Combination therapy including an SOS1 inhibitor and a MEK inhibitor

Abstract

The present invention relates to combination therapies for treating cancers associated with genetic alterations in the MAPK pathway and / or EGFR. In particular, the present invention relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SOS1 inhibitor and a MEK inhibitor, pharmaceutical compositions comprising such compositions, kits comprising such compositions, and methods 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 homolog 1 (SOS1) inhibitors and mitogen-activated protein kinase kinase (MEK) inhibitors, pharmaceutical compositions comprising the inhibitors, kits comprising the compositions, and methods of use thereof. [Background technology]

[0002] 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, growth, 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.

[0003] 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 rates of the RAS protein set. Recent biochemical analyses have demonstrated that these mutated proteins still require nucleotide cycling for activation based on their intrinsic GTPase activity and may exhibit partial sensitivity to exogenous GAPs and GEFs. Thus, mutated RAS proteins are sensitive to inhibition of upstream factors such as SOS1 GEF (Hillig, 2019; Patricelli, 2016; Lito, 2016; Nichols, 2018).

[0004] 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.

[0005] 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).

[0006] 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.

[0007] 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.

[0008] MEK inhibitors target the Ras / Raf / MEK / ERK signaling pathway, thereby inhibiting cell proliferation and inducing apoptosis.

[0009] 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).

[0010] 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; PD 198306, N-(cyclopropylmethoxy)-3,4,5-trifluoro-2-(4-iodo-2-methylbenzyl)benzamide; CI-1040, 2-(2-chloro-4-iodobenzyl)-N-(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;

[0011] 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 U.S. Pat. Nos. 10,370,374 and 10,323,035, and U.S. Patent Application Publication Nos. 20190144382, 20180370948, 20180296533, 20180147192, 20180118715, 20170231963, 20170183348, 20170183333, 20170166523, 20170101408, 20170096388, 201701 No. 60331753, No. 20160168103, No. 20160168102, No. 20160136150, No. 20160108041, No. 20150141399, No. 20150133424, No. 20150051209 , No. 20140378466, No. 20140275527, No. 20140135519, No. 20140128442, No. 20140080804, No. 20130150573, No. 20130018075, No. 201202 38599, 20120208859, 20120107307, 20120022076, 20110288092, 20110263558, 20110190257, 20110183981, 20110172191, 20110158971, 20110124622, 20110112152, 20110060049, 20110021558, 20100331334, 201002677 No. 10, No. 20100261718, No. 20100261717, No. 20100260714, No. 20100256149, No. 20100249096, No. 20100197676, No. 20100179124, No. 201 00063053, 20090291961, 20090264411, 20090233915, 20090215834, 20090209542, 20090156576, 20090149437,Same No. 20090143579, Same No. 20090143389, Same No. 20090131435, Same No. 20090082457, Same No. 200900 30058, 20080306063, 20080280957, 20080255133, 20080177082, 20080171778, 20080166359, 20080058340, 20070299063, 200702935 No. 44, No. 20070287737, No. 20070287709, No. 20070244164, No. 20070238710, No. 200 No. 70213367, No. 20070172843, No. 20070112038, No. 20070105859, No. 20060211073 , No. 20060194802, No. 20060189808, No. 20060189668, No. 20060189649, No. 200601 Nos. 54990, 20060106225, 20060089382, 20060052608, 20050256123, 20050250782, and 20050153942, the contents of which are incorporated herein by reference in their entireties.

[0012] One suitable MEK inhibitor for the compositions and methods provided is VS-6766, which has the following structure:

[0013] [ka] 3-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one

[0014] 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 described in U.S. Patent Application Publication Nos. 20190144382, 20180370948, 20180296533, 20180147192, 20180118715, 20170231963, 20170183348, 20170183333, 20170166523, 20170101408 ... No. 70096388, No. 20160331753, No. 20160168103, No. 20160168102, No. 20160136150, No. 20160108041, No. 20150141399, No. 201501334 No. 24, No. 20150051209, No. 20140378466, No. 20140275527, No. 20140135519, No. 20140128442, No. 20140080804, No. 20130150573, No. 2 0130018075, 20120238599, 20120208859, 20120107307, 20120022076, 20110288092, 20110263558, 2011019 0257, 20110183981, 20110172191, 20110158971, 20110124622, 20110112152, 20110060049, 20110021558, No. 20100331334, No. 20100267710, No. 20100261718, No. 20100261717, No. 20100260714, No. 20100256149, No. 20100249096, No. 201001 97676, 20100179124, 20100063053, 20090291961, 20090264411, 20090233915, 20090215834, 20090209542,Same No. 20090156576, Same No. 20090149437, Same No. 20090143579, Same No. 20090143389, Same No. 200901 31435, 20090082457, 20090030058, 20080306063, 20080280957, 20080255133, 20080177082, 20080171778, 20080166359, 200800583 No. 40, No. 20070299063, No. 20070293544, No. 20070287737, No. 20070287709, No. 200 No. 70244164, No. 20070238710, No. 20070213367, No. 20070172843, No. 20070112038 No. 20070105859, No. 20060211073, No. 20060194802, No. 20060189808, No. 20060 Nos. 189668, 20060189649, 20060154990, 20060106225, 20060089382, 20060052608, 20050256123, 20050250782, and 20050153942. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] U.S. Pat. No. 10,370,374 [Patent Document 2] U.S. Patent No. 10,323,035 [Patent Document 3] US Patent Application Publication No. 2019 / 144382 [Patent Document 4] US Patent Application Publication No. 2018 / 370948 [Patent Document 5] US Patent Application Publication No. 2018 / 296533 [Patent Document 6] US Patent Application Publication No. 2018 / 147192 [Patent Document 7] US Patent Application Publication No. 2018 / 118715 [Patent Document 8] US Patent Application Publication No. 2017 / 231963 [Patent Document 9] US Patent Application Publication No. 2017 / 183348 [Patent Document 10] US Patent Application Publication No. 2017 / 183333 [Patent Document 11] US Patent Application Publication No. 2017 / 166523 [Patent Document 12] US Patent Application Publication No. 2017 / 101408 [Patent Document 13] US Patent Application Publication No. 2017 / 096388 [Patent Document 14] US Patent Application Publication No. 2016 / 331753 [Patent Document 15] US Patent Application Publication No. 2016 / 168103 [Patent Document 16] US Patent Application Publication No. 2016 / 168102 [Patent Document 17] US Patent Application Publication No. 2016 / 136150 [Patent Document 18] US Patent Application Publication No. 2016 / 108041 [Patent Document 19] US Patent Application Publication No. 2015 / 141399 [Patent Document 20] US Patent Application Publication No. 2015 / 133424 [Patent Document 21] US Patent Application Publication No. 2015 / 051209 [Patent Document 22] US Patent Application Publication No. 2014 / 378466 [Patent Document 23] US Patent Application Publication No. 2014 / 275527 [Patent Document 24] US Patent Application Publication No. 2014 / 135519 [Patent Document 25] US Patent Application Publication No. 2014 / 128442 [Patent Document 26] US Patent Application Publication No. 2014 / 080804 [Patent Document 27] US Patent Application Publication No. 2013 / 150573 [Patent Document 28] US Patent Application Publication No. 2013 / 018075 [Patent Document 29] US Patent Application Publication No. 2012 / 238599 [Patent Document 30] US Patent Application Publication No. 2012 / 208859 [Patent Document 31] US Patent Application Publication No. 2012 / 107307 [Patent Document 32] US Patent Application Publication No. 2012 / 022076 [Patent Document 33] US Patent Application Publication No. 2011 / 288092 [Patent Document 34] US Patent Application Publication No. 2011 / 263558 [Patent Document 35] US Patent Application Publication No. 2011 / 190257 [Patent Document 36] US Patent Application Publication No. 2011 / 183981 [Patent Document 37] US Patent Application Publication No. 2011 / 172191 [Patent Document 38] US Patent Application Publication No. 2011 / 158971 [Patent Document 39] US Patent Application Publication No. 2011 / 124622 [Patent Document 40] US Patent Application Publication No. 2011 / 112152 [Patent Document 41] US Patent Application Publication No. 2011 / 060049 [Patent Document 42] US Patent Application Publication No. 2011 / 021558 [Patent Document 43] US Patent Application Publication No. 2010 / 331334 [Patent Document 44] US Patent Application Publication No. 2010 / 267710 [Patent Document 45] US Patent Application Publication No. 2010 / 261718 [Patent Document 46] US Patent Application Publication No. 2010 / 261717 [Patent Document 47] US Patent Application Publication No. 2010 / 260714 [Patent Document 48] US Patent Application Publication No. 2010 / 256149 [Patent Document 49] US Patent Application Publication No. 2010 / 249096 [Patent Document 50] US Patent Application Publication No. 2010 / 197676 [Patent Document 51] US Patent Application Publication No. 2010 / 179124 [Patent Document 52] US Patent Application Publication No. 2010 / 063053 [Patent Document 53] US Patent Application Publication No. 2009 / 291961 [Patent Document 54] US Patent Application Publication No. 2009 / 264411 [Patent Document 55] US Patent Application Publication No. 2009 / 233915 [Patent Document 56] US Patent Application Publication No. 2009 / 215834 [Patent Document 57] US Patent Application Publication No. 2009 / 209542 [Patent Document 58] US Patent Application Publication No. 2009 / 156576 [Patent Document 59] US Patent Application Publication No. 2009 / 149437 [Patent Document 60] US Patent Application Publication No. 2009 / 143579 [Patent Document 61] US Patent Application Publication No. 2009 / 143389 [Patent Document 62] US Patent Application Publication No. 2009 / 131435 [Patent Document 63] US Patent Application Publication No. 2009 / 082457 [Patent Document 64] US Patent Application Publication No. 2009 / 030058 [Patent Document 65] US Patent Application Publication No. 2008 / 306063 [Patent Document 66] US Patent Application Publication No. 2008 / 280957 [Patent Document 67] US Patent Application Publication No. 2008 / 255133 [Patent Document 68] US Patent Application Publication No. 2008 / 177082 [Patent Document 69] US Patent Application Publication No. 2008 / 171778 [Patent Document 70] US Patent Application Publication No. 2008 / 166359 [Patent Document 71] US Patent Application Publication No. 2008 / 058340 [Patent Document 72] US Patent Application Publication No. 2007 / 299063 [Patent Document 73] US Patent Application Publication No. 2007 / 293544 [Patent Document 74] US Patent Application Publication No. 2007 / 287737 [Patent Document 75] US Patent Application Publication No. 2007 / 287709 [Patent Document 76] US Patent Application Publication No. 2007 / 244164 [Patent Document 77] US Patent Application Publication No. 2007 / 238710 [Patent Document 78] US Patent Application Publication No. 2007 / 213367 [Patent Document 79] US Patent Application Publication No. 2007 / 172843 [Patent Document 80] US Patent Application Publication No. 2007 / 112038 [Patent Document 81] US Patent Application Publication No. 2007 / 105859 [Patent Document 82] US Patent Application Publication No. 2006 / 211073 [Patent Document 83] US Patent Application Publication No. 2006 / 194802 [Patent Document 84] US Patent Application Publication No. 2006 / 189808 [Patent Document 85] US Patent Application Publication No. 2006 / 189668 [Patent Document 86] US Patent Application Publication No. 2006 / 189649 [Patent Document 87] US Patent Application Publication No. 2006 / 154990 [Patent Document 88] US Patent Application Publication No. 2006 / 106225 [Patent Document 89] US Patent Application Publication No. 2006 / 089382 [Patent Document 90] US Patent Application Publication No. 2006 / 052608 [Patent Document 91] US Patent Application Publication No. 2005 / 256123 [Patent Document 92] US Patent Application Publication No. 2005 / 250782 [Patent Document 93] U.S. Patent Application Publication No. 2005 / 153942

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[0017] In one aspect, the combination therapy of the present invention synergistically increases the potency of the SOS1 inhibitor, resulting in improved efficacy of the SOS1 inhibitor disclosed herein.In another aspect, the combination therapy of the present invention provides patients with improved clinical benefits compared to treatment with the SOS1 inhibitor disclosed herein as a single agent.

[0018] Thus, in one aspect of the invention, SOS1 inhibitors such as those described in WO 2021 / 127429, WO 2021 / 173524, WO 2022 / 026465, U.S. Provisional Patent Application No. 63 / 213,112 (and corresponding national and international applications and publications), and those described in more detail herein, e.g.,

[0019] [ka] (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile,

[0020] [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,

[0021] [ka] (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile,

[0022] [ka] (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile,

[0023] [ka] (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile,

[0024] [ka] (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile,

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

[0026] [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; Therapeutically effective combinations with MEK inhibitor compounds, such as VS-6766, binimetinib, cobimetinib, selumetinib, trametinib, PD-325901, CI-1040, TAK733, and other small and large molecular weight MEK inhibitors are provided.

[0027] In another aspect of the present invention, there is provided a therapeutically effective combination of the SOS1 inhibitor (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, and a MEK inhibitor selected from VS-6766, binimetinib, cobimetinib, selumetinib, trametinib, PD-325901, CI-1040, CI-1040, and TAK733, as well as other small and polymeric MEK inhibitors, or a pharma- ceutically acceptable salt thereof.

[0028] In another aspect of the invention, there is provided a pharmaceutical composition for use in the method comprising a therapeutically effective amount of the SOS1 inhibitor (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, in combination with the MEK inhibitor compound VS-6766, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0029] In another aspect of the invention, there is provided a pharmaceutical composition for use in the method comprising a therapeutically effective amount of the SOS1 inhibitor (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 in combination with the MEK inhibitor compound binimetinib or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0030] In another aspect of the invention, there is provided a pharmaceutical composition for use in the method comprising a therapeutically effective amount of the SOS1 inhibitor (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 in combination with the MEK inhibitor compound cobimetinib or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0031] In another aspect of the invention, there is provided a pharmaceutical composition for use in the method comprising a therapeutically effective amount of the SOS1 inhibitor (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 in combination with the MEK inhibitor compound selumetinib or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0032] In another aspect of the invention, there is provided a pharmaceutical composition for use in the method comprising a therapeutically effective amount of the SOS1 inhibitor (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 in combination with the MEK inhibitor compound trametinib or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0033] In another aspect of the invention, there is provided a pharmaceutical composition for use in the method comprising a therapeutically effective amount of a combination of the SOS1 inhibitor (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, and a MEK inhibitor compound PD-325901, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0034] In one aspect of the invention, there is provided a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of an SOS1 inhibitor, such as (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-methylpyridazin-1-yl -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)benzonitrile, (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, or (R)-3-(1-((6 Provided herein are methods for treating a subject comprising administering to the subject a combination of -fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile and a MEK inhibitor selected from VS-6766, binimetinib, cobimetinib, selumetinib, trametinib, PD-325901, CI-1040, TAK733, and other low molecular weight and polymeric MEK inhibitors, or pharma- ceutically acceptable salts or pharmaceutical compositions thereof.

[0035] 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 the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the MEK inhibitor VS-6766, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0036] 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 the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the MEK inhibitor binimetinib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0037] 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 the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the MEK inhibitor cobimetinib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0038] 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 the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the MEK inhibitor selumetinib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0039] 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 the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the MEK inhibitor trametinib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0040] 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 the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the MEK inhibitor PD-325901, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0041] In one embodiment, the cancer is an SOS1-associated cancer.

[0042] In one embodiment, the SOS1-associated cancer is brain cancer, for example, glioblastoma. In one embodiment, the SOS1-associated cancer is lung cancer, for example, primary lung adenocarcinoma. In one embodiment, the SOS1-associated cancer is lung cancer, for example, primary lung adenocarcinoma. In one embodiment, the SOS1-associated cancer is leukemia, for example, acute myeloid leukemia.

[0043] In some aspects of the invention, the MEK inhibitor 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.In yet another aspect, the present invention provides a method for increasing the sensitivity of cancer cells to an SOS1 inhibitor or to a MEK inhibitor, comprising treating the cancer cells with a therapeutically effective amount of a MEK inhibitor compound, such as VS-6766, binimetinib, cobimetinib, selumetinib, trametinib, PD-325901, CI-1040, and TAK733, and other small and large molecular weight MEK inhibitors, or pharma- ceutically acceptable salts or pharmaceutical compositions thereof, and an SOS1 inhibitor as described herein, such as (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 ethyl-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 In one embodiment, the method comprises contacting a cancer cell with a combination of an SOS1 inhibitor comprising (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 or pharmaceutical composition thereof, to synergistically increase sensitivity of the cancer cell to an SOS1 or MEK inhibitor. In one embodiment, the contacting is in vitro.In one embodiment, the contacting is in vivo.

[0045] Also provided herein is a method of treating cancer in a subject in need thereof, the method comprising: (a) determining (e.g., as determined using a regulatory approved, e.g., FDA approved, assay or kit) that the cancer is associated with an SOS1-mediated cancer and / or a genetic alteration in the MAPK pathway (e.g., an SOS1-associated cancer); and (b) administering to the patient a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the MEK inhibitor synergistically increases sensitivity of the SOS1-associated cancer to the SOS1 inhibitor, for example, to (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile.

[0046] Also provided herein is a kit comprising an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a MEK inhibitor compound, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.Also provided is a kit comprising the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the MEK inhibitor compound VS-6766, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in treating an SOS1-associated cancer.

[0047] 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 MEK inhibitor compound, 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 containing instructions for administering the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the MEK inhibitor compound, 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 MEK inhibitor compound, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0048] 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]

[0049] [Figure 1] The mean tumor volume (mm3) of LN229 tumor-bearing mice treated with single agents (MRTX-0902, VS-6766) and combinations is shown. [Diagram 2] The mean tumor volume (mm3) of NCT-H1435 tumor-bearing mice treated with single agents (MRTX-0902, VS-6766) and in combination is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0050] The present invention relates to combination therapy for treating SOS1-related 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, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, a pharmaceutical composition comprising a therapeutically effective amount of the inhibitor, a kit comprising the composition, and a method of use thereof.

[0051] The combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, with a MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, synergistically increases the potency of the SOS1 inhibitor against cancer cells expressing SOS1, thereby increasing the efficacy and therapeutic index of the SOS1 inhibitor or a pharma- ceutically acceptable salt thereof.

[0052] 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.

[0053] As used herein, "MEK" refers to mitogen-activated protein kinase kinase. MEK inhibitors are chemicals or drugs that inhibit the mitogen-activated protein kinase kinase enzymes MEK1 and / or MEK. MEK inhibitors can be used to affect the MAPK / ERK pathway, which is often overactive in some cancers.

[0054] As used herein, "MEK" refers to compounds such as VS-6766, binimetinib, cobimetinib, selumetinib, trametinib, PD-325901, CI-1040, or TAK733, as well as other low and high molecular weight MEKs, or pharma- ceutically acceptable salts thereof, which can negatively regulate or inhibit all or a portion of the enzymatic activity of MEK, or mutant MEKs.

[0055] As used herein, a "MEK-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having EGFR mutation or overexpression.

[0056] 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.

[0057] 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.

[0058] As used herein, "SOS1-associated disease or disorder" refers to a disease or disorder associated with or mediated by SOS1 mutation. A non-limiting example of an SOS1-associated disease or disorder is SOS1-associated cancer.

[0059] 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).

[0060] 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.

[0061] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether a patient has SOS1 overexpression using a sample (e.g., a biological sample or a biopsy sample, e.g., a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having an SOS1-associated cancer, a patient having one or more symptoms of an SOS1-associated cancer, and / or a patient at high risk of developing an SOS1-associated cancer), and may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR, quantitative real-time RT-PCR, allele-specific genotyping, or ddPCR). As is well known in the art, the assay is typically performed, for example, using at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0062] 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).

[0063] 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 MEK. Such an amount may be administered as a single dose or may be administered according to a regimen whereby it is effective.

[0064] 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 MEK. Such an amount may be administered as a single dose or may be administered according to a regimen whereby it is effective.

[0065] 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 therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a MEK inhibitor compound, 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 an SOS1 inhibitor alone. In one embodiment, a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma-ceutically acceptable salt or pharmaceutical composition thereof, and a MEK inhibitor, 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 an SOS1 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, and a MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor regression in a subject compared to treatment with an SOS1 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, and a MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor growth inhibition in a subject compared to treatment with an MEK 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, and a MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in improved stable disease duration in a subject compared to treatment with an SOS1 inhibitor alone or an MEK inhibitor alone. The amount of each compound in the combination may be the same as or different from the therapeutically effective amount of each compound when administered alone as a monotherapy, 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.

[0066] 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.

[0067] 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 may result from or be associated with administration of the composition.

[0068] As used herein, the term "about" when used to modify a numerically defined parameter (e.g., the dose of a MEK inhibitor or SOS1 inhibitor, or a pharma- ceutically acceptable salt thereof, or the length of treatment time with a combination therapy described herein) means that the parameter may vary by as much as 10% above or below the numerical value recited 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.

[0069] 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.

[0070] MEK Inhibitor Compounds In one aspect of the present 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 MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0071] In one embodiment, the MEK inhibitor is

[0072] [ka] (also referred to as VS-6766), or a pharma- ceutically acceptable salt thereof.

[0073] In one embodiment, the MEK inhibitor is

[0074] [ka] (also called binimetinib), or a pharma- ceutically acceptable salt thereof.

[0075] In one embodiment, the MEK inhibitor is

[0076] [ka] (also called cobimetinib), or a pharma- ceutical acceptable salt thereof.

[0077] In one embodiment, the MEK inhibitor is

[0078] [ka] (also called selumetinib), or a pharma- ceutically acceptable salt thereof.

[0079] In one embodiment, the MEK inhibitor is

[0080] [ka] (also called trametinib), or a pharma- ceutically acceptable salt thereof.

[0081] In one embodiment, the MEK inhibitor is (also referred to as PD-325901), or a pharma- ceutically acceptable salt thereof.

[0082] In one embodiment, the MEK inhibitor is CI-1040, or a pharma- ceutically acceptable salt thereof.

[0083] In one embodiment, the MEK inhibitor is TAK733, or a pharma- ceutically acceptable salt thereof.

[0084] The MEK 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.

[0085] 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 salts 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).

[0086] Methods for producing the KRas G12C inhibitors disclosed herein are generally known.

[0087] 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-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-ethyl piperazin-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, or a compound selected from the compounds described in ____, as described in more detail herein.

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

[0089] [ka] or a pharma- ceutically acceptable salt thereof, wherein R1 is hydrogen, hydroxyl, C1-C6 alkyl, alkoxy, -N(R6)2, -NR6C(O)R6, -C(O)N(R6)2, -SO2 alkyl, -SO2NR6 alkyl, cycloalkyl, -Q-heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R2; each Q is independently a bond, O, or NR6; and X is N or CR7. each R2 is independently hydroxy, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, -N(R6)2, -SO2alkyl, -NR6C(O)C1-C3alkyl, -C(O)cycloalkyl, -C(O)heterocyclyl, or aryl, each of which is optionally substituted with one or more R11; and R3 is hydrogen, C1-C6alkyl, alkoxy, -N(R10)2, cycloalkyl, haloalkyl, heterocyclyl, aryl, or and Y is a bond or heteroarylene; R4 is an aryl or heteroaryl, each optionally substituted with one or more R5, each R5 being independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C3 alkyl, haloalkyl, -N(R6)2, -LN(R6)2, or -SO2 alkyl; and L is C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each optionally substituted with one or more R9; Y is a bond or heteroarylene; R4 is an aryl or heteroaryl, each optionally substituted with one or more R5, each R5 being independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C3 alkyl, haloalkyl, -N(R6)2, -LN(R6)2, or -SO2 alkyl; R7 is hydrogen, cyano, or alkoxy; R8 is C1-C2 alkyl or halo-C1-C2 alkyl; each R9 is independently hydroxy, halogen, amino, cyano, alkoxy, or C1-C3 alkyl; each R10 is independently hydrogen, C1-C3 alkyl, or cycloalkyl; and each R11 is independently C1-C3 alkyl or haloalkyl.These compounds include, but are not limited to, all of the exemplary compounds listed in WO 2021 / 127429, WO 2021 / 173524, WO 2022 / 026465, U.S. Provisional Patent Application No. 63 / 213,112 (and corresponding domestic and international applications and publications) and described in more detail herein, including in particular (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile.

[0090] In another embodiment, the SOS1 inhibitor is

[0091] [ka] (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile,

[0092] [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,

[0093] [ka] (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and

[0094] [ka] (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile,

[0095] [ka] (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile,

[0096] [ka] (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile,

[0097] [ka] 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and

[0098] [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.

[0099] 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.

[0100] 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).

[0101] Methods for producing the SOS1 inhibitors disclosed herein are known. For example, co-owned applications WO 2021 / 127429, WO 2021 / 173524, WO 2022 / 026465, and U.S. Provisional Patent Application No. 63 / 213,112 (and corresponding domestic and international applications and publications) describe general reaction schemes for preparing compounds, including adagrasib, and also provide detailed synthetic routes for the preparation of these compounds.

[0102] Pharmaceutical Compositions The SOS1 inhibitor and the MEK compound, or a pharma- ceutically acceptable salt thereof, can be formulated into a pharmaceutical composition.

[0103] In another aspect, the present invention provides a pharmaceutical composition comprising an SOS1 inhibitor, or a pharma- ceutically acceptable salt thereof, an MEK inhibitor, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, excipient, or diluent that can be used in the methods disclosed herein. The SOS1 inhibitor, or a pharma- ceutically acceptable salt thereof, and the MEK 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 / or the KRas G12C inhibitor, or a pharma- ceutically acceptable salt thereof, is administered intravenously in a hospital setting.

[0104] In one embodiment, administration of one or both therapeutic components may be by the oral route.

[0105] 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.

[0106] 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).

[0107] 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.

[0108] A pharmaceutical composition comprising an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, may be used in the methods of use described herein.

[0109] Simultaneous administration The SOS1 inhibitor or its pharmaceutically acceptable salt and the MEK 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.

[0110] The pharmaceutical composition for use in the method, comprising an SOS1 inhibitor or a pharma- ceutically acceptable salt thereof, and / or an MEK inhibitor or a pharma- ceutically acceptable salt thereof, may be for simultaneous, separate, or sequential use. In one embodiment, the SOS1 inhibitor or a pharma- ceutically acceptable salt thereof is administered before the administration of the MEK inhibitor 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 MEK inhibitor 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 MEK inhibitor compound or a pharma- ceutically acceptable salt thereof.

[0111] 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 MEK inhibitor 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.

[0112] 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 MEK 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 MEK 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 MEK 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 MEK 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. Administration may be timed so that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.

[0113] In one embodiment, a single dose of the MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered per day (i.e., about 24 hours apart) (i.e., QD). In another embodiment, two doses of the MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are administered per day (i.e., BID). In another embodiment, three doses of the MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are administered per day (i.e., TID).

[0114] 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.

[0115] In one embodiment, a single dose of the MEK 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 once daily.

[0116] 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- [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 zonitrile, 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.

[0117] Combination therapy In one aspect of the present invention, the present invention provides a method for treating cancer in a subject in need of such treatment, 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 an MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.In one embodiment, the cancer is an SOS1-associated cancer.In one embodiment, the SOS1-associated cancer is lung cancer.

[0118] In yet another aspect, the present invention provides a method for increasing the sensitivity of a cancer cell to an SOS1 inhibitor, comprising contacting the cancer cell with an effective amount of a combination of an SOS1 inhibitor, such as MRTX0902, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an MEK inhibitor, such as VS-6766, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the MEK inhibitor synergistically increases the sensitivity of the cancer cell to the SOS1 inhibitor. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0119] In one embodiment, the combination therapy comprises a compound having the formula

[0120] [ka] (MRTX0902), or a pharma- ceutically acceptable salt thereof, in combination with a MEK inhibitor.

[0121] In one such embodiment, the MEK inhibitor is VS-6766.

[0122] In one such embodiment, the MEK inhibitor is binimetinib.

[0123] In one such embodiment, the MEK inhibitor is cobimetinib.

[0124] In one such embodiment, the MEK inhibitor is selumetinib.

[0125] In one such embodiment, the MEK inhibitor is trametinib.

[0126] In one such embodiment, the MEK inhibitor is PD-325901.

[0127] In one such embodiment, the MEK inhibitor is CI-1040 or TAK733.

[0128] In one embodiment, the combination therapy comprises a combination of VS-6766 and an SOS1 inhibitor.

[0129] In one such embodiment, the SOS1 inhibitor is

[0130] [ka] (R)-2-Methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile (MRTX0902).

[0131] In another such embodiment, the SOS1 inhibitor is

[0132] [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.

[0133] In yet another such embodiment, the SOS1 inhibitor is

[0134] [ka] (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile.

[0135] In yet another such embodiment, the SOS1 inhibitor is

[0136] [ka] (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]]pyridazin-1-yl)amino)ethyl)benzonitrile.

[0137] In another embodiment, the SOS1 inhibitor is

[0138] [ka] (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile.

[0139] In another embodiment, the SOS1 inhibitor is

[0140] [ka] (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile.

[0141] In another embodiment, the SOS1 inhibitor is

[0142] [ka] 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile.

[0143] In another embodiment, the SOS1 inhibitor is

[0144] [ka] (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile.

[0145] The method described herein is designed to inhibit undesirable cell proliferation resulting from enhanced EGFR activity in cells.The degree of inhibitory activity of SOS1 inhibitor-EGFR inhibitor combination in cells can be monitored, for example, by measuring cell viability and the functional inhibition of both RAF / MEK / ERK and PI3K / AKT effector pathway signaling (the amount of phosphorylated ERK and AKT, respectively) to evaluate the effectiveness of treatment, and dosage can be adjusted accordingly by the attending physician.

[0146] The compositions and methods provided herein may be used for treating SOS1-associated cancer in a subject in need of such treatment, 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 MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the MEK inhibitor synergistically increases the sensitivity of the SOS1-associated cancer to the SOS1 inhibitor. In one embodiment, the SOS1-associated cancer is a cancer with a genetic alteration in the MAPK pathway. In one embodiment, the SOS1-associated cancer is a cancer mediated by SOS1. In one embodiment, the SOS1-associated cancer is a lung cancer. In one embodiment, the SOS1-associated cancer is a brain tumor.

[0147] In one embodiment, a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a MEK inhibitor, 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 an SOS1 inhibitor alone. In one embodiment, a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a MEK inhibitor, 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 an SOS1 inhibitor alone. In one embodiment, a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in an increase in tumor regression in a subject, compared to treatment with an SOS1 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, and a MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor growth inhibition in a subject compared to treatment with the SOS1 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, and a MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in improved stable disease duration in a subject compared to treatment with the SOS1 inhibitor alone.

[0148] 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.

[0149] In another embodiment, an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered in combination with a MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, when disease progression is observed with SOS1 monotherapy, and the combination therapy results in enhanced clinical benefit for the patient by increasing OS, PFS, tumor regression, tumor growth inhibition, or stable disease in the patient.

[0150] In one embodiment, the therapeutic combination comprises therapeutically effective amounts of VS-6766 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.

[0151] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of VS-6766 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.

[0152] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of VS-6766 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.

[0153] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of VS-6766 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.

[0154] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of VS-6766 and (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or pharma- ceutically acceptable salts thereof.

[0155] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of VS-6766 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.

[0156] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of VS-6766 and 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or pharma- ceutically acceptable salts thereof.

[0157] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of VS-6766 and (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or pharma- ceutically acceptable salts thereof.

[0158] 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, 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: Heart: 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, capsular carcinoma, peritoneal ... sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma); colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia); bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma); prostate (adenocarcinoma, sarcoma); testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder carcinoma, dilated carcinoma Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pineal tumor), glioblastoma multiforme, oligodendroma, Dendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma; Gynecology: uterine cancer (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (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, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (cancer);Hematological: 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: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer.;

[0159] Also provided herein is a method of treating cancer in a subject in need of such treatment, the method comprising: (a) determining that the cancer is associated with SOS1 overexpression (e.g., determined using a regulatory agency approved, e.g., FDA approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a MEK inhibitor, or a pharma-ceutically acceptable salt or pharmaceutical composition thereof, wherein the MEK inhibitor synergistically increases the sensitivity of the SOS1-associated cancer to the SOS1 inhibitor.In one embodiment, the MEK inhibitor is selected from VS-6766, binimetinib, cobimetinib, selumetinib, trametinib, PD-325901, CI-1040, and CI-1040, or TAK733, and other small and large molecular weight MEK inhibitors, and 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] In one embodiment, the SOS1 inhibitor, the MEK inhibitor, or both are administered as a tablet or capsule for a period of time. In one embodiment, the tablet or capsule formulation of the SOS1 inhibitor and / or the EGR inhibitor 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, the SOS1 inhibitor and / or MEK inhibitor is administered orally once daily (QD) every day for a period of time. In one embodiment, the SOS1 inhibitor and / or MEK inhibitor is administered orally twice daily (BID) every day for a period of time.

[0169] In one embodiment, the SOS1 inhibitor and / or MEK inhibitor is administered over a period of time at a dose of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg , approx. 20 mg ~ approx. 180 mg, approx. 20 mg ~ approx. 160 mg, approx. 20 mg ~ approx. 140 mg, approx. 20 mg ~ approx. 120 mg, approx. 20 mg ~ approx. 100 mg, approx. 20 mg ~ approx. 80 mg, approx. mg, approx. 40 mg to approx. 460 mg, approx. 40 mg to approx. 440 mg, approx. 40 mg to approx. 420 mg, approx. 40 mg to approx. 400 mg, approx. 40 mg to approx. 380 mg, approx. ~280mg, 40mg~260mg, 40mg~240mg, 40mg~220mg, 40mg~200mg, 40mg~180mg, 40mg~160mg, 40mg~140mg, 40mg~120mg, 40mg~100mg , approx. 40 mg ~ approx. 80 mg, approx. 40 mg ~ approx. 60 mg, approx. 60 mg ~ approx. 500 mg, approx. 60 mg ~ approx. 480 mg, approx. 60 mg ~ approx. 460 mg, approx. 60 mg ~ approx. 440 mg, approx. 0mg, about 60mg to about 340mg, about 60mg to about 320mg, about 60mg to about 300mg, about 60mg to about 280mg, about 60mg to about 260mg, about 60mg to about 240mg, about 60mg to about 220mg, about 60mg to about 200mg, about 60mg to about 180mg, about 60m g ~ about 160mg, about 60mg - about 140mg, about 60mg - about 120mg, about 60mg - about 100mg, about 60mg - about 80mg, about 80mg - about 500mg, about 80mg - about 480mg, about 80mg - about 460mg, about 80mg - about 440mg, about 80mg - about 420mg,About 80mg to about 400mg, about 80mg to about 380mg, about 80mg to about 360mg, about 80mg to about 340mg, about 80mg to about 320mg, about 80mg to about 300mg, about 80mg to about 280mg, about 80mg to about 260mg, about 80mg to about 240mg, about 80mg to about 220mg, about 80mg to about 200mg, about 80mg to about 180mg, about 80mg to about 160mg, about 80mg to about 140mg, about 80mg to about 120mg, about 80mg to about 100mg, about 100mg to about 500mg, about 10 0mg to about 480mg, about 100mg to about 460mg, about 100mg to about 440mg, about 100mg to about 420mg, about 100mg to about 400mg, about 100mg to about 380mg, about 100mg to about 360mg, about 100mg to about 340mg, about 100mg to about 320mg, about 100mg to about 300mg, about 100mg to about 280mg, about 100mg to about 260mg, about 100mg to about 240mg, about 100mg to about 220mg, about 100mg to about 200mg, about 100mg to about 180mg, about 100mg to about 160mg, about 100mg to about 140mg, about 100mg to about 120mg, about 120mg to about 500mg, about 120mg to about 480mg, about 120mg to about 460mg, about 120mg to about 440mg, about 120mg to about 420mg, about 120mg to about 400mg, about 120mg to about 380mg, about 120mg to about 360mg, about 120mg to about 340mg, about 120mg to about 320mg, about 120mg to about 300mg, about 120mg to about 280mg, about 120mg to about 260mg, about 120mg to about 240mg, about 120mg to about 220mg, about 120mg to about 200mg, about 120mg to about 180mg, about 120mg to about 16 0mg, about 120mg to about 140mg, about 140mg to about 500mg, about 140mg to about 480mg, about 140mg to about 460mg, about 140mg to about 440mg, about 140mg to about 420mg, about 140mg to about 400mg, about 140mg to about 380mg, about 140mg to about 360mg, about 140mg to about 340mg, about 140mg to about 320mg, about 140mg to about 300mg, about 140mg to about 280mg, about 140mg to about 260mg, about 140mg to about 240mg, about 140mg to about 220mg, about 140mg to about 200mg, about 140mg to about 180mg,about 140mg to about 160mg, about 160mg to about 500mg, about 160mg to about 480mg, about 160mg to about 460mg, about 160mg to about 440mg, about 160mg to about 420mg, about 160mg to about 400mg, about 160mg to about 380mg, about 160mg to about 360mg, about 160mg to about 340mg, about 160mg to about 320mg, about 160mg to about 300mg, about 160mg to about 280mg, about 160mg to about 260mg, about 160mg to about 240mg, about 160mg to about 220mg, about 160mg to about 200mg, about 160mg to about 18 0mg, about 180mg to about 500mg, about 180mg to about 480mg, about 180mg to about 460mg, about 180mg to about 440mg, about 180mg to about 420mg, about 180mg to about 400mg, about 180mg to about 380mg, about 180mg to about 360mg, about 180mg to about 340mg, about 180mg to about 320mg, about 180mg to about 300mg, about 180mg to about 280mg, about 180mg to about 260mg, about 180mg to about 240mg, about 180mg to about 220mg, about 180mg to about 200mg, about 200mg to about 500mg, about 200mg to About 480mg, about 200mg to about 460mg, about 200mg to about 440mg, about 200mg to about 420mg, about 200mg to about 400mg, about 200mg to about 380mg, about 200mg to about 360mg, about 200mg to about 340mg, about 200mg to about 320mg, about 200mg to about 300mg, about 200mg to about 280mg, about 200mg to about 260mg, about 200mg to about 240mg, about 200mg to about 220mg, about 220mg to about 500mg, about 220mg to about 480mg, about 220mg to about 460mg, about 220mg to about 440mg, about 22 0mg to about 420mg, about 220mg to about 400mg, about 220mg to about 380mg, about 220mg to about 360mg, about 220mg to about 340mg, about 220mg to about 320mg, about 220mg to about 300mg, about 220mg to about 280mg, about 220mg to about 260mg, about 220mg to about 240mg, about 240mg to about 500mg, about 240mg to about 480mg, about 240mg to about 460mg, about 240mg to about 440mg, about 240mg to about 420mg, about 240mg to about 400mg, about 240mg to about 380mg, about 240mg to about 360mg,about 240mg to about 340mg, about 240mg to about 320mg, about 240mg to about 300mg, about 240mg to about 280mg, about 240mg to about 260mg, about 260mg to about 500mg, about 260mg to about 480mg, about 260mg to about 460mg, about 260mg to about 440mg, about 260mg to about 420mg, about 260mg to about 400mg, about 260mg to about 380mg, about 260mg to about 360mg, about 260mg to about 340mg, about 260mg to about 320mg, about 260mg to about 300mg, about 260mg to about 280mg, about 280mg to about 50 0mg, about 280mg to about 480mg, about 280mg to about 460mg, about 280mg to about 440mg, about 280mg to about 420mg, about 280mg to about 400mg, about 280mg to about 380mg, about 280mg to about 360mg, about 280mg to about 340mg, about 280mg to about 320mg, about 280mg to about 300mg, about 300mg to about 500mg, about 300mg to about 480mg, about 300mg to about 460mg, about 300mg to about 440mg, about 300mg to about 420mg, about 300mg to about 400mg, about 300mg to about 380mg, about 300mg to About 360mg, about 300mg to about 340mg, about 300mg to about 320mg, about 320mg to about 500mg, about 320mg to about 480mg, about 320mg to about 460mg, about 320mg to about 440mg, about 320mg to about 420mg, about 320mg to about 400mg, about 320mg to about 380mg, about 320mg to about 360mg, about 320mg to about 340mg, about 340mg to about 500mg, about 340mg to about 480mg, about 340mg to about 460mg, about 340mg to about 440mg, about 340mg to about 420mg, about 340mg to about 400mg, about 34 0mg to about 380mg, about 340mg to about 360mg, about 360mg to about 500mg, about 360mg to about 480mg, about 360mg to about 460mg, about 360mg to about 440mg, about 360mg to about 420mg, about 360mg to about 400mg, about 360mg to about 380mg, about 380mg to about 500mg, about 380mg to about 480mg, about 380mg to about 460mg, about 380mg to about 440mg, about 380mg to about 420mg, about 380mg to about 400mg, about 400mg to about 500mg, about 400mg to about 480mg, about 400mg to about 460mg,about 400 mg to about 440 mg, about 400 mg to about 420 mg, about 420 mg to about 500 mg, about 420 mg to about 480 mg, about 420 mg to about 460 mg, about 420 mg to about 440 mg, about 440 mg to about 500 mg, about 440 mg to about 480 mg, about 440 mg to about 460 mg, about 460 mg to about 500 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg). In one embodiment, the SOS1 inhibitor and / or MEK inhibitor is orally administered twice a day (BID) every day for a certain period of time. In one embodiment, adagrasib is administered orally twice daily (BID) every day for a period of time.

[0170] In one embodiment, the combination therapy includes oral administration of an SOS1 inhibitor and / or a MEK inhibitor, each independently, for example, about 10 mg to about 400 mg (e.g., about 10 mg to about 380 mg, about 10 mg to about 360 mg, about 10 mg to about 340 mg, about 10 mg to about 320 mg, about 10 mg to about 300 mg, about 10 mg to about 280 mg, about 10 mg to about 260 mg, about 10 mg to about 240 mg, about 10 mg to about 220 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, g, approx. 10 mg ~ approx. 100 mg, approx. 10 mg ~ approx. 80 mg, approx. 10 mg ~ approx. 60 mg, approx. 10 mg ~ approx. 40 mg, approx. 10 mg ~ approx. 20 mg, approx. 0mg, about 20mg to about 300mg, about 20mg to about 280mg, about 20mg to about 260mg, about 20mg to about 240mg, about 20mg to about 220mg, about 20mg to about 200mg, about 20mg to about 180mg, about 20mg to about 160mg, about 20mg to about 140mg, about 20m g~120mg, approx. 20mg~approximately 100mg, approx. 20mg~approximately 80mg, approx. 20mg~approximately 60mg, approx. 20mg~approximately 40mg, approx. 40mg to about 300mg, about 40mg to about 280mg, about 40mg to about 260mg, about 40mg to about 240mg, about 40mg to about 220mg, about 40mg to about 200mg, about 40mg to about 180mg, about 40mg to about 160mg, about 40mg to about 140mg, about 40mg to about 12 0mg, about 40mg to about 100mg, about 40mg to about 80mg, about 40mg to about 60mg, about 60mg to about 400mg, about 60mg to about 380mg, about 60mg to about 360mg, about 60mg to about 340mg, about 60mg to about 320mg, about 60mg to about 300mg, about 60mg ~280mg, 60mg~260mg, 60mg~240mg, 60mg~220mg, 60mg~200mg, 60mg~180mg, 60mg~160mg, 60mg~140mg, 60mg~120mg, 60mg~100mg,About 60mg to about 80mg, about 80mg to about 400mg, about 80mg to about 380mg, about 80mg to about 360mg, about 80mg to about 340mg, about 80mg to about 320mg, about 80mg to about 300mg, about 80mg to about 280mg, about 80mg to about 260mg, about 80mg to about 240mg, about 80mg to about 220mg, about 80mg to about 200mg, about 80mg to about 180mg, about 80mg to about 160mg, about 80mg to about 140mg, about 80mg to about 120mg, about 80mg to about 100mg, about 10 0mg to about 400mg, about 100mg to about 380mg, about 100mg to about 360mg, about 100mg to about 340mg, about 100mg to about 320mg, about 100mg to about 300mg, about 100mg to about 280mg, about 100mg to about 260mg, about 100mg to about 240mg, about 100mg to about 220mg, about 100mg to about 200mg, about 100mg to about 180mg, about 100mg to about 160mg, about 100mg to about 140mg, about 100mg to about 120mg, about 120mg to about 400mg, about 120mg to about 380mg, about 120mg to about 360mg, about 120mg to about 340mg, about 120mg to about 320mg, about 120mg to about 300mg, about 120mg to about 280mg, about 120mg to about 260mg, about 120mg to about 240mg, about 120mg to about 220mg, about 120mg to about 200mg, about 120mg to about 180mg, about 120mg to about 160mg, about 120mg to about 140mg, about 140mg to about 400mg, about 140mg to about 380mg, about 140mg to about 360mg, about 140mg to about 340mg, about 140mg to about 320mg, about 140mg to about 300mg, about 140mg to about 280mg, about 140mg to about 26 0mg, about 140mg to about 240mg, about 140mg to about 220mg, about 140mg to about 200mg, about 140mg to about 180mg, about 140mg to about 160mg, about 160mg to about 400mg, about 160mg to about 380mg, about 160mg to about 360mg, about 160mg to about 360mg, about 160mg to about 340mg, about 160mg to about 320mg, about 160mg to about 300mg, about 160mg to about 280mg, about 160mg to about 260mg, about 160mg to about 240mg, about 160mg to about 220mg, about 160mg to about 200mg, about 160mg to about 180mg,Approximately 180mg to approximately 400mg, approximately 180mg to approximately 380mg, approximately 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 24 0mg, about 180mg to about 220mg, about 180mg to about 200mg, about 200mg to about 400mg, about 200mg to about 380mg, about 200mg to about 360mg, about 200mg to about 340mg, about 200mg to about 320mg, about 200mg to about 300mg, about 200mg ~280mg, 200mg~260mg, 200~240mg, 200~220mg, 220~400mg, 220~380mg, 220~360mg, 220~340mg, 220~320mg, 2 20mg to about 300mg, about 220mg to about 280mg, about 220mg to about 260mg, about 220mg to about 240mg, about 240mg to about 400mg, about 240mg to about 380mg, about 240mg to about 360mg, about 240mg to about 340mg, about 240mg to about 320mg , about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 3 00mg, about 260mg to about 280mg, about 280mg to about 400mg, about 280mg to about 380mg, about 280mg to about 360mg, about 280mg to about 340mg, about 280mg to about 320mg, about 280mg to about 300mg, about 300mg to about 400mg, about 300mg about 380 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 340 mg to about 360 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 400 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg) once or twice a day (during a certain period of time).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.

[0171] Those skilled in the art will recognize that both in vivo and in vitro testing using suitable, known and generally accepted cellular and / or animal models are predictive of the ability of a test compound or combination to treat or prevent a given disorder.

[0172] 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.

[0173] Synergy In one embodiment, the addition of a MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, synergistically increases the activity of a SOS1 inhibitor compound, such as MRTX0902, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, against a cancer or cancer cell line that overexpresses SOS1.Any method for determining whether two compounds exhibit synergistic activity may be used to determine the synergistic effect of the combination.

[0174] Several mathematical models have been developed to determine whether two compounds act synergistically, i.e. beyond merely additive effects. For example, Loewe additivity (Loewe (1928) Physiol. 27: 47-187), Bliss independence (Bliss (1939) Ann. Appl. Biol. 26: 585-615), best single agent, ZIP (Yadav et al (2015) Comput Struct Biotech J 13: 504-513) 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. These synergy scores are combined to provide a composite synergy score that can be used to evaluate and characterize MEK inhibitors, such as VS-6766, and SOS1 inhibitors, such as MRTX0902.

[0175] Generally, the mathematical model uses data obtained from single drug 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 synergistic. For example, the Bliss independence model compares the observed combination response (YO) with the predicted combination response (YP) obtained based on the assumption that there is no effect from drug-drug interactions. Typically, if YO is greater than YP, the combination effect is qualified as synergistic.

[0176] In some embodiments, "synergistic effect" as used herein refers to a combination of a MEK inhibitor or a pharma- ceutically acceptable salt thereof and a SOS1 inhibitor or a pharma- ceutically acceptable salt thereof that results in an effect, e.g., any of the beneficial or desired results, including clinical outcomes or endpoints described herein, that is greater than the sum of the effects observed when the compounds, e.g., compounds described in the SOS1 patent applications listed herein, e.g., MRTX0902, and the MEK inhibitor or a pharma- ceutically acceptable salt thereof, e.g., VS-6766, are administered alone.

[0177] 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 VS-6766. 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 VS-6766. 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 VS-6766. 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 VS-6766. 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 VS-6766. 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 VS-6766. 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 VS-6766. 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 VS-6766.

[0178] 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%).

[0179] 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.

[0180] 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%).

[0181] 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.

[0182] kit The present invention also relates to a kit comprising an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof (e.g., MRTX0902), and a MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof (e.g., VS-6766). Also provided is a kit comprising such an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and such a MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in the treatment of hematological cancers.

[0183] 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 MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, in an amount effective to inhibit the proliferation of cancer cells, particularly SOS1-overexpressing cancer cells, in a subject. The kit optionally includes a package insert containing instructions for administering the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the MEK inhibitor, 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 MEK inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0184] 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.

[0185] Example A In vivo model to investigate SOS1 inhibitor-MEK inhibitor combinations Immunocompromised nude / nude mice are inoculated with LN229 cells carrying the A72S mutation in the right hind flank. When the tumor volume reaches approximately 150 mm3 in size, the mice are divided into four groups of five mice each. The first group receives vehicle only. The second group receives a single dose of the SOS1 inhibitor MRTX0902 at a concentration of 50 mg / kg twice daily (BID), which produces a maximal biological effect but does not produce complete tumor regression. The third group receives a single dose of the MEK inhibitor VS-6766 at a concentration of 0.3 mg / kg twice daily (BID), which produces a submaximal biological effect but does not produce complete tumor regression, as a single agent on Monday, Wednesday, and Friday (Q2D). The fourth group receives a single dose of the SOS1 inhibitor in combination with a single dose of the MEK inhibitor. The treatment period was 28 days. Tumor volumes are measured every 2-3 days using calipers and tumor volume is calculated by the formula: 0.5 x (length x 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 treated subjects compared to treatment with either MEK or SOS1 inhibitors alone.

[0186] Twenty nude / nude mice were inoculated with 5 × 106 LN229 cells into the right hind limb. When tumor volumes reached approximately 150 mm3 (study day 0), five mice in each of four groups were orally dosed daily for 28 days with: vehicle alone (0.5% MC (4000 cps) / 0.2% Tween 80 in water), the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile (MRTX0902) at 50 mg / kg BID (0.5% MC (4000 cps) / 0.2% Tween 80 in water), the MEK inhibitor VS-6766 (5% DMSO, 10% HPCD in water) at 0.3 mg / kg BID Q2D, or 50 mg / kg BID MRTX0902 and 0.3 mg / kg BID Q2D. Tumor volumes measured on prespecified days for five mice per group were averaged and are reported in Table 1 and FIG. 1 for LN229 cells.

[0187] [Table 1]

[0188] As shown in Table 1 and Figure 1, MRTX0902 administered at 50 mg / kg twice daily as a single agent resulted in 37.6% tumor growth inhibition at day 28. VS-6766 administered at 0.3 mg / kg twice daily as a single agent on Monday, Wednesday, and Friday resulted in 92.5% tumor growth inhibition at day 28. The combination of MRTX0902 at 50 mg / kg BID and VS-6766 at 0.3 mg / kg BID Q2D resulted in -27.6% tumor regression at day 28.

[0189] 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 PTPN11 A72S-expressing cancers.

[0190] Example B In vivo model to investigate SOS1 inhibitor-MEK inhibitor combinations Immunocompromised nude / nude mice are inoculated with NCI-H1435 cells carrying the NF1 K615N mutation in the right hind flank. When the tumor volume reaches approximately 150 mm3 in size, the mice are divided into four groups of five mice each. The first group receives vehicle only. The second group receives a single dose of the SOS1 inhibitor MRTX0902 at a concentration of 50 mg / kg twice daily (BID), which produces a maximal biological effect but does not produce complete tumor regression. The third group receives a single dose of the MEK inhibitor VS-6766 at a concentration of 0.3 mg / kg twice daily (BID), which produces a submaximal biological effect but does not produce complete tumor regression, as a single agent on Monday, Wednesday, and Friday (Q2D). The fourth group receives a single dose of the SOS1 inhibitor in combination with a single dose of the MEK inhibitor. The treatment period was 27 days. Tumor volumes are measured every 2-3 days using calipers and tumor volume is calculated by the formula: 0.5 x (length x 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 treated subjects compared to treatment with either MEK or SOS1 inhibitors alone.

[0191] Twenty nude / nude mice were inoculated with 5 × 106 NCI-H1435 cells into the right hind limb. When tumor volumes reached approximately 150 mm3 (study day 0), five mice in each of four groups were orally dosed daily for 27 days with: vehicle alone (0.5% MC (4000 cps) / 0.2% Tween 80 in water), the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile (MRTX0902) at 50 mg / kg BID (0.5% MC (4000 cps) / 0.2% Tween 80 in water), the MEK inhibitor VS-6766 (5% DMSO, 10% HPCD in water) at 0.3 mg / kg BID Q2D, or 50 mg / kg BID MRTX0902 and 0.3 mg / kg BID Q2D. VS-6766. Tumor volumes measured on prespecified days for 5 mice per group were averaged and are reported in Table 2 and FIG. 2 for NCI-H1435 cells.

[0192] [Table 2]

[0193] As shown in Table 2 and Figure 2, MRTX0902 administered at 50 mg / kg twice daily as a single agent resulted in 49.8% tumor growth inhibition at day 27. VS-6766 administered at 0.3 mg / kg twice daily as a single agent on Mondays, Wednesdays, and Fridays resulted in 76.4% tumor growth inhibition at day 27. The combination of MRTX0902 at 50 mg / kg twice daily and VS-6766 at 0.3 mg / kg twice daily on Mondays, Wednesdays, and Fridays resulted in 98.1% tumor regression at day 27.

[0194] 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 NF1 K615N-expressing cancers.

[0195] 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 generally, within known or customary practice in the art to which the invention pertains, which may be applied to the essential features described above, and which include departures from the present disclosure as follows within the scope of the appended claims.

Claims

1. A pharmaceutical composition for use in the treatment of cancer, comprising a therapeutically effective amount of an SOS1 inhibitor: 【Chemistry 1】 A pharmaceutical composition comprising a combination of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrid[3,4-d]pyridazin-1-yl)aminoethyl)benzonitrile or a pharmaceutically acceptable salt thereof and a MEK inhibitor.

2. The pharmaceutical composition according to claim 1, wherein the MEK inhibitor is selected from VS-6766, binimetinib, cobimetinib, selumetinib, trametinib, PD-325901, CI-1040, or TAK733, or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 1 or 2, wherein the MEK inhibitor is VS-6766.

4. The pharmaceutical composition according to claim 1 or 2, wherein the MEK inhibitor is binimetinib.

5. The pharmaceutical composition according to claim 1 or 2, wherein the MEK inhibitor is cobimetinib.

6. The pharmaceutical composition according to claim 1 or 2, wherein the MEK inhibitor is CI-1040 or TAK733.

7. The pharmaceutical composition according to claim 1, wherein the SOS1 inhibitor and the MEK inhibitor are administered on the same day.

8. The pharmaceutical composition according to claim 1, wherein the SOS1 inhibitor and the MEK inhibitor are administered on different days.

9. SOS1 inhibitors: 【Chemistry 2】 A pharmaceutical composition comprising (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrid[3,4-d]pyridazin-1-yl)aminoethyl)benzonitrile or a pharmaceutically acceptable salt thereof, a MEK inhibitor, and a pharmaceutically acceptable excipient.

10. A method for increasing the sensitivity of cancer cells to an SOS1 inhibitor, comprising an effective amount of the SOS1 inhibitor: 【Transformation 3】 A method comprising administering to a subject receiving treatment with a combination of a pharmaceutically acceptable salt thereof and a MEK inhibitor, wherein the MEK inhibitor synergistically increases the sensitivity of the cancer cells to the SOS1 inhibitor.

11. The aforementioned cancers include: heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: Bronchogenic carcinoma (squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrohammartoma, mesothelioma; Gastrointestinal tract: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); urogenital tract: kidney (adenocarcinoma * Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminocarcinoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder cancer, ampulla cancer, cholangiocarcinoma; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroexostosis (osteochondroma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, Xanthomas, osteoosteitis), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); gynecological system: uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granular cancer) A pharmaceutical composition according to claim 1, selected from the group consisting of: membrane-involucular cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma; vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer); hematological system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorder, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin 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.

12. The pharmaceutical composition according to claim 11, wherein the cancer is an SOS1-related cancer.

13. The pharmaceutical composition according to claim 11, wherein the cancer is a KRas G12C-related cancer.

14. The pharmaceutical composition according to claim 13, wherein the cancer is non-small cell lung cancer.

15. A kit comprising the pharmaceutical composition according to claim 9 for treating SOS1-related cancer in a subject.

16. The kit according to claim 15, further comprising a package insert containing instructions for administering the pharmaceutical composition.

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