Combination therapy

Abstract

The present invention relates to combination therapy for treating KRas G12C cancer. Specifically, the present invention relates to a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SOS1 inhibitor and a KRas G12C inhibitor, a pharmaceutical composition comprising such a composition, a kit comprising such a composition, and a method of use thereof.

Description

[Technical field]

[0001] The present invention relates to combination therapies useful in the treatment of cancer. In particular, the present invention relates to therapeutically effective combinations of Son of sevenless (SOS1) inhibitors and KRas G12C inhibitors, pharmaceutical compositions comprising the inhibitors, kits comprising the compositions, and methods of use thereof. [Background technology]

[0002] KRas inhibitors Kirsten rat sarcoma 2 viral oncogene homolog ("KRas") is a small GTPase and a member of the Ras family of oncogenes. KRas functions as a molecular switch that cycles between inactive (GDP-bound) and active (GTP-bound) states and transmits upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a variety of processes, including cell proliferation (see, e.g., Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignancies was observed more than 30 years ago (see, e.g., Der et al., (1982) Proc. Natl Acad. Sci. USA 79(11):3637-3640). Aberrant expression of KRas accounts for up to 20% of all cancers, and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25-30% of lung adenocarcinomas. (See, e.g., Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428). Single nucleotide substitutions resulting in missense mutations at codons 12 and 13 of the KRas primary amino acid sequence comprise approximately 40% of these KRas driver mutations in lung adenocarcinoma, with the G12C transversion being the most common activating mutation (see, e.g., Dogan et al., (2012) Clin Cancer Res. 18(22):6169-6177 published online September 26, 2012 doi:10.1158 / 1078-0432. CCR-11-3265).

[0004] The well-known role of KRas in malignancies and the discovery of these frequent mutations of KRas in various tumor types have made KRas a highly attractive target for the pharmaceutical industry in cancer therapy. Despite 30 years of extensive discovery efforts to develop inhibitors of KRas for the treatment of cancer, KRas inhibitors have yet to demonstrate sufficient safety and / or efficacy to gain regulatory approval (see, e.g., McCormick (2015) Clin Cancer Res. 21(8):1797-1801).

[0005] Compounds that inhibit KRas activity remain highly desirable and under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors (see, e.g., Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143 doi:10.1002 / anie201201358), as well as those that target KRas G12C (see, e.g., Ostrem et al., (2013) Nature 503:548-551). Clearly, there remains ongoing interest and effort to develop inhibitors of KRas, particularly inhibitors that activate KRas mutations, including KRas G12C.

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

[0007] SOS1 inhibitors The Ras family includes v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRas), neuroblastoma RAS viral oncogene homolog (NRAS), and Harvey murine sarcoma viral oncogene (HRas), and critically regulates cell division, proliferation, and function under normal and altered conditions, including cancer (see, e.g., Simanshu et al. Cell, 2017.170(1):p.17-33; Matikas et al., Crit Rev Oncol Hematol, 2017.110:p.1-12). RAS proteins are activated by upstream signals, including receptor tyrosine kinases (RTKs), and transmit signals to several downstream signaling pathways, such as the mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK) pathway. Hyperactivation of RAS signaling is frequently observed in cancer as a result of mutations or alterations in RAS genes or other genes in the RAS pathway. Identification of strategies to inhibit RAS and RAS signaling is predicted to be useful in the treatment of cancer and RAS-regulated disease states.

[0008] RAS proteins are guanosine triphosphate (GTPase) enzymes that cycle between an inactive guanosine diphosphate (GDP)-bound state and an active guanosine triphosphate (GTP)-bound state. RAS proteins exhibit both intrinsic GTP hydrolysis and nucleotide exchange, which is further enhanced by exogenous GTPase activating proteins (GAPs) and guanine exchange factors (GEFs). Son of Sevenless homolog 1 (SOS1) is a GEF that mediates the exchange of GDP for GTP, thereby activating RAS proteins. This regulation through GAPs and GEFs is a mechanism by which activation and deactivation are tightly regulated under normal conditions. Mutations at several residues in all three RAS proteins are frequently observed in cancer, resulting in RAS remaining predominantly in an activated state (see Sanchez-Vega et al., Cell, 2018.173: p.321-337 Li et al., Nature Reviews Cancer, 2018.18: p.767-777). Mutations at codons 12 and 13 disrupt the GTP hydrolysis and exchange rate of RAS proteins. Recent biochemical analyses have demonstrated that these mutant proteins still require nucleotide cycling for activation based on their intrinsic GTPase activity and may exhibit partial sensitivity to exogenous GAPs and GEFs. Thus, mutant RAS proteins are sensitive to inhibition of upstream factors such as SOS1 GEF (Hillig, 2019; Patricelli, 2016; Lito, 2016; Nichols, 2018).

[0009] Three major RAS-GEF families have been identified in mammalian cells: SOS, RAS-GRF, and RAS-GRP (Rojas, 2011). RAS-GRF and RAS-GRP are expressed in cells of the central nervous system and hematopoietic cells, respectively, while the SOS family is expressed ubiquitously and is involved in transduction of RTK signaling. The SOS family includes SOS1 and SOS2, and these proteins share about 70% sequence identity. SOS1 appears to be much more active than SOS2 due to the rapid degradation of SOS2. Mouse SOS2 knockouts are viable, whereas SOS1 knockouts are embryonic lethal. A tamoxifen-inducible SOS1 knockout mouse model was used to investigate the role of SOS1 and SOS2 in adult mice, demonstrating that SOS1 knockouts were viable, whereas SOS1 / 2 double knockouts were non-viable (Baltanas, 2013), suggesting functional redundancy and that selective inhibition of SOS1 may have a sufficient therapeutic index for the treatment of SOS1-RAS activated diseases.

[0010] SOS proteins are recruited to phosphorylated RTKs through interactions with growth factor receptor bound protein 2 (GRB2). Recruitment to the plasma membrane places SOS in close proximity to RAS, allowing SOS-mediated RAS activation. SOS proteins bind RAS through a catalytic binding site that promotes nucleotide exchange, as well as through an allosteric site that binds GTP-bound RAS family proteins, increasing the catalytic function of SOS (Freedman et al., Proc. Natl. Acad. Sci, USA 2006.103(45):p.16692-97). Binding to the allosteric site relieves steric blockage of the catalytic site and is therefore required for full activation of the catalytic site. Retention of the active conformation at the catalytic site after interaction with the allosteric site is maintained in isolation due to enhanced interactions of key domains in the activated state. SOS1 mutations are found in Noonan syndrome and several cancers, including lung adenocarcinoma, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, and granular cell tumor of the skin (see, e.g., Denayer, E., et al, Genes Chromosomes Cancer, 2010.49(3):p.242-52).

[0011] GTPase-activating proteins (GAPs) are proteins that stimulate the low intrinsic GTPase activity of RAS family members, thus converting active GTP-bound RAS proteins into inactive GDP-bound RAS proteins (see, e.g., Simanshu, DK, Cell, 2017, Ras Proteins and their Regulators in Human Disease). Activating alterations in the phosphatase PTPN11 (SHP2) and the GEF SOS1 occur in cancer, while inactivating mutations and loss-of-function alterations in the GAP neurofibromin 1 (NF-1) also occur, creating a state in which SOS1 activity is unopposed and downstream activity of pathways through RAS proteins is elevated.

[0012] MEK inhibitors The mitogen-activated protein kinase (MAPK) signaling pathway is involved in the regulation of various cellular activities, including, but not limited to, cell proliferation, survival, differentiation, and motility. The classical MAPK pathway consists of Ras (a family of related proteins expressed in all animal cell lineages and organs), Raf (a family of three serine / threonine-specific protein kinases related to retroviral oncogenes), MEK (mitogen-activated protein kinase kinase), and ERK (extracellular signal-regulated kinase), which sequentially relay growth signals generated at cell surface receptors through cytoplasmic signaling into the nucleus.

[0013] MEK inhibitors target the Ras / Raf / MEK / ERK signaling pathway, thereby inhibiting cell proliferation and inducing apoptosis.

[0014] The MAPK pathway is one of the most commonly mutated oncogenic pathways in cancer, and deregulation of this pathway is frequently observed and plays a central role in the oncogenesis and maintenance of several cancers, including melanoma, pancreatic cancer, lung cancer, colorectal cancer, and breast cancer (e.g., Neuzillet et al., (2014) Pharmacology & Therapeutics 141:160-171).

[0015] Several inhibitors have been developed that exhibit activity against MEK, and many of these inhibitors are or have been studied in human clinical trials. Examples of MEK inhibitors suitable for the provided compositions and methods include selumetinib, 6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide; AZD8330, 2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide; PD0325901, N-[(2R)-2,3-dihydroxypropoxy]-1,5-dimethyl-6-oxopyridine-3-carboxamide; 5-Bromo-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide; PD318088, 5-Bromo-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide; Refametinib, N-[3,4-difluoro-2-(2-fluoro-4-iodoanilino)-6-methoxyphenyl]-1-[(2S)-2,3-dihydroxypropyl]cyclopropane-1-sulfonamide; Binimethinib Nib, 6-(4-bromo-2-fluoroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide; RO4987655, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-oxooxazinan-2-yl)methyl]benzamide, RO5126766 (VS-6766), 3-[[3-fluoro-2-(methylsulfamoylamino)pyridinyl] 7-fluoro-3-(2-fluoro-4-iodoanilino)-N-[(2S)-2-hydroxypropoxy]furo[3,2-c]pyridine-2-carboxamide; PD184161, 5-bromo-2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide;RO5068760, (2S,3S)-2-[(4R)-4-[4-[(2R)-2,3-dihydroxypropoxy]phenyl]-2,5-dioxoimidazolidin-1-yl]-N-(2-fluoro-4-iodophenyl)-3-phenylbutanamide; SL327, (Z)-3-amino-3-(4-aminophenyl)sulfanyl-2-[2-(trifluoromethyl)phenyl]prop-2-enenitrile; MEK162 (Arry-162), 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-N-(2-hydroxyethyl) (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-((2-fluoro-4-iodophenyl)amino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione; GDC-0623, 5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide; U0126, (2E,3E)-2-(amino((2-aminophenyl)thio) (E)-3-(3-((4-(dimethylamino)methyl)phenyl)amino)(phenyl)methylene)-2-oxoindolin-6-yl)-N-ethylpropionate; Trametinib, N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide; BI-847325, (E)-3-(3-(((4-((dimethylamino)methyl)phenyl)amino)(phenyl)methylene)-2-oxoindolin-6-yl)-N-ethylpropionate; lopiolamide; pimasertib, (S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide; BIX02189, (Z)-3-(((3-((dimethylamino)methyl)phenyl)amino)(phenyl)methylene)-N,N-dimethyl-2-oxoindoline-6-carboxamide; cobimetinib, (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)phenyl)(3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl)methanone;PD-98059, 2-(2-amino-3-methoxyphenyl)-4H-chromen-4-one;APS-2-79, 6,7-dimethoxy-N-(2-methyl-4-phenoxyphenyl)quinazolin-4-amine;PD198306, N-(cyclopropylmethoxy)-3,4,5-trifluoro-2-(4-iodo-2-methylbenzyl)benzamide;CI-1040, 2-(2-chloro-4-iodobenzyl)-N- Examples include, but are not limited to, (cyclopropylmethoxy)-3,4-difluorobenzamide; SL327, (Z)-3-amino-3-((4-aminophenyl)thio)-2-(2-(trifluoromethyl)phenyl)acrylonitrile, and BIX02188, (Z)-3-(((3-((dimethylamino)methyl)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxamide;

[0016] The structures of these MEK inhibitors are described, for example, in Cheng et al, Current Development Status of MEK Inhibitors, Molecules 2017, 22, 1551, as well as in U.S. Pat. Nos. 10,370,374 and 10,323,035, and U.S. Patent Application Publication Nos. 2019 / 0144382, 2018 / 0370948, 2018 / 0296533, 2018 / 0147192, 2018 / 0118715, 2017 / 0231963, 2017 / 0183348, 2017 / 0183333, 2017 / 0166523, 2017 / 0101408, 2017 / 0 No. 096388, No. 2016 / 0331753, No. 2016 / 0168103, No. 2016 / 0168102, No. 2016 / 0136150, No. 2016 / 0108041, No. 2015 / 0141399, No. 2015 / 01 33424, 2015 / 0051209, 2014 / 0378466, 2014 / 0275527, 2014 / 0135519, 2014 / 0128442, 2014 / 0080804, 2013 / 0150 No. 573, No. 2013 / 0018075, No. 2012 / 0238599, No. 2012 / 0208859, No. 2012 / 0107307, No. 2012 / 0022076, No. 2011 / 0288092, No. 2011 / 02635 No. 58, No. 2011 / 0190257, No. 2011 / 0183981, No. 2011 / 0172191, No. 2011 / 0158971, No. 2011 / 0124622, No. 2011 / 0112152, No. 2011 / 006004 No. 9, No. 2011 / 0021558, No. 2010 / 0331334, No. 2010 / 0267710, No. 2010 / 0261718, No. 2010 / 0261717, No. 2010 / 0260714, No. 2010 / 0256149 No. 2010 / 0249096, No. 2010 / 0197676, No. 2010 / 0179124, No. 2010 / 0063053, No. 2009 / 0291961, No. 2009 / 0264411, No. 2009 / 0233915,2009 / 0215834, 2009 / 0209542, 2009 / 0156576, 2009 / 0149437, 2009 / 0143579, No. 2009 / 0143389, No. 2009 / 0131435, No. 2009 / 0082457, No. 2009 / 0030058, No. 2008 / 0306063, No. 2008 / 0280957, 2008 / 0255133, 2008 / 0177082, 2008 / 0171778, 2008 / 0166359, 2 No. 008 / 0058340, No. 2007 / 0299063, No. 2007 / 0293544, No. 2007 / 0287737, No. 2007 / 0287709, No. 20 07 / 0244164, 2007 / 0238710, 2007 / 0213367, 2007 / 0172843, 2007 / 0112038, 200 7 / 0105859, 2006 / 0211073, 2006 / 0194802, 2006 / 0189808, 2006 / 0189668, 2006 2006 / 0189649, 2006 / 0154990, 2006 / 0106225, 2006 / 0089382, 2006 / 0052608, 2005 / 0256123, 2005 / 0250782, and 2005 / 0153942, the contents of which are incorporated herein by reference in their entireties.

[0017] One suitable MEK inhibitor for the compositions and methods provided is VS-6766, which has the following structure:

[0018] [ka] 3-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one

[0019] Methods for producing MEK inhibitors, or pharma- ceutically acceptable salts or pharmaceutical compositions thereof, are well known to those of skill in the art, and MEK inhibitors can be obtained from a wide variety of commercial suppliers in a form suitable for both research or human use. Additionally, MEK inhibitors suitable for use in the compositions and methods disclosed herein, as well as methods for preparing such inhibitors, are disclosed in U.S. Patent Application Publication Nos. 2019 / 0144382, 2018 / 0370948, 2018 / 0296533, 2018 / 0147192, 2018 / 0118715, 2017 / 0231963, 2017 / 0183348, 2017 / 0183333, 2017 / 0166523, 2017 / 01 No. 01408, No. 2017 / 0096388, No. 2016 / 0331753, No. 2016 / 0168103, No. 2016 / 0168102, No. 2016 / 0136150, No. 2016 / 0108041, No. 2015 / No. 0141399, No. 2015 / 0133424, No. 2015 / 0051209, No. 2014 / 0378466, No. 2014 / 0275527, No. 2014 / 0135519, No. 2014 / 0128442, No. 2014 / 0080804, 2013 / 0150573, 2013 / 0018075, 2012 / 0238599, 2012 / 0208859, 2012 / 0107307, 2012 / 0022076, 20 11 / 0288092, 2011 / 0263558, 2011 / 0190257, 2011 / 0183981, 2011 / 0172191, 2011 / 0158971, 2011 / 0124622, 2 011 / 0112152, 2011 / 0060049, 2011 / 0021558, 2010 / 0331334, 2010 / 0267710, 2010 / 0261718, 2010 / 0261717, No. 2010 / 0260714, No. 2010 / 0256149, No. 2010 / 0249096, No. 2010 / 0197676, No. 2010 / 0179124, No. 2010 / 0063053, No. 2009 / 0291961,2009 / 0264411, 2009 / 0233915, 2009 / 0215834, 2009 / 0209542, 2009 / 0156576, No. 2009 / 0149437, No. 2009 / 0143579, No. 2009 / 0143389, No. 2009 / 0131435, No. 2009 / 0082457, No. 2009 / 0030058, 2008 / 0306063, 2008 / 0280957, 2008 / 0255133, 2008 / 0177082, 2 008 / 0171778, 2008 / 0166359, 2008 / 0058340, 2007 / 0299063, 2007 / 0293544, 200 7 / 0287737, 2007 / 0287709, 2007 / 0244164, 2007 / 0238710, 2007 / 0213367, 2007 / 0172843, 2007 / 0112038, 2007 / 0105859, 2006 / 0211073, 2006 / 0194802, 2006 / 0189808, 2006 / 0189668, 2006 / 0189649, 2006 / 0154990, 2006 / 0106225, 2006 / 0089382, 2006 / 0052608, 2005 / 0256123, 2005 / 0250782, and 2005 / 0153942. [Prior art documents] [Non-patent literature]

[0020] [Non-Patent Document 1] Alamgeer et al.,(2013)Current Opin Pharmcol.13:394-401 [Non-Patent Document 2] Der et al.,(1982)Proc.Natl Acad.Sci.USA 79(11):3637-3640 [Non-Patent Document 3] Samatar and Poulikakos(2014)Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428 [Non-Patent Document 4] Dogan et al.,(2012)Clin Cancer Res.18(22):6169-6177 Online publication on September 26, 2012 doi:10.1158 / 1078-0432.CCR-11-3265 [Non-Patent Document 5] McCormick(2015)Clin Cancer Res.21(8):1797-1801 [Non-Patent Document 6] Sun et al.,(2012)Agnew Chem Int Ed Engl.51(25):6140-6143 doi:10.1002 / anie201201358 [Non-Patent Document 7] Ostrem et al.,(2013)Nature 503:548-551 [Non-Patent Document 8] Simanshu et al.Cell,2017.170(1):p.17-33 [Non-Patent Document 9] Matikas et al.,Crit Rev Oncol Hematol,2017.110:p.1-12 [Non-Patent Document 10] Sanchez-Vega et al.,Cell,2018.173:p.321-337 Li et al.,Nature Reviews Cancer,2018.18:p.767-777 [Non-Patent Document 11] Freedman et al.,Proc.Natl.Acad.Sci,USA 2006.103(45):p.16692-97 [Non-Patent Document 12] Denayer,E.,et al,Genes Chromosomes Cancer,2010.49(3):p.242-52 [Non-Patent Document 13] Simanshu,DK,Cell,2017,Ras Proteins and their Regulators in Human Disease [Non-Patent Document 14] Neuzillet et al.,(2014)Pharmacology&Therapeutics 141:160-171 Summary of the Invention

[0021] In one aspect, the combination therapy of the present invention synergistically increases the potency of the KRas G12C inhibitor, resulting in improved efficacy of the KRas G12C inhibitor disclosed herein.In another aspect, the combination therapy of the present invention provides patients with improved clinical benefit compared to treatment with the KRas G12C inhibitor disclosed herein as a single agent.

[0022] Thus, in one aspect of the invention, there are provided therapeutically effective combinations of SOS1 inhibitors, such as those described in U.S. Provisional Patent Applications Nos. 62 / 951,812, 62 / 975,645, 63 / 044,802, 62 / 980,790, and 63 / 057,563 (and corresponding U.S. and international applications and publications, including International Applications Nos. PCT / US20 / 66003, PCT / US21 / 19184, PCT / US21 / 43309, and US17 / 127,582), as described in further detail herein, e.g.

[0023] [ka] (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile,

[0024] [ka] 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile,

[0025] [ka] (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile,

[0026] [ka] (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile,

[0027] [ka] (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile,

[0028] [ka] (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile,

[0029] [ka] 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile,

[0030] [ka] (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof, and the KRas G12C inhibitor compound 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (also known as MRTX849 and adagrasib).

[0031] [ka] or a pharma- ceutically acceptable salt thereof.

[0032] In another aspect of the invention, a combination of an SOS1 inhibitor, such as BI1701963, or a pharma- ceutically acceptable salt thereof, and a KRas G12C inhibitor compound 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (also known as MRTX849, also known as adagrasib)

[0033] [ka] or a pharma- ceutically acceptable salt thereof.

[0034] In one aspect, the present invention provides a method for producing a method for treating a cancer cell comprising: formula:

[0035] [ka] or a pharma- ceutically acceptable salt thereof; and Therapeutically effective combinations with the KRas G12C inhibitor compound 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (also known as MRTX849, also known as adagrasib) are provided.

[0036] In another aspect, the present invention provides a method for producing a composition comprising: formula:

[0037] [ka] or a pharma- ceutically acceptable salt thereof; and the KRas G12C inhibitor compound 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (also known as MRTX849, also known as adagrasib); The MEK inhibitor [[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one (also known as VS-6766), having the structure

[0038] [ka] or a pharma- ceutically acceptable salt thereof.

[0039] In another aspect of the invention, a pharmaceutical composition is provided comprising a therapeutically effective amount of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzo Nitrile, (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-3-(dimethyl and (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, in combination with the KRas G12C inhibitor compound adagrasib, or a pharma- ceutical acceptable salt thereof and a pharma- ceutical acceptable excipient, are provided for use in the methods.

[0040] In some embodiments, the method may further include administering a MEK inhibitor to a subject in need thereof, such that adagrasib, an SOS1 inhibitor, and a MEK inhibitor, such as VS-6766, are administered to the subject.

[0041] In one aspect of the invention, there is provided a method of treating cancer in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[ 3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4- d]pyridazin-1-yl)amino)ethyl)benzonitrile, (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile SOS1 inhibitors such as 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile or (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile; or BI1701963, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, in combination with the KRas G12C inhibitor adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are provided herein.

[0042] In one embodiment, the cancer is a KRas G12C-associated cancer. In one embodiment, the KRas G12C-associated cancer is lung cancer.

[0043] In some aspects of the invention, the KRas G12C inhibitor compound and the SOS1 inhibitor are the only active agents in the compositions and methods provided.

[0044] Examples of SOS1 inhibitors suitable for the provided compositions and methods include (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl) Benzonitrile, (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-3-( dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and pharma- ceutically acceptable salts thereof.

[0045] Other examples of SOS1 inhibitors suitable for the provided compositions and methods include BI1701963.

[0046] In yet another aspect, the invention provides a method for inhibiting KRas G12C activity in a cell, comprising administering to the cell in which inhibition of KRas G12C activity is desired an effective amount of the KRas G12C inhibitor adagrasib.

[0047] [ka] or a pharma- ceutically acceptable salt thereof, in combination with an SOS1 inhibitor.

[0048] In one embodiment, the SOS1 inhibitor has the structure:

[0049] [ka] or a pharma- ceutically acceptable salt thereof.

[0050] In yet another aspect, the method comprises treating the cells with a compound having the structure

[0051] [ka] or a pharma- ceutically acceptable salt thereof.

[0052] In yet another aspect, the invention provides a method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor, comprising contacting the cancer cell with a therapeutically effective amount of a combination of a KRas G12C inhibitor compound adagrasib or a pharma- ceutically acceptable salt or pharmaceutical composition thereof and a SOS1 inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo. In one embodiment, the method comprises administering to a subject undergoing KRas G12C therapy an effective amount of a combination of a KRas G12C inhibitor adagrasib or a pharma- ceutically acceptable salt thereof and a SOS1 inhibitor, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor.

[0053] In one embodiment, a method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor comprises treating the cancer cell with a therapeutically effective amount of a KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a SOS1 inhibitor having the structure:

[0054] [ka] or a pharma- ceutically acceptable salt or a pharmaceutical composition thereof.

[0055] In yet another embodiment, the method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor comprises treating the cancer cell with a compound having the structure:

[0056] [ka] or a pharma- ceutically acceptable salt thereof.

[0057] Also provided herein is a method for treating cancer in a subject in need of such treatment, comprising: (a) determining (e.g., as determined using a regulatory approved, e.g., FDA approved, assay or kit) that the cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer); and (b) administering to the patient a therapeutically effective amount of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, in combination with the KRas G12C inhibitor adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the SOS1 inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to adagrasib.

[0058] Also provided herein is a kit comprising an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.Also provided is a kit comprising an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in treating KRas G12C cancer.

[0059] In a related aspect, the present invention provides a kit containing a dose of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, in an amount effective to inhibit the proliferation of cancer cells in a subject. The kit optionally includes a package insert having instructions for administering the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof. The package insert may provide the user with a set of instructions for using the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, in combination with the KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0060] In some embodiments of any of the methods described herein, prior to treatment with a composition or method of the invention, the patient has been treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, optionally where the previous treatment has been unsuccessful, and / or the patient has been subjected to surgery, optionally where the surgery has been unsuccessful, and / or the patient has been treated with a platinum-based chemotherapy agent, optionally where the patient has been previously determined to be non-responsive to treatment with a platinum-based chemotherapy agent, and / or the patient has been treated with a kinase inhibitor, optionally where the previous treatment with the kinase inhibitor has been unsuccessful, and / or the patient has been treated with one or more other therapeutic agents. [Brief description of the drawings]

[0061] [Figure 1] 1 is a chart of tumor growth inhibition in MIA PaCA-2 tumor-bearing mice by MRTX0902, adagrasib, and the combination of MRTX0902 and adagrasib. [Diagram 2] 1 is a chart of tumor growth inhibition in MIA PaCA-2 tumor-bearing mice by MRTX0902, adagrasib, and the combination of MRTX0902 and adagrasib. [Diagram 3] 1 is a chart of tumor growth inhibition in MIA PaCA-2 tumor-bearing mice by MRTX2006, adagrasib, and the combination of MRTX0902 and adagrasib. [Figure 4] 1 is a chart of tumor growth inhibition in MIA PaCA-2 tumor-bearing mice by MRTX4197, adagrasib, and the combination of MRTX0902 and adagrasib. [Diagram 5] 1 is a chart of tumor growth inhibition in LU99 tumor-bearing mice by MRTX0902, adagrasib, and the combination of MRTX0902 and adagrasib. [Figure 6] 1 is a chart of tumor growth inhibition in NCl-H2122 tumor-bearing mice by MRTX0902, adagrasib, and the combination of MRTX0902 and adagrasib. [Figure 7] 1 is a chart of tumor growth inhibition in NCI-H 2122 tumor-bearing mice by MRTX0902, adagrasib, a combination of MRTX0902 and VS-6766, and a combination of VS-6766 and adagrasib. [Figure 8] 1 is a chart of tumor growth inhibition in CR6256 tumor-bearing mice by MRTX0902, adagrasib, and the combination of MRTX0902 and adagrasib. [Figure 9] 1 is a bar graph demonstrating the efficacy of the combination of MRTX849 and MRTX0902 in various human tumor xenograft KRas G12C models. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0062] The present invention relates to combination therapies for treating KRas G12C cancer. Specifically, the present invention relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an SOS1 inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof in combination with a KRas G12C inhibitor, adagrasib or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, a pharmaceutical composition comprising a therapeutically effective amount of the inhibitor, a kit comprising the composition, and methods of use thereof.

[0063] The combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, with a KRas G12C inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, synergistically increases the potency of the KRas G12C inhibitor compound adagrasib against cancer cells expressing KRas G12C, thereby increasing the efficacy and therapeutic index of the KRas G12C inhibitor compound adagrasib or a pharma- ceutically acceptable salt thereof.

[0064] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications mentioned herein are incorporated by reference.

[0065] As used herein, "KRas G12C" refers to a mutant mammalian KRas protein containing a glycine to cysteine ​​amino acid substitution at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variant p.Gly12Cys.

[0066] As used herein, "KRas G12C inhibitor" refers to the compounds of the present invention represented by formula (I), formula IA, and formula IB as described in WO 2019 / 099524, or pharma- ceutically acceptable salts thereof (e.g., Example Nos. 234, 359, 478, or 507, or pharma- ceutically acceptable salts thereof). These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12C. The KRas G12C inhibitors of the present invention interact with and irreversibly bind to KRas G12C by forming 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. Adaglasib is an example of a KRas G12C inhibitor.

[0067] As used herein, "KRas G12C-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12C mutation. A non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12C-associated cancer.

[0068] As used herein, "SOS1" refers to the son of sevenless homolog 1 protein encoded by the SOS1 gene, which is involved in signaling through the RAS pathway.

[0069] As used herein, "SOS1 inhibitor" refers to a compound capable of negatively regulating or inhibiting all or part of the interaction between KRAS and SOS1.

[0070] As used herein, the terms "subject," "individual," or "patient," used interchangeably, refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with a KRas G12C mutation (e.g., determined using a regulatory approved, e.g., FDA approved, assay or kit). In some embodiments, the subject has a tumor that is positive for the KRas G12C mutation (e.g., determined using a regulatory approved, e.g., FDA approved, assay or kit). The subject can be a subject with a tumor that is positive for the KRas G12C mutation (e.g., identified as positive using a regulatory approved, e.g., FDA approved, assay or kit). The subject may be one whose tumor has a KRas G12C mutation (e.g., where the tumor is identified as such using a regulatory approved, e.g., FDA approved, kit or assay). In some embodiments, the subject is suspected of having a KRas G12C gene-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with a KRas G12C mutation (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0071] The term "pediatric patient" as used herein refers to a patient who is under 16 years of age at the time of diagnosis or treatment. The term "child" can be further divided into various subpopulations, including: neonates (birth to 1 month of age), infants (1 month to 2 years of age), children (2 to 12 years of age), and adolescents (12 to 21 years of age (up to but not including their 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

[0072] In some embodiments of any of the methods or uses described herein, the assays used to determine whether a patient has a KRas G12C mutation using a sample (e.g., a biological sample or biopsy sample (e.g., a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a KRas G12C-associated cancer, a patient with one or more symptoms of a KRas G12C-associated cancer, and / or a patient at increased risk of developing a KRas G12C-associated cancer) may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, the assays are typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0073] The term "regulatory authority" refers to a national agency that approves the medical use of pharmaceutical agents in that country. For example, a non-limiting example of a regulatory authority is the U.S. Food and Drug Administration (FDA).

[0074] As used herein, an "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit the activity of a desired target, i.e., SOS1 or KRas G12C. Such an amount may be administered as a single dose or according to a regimen, whereby it is effective.

[0075] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to ameliorate or in some manner reduce symptoms, or to halt or reverse the progression of a condition, or to negatively regulate or inhibit the activity of SOS1 or KRas G12C. Such an amount may be administered as a single dose or may be administered according to a regimen, whereby it is effective.

[0076] As used herein, a "therapeutically effective amount" of two compounds is an amount that synergistically increases the activity of the combination together, i.e., more than merely additive, compared to the therapeutically effective amount of each compound in the combination. Alternatively, in vivo, a combination of a therapeutically effective amount of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, with a KRas G12C inhibitor compound adagrasib, or a pharma-ceutically acceptable salt or pharmaceutical composition thereof, results in an increase in overall survival (OS) in a subject, compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SOS1 inhibitor, or a pharma-ceutically acceptable salt or pharmaceutical composition thereof, with a KRas G12C inhibitor compound adagrasib, or a pharma-ceutically acceptable salt or pharmaceutical composition thereof, results in an increase in progression-free survival (PFS) in a subject, compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, with the KRas G12C inhibitor compound adagrasib or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor regression in a subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, with the KRas G12C inhibitor compound adagrasib or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor growth inhibition in a subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, with the KRas G12C inhibitor compound adagrasib or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in improved stable disease duration in a subject compared to treatment with a KRas G12C inhibitor alone. The amount of each compound in the combination can be the same as the therapeutically effective amount of each compound when administered alone as a monotherapy, or can be different, so long as the combination is synergistic.Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

[0077] As used herein, treatment means any manner in which the symptoms or pathology of a condition, disorder, or disease are ameliorated or otherwise beneficially altered. Treatment also includes any pharmaceutical use of the compositions herein.

[0078] As used herein, "amelioration" of symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, whether permanent or temporary, persistent or transient, that can result from or be associated with administration of the composition.

[0079] As used herein, the term "about" when used to modify a numerically defined parameter (e.g., a dose of a KRas inhibitor or SOS1 inhibitor or a pharma- ceutically acceptable salt thereof described herein, or a length of treatment time) means that the parameter may vary by as much as 10% above or below the numerical value stated for that parameter. For example, a dose of about 5 mg / kg may vary from 4.5 mg / kg to 5.5 mg / kg. When used at the beginning of a list of parameters, "about" is meant to modify the respective parameter. For example, about 0.5 mg, 0.75 mg, or 1.0 mg means about 0.5 mg, about 0.75 mg, or about 1.0 mg. Similarly, about 5% or more, 10% or more, 15% or more, 20% or more, and 25% or more means about 5% or more, about 10% or more, about 15% or more, about 20% or more, and about 25% or more.

[0080] KRas G12C inhibitor compounds In one aspect of the invention, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0081] In one embodiment, the KRas G12C inhibitor is

[0082] [ka] (also referred to as adagrasib, MRTX849, and Example 478 in WO 2019 / 099524) or a pharma- ceutically acceptable salt thereof.

[0083] The KRas G12C inhibitors used in the methods of the present invention may have one or more chiral centers and may be synthesized as stereoisomeric mixtures, isomers of the same constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures, or the individual components / isomers may be separated using commercially available reagents and conventional methods for isolating stereoisomers and enantiomers well known to those skilled in the art, for example, using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatography HPLC columns according to the manufacturer's instructions. Alternatively, the compounds of the present invention may be synthesized using optically pure chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Unless otherwise specified, whenever the specification, including the claims, refers to a compound of the present invention, the term "compound" should be understood to include all chiral (enantiomers and diastereomers) and racemic forms.

[0084] In one embodiment, the KRas G12C inhibitor compound adagrasib used in the method includes salts of the above compounds, for example salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like, salts formed 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, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid, and salts formed from quaternary ammonium of the formula --NRZ-; where R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzilate, and diphenylacetate).

[0085] Methods for producing the KRas G12C inhibitors disclosed herein are known. For example, commonly owned published International PCT Application Nos. 2017 / 201161 and 2019 / 099524 describe general reaction schemes for preparing compounds including adagrasib, and also provide detailed synthetic routes for the preparation of these compounds.

[0086] SOS1 inhibitor compounds In one embodiment, the SOS1 inhibitor is (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(1-((7-(3-(dimethylamino)-3-methylazeti (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl 3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methyl Benzonitriles, or pharma- ceutically acceptable salts thereof, or selected from the compounds described in U.S. Provisional Patent Applications Nos. 62 / 951,812, 62 / 975,645, 63 / 044,802, 62 / 980,790, and 63 / 057,563 (and corresponding international applications and publications, including International Application No. PCT / US20 / 06603 and U.S. Patent No. 17 / 127,582), as described in more detail herein.

[0087] In another embodiment, the SOS1 inhibitor is BI1701963.

[0088] In another embodiment, the SOS1 inhibitor is a compound of the formula

[0089] [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is hydrogen, hydroxyl, C1-C6 alkyl, alkoxy, -N(R 6 )2, -NR 6 C(O)R 6 , -C(O)N(R 6 )2, -SO2 alkyl, -SO2NR 6 alkyl, cycloalkyl, -Q-heterocyclyl, aryl, or heteroaryl, each of which is optionally represented by one or more R 2 and each Q is independently a bond, O, or NR 6 and X is N or CR 7 And each R 2 are independently hydroxy, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, -N(R 6 )2, -SO2 alkyl, -NR 6 C(O)C1-C3 alkyl, -C(O)cycloalkyl, -C(O)heterocyclyl, or aryl, each of which is optionally represented by one or more R 11 is replaced by R 3 is hydrogen, C1-C6 alkyl, alkoxy, -N(R 10 )2, cycloalkyl, haloalkyl, heterocyclyl, aryl, or heteroaryl, wherein C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally represented by one or more R 9 and Y is a bond or heteroarylene; R 4 Each optionally contains one or more R 5 and each R is an aryl or heteroaryl substituted with 5 are independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C3 alkyl, haloalkyl, -N(R6 )2, -LN(R 6 )2, or -SO2 alkyl, L is C1-C3 alkylene, and each R 6 are independently hydrogen, C1-C3 alkyl, haloalkyl, or cycloalkyl; R 7 is hydrogen, cyano, or alkoxy; R 8 is C1-C2 alkyl or halo-C1-C2 alkyl, and each R 9 is independently hydroxy, halogen, amino, cyano, alkoxy, or C1-C3 alkyl; 10 is independently hydrogen, C1-C3 alkyl, or cycloalkyl; 11 are independently C1-C3 alkyl or haloalkyl. These compounds include the following compounds:

[0090] [ka]

[0091] [ka]

[0092] [ka]

[0093] [ka]

[0094] [ka]

[0095] [ka]

[0096] [ka]

[0097]

change

[0098]

change

[0099]

change

[0100]

change

[0101]

change

[0102]

change

[0103]

change

[0104]

change

[0105]

change

[0106]

change

[0107] [ka]

[0108] [ka] and pharma- ceutically acceptable salts thereof, but are not limited to these.

[0109] In another embodiment, the SOS1 inhibitor is a compound of the formula

[0110] [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is hydrogen, hydroxy, C1-C6 alkyl, alkoxy, -N(R 6 )2, -NR 6 C(O)R 6 , -C(O)N(R 6 )2, -SO2 alkyl, -SO2NR 6 alkyl, cycloalkyl, -Q-heterocyclyl, aryl, or heteroaryl, each of which is optionally represented by one or more R 2 and each Q is independently a bond or O; and X is N or CR 7 And each R 2 are independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, -N(R 6 )2, -SO2 alkyl, -NR 6 C(O)R 6 C1-C3 alkyl, haloalkyl, cycloalkyl, or aryl; R 3 is hydrogen, halogen, cyano, C1-C6 alkyl, alkoxy, -N(R 10 )2,-NR 10 C(O)NR 10 , -C(O)N(R 10 )2, -SO2 alkyl, -SO2NR 10 Alkyl, -SO2N(R10 )2, cycloalkyl, haloalkyl, heterocyclyl, aryl, or heteroaryl, wherein C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally represented by one or more R 9 and Y is a bond or heteroarylene; R 4 Each optionally contains one or more R 5 and each R is an aryl or heteroaryl substituted with 5 are independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C3 alkyl, haloalkyl, or -LN(R 6 ) 2, L is C1-C3 alkylene, and each R 6 are independently hydrogen, C1-C3 alkyl, or cycloalkyl; R 7 is hydrogen or alkoxy; R 8 is C1-C2 alkyl or halo-C1-C2 alkyl, and each R 9 is independently hydroxy, halogen, amino, cyano, alkoxy, or C1-C6 alkyl; each R 10 are independently hydrogen, C1-C3 alkyl, or cycloalkyl; R 11 is hydrogen, C1-C3 alkyl, cycloalkyl, or haloalkyl. These compounds include the following compounds:

[0111] [ka] and pharma- ceutically acceptable salts thereof, but are not limited to these.

[0112] In another embodiment, the SOS1 inhibitor is a compound of the formula

[0113] [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is hydrogen, hydroxyl, C1-C6 alkyl, alkoxy, -N(R 6)2, -NR 6 C(O)R 6 , -C(O)N(R 6 )2, -SO2 alkyl, -SO2NR 6 alkyl, cycloalkyl, -Q-heterocyclyl, aryl, or heteroaryl, each of which is optionally represented by one or more R 2 and each Q is independently a bond, O, or NR 6 and X is N or CR 7 with the proviso that if X is N, then R 1 is not a hydroxyl, each R 2 are independently hydroxy, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, -N(R 6 )2, -SO2 alkyl, -NR 6 C(O)C1-C3 alkyl, -C(O)cycloalkyl, -C(O)heterocyclyl, or aryl, each of which is optionally represented by one or more R 9 is replaced by R 3 is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or cycloalkyl; Y is a bond or heteroarylene; R 4 Each optionally contains one or more R 5 and each R is an aryl or heteroaryl substituted with 5 are independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C4 alkyl, haloalkyl, -N(R 6 )2, -LN(R 6 )2, or -SO2 alkyl, L is C1-C3 alkylene, and each R 6 are independently hydrogen, C1-C3 alkyl, haloalkyl, or cycloalkyl; R 7 is hydrogen, cyano, or alkoxy; R 8 is C1-C2 alkyl or halo-C1-C2 alkyl, and each R 9 are independently C1-C3 alkyl or haloalkyl. These compounds include the following compounds:

[0114] [ka] and pharma- ceutically acceptable salts thereof, but are not limited to these.

[0115] In another embodiment, the SOS1 inhibitor is

[0116] [ka] (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile,

[0117] [ka] 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile,

[0118] [ka] (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and

[0119] [ka] (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile,

[0120] [ka] (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile,

[0121] [ka] (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, and

[0122] [ka] 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile,

[0123] [ka] The compound is selected from (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and pharma- ceutically acceptable salts thereof.

[0124] The SOS1 inhibitors used in the methods of the present invention may have one or more chiral centers and may be synthesized as stereoisomeric mixtures, isomers of the same constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures, or the individual components / isomers may be separated using commercially available reagents and conventional methods for isolating stereoisomers and enantiomers well known to those skilled in the art, for example, using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatography HPLC columns according to the manufacturer's instructions. Alternatively, the compounds of the present invention may be synthesized using optically pure chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Unless otherwise specified, whenever the specification, including the claims, refers to a compound of the present invention, the term "compound" should be understood to include all chiral (enantiomers and diastereomers) and racemic forms.

[0125] In one embodiment, the SOS1 inhibitor compound includes salts thereof, for example salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; salts formed 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, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid; and salts formed from quaternary ammonium salts of the formula --NRZ-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzilate, and diphenylacetate).

[0126] Methods for producing the SOS1 inhibitors disclosed herein are known.For example, commonly owned application numbers 62 / 951,812, 62 / 975,645, 63 / 044,802, 62 / 980,790, and 63 / 057,563, and corresponding international and published international applications PCT / US2020 / 066003 (WO 21 / 127429), PCT / US2021 / 019184 (WO 2021 / 173524), and PCT / US2021 / 043309 (WO 2022 / 026465) describe general reaction schemes for preparing compounds and also provide detailed synthetic routes for the preparation of these compounds.

[0127] Pharmaceutical Compositions The SOS1 inhibitor and the KRas G12C compound adagrasib, or a pharma- ceutically acceptable salt thereof, may be formulated into a pharmaceutical composition.

[0128] In another aspect, the present invention provides a pharmaceutical composition comprising an SOS1 inhibitor, or a pharma- ceutically acceptable salt thereof, a KRas G12C inhibitor adagrasib, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, excipient, or diluent, which can be used in the methods disclosed herein. The SOS1 inhibitor, or a pharma- ceutically acceptable salt thereof, and the KRas G12C inhibitor, or a pharma- ceutically acceptable salt thereof, can be independently formulated by any method known in the art and prepared for administration by any route, including, but not limited to, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain embodiments, the SOS1 inhibitor, or a pharma- ceutically acceptable salt thereof, and the KRas G12C inhibitor, or a pharma- ceutically acceptable salt thereof, are administered intravenously in a hospital setting. In one embodiment, administration can be by oral route.

[0129] The characteristics of the carrier depend on the route of administration. As used herein, the term "pharmaceutical acceptable" refers to a non-toxic material that is compatible with a biological system, such as a cell, a cell culture, a tissue, or an organism, and does not interfere with the effectiveness of the biological activity of the active ingredient. Thus, in addition to the inhibitor, the composition may contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutical acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0130] As used herein, the term "pharmaceutical acceptable salt" refers to a salt that retains the desired biological activity of the above-identified compound and exhibits minimal or no undesired toxicological effects.Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds may also be administered as pharma- ceutically acceptable quaternary salts known to those of skill in the art, specifically including quaternary ammonium salts of the formula --NR+Z-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzilate, and diphenylacetate).

[0131] The active compound is included in a pharma- ceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing serious toxic effects to the patient being treated. In one embodiment, the dose of the active compound for all the above conditions ranges from about 0.01 to 300 mg / kg per day, e.g., 0.1 to 100 mg / kg, and as a further example, 0.5 to about 25 mg per kilogram of recipient body weight per day. A typical topical dose will be in the range of 0.01 to 3% weight / weight in a suitable carrier. The effective dosage range of the pharma- ceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative or by other means known to those skilled in the art.

[0132] A pharmaceutical composition comprising an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, may be used in the methods of use described herein.

[0133] Simultaneous administration The SOS1 inhibitor or its pharmaceutically acceptable salt and the KRas G12C inhibitor or its pharmaceutically acceptable salt can be formulated into separate dosage forms or individual dosage forms, and can be co-administered one after the other.Another option is that when the administration route is the same (e.g., oral), the two active compounds can be formulated into a single form for co-administration, but both methods of co-administration are part of the same therapeutic treatment or regimen.

[0134] The pharmaceutical compositions comprising an SOS1 inhibitor, or a pharma- ceutically acceptable salt thereof, and / or a KRas G12C inhibitor, or a pharma- ceutically acceptable salt thereof, for use in the method may be for simultaneous, separate, or sequential use. In one embodiment, the SOS1 inhibitor, or a pharma- ceutically acceptable salt thereof, is administered prior to the administration of the KRas G12C inhibitor compound adagrasib or a pharma- ceutically acceptable salt thereof. In another embodiment, the SOS1 inhibitor, or a pharma- ceutically acceptable salt thereof, is administered after the administration of the KRas G12C inhibitor compound adagrasib or a pharma- ceutically acceptable salt thereof. In another embodiment, the SOS1 inhibitor, or a pharma- ceutically acceptable salt thereof, is administered approximately simultaneously with the administration of the KRas G12C inhibitor compound adagrasib or a pharma- ceutically acceptable salt thereof.

[0135] In some cases, separate administration of each inhibitor at different times and by different routes may be advantageous. Thus, the components of the combination, i.e., the KRas G12C inhibitor compound adagrasib or a pharma- ceutically acceptable salt thereof, and the SOS1 inhibitor, or a pharma- ceutically acceptable salt thereof, do not necessarily have to be administered essentially simultaneously or in any order.

[0136] Anticancer drugs are typically administered at a maximum tolerated dose ("MTD"), which is the highest dose of a drug that does not cause unacceptable side effects. In one embodiment, the KRas G12C inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are each administered at their respective MTD. In one embodiment, the KRas G12C inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered at its MTD, and the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered in an amount less than its MTD. In one embodiment, the KRas G12C inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered in an amount less than its MTD, and the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered at its MTD. In one embodiment, the KRas G12C inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are each administered below their respective MTDs. Administration may be timed such that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.

[0137] In one embodiment, a single dose of the KRas G12C inhibitor compound adagrasib or its pharma- ceutically acceptable salt or pharmaceutical composition is administered per day (i.e., about 24 hours apart) (i.e., QD). In another embodiment, two doses of the KRas G12C inhibitor compound adagrasib or its pharma- ceutically acceptable salt or pharmaceutical composition are administered per day (i.e., BID). In another embodiment, three doses of the KRas G12C inhibitor compound adagrasib or its pharma- ceutically acceptable salt or pharmaceutical composition are administered per day (i.e., TID).

[0138] In one embodiment, the SOS1 inhibitor, or its pharma- ceutically acceptable salt or pharmaceutical composition, is administered QD. In another embodiment, the SOS1 inhibitor, or its pharma- ceutically acceptable salt or pharmaceutical composition, is administered BID. In another embodiment, the SOS1 inhibitor of the present invention, or its pharma- ceutically acceptable salt or pharmaceutical composition, is administered TID.

[0139] In one embodiment, a single dose of the KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are each administered once daily.

[0140] Examples of SOS1 inhibitors suitable for the provided compositions and methods include those described herein, such as, for example, (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyridazin-1-yl)amino)ethyl)benzonitrile, do[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido [3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof, or an SOS1 inhibitor such as BI1701963.

[0141] Combination therapy In one aspect of the present invention, provided herein is a method for treating cancer in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRasKRas G12C inhibitor compound adagrasib, or a pharma-ceutically acceptable salt or pharmaceutical composition thereof.In one embodiment, the cancer is a KRas G12C-associated cancer.In one embodiment, the KRas G12C-associated cancer is lung cancer.

[0142] In yet another aspect, the invention provides a method for inhibiting KRas G12C activity in a cell, comprising administering to the cell in which inhibition of KRas G12C activity is desired an effective amount of the KRas G12C inhibitor adagrasib.

[0143] [ka] or a pharma- ceutically acceptable salt thereof, in combination with an SOS1 inhibitor.

[0144] In one embodiment, the SOS1 inhibitor has the structure:

[0145] [ka] or a pharma- ceutically acceptable salt thereof.

[0146] In yet another aspect, the method comprises treating the cells with a compound having the structure

[0147] [ka] or a pharma- ceutically acceptable salt thereof.

[0148] In yet another aspect, the invention provides a method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor, comprising contacting the cancer cell with an effective amount of a KRas G12C inhibitor compound adagrasib or a pharma- ceutically acceptable salt or pharmaceutical composition thereof in combination with a SOS1 inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo. In one embodiment, the method comprises administering to a subject undergoing KRas G12C therapy an effective amount of a combination of the KRas G12C inhibitor adagrasib or a pharma- ceutically acceptable salt thereof and a SOS1 inhibitor, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor.

[0149] In one embodiment, a method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor comprises treating the cancer cell with a therapeutically effective amount of a KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a SOS1 inhibitor having the structure:

[0150] [ka] or a pharma- ceutically acceptable salt or a pharmaceutical composition thereof.

[0151] In yet another embodiment, the method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor comprises treating the cancer cell with a compound having the structure:

[0152] [ka] or a pharma- ceutically acceptable salt thereof.

[0153] In one embodiment, the combination therapy comprises a compound having the formula

[0154] [ka] (adagrasib) or a pharma- ceutical acceptable salt thereof and an SOS1 inhibitor.

[0155] In one such embodiment, the SOS1 inhibitor is

[0156] [ka] It is.

[0157] In another such embodiment, the SOS1 inhibitor is

[0158] [ka] It is.

[0159] In yet another such embodiment, the SOS1 inhibitor is

[0160] [ka] It is.

[0161] In yet another such embodiment, the SOS1 inhibitor is

[0162] [ka] It is.

[0163] In another embodiment, the SOS1 inhibitor is

[0164] [ka] It is.

[0165] In another embodiment, the SOS1 inhibitor is

[0166] [ka] It is.

[0167] In another embodiment, the SOS1 inhibitor is

[0168] [ka] It is.

[0169] In another embodiment, the SOS1 inhibitor is

[0170] [ka] It is.

[0171] In still yet another embodiment, the SOS1 inhibitor is BI1701963.

[0172] In yet another embodiment, the present invention provides a method for producing formula:

[0173] [ka] or a pharma- ceutically acceptable salt thereof; and Therapeutically effective combinations with the KRas G12C inhibitor compound 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (also known as MRTX849, also known as adagrasib) are provided.

[0174] In another embodiment, the present invention provides formula:

[0175] [ka] or a pharma- ceutically acceptable salt thereof; and the KRas G12C inhibitor compound 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (also known as MRTX849, also known as adagrasib); The MEK inhibitor [[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one (also known as VS-6766), having the structure

[0176] [ka] or a pharma- ceutically acceptable salt thereof.

[0177] As used herein, the term "contacting" refers to bringing together the indicated moieties in an in vitro or in vivo system. For example, "contacting" a cancer cell includes administering a combination provided herein to an individual or subject (e.g., a human) having KRas G12C, as well as introducing, for example, a combination provided herein into a sample containing a cell or purified preparation containing KRas G12C.

[0178] By negatively regulating the activity of KRas G12C, the methods described herein are designed to inhibit undesirable cell proliferation resulting from enhanced KRas G12C activity in cells. The degree of covalent modification of KRas G12C can be monitored in vitro using known methods, including those described in published International PCT Applications Nos. 2017 / 201161 and 2019 / 099524. In addition, the inhibitor activity of the combination in cells can be monitored, for example, by measuring the inhibition of KRas G12C activity of the amount of phosphorylated ERK to assess the effectiveness of the treatment, and the dosage can be adjusted accordingly by the attending physician.

[0179] The compositions and methods provided herein may be used for the treatment of KRas G12C-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, in combination with a KRas G12C inhibitor compound adagrasib, or a pharma-ceutically acceptable salt or pharmaceutical composition thereof, wherein the SOS1 inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor. In one embodiment, the KRas G12C-associated cancer is lung cancer.

[0180] In one embodiment, the combination of a therapeutically effective amount of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, with the KRas G12C inhibitor compound adagrasib or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in an increase in overall survival ("OS") in a subject, compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, with the KRas G12C inhibitor compound adagrasib or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in an increase in progression-free survival ("PFS") in a subject, compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, with the KRas G12C inhibitor compound adagrasib or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in an increase in tumor regression in a subject, compared to treatment with a KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, with the KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor growth inhibition in a subject compared to treatment with the KRas G12C inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, with the KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in improved stable disease duration in a subject compared to treatment with the KRas G12C inhibitor adagrasib alone.In one embodiment, the SOS1 inhibitor is (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl) -2-Methylbenzonitrile, (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl )benzonitrile, (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof. In another embodiment, the SOS1 inhibitor is BI1701963.

[0181] In another embodiment, the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered in combination with a KRas G12C inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, once disease progression is observed for KRas G12C monotherapy, wherein the combination therapy provides an enhanced clinical benefit to the patient by increasing OS, PFS, tumor regression, tumor growth inhibition, or stable disease duration in the patient. In one embodiment, the KRas G12C inhibitor is a compound selected from compound numbers 1-678 (numbered in WO 2019 / 099524), or a pharma- ceutically acceptable salt thereof (e.g., Example Nos. 234, 359, 478, or 507, or a pharma- ceutically acceptable salt thereof).

[0182] In one embodiment, the SOS1 inhibitor is (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)- 2-Methylbenzonitrile, (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl) benzonitrile, (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof. In another embodiment, the SOS1 inhibitor is BI1701963.

[0183] In one embodiment, the therapeutic combination comprises therapeutically effective amounts of adagrasib and (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt thereof.

[0184] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of adagrasib and 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof.

[0185] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of adagrasib and (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof.

[0186] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of adagrasib and (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt thereof.

[0187] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of adagrasib and (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof.

[0188] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of adagrasib and (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt thereof.

[0189] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of adagrasib and 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof.

[0190] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of adagrasib and (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof.

[0191] In another embodiment, the therapeutic combination comprises a therapeutically effective amount of adagrasib and the SOS1 inhibitor is BI1701963.

[0192] The compositions and methods provided herein may be used to treat a variety of cancers, including tumors such as lung, colon, pancreatic, prostate, breast, brain, skin, cervical, testicular cancer, etc. More specifically, cancers that may be treated by the compositions and methods of the present invention include, but are not limited to, astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid cancers and sarcomas. More specifically, these compounds may be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrohamartoma, mesothelioma; Gastrointestinal: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), Stomach (carcinoma, lymphoma, leiomyosarcoma, ), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenocarcinoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (glandular sarcoma); testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, breast fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder cancer, ampullary carcinoma, cholangiocarcinoma; bone: osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor of the notochord tumors, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);Gynecological system: Uterus (endometrial cancer), Cervix (cervical cancer, atypical cervical preneoplasia), Ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), Vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, botulisoid sarcoma (embryonal rhabdomyosarcoma), Fallopian tubes (cancer); Blood system: Blood ( Myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentigo dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer.;

[0193] Also provided is a method for treating cancer in a patient in need of such treatment, comprising: (a) determining (e.g., using a regulatory approved, e.g., FDA approved, assay or kit) that the cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer); and (b) administering to the patient a therapeutically effective amount of a SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, in combination with a KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the SOS1 inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor. In one embodiment, the KRas G12C inhibitor is a compound selected from compound numbers 1 to 678 (numbered in WO 2019 / 099524), or a pharma- ceutically acceptable salt thereof (e.g., one of example numbers 234, 359, 478, or 507, or a pharma- ceutically acceptable salt thereof).In one embodiment, the SOS1 inhibitor is (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzamide, benzonitrile, (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, (R)- 3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidinyl)

[0046] In one embodiment, the SOS1 inhibitor is selected from (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof, or the SOS1 inhibitor is BI1701963.

[0194] In one embodiment, the therapeutic combination comprises a therapeutically effective amount of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile or a pharma- ceutically acceptable salt thereof.

[0195] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile or a pharma- ceutically acceptable salt thereof.

[0196] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile or a pharma- ceutically acceptable salt thereof.

[0197] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile or a pharma- ceutically acceptable salt thereof.

[0198] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile or a pharma- ceutically acceptable salt thereof.

[0199] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile or a pharma- ceutically acceptable salt thereof.

[0200] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile or a pharma- ceutically acceptable salt thereof.

[0201] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile or a pharma- ceutically acceptable salt thereof.

[0202] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of BI1701963.

[0203] In one embodiment, the KRas G12C compound adagrasib is administered as a tablet or capsule for a period of time. In one embodiment, the tablet or capsule formulation of adagrasib comprises one or more of about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, and about 2000 mg. In one embodiment, adagrasib is administered orally once daily (QD) every day for a period of time. In one embodiment, adagrasib is administered orally twice daily (BID) every day for a period of time.

[0204] In one embodiment, the SOS1 compound is administered 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, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg ~160mg, 20mg~140mg, 20mg~120mg, 20mg~100mg, 20mg~80mg, 20mg~60mg, 20mg~40mg, 40mg~500mg, 40mg~480mg, 40mg~460mg, 4 0mg to about 440mg, about 40mg to about 420mg, about 40mg to about 400mg, about 40mg to about 380mg, about 40mg to about 360mg, about 40mg to about 340mg, about 40mg to about 320mg, about 40mg to about 300mg, about 40mg to about 280mg, about 40mg to about 26 0mg, about 40mg to about 240mg, about 40mg to about 220mg, about 40mg to about 200mg, about 40mg to about 180mg, about 40mg to about 160mg, about 40mg to about 140mg, about 40mg to about 120mg, about 40mg to about 100mg, about 40mg to about 80mg, about 40 mg~60mg, 60mg~500mg, 60mg~480mg, 60mg~460mg, 60mg~440mg, 60mg~420mg, 60mg~400mg, 60mg~380mg, 60mg~360mg, 60mg~340m g, approx. 60 mg to approx. 320 mg, approx. 60 mg to approx. 300 mg, approx. 60 mg to approx. 280 mg, approx. 60 mg to approx. 260 mg, approx. 60 mg to approx. 240 mg, approx. ~140mg, 60mg~120mg, 60mg~100mg, 60mg~80mg, 80mg~500mg, 80mg~480mg, 80mg~460mg, 80mg~440mg, 80mg~420mg, 80mg~400mg,about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 mg to about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg to about 480 mg, about 100 mg to about 460 mg, about 100 mg to about 440 mg, about 100 mg to about 420 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 mg to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 500 mg, about 120 mg to about 480 mg, about 120 mg to about 460 mg, about 120 mg to about 440 mg, about 120 mg to about 420 mg, about 120 mg to about 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 500 mg, about 140 mg to about 480 mg, about 140 mg to about 460 mg, about 140 mg to about 440 mg, about 140 mg to about 420 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mgAbout 160 mg to about 500 mg, about 160 mg to about 480 mg, about 160 mg to about 460 mg, about 160 mg to about 440 mg, about 160 mg to about 420 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 500 mg, about 180 mg to about 480 mg, about 180 mg to about 460 mg, about 180 mg to about 440 mg, about 180 mg to about 420 mg, about 180 mg to about 400 mg, about 180 mg to about 380 mg, about 180 mg to about 360 mg, about 180 mg to about 340 mg, about 180 mg to about 320 mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about 260 mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about 200 mg, about 200 mg to about 500 mg, about 200 mg to about 480 mg, about 200 mg to about 460 mg, about 200 mg to about 440 mg, about 200 mg to about 420 mg, about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about 340 mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about 200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about 220 mg, about 220 mg to about 500 mg, about 220 mg to about 480 mg, about 220 mg to about 460 mg, about 220 mg to about 440 mg, about 220 mg to about 420 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about 280 mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about 500 mg, about 240 mg to about 480 mg, about 240 mg to about 460 mg, about 240 mg to about 440 mg, about 240 mg to about 420 mg, about 240 mg to about 400 mg, about 240 mg to about 380 mg, about 240 mg to about 360 mg, about 240 mg to about 340 mgAbout 240 mg to about 320 mg, about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 500 mg, about 260 mg to about 480 mg, about 260 mg to about 460 mg, about 260 mg to about 440 mg, about 260 mg to about 420 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 500 mg, about 280 mg to about 480 mg, about 280 mg to about 460 mg, about 280 mg to about 440 mg, about 280 mg to about 420 mg, about 280 mg to about 400 mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about 340 mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg, about 300 mg to about 500 mg, about 300 mg to about 480 mg, about 300 mg to about 460 mg, about 300 mg to about 440 mg, about 300 mg to about 420 mg, about 300 mg to about 400 mg, about 300 mg to about 380 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 500 mg, about 320 mg to about 480 mg, about 320 mg to about 460 mg, about 320 mg to about 440 mg, about 320 mg to about 420 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 320 mg to about 340 mg, about 340 mg to about 500 mg, about 340 mg to about 480 mg, about 340 mg to about 460 mg, about 340 mg to about 440 mg, about 340 mg to about 420 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 500 mg, about 360 mg to about 480 mg, about 360 mg to about 460 mg, about 360 mg to about 440 mg, about 360 mg to about 420 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 500 mg, about 380 mg to about 480 mg, about 380 mg to about 460 mg, about 380 mg to about 440 mg, about 380 mg to about 420 mg, about 380 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 480 mg, about 400 mg to about 460 mg, about 400 mg to about 440 mgabout 400 mg to about 420 mg, about 420 mg to about 500 mg, about 420 mg to about 480 mg, about 420 mg to about 460 mg, about 420 mg to about 440 mg, about 440 mg to about 500 mg, about 440 mg to about 480 mg, about 440 mg to about 460 mg, about 460 mg to about 500 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg) and administered over a period of time. In one embodiment, the SOS1 compound is orally administered twice a day (BID) every day for a period of time. In one embodiment, adagrasib is administered orally twice daily (BID) every day for a period of time.

[0205] In one embodiment, the combination therapy comprises a 20 mg to about 400 mg (e.g., about 10 mg to about 380 mg, about 10 mg to about 360 mg, about 10 mg to about 340 mg, about 10 mg to about 320 mg, about 10 mg to about 300 mg, about 10 mg to about 280 mg, about 10 mg to about 260 mg, about 10 mg to about 240 mg, about 10 mg to about 220 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg) of adagrasib. g, approx. 10 mg ~ approx. 60 mg, approx. 10 mg ~ approx. 40 mg, approx. 10 mg ~ approx. 20 mg, approx. 20 mg ~ approx. 400 mg, approx. 20 mg ~ approx. 380 mg, approx. 80mg, about 20mg to about 260mg, about 20mg to about 240mg, about 20mg to about 220mg, about 20mg to about 200mg, about 20mg to about 180mg, about 20mg to about 160mg, about 20mg to about 140mg, about 20mg to about 120mg, about 20mg to about 100mg, about 20 mg ~ about 80mg, about 20mg - about 60mg, about 20mg - about 40mg, about 40mg - about 400mg, about 40mg - about 380mg, about 40mg - about 360mg, about 40mg - about 340mg, about 40mg - about 320mg, about 40mg - about 300mg, about 40mg - about 280mg, About 40mg to about 260mg, about 40mg to about 240mg, about 40mg to about 220mg, about 40mg to about 200mg, about 40mg to about 180mg, about 40mg to about 160mg, about 40mg to about 140mg, about 40mg to about 120mg, about 40mg to about 100mg, about 40mg to about 8 0mg, about 40mg to about 60mg, about 60mg to about 400mg, about 60mg to about 380mg, about 60mg to about 360mg, about 60mg to about 340mg, about 60mg to about 320mg, about 60mg to about 300mg, about 60mg to about 280mg, about 60mg to about 260mg, about 60m g ~ about 240mg, about 60mg - about 220mg, about 60mg - about 200mg, about 60mg - about 180mg, about 60mg - about 160mg, about 60mg - about 140mg, about 60mg - about 120mg, about 60mg - about 100mg, about 60mg - about 80mg, about 80mg - about 400mg,About 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 mg to about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 mg to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 400 mg, about 180 mg to about 380 mgApproximately 180mg to approximately 360mg, approximately 180mg to approximately 340mg, approximately 180mg to approximately 320mg, approximately 180mg to approximately 300mg, approximately 180mg to approximately 280mg, approximately 180mg to approximately 260mg, approximately 180mg to approximately 240mg, approximately 180mg to approximately 220mg, approximately 180mg to approximately 20 0mg, about 200mg to about 400mg, about 200mg to about 380mg, about 200mg to about 360mg, about 200mg to about 340mg, about 200mg to about 320mg, about 200mg to about 300mg, about 200mg to about 280mg, about 200mg to about 260mg, about 200mg to about Approx. 240 mg, approx. 200 mg ~ approx. 220 mg, approx. 220 mg ~ approx. 400 mg, approx. 220 mg ~ approx. 380 mg, approx. 220 mg ~ approx. 360 mg, approx. 220 mg ~ approx. 0mg to about 260mg, about 220mg to about 240mg, about 240mg to about 400mg, about 240mg to about 380mg, about 240mg to about 360mg, about 240mg to about 340mg, about 240mg to about 320mg, about 240mg to about 300mg, about 240mg to about 280mg, Approximately 240mg to approximately 260mg, approximately 260mg to approximately 400mg, approximately 260mg to approximately 380mg, approximately 260mg to approximately 360mg, approximately 260mg to approximately 340mg, approximately 260mg to approximately 320mg, approximately 260mg to approximately 300mg, approximately 260mg to approximately 280mg, approximately 280mg to approximately 40 0mg, about 280mg to about 380mg, about 280mg to about 360mg, about 280mg to about 340mg, about 280mg to about 320mg, about 280mg to about 300mg, about 300mg to about 400mg, about 300mg to about 380mg, about 300mg to about 360mg, about 300mg about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 340 mg to about 360 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 400 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg) once or twice daily (during a certain period of time); and an SOS1 inhibitor administered, for example, once daily (during a certain period of time),or a pharma- ceutically acceptable salt or pharmaceutical composition thereof. In one embodiment, the KRas G12C inhibitor adagrasib or a pharma- ceutically acceptable salt or pharmaceutical composition thereof is orally administered once daily. In another embodiment, the KRas G12C inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof is orally administered twice daily.

[0206] Those of skill in the art will recognize that both in vivo and in vitro tests using suitable, known and generally accepted cellular and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0207] One of ordinary skill in the art will further recognize that human clinical trials, including first-in-human dose ranging and efficacy studies in healthy patients and / or patients afflicted with a given disorder, can be completed according to methods well known in the clinical and medical arts.

[0208] Synergy In one embodiment, the addition of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, synergistically increases the activity of the KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, against a cancer or cancer cell line expressing KRas G12C. Any method for determining whether two compounds exhibit synergy may be used to determine the synergistic effect of the combination.

[0209] Several mathematical models have been developed to determine whether two compounds act synergistically, i.e., beyond a simple additive effect. For example, Loewe Additivity (Loew(1928) Physiol.27:47-187), Bliss Independence (Bliss(1939) Ann.Appl.Biol.26:585-615), Highest Single Agent, 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 score" that indicates whether synergy is detected and the magnitude of such synergy. Combining these synergy scores results in a composite synergy score that can be used to evaluate and characterize the KRas G12C inhibitor compound adagrasib-B in combination with an SOS1 inhibitor.

[0210] Generally, the mathematical model uses data obtained from the single agent values ​​to determine the predicted additive effect of the combination, which is compared to the observed effect for the combination. If the observed effect is greater than the predicted effect, the combination is considered to be synergistic. For example, the Bliss independence model uses the observed combination response (Y O ) to the predicted combination response (Y P ) typically compared with Y O Y P If it is greater, the combined effect is deemed to be synergistic.

[0211] In some embodiments, "synergistic effect" as used herein refers to a combination of a KRasKRas inhibitor or a pharma- ceutically acceptable salt thereof and a SOS1SOS1 inhibitor or a pharma- ceutically acceptable salt thereof that results in any beneficial or desired outcome, including, for example, a clinical outcome or endpoint described herein, that is greater than the sum of the effects observed when a compound, such as those described in WO 2019 / 099524 numbered compound numbers 1-678, such as adagrasib, and a SOS1 inhibitor or a pharma- ceutically acceptable salt thereof, is administered alone. In one embodiment, the KRas G12C inhibitor is adagrasib (MRTX-849, Example No. 478 in WO 2019 / 099524) or a pharma- ceutically acceptable salt thereof). In one embodiment, the SOS1 inhibitor is (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido [3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof, or an SOS1 inhibitor such as BI1701963.

[0212] In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile and adagrasib. In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile and adagrasib. In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile and adagrasib. In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile and adagrasib. In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile and adagrasib. In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile and adagrasib. In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile and adagrasib. In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile and adagrasib.

[0213] In one embodiment, the therapeutic combination comprises therapeutically effective amounts of BI1701963 and adagrasib.

[0214] In some embodiments, the methods provided herein provide a method for administering a therapeutically effective amount of a compound to a patient for 1 day to 2 years (e.g., 1 day to 22 months, 1 day to 20 months, 1 day to 18 months, 1 day to 16 months, 1 day to 14 months, 1 day to 12 months, 1 day to 10 months, 1 day to 9 months, 1 day to 8 months, 1 day to 7 months, 1 day to 6 months, 1 day to 5 months, 1 day to 4 months, 1 day to 3 months, 1 day to 2 months, 1 day to 1 month, 1 week to 2 years, 1 week to 22 months, 1 week to 20 months, 1 week to 18 months, 1 week to 16 months, 1 week to 14 months, 1 week to 12 months, 1 week to 10 months, 1 week to 9 months, 1 week to 8 months, 1 week to 7 months, 1 week to 6 months, 1 week to 5 months, 1 week to 5 months, 1 week to 6 months, 1 week to 7 months, 1 week to 5 months, 1 week to 8 months, 1 week to 9 months, 1 week to 8 ... months, 1 week to 4 months, 1 week to 3 months, 1 week to 2 months, 1 week to 1 month, 2 weeks to 2 years, 2 weeks to 22 months, 2 weeks to 20 months, 2 weeks to 18 months, 2 weeks to 16 months, 2 weeks to 14 months, 2 weeks to 12 months, 2 weeks to 10 months, 2 weeks to 9 months, 2 weeks to 8 months, 2 weeks to 7 months, 2 weeks to 6 months, 2 weeks to 5 months, 2 weeks to 4 months, 2 weeks to 3 months, 2 weeks to 2 months, 2 weeks to 1 month, 1 month to 2 years, 1 month to 22 months, 1 month to 20 months, 1 month to 18 months, 1 month to 16 months, 1 month to 14 months, 1 month to 12 months, 1 month to 10 months, 1 month to 9 months, 1 month to 8 months, 1 month to 7 months , 1 month to 6 months, 1 month to 6 months, 1 month to 5 months, 1 month to 4 months, 1 month to 3 months, 1 month to 2 months, 2 months to 2 years, 2 months to 22 months, 2 months to 20 months, 2 months to 18 months, 2 months to 16 months, 2 months to 14 months, 2 months to 12 months, 2 months to 10 months, 2 months to 9 months, 2 months to 8 months, 2 months to 7 months, 2 months to 6 months, or 2 months to 5 months, 2 months to 4 months, 3 months to 2 years, 3 months to 22 months, 3 months to 20 months, 3 months to 18 months, 3 months to 16 months, 3 months to 14 months, 3 months to 12 months, 3 months to 10 months, 3 months to 8 months, 3 months between 1% and 99% (e.g., compared to the size of the patient's one or more solid tumors prior to treatment) of the volume of one or more solid tumors in a patient treated with the combination therapy within a period of 4 months to 6 months, 4 months to 2 years, 4 months to 22 months, 4 months to 20 months, 4 months to 18 months, 4 months to 16 months, 4 months to 14 months, 4 months to 12 months, 4 months to 10 months, 4 months to 8 months, 4 months to 6 months, 6 months to 2 years, 6 months to 22 months, 6 months to 20 months, 6 months to 18 months, 6 months to 16 months, 6 months to 14 months, 6 months to 12 months, 6 months to 10 months, or 6 months to 8 months1%~98%、1%~95%、1%~90%、1~85%、1~80%、1%~75%、1%~70%、1%~65%、1%~60%、1%~55%、1%~50%、1%~45%、1%~40%、1%~35%、1%~30%、1%~25%、1%~20%、1%~15%、1%~10%、1%~5%、2%~99%、2%~90%、2%~85%、2%~80%、2%~75%、2%~70%、2%~65%、2%~60%、2%~55%、2%~50%、2%~45%、2%~40%、2%~35%、2%~30%、2%~25%、2%~20%、2%~15%、2%~10%、2%~5%、4%~99%、4%~95%、4%~90%、4%~85%、4%~80%、4%~75%、4%~70%、4%~65%、4%~60%、4%~55%、4%~50%、4%~45%、4%~40%、4%~35%、4%~30%、4%~25%、4%~20%、4%~15%、4%~10%、6%~99%、6%~95%、6%~90%、6%~85%、6%~80%、6%~75%、6%~70%、6%~65%、6%~60%、6%~55%、6%~50%、6%~45%、6%~40%、6%~35%、6%~30%、6%~25%、6%~20%、6%~15%、6%~10%、8%~99%、8%~95%、8%~90%、8%~85%、8%~80%、8%~75%、8%~70%、8%~65%、8%~60%、8%~55%、8%~50%、8%~45%、8%~40%、8%~35%、8%~30%、8%~25%、8%~20%、8%~15%、10%~99%、10%~95%、10%~90%、10%~85%、10%~80%、10%~75%、10%~70%、10%~65%、10%~60%、10%~55%、10%~50%、10%~45%、10%~40%、10%~35%、10%~30%、10%~25%、10%~20%、10%~15%、15%~99%、15%~95%、15%~90%、15%~85%、15%~80%、15%~75%、15%~70%、15%~65%、15%~60%、15%~55%、15%~50%、15%~55%、15%~50%、15%~45%、15%~40%、15%~35%、15%~30%、15%~25%、15%~20%、20%~99%、20%~95%、20%~90%、20%~85%、20%~80%、20%~75%、20%~70%、20%~65%、20%~60%、20%~55%、20%~50%、20%~45%、20%~40%、20%~35%、20%~30%、20%~25%、25%~99%、25%~95%、25%~90%、25%~85%、25%~80%、25%~75%、25%~70%、25%~65%、25%~60%、25%~55%、25%~50%、25%~45%、25%~40%、25%~35%、25%~30%、30%~99%、30%~95%、30%~90%、30%~85%、30%~80%、30%~75%、30%~70%、30%~65%、30%~60%、30%~55%、30%~50%、30%~45%、30%~40%、30%~35%、35%~99%、35%~95%、35%~90%、35%~85%、35%~80%、35%~75%、35%~70%、35%~65%、35%~60%、35%~55%、35%~50%、35%~45%、35%~40%、40%~99%、40%~95%、40%~90%、40%~85%、40%~80%、40%~75%、40%~70%、40%~65%、40%~60%、40%~55%、40%~60%、40%~55%、40%~50%、40%~45%、45%~99%、45%~95%、45%~95%、45%~90%、45%~85%、45%~80%、45%~75%、45%~70%、45%~65%、45%~60%、45%~55%、45%~50%、50%~99%、50%~95%、50%~90%、50%~85%、50%~80%、50%~75%、50%~70%、50%~65%、50%~60%、50%~55%、55%~99%、55%~95%、55%~90%、55%~85%、55%~80%、55%~75%、55%~70%、55%~65%、55%~60%、60%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、65%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、70%~99%、70%~95%、70%~90%、70%~85%、70%~80%、70%~75%、75%~99%、75%~95%、75%~90%、75%~85%、75%~80%、This may result in a reduction of 80% to 99%, 80% to 95%, 80% to 90%, 80% to 85%, 85% to 99%, 85% to 95%, 85% to 90%, 90% to 99%, 90% to 95%, or 95% to 100%).

[0215] The phrase "survival time" refers to the length of time between the identification or diagnosis of cancer (e.g., any of the cancers described herein) in a mammal by a medical professional and the time of death of the mammal (caused by the cancer). Methods of increasing survival time in a mammal having cancer are described herein.

[0216] In some embodiments, any of the methods described herein provide an improvement or reduction in patient survival (e.g., between 1% and 400%, between 1% and 380%, between 1% and 360%, between 1% and 340%, between 1% and 320%, between 1% and 300%, between 1% and 280%, between 1% and 260%, between 1% and 240%, between 1% and 220%, between 1% and 200%, between 1% and 180%, between 1% and 160%, between 1% and 140%, between 1% and 120%, between 1% and 100%, between 1% and 95%, between 1% and 90%, between 1% and 85%, between 1% and 80%, between 1% and 75%, 1%~70%, 1%~65%, 1%~60%, 1%~55%, 1%~50%, 1%~45%, 1%~40%, 1%~35%, 1%~30%, 1%~25%, 1%~20%, 1%~15%, 1%~10%, 1%~5%, 5%~400%, 5%~380%, 5%~360%, 5%~3 40%, 5%~320%, 5%~300%, 5%~280%, 5%~260%, 5%~240%, 5%~220%, 5%~200%, 5%~180%, 5%~160%, 5%~140%, 5%~120%, 5%~100%, 5%~90%, 5%~80%, 5%~70%, 5%~6 0%, 5%~50%, 5%~40%, 5%~30%, 5%~20%, 5%~10%, 10%~400%, 10%~380%, 10%~360%, 10%~340%, 10%~320%, 10%~300%, 10%~280%, 10%~260%, 10%~240%, 10%~22 0%, 10%~200%, 10%~180%, 10%~160%, 10%~140%, 10%~120%, 10%~100%, 10%~90%, 10%~80%, 10%~70%, 10%~60%, 10%~50%, 10%~40%, 10%~30%, 10%~20%, 20%~ 400%, 20%~380%, 20%~360%, 20%~340%, 20%~320%, 20%~300%, 20%~280%, 20%~260%, 20%~240%, 20%~220%, 20%~200%, 20%~180%, 20%~160%, 20%~140%, 20% ~120%, 20%~100%, 20%~90%, 20%~80%, 20%~70%, 20%~60%, 20%~50%, 20%~40%, 20%~30%, 30%~400%, 30%~380%, 30%~360%, 30%~340%, 30%~320%, 30%~300%,30%~280%、30%~260%、30%~240%、30%~220%、30%~200%、30%~180%、30%~160%、30%~140%、30%~120%、30%~100%、30%~90%、30%~80%、30%~70%、30%~60%、30%~50%、30%~40%、40%~400%、40%~380%、40%~360%、40%~340%、40%~320%、40%~300%、40%~280%、40%~260%、40%~240%、40%~220%、40%~200%、40%~180%、40%~160%、40%~140%、40%~120%、40%~100%、40%~90%、40%~80%、40%~70%、40%~60%、40%~50%、50%~400%、50%~380%、50%~360%、50%~340%、50%~320%、50%~300%、50%~280%、50%~260%、50%~240%、50%~220%、50%~200%、50%~180%、50%~160%、50%~140%、50%~140%、50%~120%、50%~100%、50%~90%、50%~80%、50%~70%、50%~60%、60%~400%、60%~380%、60%~360%、60%~340%、60%~320%、60%~300%、60%~280%、60%~260%、60%~240%、60%~220%、60%~200%、60%~180%、60%~160%、60%~140%、60%~120%、60%~100%、60%~90%、60%~80%、60%~70%、70%~400%、70%~380%、70%~360%、70%~340%、70%~320%、70%~300%、70%~280%、70%~260%、70%~240%、70%~220%、70%~200%、70%~180%、70%~160%、70%~140%、70%~120%,~100%、70%~90%、70%~80%、80%~400%、80%~380%、80%~360%、80%~340%、80%~320%、80%~300%、80%~280%、80%~260%、80%~240%、80%~220%、80%~200%、80%~180%、80%~160%、80%~140%、80%~120%、80%~100%、80%~90%、90%~400%、90%~380%、90%~360%、90%~340%、90%~320%、90%~300%、90%~280%、90%~260%、90%~240%、90%~220%、90%~200%、90%~180%、90%~160%、90%~140%、90%~120%、90%~100%、100%~400%、100%~380%、100%~360%、100%~340%、100%~320%、100%~300%、100%~280%、100%~260%、100%~240%、100%~220%、100%~200%、100%~180%、100%~160%、100%~140%、100%~120%、120%~400%、120%~380%、120%~360%、120%~340%、120%~320%、120%~300%、120%~280%、120%~260%、120%~240%、120%~220%、120%~200%、120%~180%、120%~160%、120%~140%、140%~400%、140%~380%、140%~360%、140%~340%、140%~320%、140%~300%、140%~280%、140%~260%、140%~240%、140%~220%、140%~200%、140%~180%、140%~160%、160%~400%、160%~380%、160%~360%、160%~340%、160%~320%、160%~300%、160%~280%、160%~260%、160%~240%、160%~220%、160%~200%、160%~180%、180%~400%、180%~380%、180%~360%、180%~340%、180%~320%、180%~300%、180%~280%、180%~260%、180%~240%、180%~220%、180%~200%、200%~400%、200%~380%、200%~360%、200%~340%、200%~320%、200%~300%、200%~280%、200%~260%、200%~240%、200%~220%、220%~400%、220%~380%、220%~360%、220%~340%、220%~320%、220%~300%、220%~280%、220%~260%、220%~240%、240%~400%、240%~380%、240%~360%, 240%~340%, 240%~320%, 240%~300%, 240%~280%, 240%~260%, 260%~400%, 260%~380%, 260%~360%, 260%~340%, 260%~320%, 260%~300%, 260%~2 80%, 280% to 400%, 280% to 380%, 280% to 360%, 280% to 340%, 280% to 320%, 280% to 300%, 300% to 400%, 300% to 380%, 300% to 360%, 300% to 340%, or 300% to 320%).

[0217] In some embodiments of any of the methods described herein, prior to treatment with a composition or method of the invention, the patient has been treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, optionally where the previous treatment has been unsuccessful, and / or the patient has been subjected to surgery, optionally where the surgery has been unsuccessful, and / or the patient has been treated with a platinum-based chemotherapy agent, optionally where the patient has been previously determined to be non-responsive to treatment with a platinum-based chemotherapy agent, and / or the patient has been treated with a kinase inhibitor, optionally where the previous treatment with the kinase inhibitor has been unsuccessful, and / or the patient has been treated with one or more other therapeutic agents.

[0218] kit The present invention also relates to a kit comprising an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof. Also provided is a kit comprising an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in the treatment of hematological cancers.

[0219] In a related aspect, the present invention provides a kit containing a dose of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a dose of a KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, in an amount effective to inhibit the proliferation of cancer cells, particularly KRas G12C-expressing cancer cells, in a subject. The kit optionally includes a package insert having instructions for administering the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof. The package insert may provide the user with a set of instructions for using the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, in combination with the KRas G12C inhibitor compound adagrasib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0220] The following examples are intended to illustrate further certain embodiments of the present invention and are not intended to limit the scope of the invention.

[0221] Example A In vivo model to investigate KRas G12C inhibitor-SOS1 inhibitor combinations Immunocompromised nude / nude mice were inoculated with cells carrying the KRas G12C mutation or patient-derived tumor samples in the right hind flank. The tumor volume was adjusted to a size of 200–400 mm. 3When the tumor cell count reaches 100%, the mice are divided into 4 groups of 4-12 mice each. The first group receives vehicle only. The second group receives a single dose of a KRas G12C inhibitor at a concentration that produces a maximal or submaximal biological effect that does not result in complete tumor regression, depending on the cell line and single agent activity. The third group receives a single dose of a SOS1 inhibitor at a concentration that produces a maximal or submaximal biological effect that also does not result in complete tumor regression, depending on the cell line and single agent activity. The optional group receives a single dose of a MEK inhibitor (VS-6766) that produces a submaximal biological effect. The final group receives a single dose of a KRas G12C inhibitor in combination with a single dose of a SOS1 inhibitor, or a single dose of a KRas G12C inhibitor in combination with a single dose of a SOS1 inhibitor and single agent VS-6766. The duration of treatment varies by cell line, but is typically 20-42 days. Tumor volumes were measured every 2-3 days using calipers and calculated as tumor volume using the formula: 0.5×(length×width) 2 The greater degree of tumor growth inhibition for the combination in this model demonstrates that the combination therapy is likely to have a clinically meaningful benefit to the treated subjects compared to treatment with a KRas G12C inhibitor alone.

[0222] 16–32 nude / nude, Balb / c nude, or NOD / SCID mice per study were dosed at 5 × 10 6 The indicated cell lines or tumor fragments were inoculated into the right hind leg. 3When the IL-16 concentration reached 100 mg / kg (study day 0), four or more mice in each of four to six groups were orally administered daily for 20 to 42 days: vehicle alone (0.5% MC (4000 cps) / 0.2% Tween 80 in water), 10, 30, or 100 mg / kg KRas. G12C inhibitor adagrasib (10% Captisol in 50 mM citrate buffer, pH 5.0), MEK inhibitor VS-6766 at 0.3 mg / kg (5% DMSO with 10% hydroxypropyl-β-cyclodextrin in water), SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile (MRTX-0902) at 50 or 100 mg / kg (0.5% MC (4000 cps) in water / 0.2% Tween 80), 3-((R)-1-((7-((S)-hexahydro pyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (MRTX-2006) (20% SBE-β-CD / 50 mM citric acid pH 5), or (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile (MRTX-4197) (20% SBE-β-CD / 50 mM citric acid pH 5), or 10, 30, or 100 mg / kg of KRas Additional combination groups with the G12C inhibitor adagrasib and 50 or 100 mg / kg of MRTX-0902, MRTX-2006, or MRTX-4197. The MEK inhibitor VS-6766 at 0.3 mg / kg were included in the triple combination study. Tumor volumes measured on pre-specified days for 4-8 mice per group were averaged and reported in Tables 1, 2, 3, and 4 for MIA PaCa-2 cells; Table 5 for LU99 cells; Tables 6 and 7 for NCI-H2122 cells; and Table 8 for CR6256 colorectal patient-derived tumors.

[0223] [Table 1]

[0224] As shown in Figure 1 and Table 1, administration of adagrasib or MRTX-0902 as single agents resulted in 76.3% and 37.5% tumor growth, respectively, at day 27. The combination of the SOS1 inhibitor MRTX-0902 with adagrasib resulted in -73.4%% tumor regression at day 27.

[0225] [Table 2]

[0226] As shown in Figure 2 and Table 2, administration of single agent adagrasib or 25 and 50 mg / kg BID MRTX-0902 resulted in 93.5%, 41.2%, and 52.9% tumor growth, respectively, at day 25. The combination of the SOS1 inhibitor MRTX-0902 (25 and 50 mg / kg BID) with adagrasib resulted in -54.1% and -92.1% tumor regression, respectively, at day 25.

[0227] [Table 3]

[0228] As shown in Figure 3 and Table 3, administration of adagrasib or MRTX-2006 as single agents resulted in 77.4% and 29.7% tumor growth, respectively, at day 27. The combination of the SOS1 inhibitor MRTX-2006 with adagrasib resulted in 96.0% tumor growth inhibition at day 27.

[0229] [Table 4]

[0230] As shown in Figure 4 and Table 4, administration of adagrasib or MRTX-4197 as single agents resulted in 89.2% and 78.0% tumor growth, respectively, at day 20. The combination of the SOS1 inhibitor MRTX-4197 with adagrasib resulted in -73.0% tumor regression at day 28.

[0231] [Table 5]

[0232] As shown in Figure 5 and Table 5, administration of adagrasib or MRTX-0902 as single agents resulted in 98.6% and 21.4% tumor growth, respectively, at day 28. The combination of the SOS1 inhibitor MRTX-0902 with adagrasib resulted in -90.9% tumor regression at day 26.

[0233] [Table 6]

[0234] As shown in Figure 6 and Table 6, administration of adagrasib or MRTX-0902 as single agents resulted in 86.3% and 9.2% tumor growth, respectively, at day 28. The combination of the SOS1 inhibitor MRTX-0902 with adagrasib resulted in 95.4% tumor growth inhibition at day 20.

[0235] [Table 7]

[0236] As shown in Figure 7 and Table 7, administration of adagrasib, MRTX-0902, or VS-6766 as single agents resulted in 86.9%, 13.7%, and 81.1% tumor growth, respectively, at day 23. The combination of the SOS1 inhibitors MRTX-0902, VS-6766, and adagrasib resulted in -61.9% regression at day 23.

[0237] [Table 8]

[0238] As shown in Figure 8 and Table 8, administration of adagrasib or MRTX-0902 as single agents resulted in 99.0% and 6.1% tumor growth, respectively, at day 42. The combination of the SOS1 inhibitor MRTX-0902 with adagrasib resulted in -80.4% regression at day 42.

[0239] As shown in Figure 9, administration of MRTX-0902 with adagrasib results in broad antitumor activity in KRASG 12C mutant human tumor cell line-derived and patient-derived xenograft models from pancreatic, non-small cell lung, colorectal, and esophageal cancers. These results demonstrate that the combination therapy resulted in a greater amount of tumor growth inhibition compared to either single agent alone, demonstrating enhanced in vivo antitumor efficacy of the combination against KRas G12C-expressing cancers.

[0240] While the invention has been described in relation to particular embodiments thereof, it will be understood that it is capable of further modifications, and this application is intended to cover any variations, uses, or adaptations of the invention in accordance with the principles of the invention, within known or customary practice in the art to which the invention pertains, which may be applied to the essential features described above, including departures from the present disclosure as follows in the appended claims.

Claims

1. 1. A pharmaceutical composition for use in a method for treating cancer in a subject in need thereof, comprising the KRas G12C inhibitor adagrasib 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof and / or a SOS1 inhibitor, wherein the method comprises administering to the subject a therapeutically effective amount of a combination of the KRas G12C inhibitor adagrasib and the SOS1 inhibitor.

2. The SOS1 inhibitor is 【Chemistry 2】 (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 【Chemistry 3】 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, 【Chemistry 4】 (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and 【Chemistry 5】 (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 【Chemistry 6】 (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, 【Chemistry 7】 (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, and 【Chemistry 8】 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and 【Chemistry 9】 2. The pharmaceutical composition of claim 1, wherein the compound is selected from (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and pharma- ceutically acceptable salts thereof.

3. The SOS1 inhibitor is 【Chemistry 10】 or a pharma- ceutically acceptable salt thereof.

4. The method comprises the step of: 【Chemistry 11】 or a pharma- ceutically acceptable salt thereof to a subject in need of said cancer treatment.

5. 1. A pharmaceutical composition for use in a method of treating cancer in a subject in need thereof, comprising: -KRas G12C inhibitor adagrasib 【Chemistry 12】 or a pharma- ceutically acceptable salt thereof, -SOS1 inhibitor 【Chemistry 13】 or a pharma- ceutically acceptable salt thereof, and / or -MEK inhibitors 【Chemistry 14】 or a pharma- ceutical acceptable salt thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a combination of a KRas G12C inhibitor adagrasib or a pharma- ceutical acceptable salt thereof, said SOS1 inhibitor or a pharma- ceutical acceptable salt thereof, and said MEK inhibitor or a pharma- ceutical acceptable salt thereof.

6. 2. The pharmaceutical composition of claim 1, wherein the SOS1 inhibitor compound is BI1701963.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the SOS1 inhibitor and the KRas G12C inhibitor are administered on the same day.

8. The pharmaceutical composition of any one of claims 1 to 6, wherein the SOS1 inhibitor and the KRas G12C inhibitor are administered on different days.

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

10. The pharmaceutical composition according to any one of claims 1 to 8, wherein the SOS1 inhibitor is administered at a maximum tolerated dose.

11. The pharmaceutical composition of any one of claims 1 to 8, wherein the SOS1 inhibitor and the KRas G12C inhibitor are each administered at a maximum tolerated dose.

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

13. The pharmaceutical composition of any one of claims 1 to 8, wherein the SOS 1 inhibitor is administered at less than the maximum tolerated dose.

14. The pharmaceutical composition of any one of claims 1 to 8, wherein the SOS1 inhibitor and the KRas G12C inhibitor are each administered at less than the maximum tolerated dose.

15. 15. The pharmaceutical composition of any one of claims 1 to 14, wherein the therapeutically effective amount of the combination of the SOS1 inhibitor and the KRas G12C inhibitor results in increased overall survival, increased progression-free survival, increased tumor growth regression, increased tumor growth inhibition, or increased stable disease in the subject compared to treatment with the KRas G12C inhibitor alone.

16. 15. The pharmaceutical composition of any one of claims 1 to 14, wherein the therapeutically effective amount of the combination of the SOS1 inhibitor and the KRas G12C inhibitor results in increased overall survival, increased progression free survival, increased tumor growth regression, increased tumor growth inhibition, or increased stable disease in the subject compared to treatment with the SOS1 inhibitor alone.

17. A pharmaceutical composition according to any one of claims 1 to 16, comprising a pharma- ceutically acceptable excipient.

18. A pharmaceutical composition for use in a method for inhibiting KRas G12C activity in a cell, comprising the KRas G12C inhibitor adagrasib 【Chemistry 15】 or a pharma- ceutically acceptable salt thereof and / or a SOS1 inhibitor, wherein the method comprises contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a combination of the KRas G12C inhibitor adagrasib, or a pharma- ceutically acceptable salt thereof, and a SOS1 inhibitor.

19. The SOS1 inhibitor is 【Chemistry 16】 (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 【Chemistry 17】 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, 【Chemistry 18】 (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and 【Chemistry 19】 (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 【Chemistry 20】 (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, 【Chemistry 21】 (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, and 【Chemical 22】 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and 【Chemistry 23】 19. The pharmaceutical composition of claim 18, wherein the compound is selected from (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and pharma- ceutically acceptable salts thereof.

20. The SOS1 inhibitor is 【Chemistry 24】 or a pharma- ceutically acceptable salt thereof.

21. The method of claim 20, further comprising treating the cells with a compound having the structure: 【Chemistry 25】 or a pharma- ceutically acceptable salt thereof.

22. The pharmaceutical composition according to any one of claims 1 to 16 and 18 to 21, wherein the SOS1 inhibitor synergistically increases the sensitivity of cancer cells to the KRas G12C inhibitor.

23. A pharmaceutical composition for use in a method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor, comprising the KRas G12C inhibitor adagrasib 【Chemistry 26】 or a pharma- ceutically acceptable salt thereof and / or a SOS1 inhibitor, wherein the method comprises administering to a subject undergoing KRas G12C therapy an effective amount of a combination of the KRas G12C inhibitor adagrasib or a pharma- ceutically acceptable salt thereof and a SOS1 inhibitor, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cells to the KRas G12C inhibitor.

24. The SOS inhibitor, 【Chemical 27】 or a pharma- ceutically acceptable salt thereof.

25. The method comprises the step of: 【Chemistry 28】 or a pharma- ceutically acceptable salt thereof to a subject in need of said treatment for cancer.

26. 26. The pharmaceutical composition of any one of claims 1-16 or 18-25, wherein the therapeutically effective amount of said KRas G12C inhibitor in said combination is about 0.01-100 mg / kg per day.

27. 27. The pharmaceutical composition of claim 26, wherein the therapeutically effective amount of said KRas G12C inhibitor in said combination is about 0.1 to 50 mg / kg per day.

28. 28. The pharmaceutical composition of any one of claims 1-16 or 18-27, wherein the therapeutically effective amount of said SOS1 inhibitor in said combination is about 0.01-100 mg / kg per day.

29. 29. The pharmaceutical composition of claim 28, wherein the therapeutically effective amount of the SOS1 inhibitor in the combination is about 0.1 to 50 mg / kg per day.

30. The cancer is cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrohamartoma, mesothelioma; Gastrointestinal: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenocarcinoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: Kidney (adenocarcinoma) , Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, breast fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder cancer, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, deformities) osteomyelitis), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); gynecology: uterine cancer (endometrial cancer (serous cystic carcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, certoblastoma) 30. The pharmaceutical composition according to any one of claims 1 to 16 and 18 to 29, wherein the tumor is selected from the group consisting of: uterine (leydig cell carcinoma, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botulisoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (cancer); blood system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentigo dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

31. 31. The pharmaceutical composition of claim 30, wherein the cancer is a KRas G12C associated cancer.

32. 31. The pharmaceutical composition of claim 30, wherein the cancer is non-small cell lung cancer.

33. A kit comprising the pharmaceutical composition of any one of claims 1 to 17 for treating KRas G12C cancer in a subject.

34. 34. The kit of claim 33, further comprising a package insert having instructions for administration of the pharmaceutical composition.

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