from about 20 mg to about 140 mg, from about 20 mg to about 120 mg, from 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 400 mg, about 40 mg to about 380 mg, from about 40 mg to about 360 mg, from about 40 mg to about 340 mg, from about 40 mg to about 320 mg, from about 40 mg to about 300 mg, from about 40 mg to about 280 mg, from about 40 mg to about 260 mg, about 40 mg to about 240 mg, about 40 mg to about

- 80 044829

220 mg, from about 40 mg to about 200 mg, from about 40 mg to about 180 mg, from about 40 mg to about 160 mg, from about 40 mg to about 140 mg, from about 40 mg to about 120 mg, from 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 400 mg, about 60 mg to about 380 mg, about 60 mg to about 360 mg, from about 60 mg to about 340 mg, from about 60 mg to about 320 mg, from about 60 mg to about 300 mg, from about 60 mg to about 280 mg, from about 60 mg to about 260 mg, from about 60 mg to about 240 mg, about 60 mg to about 220 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg , from about 60 mg to about 120 mg, from about 60 mg to about 100 mg, from about 60 mg to about 80 mg, from about 80 mg to about 400 mg, from about 80 mg to about 380 mg, from about 80 mg to about 360 mg, from about 80 mg to about 340 mg, from about 80 mg to about 320 mg, from about 80 mg to about 300 mg, from about 80 mg to about 280 mg, from about 80 mg to about 260 mg, from about 80 mg to about 240 mg, from about 80 mg to about 220 mg, from about 80 mg to about 200 mg, from about 80 mg to about 180 mg, from about 80 mg to about 160 mg, from about 120 mg , about 80 mg to about 100 mg to about 380 mg, from about 340 mg, from about 100 mg to about 100 mg to about 280 mg, from about 240 mg, from about 100 mg to about 100 mg to about 180 mg, from about 140 mg, from about 100 mg to about 120 mg to about 380 mg, from about 340 mg, from about 120 mg to about 120 mg to about 280 mg, from about 240 mg , from about 120 mg to about 120 mg to about 180 mg, from about 140 mg, from about 140 mg to about 140 mg to about 360 mg, from about 320 mg, from about 140 mg to about 140 mg to about 260 mg, from about 220 mg, from about 140 mg to about 140 mg to about 160 mg, from about 380 mg, from about 160 mg to about 160 mg to about 340 mg, from about 300 mg , from about 160 mg to about 160 mg to about 240 mg, from about 200 mg, from about 160 mg to about 180 mg to about 380 mg, from about 340 mg, from about 180 mg to about 180 mg to about 280 mg, from about 240 mg, from about 180 mg to about 200 mg to about 400 mg, from about 360 mg, from about 200 mg to about 200 mg to about 300 mg, from about 260 mg , from about 200 mg to about 220 mg to about 400 mg, from about 360 mg, from about 220 mg to about 220 mg to about 300 mg, from about 260 mg, from about 220 mg to about 240 mg to about 380 mg, from about 340 mg, from about 240 mg to about 240 mg to about 280 mg, from about 400 mg, from about 260 mg to about 260 mg to about 340 mg, from about 300 mg , from about 260 mg to about 280 mg to about 380 mg, from about 340 mg, from about 280 mg to about 300 mg to about 400 mg, from about 360 mg, from about 300 mg to about 320 mg to about 400 mg, from about 360 mg, from about 340 mg to about mg to about 140 mg, from about 80 mg to 100 mg, from about 100 mg to about 400 mg, from 100 mg to about 360 mg, from about 100 mg to 320 mg, from about 100 mg to about 300 mg, from 100 mg to about 260 mg, from about 100 mg to 220 mg, from about 100 mg to about 200 mg, from 100 mg to about 160 mg, from about 100 mg to 120 mg, from about 120 mg to about 400 mg, from 120 mg to about 360 mg, from about 120 mg to 320 mg, from about 120 mg to about 300 mg, from 120 mg to about 260 mg, from about 120 mg to 220 mg, from about 120 mg to about 200 mg, from 120 mg to about 160 mg, from about 120 mg to 400 mg, from about 140 mg to about 380 mg, from 140 mg to about 340 mg, from about 140 mg to 300 mg, from about 140 mg to about 280 mg, from 140 mg to about 240 mg, from about 140 mg to 200 mg, from about 140 mg to about 180 mg, from 160 mg to about 400 mg, from about 160 mg to 360 mg, from about 160 mg to about 360 mg, from 160 mg to about 320 mg, from about 160 mg to 280 mg, from about 160 mg to about 260 mg, from 160 mg to about 220 mg, from about 160 mg to 180 mg, from about 180 mg to about 400 mg, from 180 mg to about 360 mg, from about 180 mg to 320 mg, from about 180 mg to about 300 mg, from 180 mg to about 260 mg, from about 180 mg to 220 mg, from about 180 mg to about 200 mg, from 200 mg to about 380 mg, from about 200 mg to 340 mg, from about 200 mg to about 320 mg, from 200 mg to about 280 mg, from about 200 mg to 240 mg, from about 200 mg to about 220 mg, from 220 mg to about 380 mg, from about 220 mg to 340 mg, from about 220 mg to about 320 mg, from 220 mg to about 280 mg, from about 220 mg to 240 mg, from about 240 mg to about 400 mg, from 240 mg to about 360 mg, from about 240 mg to 320 mg, from about 240 mg to about 300 mg, from 240 mg to about 260 mg, from about 260 mg to 380 mg, from about 260 mg to about 360 mg, from 260 mg to about 320 mg, from about 260 mg to 280 mg, from about 280 mg to about 400 mg, from 280 mg to about 360 mg, from about 280 mg to 320 mg, from about 280 mg to about 300 mg, from 300 mg to about 380 mg, from about 300 mg to 340 mg, from about 300 mg to about 320 mg, from 320 mg to about 380 mg, from about 320 mg before

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360 mg, from about 340 mg to about 400 mg, from about 340 mg to about 380 mg, from about 340 mg to about 360 mg, from about 360 mg to about 400 mg, from about 360 mg to about 380 mg, from about 380 mg to about 400 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg) and oral administration of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, which is administered, for example, once a day every day (for a period of time). In one embodiment, the KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, is administered orally once daily. In one embodiment, the KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, is administered orally twice daily.

One skilled in the art will appreciate that both in vivo and in vitro testing, using appropriate, known and established cellular and/or animal models, will predict the ability of a test compound in a combination or combination to treat or prevent a given disorder.

One skilled in the art will also appreciate that human clinical trials, including first-in-human trials, dose titration trials, and efficacy trials, on healthy patients and/or patients suffering from a given disorder, can be conducted according to methods well known in clinical practice and in the medical field.

Synergy

In one embodiment, the addition of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, synergistically increases the activity of a KRas G12C inhibitor compound of formula (I), formula I-A or formula I-B or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same compositions for cancer or cancer cell lines expressing KRas G12C. To determine the synergistic effect of a combination, any method for determining whether two compounds may exhibit synergy can be used.

Several mathematical models have been developed to determine the possible synergistic effects of the two compounds, i.e. presence of more than just an additive effect. For example, Loewe's additivity model (Loewe (1928) Physiol. 27: 47-187), Bliss's independence model (Bliss (1939) Ann. Appl. Biol. 26: 585-615), single agent maximum effect model, ZIP (Yadav et al. (2015) Comput Struct Biotech J 13: 504-513) and other models (Chou & Talalay (1984) Adv Enzyme Regul 22: 27-55. #6382953; and Greco et al. (1995) Pharmacol Rev 47(2 ): 331-85. #7568331) are well-known models in the pharmaceutical industry and can be used to calculate a synergy index, which indicates the possible presence of synergy and the magnitude of said synergy. Collectively, these synergy indices constitute a comprehensive synergy index that can be used to evaluate and describe the characteristics of KRas G12C inhibitor compounds of formula (I), formula I-A, or formula I-B in combination with an SHP-2 inhibitor.

In general, mathematical models use data derived from values for individual agents to determine the predictive additive effect of the combination, which is compared with the observed effect of the combination. If the observed effect exceeds the predictive effect, then the combination is considered synergistic. For example, the Bliss independence model compares the observed response to the combination (Y _O ) with the predicted response to the combination (Y _P ), which is determined based on the assumption that there is no effect of drug-drug interactions. As a rule, the effect of a combination is considered synergistic if _YO exceeds YP.

In some embodiments, a synergistic effect as used herein refers to a combination of a KRAS inhibitor or a pharmaceutically acceptable salt thereof and an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof if it provides an effect, such as any of the beneficial or desired outcomes, including clinical outcomes or endpoints , such as those described herein, which exceeds the sum of the effects observed when separately administering a compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., a compound selected from Compounds No. 1-678 as numbered in WO2019099524) and an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the KRas G12C inhibitor is a compound selected from Compound Nos. 1-678 (as numbered in WO2019099524) or pharmaceutically acceptable salts thereof (e.g., Examples No. 234, 359, 478, or 507, or pharmaceutically acceptable salts thereof ). In one embodiment, the SHP-2 inhibitor is selected from SHP-099, RMC-4550, and TNO155. In one embodiment, the therapeutic combination contains therapeutically effective amounts of a compound according to Example No. 234 and SHP-099. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 234 and RMC-4550. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 234 and TNO155. In one embodiment, the therapeutic combination contains therapeutically effective amounts of a compound according to Example No. 359 and SHP-099. In one of the

- 82 044829 ant implementation therapeutic combination contains therapeutically effective amounts of the compound according to example No. 359 and RMC-4550. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 359 and TNO155. In one embodiment, the therapeutic combination contains therapeutically effective amounts of a compound according to Example No. 478 and SHP-099. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 478 and RMC-4550. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 478 and TNO155. In one embodiment, the therapeutic combination contains therapeutically effective amounts of a compound according to Example No. 507 and SHP-099. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 507 and RMC-4550. In one embodiment, the therapeutic combination contains therapeutically effective amounts of the compound of Example No. 507 and TNO155.

In some embodiments, the methods provided herein may provide a reduction in volume of one or more solid tumors in a patient after treatment with a combination therapy of 1% to 99% (e.g., 1% to 98%, 1% to 95 %, from 1% to 90%, from 1 to 85%, from 1 to 80%, from 1% to 75%, from 1% to 70%, from 1% to 65%, from 1% to 60%, from 1% to 55%, from 1% to 50%, from 1% to 45%, from 1% to 40%, from 1% to 35%, from 1% to 30%, from 1% to 25%, from 1 % to 20%, from 1% to 15%, from 1% to 10%, from 1% to 5%, from 2% to 99%, from 2% to 90%, from 2% to 85%, from 2% up to 80%, from 2% to 75%, from 2% to 70%, from 2% to 65%, from 2% to 60%, from 2% to 55%, from 2% to 50%, from 2% to 45%, from

2% to 40%, from 2% to 35%, from 2% to 30%, from 2% to 25%, from 2% to 20%, from 2% to 15%, from 2% to 10%, from

2% to 5%, from 4% to 99%, from 4% to 95%, from 4% to 90%, from 4% to 85%, from 4% to 80%, from 4% to 75%, from 4 % to 70%, from 4% to 65%, from 4% to 60%, from 4% to 55%, from 4% to 50%, from 4% to 45%, from 4% to 40%, from

4% to 35%, from 4% to 30%, from 4% to 25%, from 4% to 20%, from 4% to 15%, from 4% to 10%, from 6% to 99%, from

6% to 95%, from 6% to 90%, from 6% to 85%, from 6% to 80%, from 6% to 75%, from 6% to 70%, from 6% to 65%, from

6% to 60%, from 6% to 55%, from 6% to 50%, from 6% to 45%, from 6% to 40%, from 6% to 35%, from 6% to 30%, from

6% to 25%, from 6% to 20%, from 6% to 15%, from 6% to 10%, from 8% to 99%, from 8% to 95%, from 8% to 90%, from

8% to 85%, from 8% to 80%, from 8% to 75%, from 8% to 70%, from 8% to 65%, from 8% to 60%, from 8% to 55%, from

8% to 50%, from 8% to 45%, from 8% to 40%, from 8% to 35%, from 8% to 30%, from 8% to 25%, from 8% to 20%, from

8% to 15%, from 10% to 99%, from 10% to 95%, from 10% to 90%, from 10% to 85%, from 10% to 80%, from 10% to 75%, from 10 % to 70%, from 10% to 65%, from 10% to 60%, from 10% to 55%, from 10% to 50%, from 10% to 45%, from 10% to 40%, from 10% up to 35%, from 10% to 30%, from 10% to 25%, from 10% to 20%, from 10% to 15%, from 15% to 99%, from 15% to 95%, from 15% to 90%, from 15% to 85%, from 15% to 80%, from 15% to 75%, from 15% to 70%, from 15% to 65%, from 15% to 60%, from 15% to 55 %, from 15% to 50%, from 15% to 55%, from 15% to 50%, from 15% to 45%, from 15% to 40%, from 15% to 35%, from 15% to 30% , from 15% to 25%, from 15% to 20%, from 20% to 99%, from 20% to 95%, from 20% to 90%, from 20% to 85%, from 20% to 80%, from 20% to 75%, from 20% to 70%, from 20% to 65%, from 20% to 60%, from 20% to 55%, from 20% to 50%, from 20% to 45%, from 20% to 40%, from 20% to 35%, from 20% to 30%, from 20% to 25%, from 25% to 99%, from 25% to 95%, from 25% to 90%, from 25 % to 85%, from 25% to 80%, from 25% to 75%, from 25% to 70%, from 25% to 65%, from 25% to 60%, from 25% to 55%, from 25% up to 50%, from 25% to 45%, from 25% to 40%, from 25% to 35%, from 25% to 30%, from 30% to 99%, from 30% to 95%, from 30% to 90%, from 30% to 85%, from 30% to 80%, from 30% to 75%, from 30% to 70%, from 30% to 65%, from 30% to 60%, from 30% to 55 %, from 30% to 50%, from 30% to 45%, from 30% to 40%, from 30% to 35%, from 35% to 99%, from 35% to 95%, from 35% to 90% , from 35% to 85%, from 35% to 80%, from 35% to 75%, from 35% to 70%, from 35% to 65%, from 35% to 60%, from 35% to 55%, from 35% to 50%, from 35% to 45%, from 35% to 40%, from 40% to 99%, from 40% to 95%, from 40% to 90%, from 40% to 85%, from 40% to 80%, from 40% to 75%, from 40% to 70%, from 40% to 65%, from 40% to 60%, from 40% to 55%, from 40% to 60%, from 40 % to 55%, from 40% to 50%, from 40% to 45%, from 45% to 99%, from 45% to 95%, from 45% to 95%, from 45% to 90%, from 45% up to 85%, from 45% to 80%, from 45% to 75%, from 45% to 70%, from 45% to 65%, from 45% to 60%, from 45% to 55%, from 45% to 50%, from 50% to 99%, from 50% to 95%, from 50% to 90%, from 50% to 85%, from 50% to 80%, from 50% to 75%, from 50% to 70 %, from 50% to 65%, from 50% to 60%, from 50% to 55%, from 55% to 99%, from 55% to 95%, from 55% to 90%, from 55% to 85% , from 55% to 80%, from 55% to 75%, from 55% to 70%, from 55% to 65%, from 55% to 60%, from 60% to 99%, from 60% to 95%, from 60% to 90%, from 60% to 85%, from 60% to 80%, from 60% to 75%, from 60% to 70%, from 60% to 65%, from 65% to 99%, from 60% to 95%, from 60% to 90%, from 60% to 85%, from 60% to 80%, from 60% to 75%, from 60% to 70%, from 60% to 65%, from 70 % to 99%, from 70% to 95%, from 70% to 90%, from 70% to 85%, from 70% to 80%, from 70% to 75%, from 75% to 99%, from 75% up to 95%, from 75% to 90%, from 75% to 85%, from 75% to 80%, from 80% to 99%, from 80% to 95%, from 80% to 90%, from 80% to 85%, 85% to 99%, 85% to 95%, 85% to 90%, 90% to 99%, 90% to 95% or 95% to 100%) over a period of time from 1 day to 2 years (for example, from 1 day to 22 months, from 1 day to 20 months, from 1 day to 18 months, from 1 day to 16 months, from 1 day to 14 months, from 1 day to 12 months, from 1 day to 10 months, from 1 day to 9 months, from 1 day to 8 months, from 1 day to 7 months, from 1 day to 6 months, from 1 day to 5 months, from 1 day to 4 months, from 1 day to 3 months, from 1 day to 2 months, from 1 day to 1 month, from one week to 2 years, from 1 week to 22 months, from 1 week to 20 months, from 1 week to 18 months, from 1 weeks to 16 months, from 1 week to 14 months,

- 83 044829 from 1 week to 12 months, from 1 week to 10 months, from 1 week to 9 months, from 1 week to 8 months, from 1 week to 7 months, from 1 week to 6 months, from 1 week to 5 months, from 1 week to 4 months, from 1 week to 3 months, from 1 week to 2 months, from 1 week to 1 month, from 2 weeks to 2 years, from 2 weeks to 22 months, from 2 weeks to 20 months , from 2 weeks to 18 months, from 2 weeks to 16 months, from 2 weeks to 14 months, from 2 weeks to 12 months, from 2 weeks to 10 months, from 2 weeks to 9 months, from 2 weeks to 8 months, from 2 weeks to 7 months, from 2 weeks to 6 months, from 2 weeks to 5 months, from 2 weeks to 4 months, from 2 weeks to 3 months, from 2 weeks to 2 months, from 2 weeks to 1 month, from 1 month to 2 years, from 1 month to 22 months, from 1 month to 20 months, from 1 month to 18 months, from 1 month to 16 months, from 1 month to 14 months, from 1 month to 12 months, from 1 months to 10 months, from 1 month to 9 months, from 1 month to 8 months, from 1 month to 7 months, from 1 month to 6 months, from 1 month to 6 months, from 1 month to 5 months, from 1 month up to 4 months, from 1 month to 3 months, from 1 month to 2 months, from 2 months to 2 years, from 2 months to 22 months, from 2 months to 20 months, from 2 months to 18 months, from 2 months to 16 months, from 2 months to 14 months, from 2 months to 12 months, from 2 months to 10 months, from 2 months to 9 months, from 2 months to 8 months, from 2 months to 7 months, from 2 months to 6 months or from 2 months to 5 months, from 2 months to 4 months, from 3 months to 2 years, from 3 months to 22 months, from 3 months to 20 months, from 3 months to 18 months, from 3 months to 16 months , from 3 months to 14 months, from 3 months to 12 months, from 3 months to 10 months, from 3 months to 8 months, from 3 months to 6 months, from 4 months to 2 years, from 4 months to 22 months, from 4 months to 20 months, from 4 months to 18 months, from 4 months to 16 months, from 4 months to 14 months, from 4 months to 12 months, from 4 months to 10 months, from 4 months to 8 months, from 4 months to 6 months, from 6 months to 2 years, from 6 months to 22 months, from 6 months to 20 months, from 6 months to 18 months, from 6 months to 16 months, from 6 months to 14 months, from 6 months to 12 months, 6 months to 10 months, or 6 months to 8 months) (eg, compared to the size of one or more solid tumors in the patient before treatment).

The phrase survival duration refers to the length of time between detection or diagnosis of cancer (eg, any of the cancers described herein) in a mammal by a health care professional and the time of death of the mammal (due to cancer). Disclosed herein are methods for increasing the survival time of a mammal suffering from cancer.

In some embodiments, any of the methods described herein may provide an increase in patient survival time (e.g., 1% to 400%, 1% to 380%, 1% to 360%, 1% to 340 %, from 1% to 320%, from 1% to 300%, from 1% to 280%, from 1% to 260%, from 1% to 240%, from 1% to 220%, from 1% to 200% , from 1% to 180%, from 1% to 160%, from 1% to 140%, from 1% to 120%, from 1% to 100%, from 1% to 95%, from 1% to 90%, from 1% to 85%, from 1% to 80%, from 1% to 75%, from 1% to 70%, from 1% to 65%, from 1% to 60%, from 1% to 55%, from 1% to 50%, from 1% to 45%, from 1% to 40%, from 1% to 35%, from 1% to 30%, from 1% to 25%, from 1% to 20%, from 1 % to 15%, from 1% to 10%, from 1% to 5%, from 5% to 400%, from 5% to 380%, from 5% to 360%, from 5% to 340%, from 5% up to 320%, from 5% to 300%, from

5% to 280%, from 5% to 260%, from 5% to 240%, from 5% to 220%, from 5% to 200%, from 5% to 180%, from 5% to 160%, from 5 % to 140%, from 5% to 120%, from 5% to 100%, from 5% to 90%, from 5% to 80%, from 5% to 70%, from 5% to 60%, from 5% up to 50%, from 5% to 40%, from 5% to 30%, from 5% to 20%, from 5% to 10%, from 10% to 400%, from 10% to 380%, from 10% to 360%, from 10% to 340%, from 10% to 320%, from 10% to 300%, from 10% to 280%, from 10% to 260%, from 10% to 240%, from 10% to 220 %, from 10% to 200%, from 10% to 180%, from 10% to 160%, from 10% to 140%, from 10% to 120%, from 10% to 100%, from 10% to 90% , from 10% to 80%, from 10% to 70%, from 10% to 60%, from 10% to 50%, from 10% to 40%, from 10% to 30%, from 10% to 20%, from 20% to 400%, from 20% to 380%, from 20% to 360%, from 20% to 340%, from 20% to 320%, from 20% to 300%, from 20% to 280%, from 20% to 260%, from 20% to 240%, from 20% to 220%, from 20% to 200%, from 20% to 180%, from 20% to 160%, from 20% to 140%, from 20 % to 120%, from 20% to 100%, from 20% to 90%, from 20% to 80%, from 20% to 70%, from 20% to 60%, from 20% to 50%, from 20% up to 40%, from 20% to 30%, from 30% to 400%, from 30% to 380%, from 30% to 360%, from

30% to 340%, from 30% to 320%, from 30% to 300%, from 30% to 280%, from 30% to 260%, from 30% to 240%, from

30% to 220%, from 30% to 200%, from 30% to 180%, from 30% to 160%, from 30% to 140%, from 30% to 120%, from

30% to 100%, from 30% to 90%, from 30% to 80%, from 30% to 70%, from 30% to 60%, from 30% to 50%, from 30% to

40%, from 40% to 400%, from 40% to 380%, from 40% to 360%, from 40% to 340%, from 40% to 320%, from 40% to 300%, from 40% to 280 %, from 40% to 260%, from 40% to 240%, from 40% to 220%, from 40% to 200%, from 40% to 180%, from 40% to 160%, from 40% to 140% , from 40% to 120%, from 40% to 100%, from 40% to 90%, from 40% to 80%, from 40% to 70%, from 40% to 60%, from 40% to 50%, from 50% to 400%, from 50% to 380%, from 50% to 360%, from 50% to 340%, from 50% to 320%, from 50% to 300%, from 50% to 280%, from 50% to 260%, from 50% to 240%, from 50% to 220%, from 50% to 200%, from 50% to 180%, from 50% to 160%, from 50% to 140%, from 50 % to 140%, from 50% to 120%, from 50% to 100%, from 50% to 90%, from 50% to 80%, from 50% to 70%, from 50% to 60%, from 60% up to 400%, from 60% to 380%, from 60% to 360%, from 60% to 340%, from 60% to 320%, from 60% to 300%, from 60% to 280%, from 60% to 260%, from 60% to 240%, from 60% to 220%, from 60% to 200%, from 60% to 180%, from 60% to 160%, from 60% to 140%, from 60% to 120 %, from 60% to 100%, from 60% to 90%, from 60% to 80%, from 60% to 70%, from 70% to 400%, from 70% to 380%, from 70% to 360% , from 70% to 340%, from 70% to 320%, from 70% to 300%, from

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70% to 280%, from 70% to 260%, from 70% to 240%, from 70% to 220%, from 70% to 200%, from 70% to 180%, from 70% to 160%, from 70 % to 140%, from 70% to 120%, from 70% to 100%, from 70% to 90%, from 70% to 80%, from 80% to 400%, from 80% to 380%, from 80% up to 360%, from 80% to 340%, from 80% to 320%, from 80% to 300%, from 80% to 280%, from 80% to 260%, from 80% to 240%, from 80% to 220%, from 80% to 200%, from 80% to 180%, from 80% to 160%, from 80% to 140%, from 80% to 120%, from 80% to 100%, from 80% to 90 %, from 90% to 400%, from 90% to 380%, from 90% to 360%, from 90% to 340%, from 90% to 320%, from 90% to 300%, from 90% to 280% , from 90% to 260%, from 90% to 240%, from 90% to 220%, from 90% to 200%, from 90% to 180%, from 90% to 160%, from 90% to 140%, from 90% to 120%, from 90% to 100%, from 100% to 400%, from 100% to 380%, from 100% to 360%, from 100% to 340%, from 100% to 320%, from 100% to 300%, from 100% to 280%, from 100% to 260%, from 100% to 240%, from 100% to 220%, from 100% to 200%, from 100% to 180%, from 100 % to 160%, from 100% to 140%, from 100% to 120%, from 120% to 400%, from 120% to 380%, from 120% to 360%, from 120% to 340%, from 120% up to 320%, from 120% to 300%, from 120% to 280%, from 120% to 260%, from 120% to 240%, from 120% to 220%, from 120% to 200%, from 120% to 180%, from 120% to 160%, from 120% to 140%, from 140% to 400%, from 140% to 380%, from 140% to 360%, from 140% to 340%, from 140% to 320 %, from 140% to 300%, from 140% to 280%, from 140% to 260%, from 140% to 240%, from 140% to 220%, from 140% to 200%, from 140% to 180% , from 140% to 160%, from 160% to 400%, from 160% to 380%, from 160% to 360%, from 160% to 340%, from 160% to 320%, from 160% to 300%, from 160% to 280%, from 160% to 260%, from 160% to 240%, from 160% to 220%, from 160% to 200%, from 160% to 180%, from 180% to 400%, from 180% to 380%, from 180% to 360%, from 180% to 340%, from 180% to 320%, from 180% to 300%, from 180% to 280%, from 180% to 260%, from 180 % to 240%, from 180% to 220%, from 180% to 200%, from 200% to 400%, from 200% to 380%, from 200% to 360%, from 200% to 340%, from 200% up to 320%, from 200% to 300%, from 200% to 280%, from 200% to 260%, from 200% to 240%, from 200% to 220%, from 220% to 400%, from 220% to 380%, from 220% to 360%, from 220% to 340%, from 220% to 320%, from 220% to 300%, from 220% to 280%, from 220% to 260%, from 220% to 240 %, from 240% to 400%, from 240% to 380%, from 240% to 360%, from 240% to 340%, from 240% to 320%, from 240% to 300%, from 240% to 280% , from 240% to 260%, from 260% to 400%, from 260% to 380%, from 260% to 360%, from 260% to 340%, from 260% to 320%, from 260% to 300%, from 260% to 280%, from 280% to 400%, from 280% to 380%, from 280% to 360%, from 280% to 340%, from 280% to 320%, from 280% to 300%, from 300% to 400%, 300% to 380%, 300% to 360%, 300% to 340%, or 300% to 320%) (for example, compared to a patient suffering from a similar cancer who receives other treatment or not receiving treatment).

In some embodiments of any of the methods described herein, prior to treatment with the compositions or methods of the invention, the patient has been treated with one or more of chemotherapy, a targeted anticancer agent, radiation therapy, and surgery, and optionally the prior treatment has been ineffective; and/or the patient underwent surgery, and, optionally, the surgery was ineffective; and/or the patient has been treated with a platinum-based chemotherapeutic agent, and, optionally, the patient has previously been determined to be refractory to treatment with a platinum-based chemotherapeutic agent; and/or the patient was treated with a kinase inhibitor, and, optionally, previous treatment with a kinase inhibitor was ineffective; and/or the patient has been treated with one or more other therapeutic agents.

Sets

The present invention also relates to a kit containing an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing thereof, and a KRas G12C inhibitor compound of formula (I), formula I-A or formula I-B or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. Also provided is a kit containing an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, and a KRas G12C inhibitor compound of formula (I), formula I-A or formula I-B or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, for applications in the treatment of hematological cancer.

According to a related aspect, the invention provides a kit containing a dose of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing thereof, and a dose of a KRas G12C inhibitor compound of formula (I), formula I-A or formula I-B or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, in an amount effective to inhibit the proliferation of cancer cells, in particular cancer cells expressing KRas G12C, in a subject. The kit in some cases includes an insert with instructions for administration of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing thereof, and a KRas G12C inhibitor compound of formula (I), formula I-A or formula I-B or a pharmaceutically acceptable salt thereof, or containing its pharmaceutical composition. The package insert may provide the user with a set of instructions for use of an SHP-2 inhibitor or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing thereof, in combination with a KRas G12C inhibitor compound of formula (I), formula I-A or formula I-B or a pharmaceutically acceptable salt thereof, or containing its pharmaceutical composition.

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Example A: SHP-2 inhibitors synergistically enhance the activity of KRas G12C inhibitors against cell lines expressing KRas G12C.

This example illustrates that the combination of the proposed inhibitor compounds

KRas G12C of formula I, formula I-A and formula 1-B and SHP-2 inhibitor synergistically inhibit the growth of tumor cell lines expressing KRas G12C.

A panel of 8 lung cancer cell lines and 1 colorectal cancer cell line that had KRas G12C mutations was selected to determine possible synergistic activity when combining SHP-2 inhibitors with the proposed KRas G12C inhibitors described herein. The collection included NCI-H1373 (ATCC CRL-5866); NCI-H1792 (ATCC CRL-5895); NCI-H2030 (ATCC CRL-5985); NCI-H2122 (ATCC CRL-5985); HCC1171 (KCLB 71171); HCC44 (DSMZ ACC-534); LU99 (RCB1900); SW1573 (ATCC CRL-2170) and SW837 (ATCC CCL-235).

Studies to determine the synergy index for pairwise combinations for each cell line were performed in triplicate. Three 96-well plates, as well as 4 wells of a separate control 96-well plate, were seeded with 2000 cells/well of a specific cell line in a total volume of 90 μl in a culture medium suitable for the cell line, e.g. RPMI 1640 supplemented with 10% FBS or any specific reagents required for growth of the cell line. The plates were incubated overnight at 37°C in an atmosphere of 5% CO ₂ .

30 μl of Cell-Titer Glo reagent (CTG; Promega Corporation) was added to each of the designated baseline wells, and the plates were incubated for 20 min with shaking at room temperature. Luminescence at baseline was quantified on a BMG ClarioStar multimodal plate reader according to the manufacturer's instructions.

A set of working drug stock solutions diluted 1000X in 100% DMSO was prepared, which included 8 different dilution levels of the proposed KRas G12C inhibitor of formula (I), Formula I-A and Formula I-B and 5 different dilution levels of the SHP-2 inhibitor. The dilution levels of the KRas inhibitor G12C and the SHP-2 inhibitor were different for each specific compound, but corresponded to approximately 3-6-fold/serial dilution.

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Proposed KRas G12C inhibitors that were tested in this example included the following.

* Example No. refers to the example number of each compound as described in published international PCT application WO2019099524.

A 10X intermediate dosage plate was prepared in serum-free RPMI medium, which contained individually diluted rows of the proposed KRas G12C inhibitor of formula (I) or the SHP-2 inhibitor. In addition, a matrix of 40 combinations of diluted proposed KRas G12C inhibitor of formula (I), formula I-A or formula I-B and SHP-2 inhibitor was prepared as test samples.

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To each appropriate well in three 96-well plates in which the corresponding cell lines above were seeded, 10 µl of each of the individual agents at a 10X dilution and 40 combinations selected from the dose matrix were added and the plates were incubated for 72 hours at 37°C C in the atmosphere is 5% CO ₂ . A 30 μl aliquot of CellTiter Glo (CTG) reagent was added to each test well, the plates were incubated for 20 min with shaking at room temperature, and baseline luminescence was quantified on a BMG ClarioStar multimodal plate reader according to the manufacturer's instructions.

Used raw data and metadata files as input files to calculate the percentage effect for each treatment condition and analyzed using four independent mathematical reference models designed to determine the possible synergy of the two test compounds: Leve's additivity model, Bliss independence model, maximum effect model separate agent and ZIP.

The output of each mathematical model allowed us to determine the relative synergy index. The data presented in table. 1, represent the cumulative sum of the indices of Leve's additivity, Bliss independence, maximum effect of an individual agent and ZIP (complex index of synergy).

Table 1

Comprehensive synergy indices for the proposed SHP-2 inhibitors in combination with the proposed KRas G12C inhibitors of formula (I), formula I-A and formula I-B in relation to KRas G12C cell lines

SHP-2 inhibitor RM S-4550 KRas G12C, example no. 478 Cell line H1792 5.2 H2030 -6.0 H2122 12.3 NSS1171 3.0 NSS44 -4.3 KYSE410 15.0 LU99 -5.8 SW1573 9.6 SW837 -0.5

A composite index of 27 or greater was interpreted as a definite presence of synergy, with a composite index of 17 to 26 indicating possible synergy. The results obtained demonstrate that the combination of the SHP-2 inhibitor with the proposed KRas G12C inhibitor compounds of formula (I), formula I-A and formula I-B provided a small synergistic effect against certain members of a panel of cell lines expressing KRas G12C, which provided the basis for further study effectiveness of combinations in in vivo models.

Example B: Models for evaluating KRas G12C inhibitor-SHP-2 inhibitor combinations in vivo.

Immunocompromised athymic/nude mice were inoculated into the right hind flank with cells or patient-derived tumor samples harboring the KRas G12C mutation. When the tumor volume reached 200-400 mm ³ , the mice were divided into four groups of 5-12 mice. The first group was administered vehicle alone. The second group was dosed with the KRas G12C inhibitor alone at a concentration that provided maximum biological effect or less than maximum biological effect, depending on the cell line and activity of the individual agent, and did not result in complete tumor regression.

The third group was dosed with SHP-2 inhibitor alone at a concentration that provided maximum biological effect or less than maximum biological effect, depending on the cell line and activity of the individual agent, and also did not result in complete tumor regression. The fourth group received one dose of the KRas inhibitor G12C in combination with one dose of the SHP-2 inhibitor. The treatment period varied among different cell lines but was generally 21–35 days. The size of the tumors was measured with a caliper every two to three days and the tumor volume was calculated using the formula: 0.5 x (length x width) ² . The greater suppression of tumor growth with the combination in this model demonstrates that combination therapy is more likely to provide clinically significant benefit in post-treatment subjects compared to treatment with a KRas G12C inhibitor alone.

Nude/nude mice were inoculated with 5 x 10 ⁶ SW1573 cells, KYSE410 cells or H358 cells into the right hind limb in each study. When the tumor volume reached ~300-350 mm ³ (day 0 of the study), 5 mice in each of the four groups were injected with p.o. daily for 28 days: vehicle only (10% captisol in 50 mM citrate buffer, pH 5.0), 100 mg/kg KRas G12C inhibitor compound 478 (10% captisol in 50 mM citrate buffer, pH 5.0), 30 mg/kg SHP-2 inhibitor RMC-4550 (10% captisol in 50 mM citrate buffer, pH 5.0) or 100 mg/kg KRas G12C inhibitor compound 478 and 30 mg/kg RMC-4550. The average tumor volume measured on predetermined days in five mice in each group was determined, the results for SW1573 cells, KYSE410 cells and H358 cells are shown in table. 2-4, respectively.

table 2

Mean tumor volume (mm ³ ) in SW1573 tumor-bearing mice after treatment with single agents or combination

Research day Carrier Compound 478 RMC-4550 Combination Connection 478 ± RMC-4550 0 328 335 336 343 2 369 281 280 310 4 388 318 286 288 7 449 345 336 239 9 446 336 305 230

eleven 521 346 326 240 14 554 363 418 284 16 631 379 421 258 18 636 380 375 252 21 655 419 392 284 22 891 433 510 264

As shown in table. 2, administration of compound 478 or RMC-4550 as a single agent provided 81% and 68% tumor growth suppression at day 22, respectively. The combination of the SHP-2 inhibitor RMC-4550 and compound 478 provided 23% tumor regression at day 22.

Table 3

Mean tumor volume ( ^mm3 ) in KYSE410 tumor-bearing mice after treatment with single agents or combination

Research day Carrier Compound 478 RMC-4550 Combination Connection 478 ± RMC4550 0 309 312 314 315 2 355 320 311 241 4 433 302 316 148 7 570 281 299 107 9 654 265 316 102 eleven 710 277 309 91 14 819 340 309 75 18 890 349 303 76 21 992 384 372 74 22 1011 359 377 71

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As shown in table. 3, administration of compound 478 or RMC-4550 as a single agent provided 93% and 90% tumor growth suppression at day 22, respectively. The combination of the SHP-2 inhibitor RMC-4550 and compound 478 provided 78% tumor regression at day 22.

Table 4

Mean tumor volume (mm ³ ) in H358 tumor-bearing mice after treatment with single agents or combination

Research day Carrier Compound 478 RMC-4550 Combination Connection 478 ± RMC4550 0 336 335 333 336 4 407 277 336 237 6 478 244 343 193 8 523 200 372 150 12 558 156 388 120 15 589 133 399 110 18 617 120 422 87 20 631 113 454 71 22 536 109 492F 63 25 557 90 54 27 622 92 49 29 605 81 46 32 606 82 43 34 615 84 43 36 623 81 40 39 641 73 25 41 643 58 10

F - After 22 days, administration was stopped

As shown in table. 4, administration of compound 478 or RMC-4550 as a single agent provided 68% tumor regression and 22% tumor growth inhibition at day 22, respectively. The combination of the SHP-2 inhibitor RMC-4550 and compound 478 provided 81% tumor regression at day 22.

Similarly, 25 athymic/nude mice were inoculated with 5 x 10 ⁶ H2122 cells into the right hind limb. When the tumor volume reached ~350 mm ³ (day 0 of the study), 5 mice in each of the five groups were injected with p.o. daily for 21 days: vehicle only (10% captisol in 50 mM citrate buffer, pH 5.0), 100 mg/kg KRas G12C inhibitor compound 478 (10% captisol in 50 mM citrate buffer, pH 5.0), 30 mg/kg SHP-2 inhibitor RMC-4550 (10% captisol in 50 mM citrate buffer, pH 5.0), 100 mg/kg KRas G12C inhibitor compound 478, and 30 mg/kg RMC-4550 or 100 mg/kg kg of the KRas G12C inhibitor compound 478 for sixteen days, followed by continued administration of compound 478 along with 30 mg/kg RMC-4550 for an additional 13 days (separate group). The average tumor volume measured on predetermined days in five mice in each group was determined, the results are shown in table. 5.

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Claims (14)

Table 5 Mean tumor volume (mm ³ ) in H2122 tumor-bearing mice after treatment with single agents or combination Research day Carrier Compound 478 RMC- 4550 Combination Connections 478 ±RM C-4550 Conn. 478, days 1-16; 478 ± RMC4550, days 17-29 0 346 347 350 354 353 4 567 369 515 312 368 6 659 379 578 286 381 8 842 387 614 259 373 eleven 1053 382 683 248 370 13 1298 391 750 249 377 15 1429 396 856 250 401 18 1618 405 880 241 399 21 1685 430 916 252 398 24 1781 427 1026 259 398 27 1854 444 1137 262 384 29 1894 455 1166 252 373 As shown in table. 5, administration of compound 478 or RMC-4550 as a single agent provided 93% and 47% tumor growth suppression at day 29, respectively. The combination of the SHP-2 inhibitor RMC-4550 and compound 478 provided 29% tumor regression at day 29. The results demonstrate that the combination therapy provided increased levels of tumor growth inhibition compared with either agent alone, supporting increased in vivo antitumor efficacy of the combination against KRas G12C-expressing cancers. It should be understood that while the invention has been described in conjunction with specific embodiments, further modifications thereto are possible, and this application is intended to cover any modified variations, uses, or adaptations of the invention consistent generally with the basic principles of the invention, including deviations from the present invention, which are consistent with known or generally accepted practice in the field of technology to which the invention relates, and modifications that may be applied to the key features set forth herein above, as well as to the scope of the following appended claims. CLAIM 1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SHP-2 inhibitor and a KRAS G12C inhibitor, wherein said KRas G12C inhibitor is or a pharmaceutically acceptable salt thereof. 2. The method according to claim 1, characterized in that said SHP-2 inhibitor is SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazine dihydrochloride -2-amine); RMC-4550 (3-(((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-(2,3-dichlorophenyl)-5 -methylpyrazin-2yl)methanol), RMC-4360 or TNO155 (Novartis). - 91 044829 3. The method according to claim 2, characterized in that said SHP-2 inhibitor is SHP-099. 4. The method according to claim 2, characterized in that said SHP-2 inhibitor is RMC-4550. 5. The method according to claim 2, characterized in that said SHP-2 inhibitor is RMC4360 or TNO155. 6. The method of claim 1, wherein a therapeutically effective amount of said combination of an SHP-2 inhibitor and a KRAS G12C inhibitor provides increased duration of overall survival, increased duration of progression-free survival, increased regression of tumor growth, increased suppression of tumor growth, or increased duration of stabilization disease in subjects compared to treatment with a KRas G12C inhibitor alone. 7. A pharmaceutical composition for the treatment of cancer expressing KRas G12C, containing a therapeutically effective amount of the combination of an SHP-2 inhibitor and a KRas G12C inhibitor according to claim 1 and a pharmaceutically acceptable excipient. 8. A method of inhibiting KRas G12C activity in a cell, comprising contacting the cell in which it is desired to inhibit KRas G12C activity with an effective amount of an SHP-2 inhibitor and a KRas G12C inhibitor compound according to claim 1 or a pharmaceutically acceptable salt thereof, or containing them pharmaceutical compositions. 9. A method of increasing the susceptibility of a cancer cell expressing KRas G12C to a KRas G12C inhibitor compound, comprising administering to a subject undergoing treatment targeting KRas G12C the compound or a pharmaceutically acceptable salt thereof according to claim 1, alone or in combination with pharmaceutically acceptable carriers , excipients or diluents, and a therapeutically effective amount of an SHP-2 inhibitor. 10. The method according to claim 9, characterized in that said therapeutically effective amount of the KRas G12C inhibitor in combination is from 0.01 to 100 mg/kg per day. 11. Method according to any one of claims 1-6 and 9-10, characterized in that said cancer is a cancer expressing KRas G12C selected from the group consisting of heart diseases: sarcomas (angiosarcomas, fibrosarcomas, rhabdomyosarcomas, liposarcoma), myxomas, rhabdomyomas, fibromas, lipomas and teratomas; lungs: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; The gastrointestinal tract: esophagus (plane cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinomas, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinomas, gastrinomas, carcinoid tumors, viopolum), vijah), viopolum), vija), viopolum), vija) small intestine (adenocarcinoma, lymphoma , carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary system: kidneys (adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate gland (adenocarcinoma, sarcoma), testicles (seminoma, teratoma, embryonal carcinoma, teratocarcinomas, choriocarcinomas, sarcomas, interstitial cell carcinomas, fibromas, fibroadenomas, adenomatoid tumors, lipomas); liver: hematomas (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, renal cell adenoma, hemangioma; biliary tract: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; bone: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulocellular sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteocartilaginous exostosis), benign chondroma, chondrobe lastomas, chondromyxofibromas, osteoid osteoma and giant cell tumors; nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), soft shell of the brain (meningiomas, meningiosarcoma, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); gynecological diseases: uterus (endometrial carcinomas (serous cystadenocarcinoma, mucinosis cystadenocarcinoma, non-classified carcinoma), granulosis-cell tumors, tumors of cells of the granol-ladig, dyserminoma, malignant teratoma), external genitalia (plane cell cells, intra-rumines. telial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (carcinoma); hematological diseases: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myelopro proliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus syndrome, lipoma, angioma, dermatofibroma, keloids, psoriasis; and adrenal glands: neuroblastoma. - 92 044829 12. The method according to claim 11, characterized in that said cancer is non-small cell lung cancer. 13. A kit for treating KRas G12C expressing cancer in a subject, comprising the pharmaceutical composition of claim 7 and an insert with instructions for administering said composition. 14. A kit for the treatment of a KRas G12C expressing cancer in a subject, comprising: a) a pharmaceutical composition containing an SHP-2 inhibitor, and b) a pharmaceutical composition containing a KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof, and an insert with instructions for the administration of these compositions. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2