CN117615762A

CN117615762A - Combination therapy

Info

Publication number: CN117615762A
Application number: CN202280048697.2A
Authority: CN
Inventors: 雅各布·哈林; 约翰·迈克尔·凯查姆; 希尔皮·卡雷
Original assignee: Mirati Therapeutics Inc
Current assignee: Mirati Therapeutics Inc
Priority date: 2021-05-27
Filing date: 2022-05-24
Publication date: 2024-02-27

Abstract

The present invention relates to combination therapies for the treatment of KRas G12C cancer. In particular, the present invention relates to methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SOS1 inhibitor and a KRas G12C inhibitor, pharmaceutical compositions comprising such compositions, kits comprising such compositions, and methods of use thereof.

Description

Combination therapy

Technical Field

The present invention relates to combination therapies that may be used to treat cancer. In particular, the present invention relates to a therapeutically effective combination of a Son of sevenless homolog 1 (SOS 1) inhibitor and a KRas G12C inhibitor, pharmaceutical compositions comprising the inhibitors, kits comprising the compositions, and methods of use thereof.

Background

KRAS inhibitors

Ke Ersi the rat sarcoma (Kirsten Rat Sarcoma) 2 viral oncogene homolog ("KRas") is a member of the small gtpase and Ras oncogene families. KRas acts as a molecular switching cycle between an inactive (GDP-bound) state and an active (GTP-bound) state to convert upstream cellular signals received from multiple tyrosine kinases into downstream effectors that regulate a wide variety of processes including cell proliferation (see, e.g., alameger et al, (2013) pharmacological novelties (Current Opin pharmacol.)) 13:394-401.

The role of activated KRAS in malignant disease was observed more than thirty years ago (see, e.g., der et al, (1982) Proc. Natl Acad. Sci. USA) 79 (11): 3637-3640). Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and cause constitutive activation of KRas, and downstream signaling has been reported in 25% -30% of lung adenocarcinomas. (see, for example, samatar and Poulikakos (2014) for a natural review: drug discovery (Nat Rev Drug Disc) 13 (12): 928-942 doi:10.1038/nrd 428). Single nucleotide substitutions at codons 12 and 13 of the KRas primary amino acid sequence that result in missense mutations account for about 40% of these KRas driver mutations in lung adenocarcinoma, with G12C transversions to the most common activating mutations (see e.g., douan et al, (2012) clinical Cancer research (Clin Cancer res.) 18 (22): 6169-6177, published online at 9 months 26 in 2012, doi:10.1158/1078-0432. Ccr-11-3265).

The well-known role of KRas in malignant disease and the discovery of these frequent mutations of KRas in various tumor types make KRas a highly attractive target for cancer therapies in the pharmaceutical industry. Despite thirty years of extensive discovery efforts to develop KRas inhibitors for the treatment of cancer, KRas inhibitors do not exhibit sufficient safety and/or efficacy to obtain regulatory approval (see, e.g., mccormik (2015) clinical cancer research 21 (8): 1797-1801).

Compounds that inhibit KRas activity are still highly desirable and under investigation, including compounds that disrupt effectors such as guanine nucleotide exchange factors (see, e.g., sun et al, (2012) international english edition (Agnew Chem Int Ed engl.) 51 (25): 6140-6143doi:10.1002/anie 201201358) and compounds that target KRas G12C (see, e.g., ostrem et al, (2013) Nature (Nature) 503: 548-551). Clearly, there is still a continuing interest and effort in the development of KRas inhibitors, particularly activated KRas mutant inhibitors including KRas G12C.

Although the KRas G12C inhibitors disclosed herein are potent inhibitors of KRas G12C enzymatic activity and exhibit single agent activity to inhibit proliferation in vitro of cell lines having KRas G12C mutations, the relative potency and/or maximum effect observed for any given KRas G12C inhibitor may vary between KRas mutant cell lines. One or more reasons for the range of efficacy and maximum effect observed are not fully understood, but specific cell lines appear to have different intrinsic tolerability. Thus, there is a need to develop alternative approaches to maximize the efficacy, therapeutic index and/or clinical benefit of KRas G12C inhibitors in vitro and in vivo.

SOS1 inhibitors

The Ras family includes v-Ki-Ras2 Kirsten rat sarcoma viral oncogene homolog (KRas), neuroblastoma Ras viral oncogene homolog (NRAS), and hav mouse sarcoma viral oncogene (HRas), and strictly regulates Cell division, growth, and function under normal and altered conditions involving cancer (see, e.g., simansu et al, cell, 2017, 170 (1): pages 17-33; matikas et al, crit Rev Oncol-Hemol, 2017, 110: pages 1-12). RAS proteins are activated by upstream signals comprising Receptor Tyrosine Kinases (RTKs) and transduce signals to several downstream signal pathways, such as the Mitogen Activated Protein Kinase (MAPK)/extracellular signal regulated kinase (ERK) pathway. Overactivation of RAS signaling is often observed in cancer due to mutations or alterations in the RAS gene or other genes in the RAS pathway. Strategies to inhibit RAS and RAS signaling are being investigated, which would be expected to be helpful in treating cancer and RAS-mediated disease states.

The RAS protein is a guanosine triphosphate (gtpase) that circulates between an inactive Guanosine Diphosphate (GDP) bound state and an active Guanosine Triphosphate (GTP) bound state. RAS proteins exhibit intrinsic GTP hydrolysis and nucleotide exchange, which is further enhanced by the extrinsic Gtpase Activating Proteins (GAPs) and Guanine Exchange Factors (GEFs). Son of sevenless homolog 1 (SOS 1) is a gene that mediates the exchange of GDP to GTP, thereby activating GEF of RAS proteins. This regulation by GAP and GEF is a mechanism that tightly regulates activation and deactivation under normal conditions. Mutations at several residues in all three RAS proteins are often observed in cancer, and these mutations result in RAS being predominantly maintained in an activated state (Sanchez-Vega et al, cell, 2018, 173: pages 321-337; li et al, nature comment-cancer (Nature Reviews Cancer), 2018, 18: pages 767-777). Mutations at codons 12 and 13 disrupt GTP hydrolysis and the rate of RAS protein exchange. Recent biochemical analysis has shown that these mutant proteins still require nucleotide cycling to activate based on their intrinsic gtpase activity and may exhibit partial sensitivity to extrinsic GAP and GEF. Thus, mutant RAS proteins are sensitive to inhibition by upstream factors such as SOS1 GEF (hillg, 2019; patricelli, 2016; lito, 2016; nichols, 2018).

Three major RAS-GEF families that have been identified in mammalian cells are SOS, RAS-GRF and RAS-GRP (Rojas, 2011). RAS-GRF and RAS-GRP are expressed in central nervous system cells and hematopoietic cells, respectively, while SOS family is widely expressed and responsible for RTK signaling. The SOS family includes SOS1 and SOS2, which proteins have approximately 70% sequence identity. SOS1 appears to be more active than SOS2 due to the rapid degradation of SOS 2. Mouse SOS2 gene knockout is feasible, while SOS1 gene knockout is embryonic lethal. Tamoxifen-induced SOS1 gene knockout mouse models were used to study the roles of SOS1 and SOS2 in adult mice and demonstrate that SOS1 gene knockout is feasible, but SOS1/2 double gene knockout is not feasible (Baltanas, 2013), suggesting that functional redundancy, selective inhibition of SOS1 may have sufficient therapeutic indicators to treat SOS1-RAS activated disease.

SOS proteins are recruited to phosphorylated RTKs by interactions with growth factor receptor binding protein 2 (GRB 2). Replenishment to the plasma membrane brings SOS in close proximity to the RAS and supports SOS-mediated RAS activation. SOS proteins bind to the RAS through catalytic binding sites that promote nucleotide exchange and allosteric sites of RAS family proteins that bind GTP by increasing SOS catalytic function (Freedman et al, proc. Natl. Acad. Sci. USA (Proc.Natl.Acad.Sci, USA), 2006, 103 (45): pages 16692-16697). Binding to the allosteric site reduces the steric occlusion of the catalytic site and is therefore necessary for complete activation of the catalytic site. Due to the enhanced interaction of the critical domains in the activated state, the retention of the active conformation at the catalytic site remains in an isolated state after interaction with the allosteric site. SOS1 mutations are found in noonan syndrome and several cancers, including lung adenocarcinoma, embryonal rhabdomyosarcoma, seltoli's cell testis tumor, and skin granulocytoma (see Denayer, E. Et al, gene chromosomes and Cancer (Genes-Chromes-Cancer), 2010, 49 (3): pages 242-252).

Gtpase Activating Proteins (GAPs) are proteins that stimulate low intrinsic gtpase activity of RAS family members, thus converting active GTP-bound RAS proteins into inactive GDP-bound RAS proteins (see, e.g., simansu, d.k., (Cell), 2017, RAS proteins in human disease and their modulators (Ras Proteins and their Regulators in Human Disease)). Although changes in the activation of the phosphatases PTPN11 (SHP 2) and GEF SOS1 occur in cancer, inactivating mutations and loss of function changes in GAP neurofibrin 1 (NF-1) also occur, resulting in uninhibited SOS1 activity and increased activity downstream of the pathway through the RAS protein.

MEK inhibitors

Mitogen-activated protein kinase (MAPK) signaling pathways are involved in regulating a variety of 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 lines and organs), raf (a family of three serine/threonine-specific protein kinases associated with retroviral oncogenes), MEK (mitogen-activated protein kinase) and ERK (extracellular signal-regulated kinase), which sequentially transmit proliferative signals generated at cell surface receptors into the nucleus through cytoplasmic signaling.

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

The MAPK pathway is one of the most commonly mutated oncogenic pathways in cancer, deregulation of this pathway is often observed, and it plays an important role in the oncogenic action and maintenance of several cancers including melanoma, pancreatic, lung, colorectal and breast. (e.g., neuzillet et al, (2014) Pharmacology & Therapeutics) 141:160-171.

Several inhibitors have been developed that exhibit anti-MEK activity, and many of these inhibitors are or have been studied in human clinical trials. Examples of MEK inhibitors suitable for use in the provided compositions and methods include, but are not limited to, semtinib, 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 ] -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; refatinib, N- [3, 4-difluoro-2- (2-fluoro-4-iodoanilino) -6-methoxyphenyl ] -1- [ (2S) -2, 3-dihydroxypropyl ] cyclopropane-1-sulfonamide; bemetinib, 6- (4-bromo-2-fluoroanilino) -7-fluoro-N- (2-hydroxyethoxy) -3-methylbenzimidazole-5-carboxamide; RO 4987553, 4-difluoro-2- (2-fluoro-4-iodoanilino) -N- (2-hydroxyethoxy) -5- [ (3-oxooxazin-2-yl) methyl ] benzamide; RO5126766 (VS-6766), 3- [ [ 3-fluoro-2- (methylsulfamoylamino) pyridin-4-yl ] methyl ] -4-methyl-7-pyrimidin-2-yloxy-benzopyran-2-one; WX-554, HL-085; clnQ-03; g-573,7-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-phenylbutyramide; 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-hydroxyethoxy) -1-methyl-1H-benzo [ d ] imidazole-6-carboxamide; tak-733, (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, (2 e,3 e) -2- (amino ((2-aminophenyl) thio) methylene) -3- (amino ((3-aminophenyl) thio) methylene) succinonitrile; tramatinib, 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-oxoindol-6-yl) -N-ethyl propynylamide; pitutinib, (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; cobicitinib, (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-benzopyran-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; BIX02188, (Z) -3- (((3- ((dimethylamino) methyl) phenyl) amino) (phenyl) methylene) -2-oxoindoline-6-carboxamide.

The structure of these MEK inhibitors can be found, for example, in Cheng et al, state of the art for MEK inhibitors (Current Development Status of MEK Inhibitors), molecules (Molecules), 2017, 22,1551, and U.S. Pat. Nos. 10,370,374 and 10,323,035, and U.S. patent application publication nos. 20190144382, a 20190144382, and 20190144382, the contents of which are hereby incorporated by reference in their entirety.

One of the MEK inhibitors suitable for the provided compositions and methods is VS-6766 having the structure:

3- [ [ 3-fluoro-2- (methylsulfamoylamino) pyridin-4-yl ] methyl ] -4-methyl-7-pyrimidin-2-yloxy-benzopyran-2-one

Methods for manufacturing MEK inhibitors, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, are well known to those skilled in the art, and MEK inhibitors are available from a wide variety of commercial suppliers in a form suitable for both research or human use. In addition, suitable MEK inhibitors for use in the compositions and methods disclosed herein and methods for preparing such inhibitors are disclosed in U.S. patent application publication nos.: 20190144382, 20180370948, 20180296533, 20180147192, 20180118715, 20170231963, 20170183348, 20170183333, 20170166523 5237, 20170166523 5237, 20170166523.

Disclosure of Invention

In one aspect, the combination therapies of the invention synergistically increase the efficacy of the KRas G12C inhibitor, resulting in improved efficacy of the KRas G12C inhibitor disclosed herein. In another aspect, the combination therapies of the invention provide improved clinical benefit to patients compared to treatment with the KRas G12C inhibitors disclosed herein as a single agent.

Thus, in one aspect of the invention, there is provided a therapeutically effective combination of SOS1 inhibitors, such as those described in U.S. provisional patent applications 62/951,812, 62/975,645, 63/044,802, 62/980,790 and 63/057,563 (and corresponding U.S. and international applications and publications, including PCT/US20/66003, PCT/US21/19184, PCT/US21/43309 and US 17/127,582) as described in detail herein, for example:

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

3- ((R) -1- ((7- ((S) -hexahydropyrazine [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) no

[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 pharmaceutically acceptable salt thereof,

the KRas G12C inhibitor compound 2- [ (2S) -4- [7- (8-chloro-1-naphthyl) -2- [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -6, 8-dihydro-5H-pyrido [3,4-d ] pyrimidin-4-yl ] -1- (2-fluoroprop-2-enoyl) piperazin-2-yl ] acetonitrile (also known as MRTX849, also known as adaglazei)

Cloth):

or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, there is provided a therapeutically effective combination of: SOS1 inhibitors such as BI1701963 or a pharmaceutically acceptable salt thereof with KRAS G12C inhibitor compound 2- [ (2S) -4- [7- (8-chloro-1-naphthyl) -2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -6, 8-dihydro-5H-pyrido [3,4-d ] pyrimidin-4-yl ] -1- (2-fluoroprop-2-enoyl) piperazin-2-yl ] acetonitrile (also known as MRTX849, also known as adaglazeb):

Or a pharmaceutically acceptable salt thereof.

In one aspect, the invention provides the following therapeutically effective combinations:

SOS1 inhibitor (R) -2-methyl-3- (1- ((4-methyl-7-morpholinopyridao [3,4-d ] pyridazin-1-yl) amino) ethyl) benzonitrile (also known as MRTX 0902) having the formula:

or a pharmaceutically acceptable salt thereof

The KRas G12C inhibitor compound 2- [ (2S) -4- [7- (8-chloro-1-naphthyl) -2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -6, 8-dihydro-5H-pyrido [3,4-d ] pyrimidin-4-yl ] -1- (2-fluoroprop-2-enoyl) piperazin-2-yl ] acetonitrile (also known as MRTX849, also known as adaglazeb).

In another aspect, the invention provides a therapeutically effective combination of:

or a pharmaceutically acceptable salt thereof,

the KRas G12C inhibitor compound 2- [ (2S) -4- [7- (8-chloro-1-naphthyl) -2- [ [ (2S) -1-methylpyrrolidin-2-yl ] methoxy ] -6, 8-dihydro-5H-pyrido [3,4-d ] pyrimidin-4-yl ] -1- (2-fluoroprop-2-enoyl) piperazin-2-yl ] acetonitrile (also known as MRTX849, also known as adaglazeb); and

MEK inhibitors [ [ 3-fluoro-2- (methylsulfamoylamino) pyridin-4-yl ] methyl ] -4-methyl-7-pyrimidin-2-yloxy-benzopyran-2-one (also known as VS-6766) having the structure:

Or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, there is provided a pharmaceutical composition for use in the method comprising the following therapeutically effective amounts of a combination: SOS1 inhibitors such as (R) -2-methyl-3- (1- ((4-methyl-7-morpholinopyridao [3,4-d ] pyridazin-1-yl) amino) ethyl) benzonitrile, 3- ((R) -1- ((7- ((S) -hexahydropyrazin [2,1-c ] [1,4] oxazin-8 (1H) -yl) -4-methylpyridazo [3,4-d ] pyridazin-1-yl) amino) ethyl) -2-methylbenzonitrile, (R) -3- (1- ((7- (3- (dimethylamino) -3-methylazetidin-1-yl) -4-methylpyridazo [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-methylpyridazin-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 or (R) -3- (1- ((6-fluoro-4-methyl-7- (4-methylpiperazin-1-yl) amino) ethyl) -2-methylbenzonitrile, or SOS1 inhibitors such as BI1701963, KRas G12C inhibitor compound adaxacillin, or a pharmaceutically acceptable salt and pharmaceutically acceptable excipient thereof.

In some embodiments, the method may further comprise administering a MEK inhibitor to a subject in need thereof, such that the subject is administered adaglazeb, an SOS1 inhibitor, and a MEK inhibitor, e.g., VS-6766.

In one aspect of the invention, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of: SOS1 inhibitors such as (R) -2-methyl-3- (1- ((4-methyl-7-morpholinopyridao [3,4-d ] pyridazin-1-yl) amino) ethyl) benzonitrile, 3- ((R) -1- ((7- ((S) -hexahydropyrazin [2,1-c ] [1,4] oxazin-8 (1H) -yl) -4-methylpyridazo [3,4-d ] pyridazin-1-yl) amino) ethyl) -2-methylbenzonitrile, (R) -3- (1- ((7- (3- (dimethylamino) -3-methylazetidin-1-yl) -4-methylpyridazo [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-methylpyridazin-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-methylpyridazo [3,4-d ] pyridazin-1-yl) amino) ethyl) -2-methylbenzonitrile or (R) -3- (1- ((6-fluoro-4-methyl-7- (4-methylpiperazin-1-yl) amino) ethyl) -2-methylbenzonitrile,

Or SOS1 inhibitors such as BI1701963 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and KRAS G12C inhibitor adagransie, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

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

In some aspects of the invention, KRas G12C inhibitor compounds and SOS1 inhibitors are the only active agents in the provided compositions and methods.

Examples of SOS1 inhibitors suitable for use in the provided compositions and methods include, but are not limited to, (R) -2-methyl-3- (1- ((4-methyl-7-morpholinopyridao [3,4-d ] pyridazin-1-yl) amino) ethyl) benzonitrile, 3- ((R) -1- ((7- ((S) -hexahydropyrazin [2,1-c ] [1,4] oxazin-8 (1H) -yl) -4-methylpyridazo [3,4-d ] pyridazin-1-yl) amino) ethyl) -2-methylbenzonitrile, (R) -3- (1- ((7- (3- (dimethylamino) -3-methylazetidin-1-yl) -4-methylpyridazo [3,4-d ] pyridazin-1-yl) amino) ethyl) -2-methylbenzonitrile, (R) -2-methyl-3- (1- ((4-methyl-7- (4-methylpiperazin-1-yl) pyrido-1-yl) amino) ethyl) benzonitrile, (R) -3- (1- ((7- (4-ethylpiperazin-1-yl) -4-methylpyridazin-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-methylpyridazo [3,4-d ] pyridazin-1-yl) amino) ethyl) -2-methylbenzonitrile and (R) -3- (1- ((6-fluoro-4-methyl-7- (4-methylpiperazin-1-yl) amino) ethyl) -2-methylbenzonitrile, and pharmaceutically acceptable salts thereof.

Other examples of SOS1 inhibitors suitable for use in the provided compositions and methods include BI1701963.

In yet another aspect, the invention provides a method for inhibiting KRas G12C activity in a cell comprising contacting a cell in which inhibition of KRas G12C activity is desired with an effective amount of a combination of: KRAS G12C inhibitor adaglazeb:

or a pharmaceutically acceptable salt thereof, and an SOS1 inhibitor.

In one embodiment, the SOS1 inhibitor has the following structure:

or a pharmaceutically acceptable salt thereof.

In yet another aspect, the method further comprises contacting the cell with a compound having the structure:

or a pharmaceutically acceptable salt thereof.

In yet another aspect, the invention provides a method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor, the method comprising contacting the cancer cell with a therapeutically effective amount of the KRas G12C inhibitor compound adaglazeb or pharmaceutically acceptable salt or pharmaceutical composition thereof in combination with a SOS1 inhibitor or pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor. In one embodiment, the contacting is performed ex vivo. In one embodiment, the contacting is performed in vivo. In one embodiment, the method comprises administering to a subject undergoing KRas G12C treatment an effective amount of a combination of the KRas G12C inhibitor adaglazeb or a pharmaceutically acceptable salt thereof and an SOS1 inhibitor, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cells to the KRas G12C inhibitor.

In one embodiment, a method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor comprises contacting the cancer cell with a therapeutically effective amount of the KRas G12C inhibitor compound adagransieb or a pharmaceutically acceptable salt or pharmaceutical composition thereof with an SOS1 inhibitor having the structure:

or a pharmaceutically acceptable salt thereof, or a combination of pharmaceutically acceptable salts or pharmaceutical compositions thereof.

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

or a pharmaceutically acceptable salt thereof.

Also provided herein are methods for treating cancer in a subject in need thereof, the methods comprising: (a) Determining that the cancer is associated with a KRas G12C mutation (e.g., KRas G12C-associated cancer) (e.g., determined using regulatory agency-approved (e.g., FDA-approved) assays or kits); and (b) administering to the patient a therapeutically effective amount of a combination of an SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the SOS1 inhibitor synergistically increases the sensitivity of the KRas G12C-related cancer to adaglazeb.

Also provided herein are kits comprising an SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof. Also provided are kits comprising an SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and an KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in the treatment of KRas G12C cancer.

In a related aspect, the invention provides a kit comprising a dose of an SOS1 inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound adagransie, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in an amount effective to inhibit proliferation of cancer cells in a subject. In some cases, the kit includes instructions for administering the SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and the KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof. The instructions may provide the user with a set of instructions for using the SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof in combination with the KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

In some aspects of any of the methods described herein, the patient has received treatment with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery prior to treatment with the compositions or methods of the invention, and optionally, prior treatment was unsuccessful; and/or a surgical procedure has been performed on the patient, and optionally, the surgical procedure is unsuccessful; and/or the patient has received treatment with a platinum-based chemotherapeutic agent, and optionally, the patient has been previously determined to be non-responsive to treatment with the platinum-based chemotherapeutic agent; and/or the patient has received treatment with a kinase inhibitor, and optionally, prior treatment with a kinase inhibitor has been unsuccessful; and/or the patient has received treatment with one or more other therapeutic agents.

Drawings

FIG. 1 is a graph of tumor growth inhibition by MRTX0902, adaglazeb, and a combination of MRTX0902 and adaglazeb in mice bearing MIA PaCA-2 tumors.

FIG. 2 is a graph of tumor growth inhibition by MRTX0902, adaglazeb, and a combination of MRTX0902 and adaglazeb in mice bearing MIA PaCA-2 tumors.

FIG. 3 is a graph of tumor growth inhibition by MRTX2006, adaglazeb, and a combination of MRTX0902 and adaglazeb in mice bearing MIA PaCA-2 tumors.

FIG. 4 is a graph of tumor growth inhibition by MRTX4197, adaglazeb, and a combination of MRTX0902 and adaglazeb in mice bearing MIA PaCA-2 tumors.

Fig. 5 is a graph of tumor growth inhibition by MRTX0902, adaglazeb, and combinations of MRTX0902 and adaglazeb on LU99 tumor-bearing mice.

FIG. 6 is a graph of tumor growth inhibition by MRTX0902, adaglazeb, and combinations of MRTX0902 and adaglazeb on mice bearing NCl-H2122 tumors.

FIG. 7 is a graph of tumor growth inhibition of NCl-H2122 tumor bearing mice by MRTX0902, adaglazeb, a combination of MRTX0902 and VS-6766, and a combination of VS-6766 and adaglazeb.

Fig. 8 is a graph of tumor growth inhibition by MRTX0902, adaglazeb, and combinations of MRTX0902 and adaglazeb on mice bearing CR6256 tumors.

Fig. 9 is a bar graph demonstrating the efficacy of a combination of MRTX849 and MRTX0902 in a variety of human tumor xenograft KRas G12C models.

Detailed Description

The present invention relates to combination therapies for the treatment of KRas G12C cancer. In particular, the present invention relates to a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a SOS1 inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in combination with KRas G12C inhibitor adaglazeb, or a pharmaceutically acceptable salt or pharmaceutical composition thereof; pharmaceutical compositions comprising a therapeutically effective amount of an inhibitor, kits comprising the compositions, and methods of use thereof.

The combination of the SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and the KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition synergistically increases the efficacy of the KRas G12C inhibitor compound adaglazeb against KRas G12C expressing cancer cells, thereby increasing the efficacy and therapeutic index of the KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt thereof.

Definition of the definition

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

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

As used herein, "KRas G12C inhibitor" refers to a compound of the invention represented by formula (I), formula I-a, and formula I-B as described in WO2019099524, or a pharmaceutically acceptable salt thereof (e.g., example No. 234, 359, 478, or 507, or a pharmaceutically acceptable salt thereof). These compounds are capable of down-regulating or inhibiting all or a portion of the enzymatic activity of KRas G12C. The KRas G12C inhibitors of the invention interact with KRas G12C by forming covalent adducts with the sulfhydryl side chain of the cysteine residue at position 12 and bind irreversibly thereto, resulting in inhibition of the enzymatic activity of KRas G12C. Adaglazeb is an example of a KRas G12C inhibitor,

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

As used herein, "SOS1" refers to the Son of sevenless homolog 1 protein encoded by the SOS1 gene involved in signaling through the RAS pathway.

As used herein, "SOS1 inhibitor" refers to a compound capable of down-regulating or inhibiting all or a portion of the interaction between KRAS and SOS 1.

The term "subject" or "patient" as used herein interchangeably refers to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the 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., as determined using regulatory agency approved, e.g., FDA approved, assays or kits). In some embodiments, the subject has a tumor positive for the KRas G12C mutation (e.g., determined using regulatory agency approved assays or kits). The subject may be a subject having one or more tumors that are positive for the KRas G12C mutation (e.g., positive using regulatory agency approved, e.g., FDA approved, assays or kit identification). The subject may be a subject whose tumor has a KRas G12C mutation (e.g., wherein the tumor is identified using a regulatory agency 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 a clinical record indicative of: the subject has a tumor with a KRas G12C mutation (and optionally, a clinical record indicates that the subject should be treated with any of the compositions provided herein).

The term "pediatric patient" as used herein refers to a patient less than 16 years of age at the time of diagnosis or treatment. The term "pediatric" may be further divided into various subgroups, including: neonates (first month from birth to life); infants (1 month up to two years); children (two years up to 12 years); and teenagers (12 to 21 years old (up to but not including the twenty-second year of birth)). Berhman RE, kliegman R, arvin AM, nelson WE., nelson science (Nelson Textbook of Pediatrics), 15 th edition, philadelphia (Philadelphia): W.B. Mordes Company (W.B. Saunders Company), 1996; rudolph AM et al, rudolph's Pediatrics, 21 st edition, new York (New York): mcGraw-Hill, 2002; and Avery MD, first LR., "pediatric medicine (Pediatric Medicine), 2 nd edition, barlmo: williams Wilkins (Williams & Wilkins); 1994.

in some embodiments of any of the methods or uses described herein, an assay for determining whether a patient has a KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample (such as a paraffin embedded biopsy sample)) from a patient (e.g., a patient suspected of having KRas G12C-related cancer, a patient having one or more symptoms of KRas G12C-related cancer, and/or a patient with an increased risk of having KRas G12C-related cancer), which may include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, split 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) is used. As is well known in the art, analysis is typically performed, for example, with at least one labeled nucleic acid probe or at least one labeled antibody or antigen binding fragment thereof.

The term "regulatory agency" is a national agency approving the medical use of pharmaceutical agents in the country. For example, a non-limiting example of a regulatory agency is the U.S. food and drug administration (U.S. food and Drug Administration, FDA).

As used herein, an "effective amount" of a compound is an amount sufficient to down-regulate or inhibit the activity of a desired target, i.e., SOS1 or KRas G12C. The amount may be administered in a single dosage form or may be administered according to a regimen whereby it is effective.

As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to ameliorate or somehow reduce symptoms, or stop or reverse exacerbation of a condition, or down regulate or inhibit the activity of SOS1 or KRas G12C. The amount may be administered in a single dosage form or may be administered according to a regimen whereby it is effective.

As used herein, a "therapeutically effective amount" of a combination of two compounds is an amount that together synergistically increases the activity of the combination (i.e., not just the additive effect) compared to the therapeutically effective amount of each compound in the combination. Alternatively, in vivo, a combination of a therapeutically effective amount of a SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof causes an increase in the overall survival ("OS") duration of the subject relative to treatment with the KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and an inhibitor compound of formula KRas G12C, adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an extended progression free survival ("PFS") duration in a subject relative to treatment with the KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof causes increased tumor regression in a subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof causes an increase in tumor growth inhibition in a subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof causes an increase in the duration of disease stabilization in a subject as compared to treatment with a KRas G12C inhibitor alone. The amount of each compound in the combination may be the same or different from the therapeutically effective amount of each compound when administered alone as a monotherapy, so long as the combination has a synergistic effect. The amount may be administered in a single dosage form or may be administered according to a regimen whereby it is effective.

As used herein, "treating" means any manner in which the symptoms or pathology of a condition, disorder or disease is ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.

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

As used herein, the term "about" when used to modify a numerically defined parameter (e.g., the dosage of a KRas inhibitor or SOS1 inhibitor or a pharmaceutically acceptable salt thereof, or the duration of treatment with a combination therapy described herein) means that the degree of change in the parameter may be as low as or as high as 10% from the stated value for the parameter. For example, a dose of about 5mg/kg may vary between 4.5mg/kg and 5.5 mg/kg. "about" when used at the beginning of a parameter list is intended to modify each parameter. For example, about 0.5mg, 0.75mg, or 1.0mg means about 0.5mg, about 0.75mg, or about 1.0mg. Also, 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.

KRAS G12C inhibitor compounds

In one aspect of the invention, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a SOS1 inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in combination with the KRas G12C inhibitor compound adaglazeb, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

In one embodiment, the KRas G12C inhibitor is:

(also known as adaglazeb, MRTX849 and example 478 in WO 2019099524) or a pharmaceutically acceptable salt thereof.

The KRas G12C inhibitors used in the methods of the present invention may have one or more chiral centers and may be synthesized as a stereoisomeric mixture, i.e., isomers that constitute the same, spatially diverse arrangements of atoms. The compounds may be used as mixtures, or the individual components/isomers may be prepared according to manufacturer's instructions using commercially available reagents and conventional methods for separating stereoisomers and enantiomers, as known to those skilled in the art, e.g., using(Sigma-Aldrich) or +.>Chiral chromatographic HPLC column (celluloid Corp). Alternatively, the compounds of the invention may be synthesized using optically pure chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Unless otherwise indicated, whenever the specification including the claims refers to a compound of the present invention, the term "compound" is understood to encompass all chiral (enantiomeric and diastereomeric) and racemic forms.

In one embodiment, the KRas G12C inhibitor compound adagranib used in the method includes salts of the above compounds, for example salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, salts 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 amines of the formula —nr+z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, — O-alkyl, tosylate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzoate, and diphenylacetate).

Methods for making the KRas G12C inhibitors disclosed herein are known. For example, commonly owned published International PCT application Nos. WO2017201161 and WO 2019099524 describe general reaction schemes for the preparation of compounds including adaglazepine, and also provide detailed synthetic routes for the preparation of these compounds.

SOS1 inhibitor compounds

In one embodiment, the SOS1 inhibitor is a compound selected from the group consisting of: (R) -2-methyl-3- (1- ((4-methyl-7-morpholinopyridazin-1-yl) amino) ethyl) benzonitrile, 3- ((R) -1- ((7- ((S) -hexahydropyrazine [2,1-c ] [1,4] oxazin-8 (1H) -yl) -4-methylpyridazin-1-yl) amino) ethyl) -2-methylbenzonitrile, (R) -3- (1- ((7- (3- (dimethylamino) -3-methylazetidin-1-yl) -4-methylpyridazin-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-methylpyridazin-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-methylpyridazo [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 pharmaceutically acceptable salt thereof; or selected from the compounds described in U.S. provisional patent applications 62/951,812, 62/975,645, 63/044,802, 62/980,790 and 63/057,563 (and corresponding international applications and publications, including PCT/US20/06603 and US17/127,582) as described in more detail herein.

In another embodiment, the SOS1 inhibitor is BI1701963.

In another embodiment, the SOS1 inhibitor is a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: r is R ¹ Is hydrogen, hydroxy, C1-C6 alkyl, alkoxy, -N (R) ⁶ ) ₂ 、-NR ⁶ C(O)R ⁶ 、-C(O)N(R ⁶ ) ₂ 、-SO ₂ Alkyl, -SO ₂ NR ⁶ Alkyl, cycloalkyl, -Q-heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more R ² Substitution; each Q is independently a bond, O or NR ⁶ The method comprises the steps of carrying out a first treatment on the surface of the X is N or CR ⁷ The method comprises the steps of carrying out a first treatment on the surface of the Each R ² Independently is hydroxy, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, -N (R) ⁶ ) ₂ 、-SO ₂ Alkyl, -NR ⁶ C (O) C1-C3 alkyl, -C (O) cycloalkyl, -C (O) heterocyclyl or aryl, wherein cycloalkyl, heterocyclyl or aryl are each optionally substituted with one or more R ¹¹ Substitution; r is R ³ Is hydrogen, C1-C6 alkyl, alkoxy, -N (R) ¹⁰ ) ₂ Cycloalkyl, haloalkyl, heterocyclyl, aryl or heteroaryl, wherein C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more R ⁹ Substitution; y is a bond or heteroarylene; r is R ⁴ Is aryl or heteroaryl, each optionally substituted with one or more R ⁵ Substitution; each R ⁵ Independently is hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C3 alkyl, haloalkyl, -N (R) ⁶ ) ₂ 、-L-N(R ⁶ ) ₂ or-SO ₂ An alkyl group; l is a C1-C3 alkylene group; each R ⁶ Independently hydrogen, C1-C3 alkyl, haloalkyl or cycloalkyl; r is R ⁷ Is hydrogen, cyano or alkoxy; r is R ⁸ Is C1-C2 alkyl or halo-C1-C2 alkyl; each R ⁹ Independently is hydroxy, halogen, amino, cyano, alkoxy or C1-C3 alkyl; each R ¹⁰ Independently hydrogen, C1-C3 alkyl or cycloalkyl; and each R ¹¹ Independently is a C1-C3 alkyl or haloalkyl. These compounds include, but are not limited to, compounds such as:

/>

and pharmaceutically acceptable salts thereof.

In another embodiment, the SOS1 inhibitor is a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: r is R ¹ Is hydrogen, hydroxy, C1-C6 alkyl, alkoxy, -N (R) ⁶ ) ₂ 、-NR ⁶ C(O)R ⁶ 、-C(O)N(R ⁶ ) ₂ 、-SO ₂ Alkyl, -SO ₂ NR ⁶ Alkyl, cycloalkyl, -Q-heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more R ² Substitution; each Q is independently a bond or O; x is N or CR ⁷ The method comprises the steps of carrying out a first treatment on the surface of the Each R ² Independently is hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, -N (R) ⁶ ) ₂ 、-SO ₂ Alkyl, -NR ⁶ C(O)R ⁶ C1-C3 alkyl, haloalkyl, cycloalkyl or aryl; r is R ³ Is hydrogen, halogen, cyano, C1-C6 alkyl, alkoxy, -N (R) ¹⁰ ) ₂ 、-NR ¹⁰ C(O)NR ¹⁰ 、-C(O)N(R ¹⁰ ) ₂ 、-SO ₂ Alkyl, -SO ₂ NR ¹⁰ Alkyl, -SO ₂ N(R ¹⁰ ) ₂ Cycloalkyl, haloalkyl, heterocyclyl, aryl or heteroaryl, wherein C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more R ⁹ Substitution; y is a bond or heteroarylene; r is R ⁴ Is aryl or heteroaryl, each optionally substituted with one or more R ⁵ Substitution; each R ⁵ Independently is hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C3 alkyl, haloalkyl or-L-N (R) ⁶ ) ₂ The method comprises the steps of carrying out a first treatment on the surface of the L is a C1-C3 alkylene group; each R ⁶ Independently hydrogen, C1-C3 alkyl or cycloalkyl; r is R ⁷ Is hydrogen or alkoxy; r is R ⁸ Is a C1-C2 alkaneA group or halo-C1-C2 alkyl; each R ⁹ Independently is hydroxy, halogen, amino, cyano, alkoxy or C1-C6 alkyl; each R ¹⁰ Independently hydrogen, C1-C3 alkyl or cycloalkyl; and R is ¹¹ Is hydrogen, C1-C3 alkyl, cycloalkyl or haloalkyl. These compounds include, but are not limited to, compounds such as:

and pharmaceutically acceptable salts thereof.

In another embodiment, the SOS1 inhibitor is a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein R ¹ Is hydrogen, hydroxy, C1-C6 alkyl, alkoxy, -N (R) ⁶ ) ₂ 、-NR ⁶ C(O)R ⁶ 、-C(O)N(R ⁶ ) ₂ 、-SO ₂ Alkyl, -SO ₂ NR ⁶ Alkyl, cycloalkyl, -Q-heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with one or more R ² Substitution; each Q is independently a bond, O or NR ⁶ The method comprises the steps of carrying out a first treatment on the surface of the X is N or CR ⁷ The method comprises the steps of carrying out a first treatment on the surface of the Provided that when X is N, R ¹ Not hydroxy; each R ² Independently is hydroxy, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, -N (R) ⁶ ) ₂ 、-SO ₂ Alkyl, -NR ⁶ C (O) C1-C3 alkyl, -C (O) cycloalkyl, -C (O) heterocyclyl or aryl, wherein cycloalkyl, heterocyclyl or aryl are each optionally substituted with one or more R ⁹ Substitution; r is R ³ Is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl or cycloalkyl; y is a bond or heteroarylene; r is R ⁴ Is aryl or heteroaryl, each optionally substituted with one or more R ⁵ Substitution; each R ⁵ Independently is hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C4 alkyl, haloalkyl, -N (R) ⁶ ) ₂ 、-L-N(R ⁶ ) ₂ or-SO ₂ An alkyl group; l is a C1-C3 alkylene group; each R ⁶ Independently hydrogen, C1-C3 alkyl, haloalkyl or cycloalkyl; r is R ⁷ Is hydrogen, cyano or alkoxy; r is R ⁸ Is C1-C2 alkyl or halo-C1-C2 alkyl; and each R ⁹ Independently is a C1-C3 alkyl or haloalkyl. These compounds include, but are not limited to, compounds such as:

and pharmaceutically acceptable salts thereof.

In another embodiment, the SOS1 inhibitor is a compound selected from the group consisting of:

3- ((R) -1- ((7- ((S) -hexahydropyrazine [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, and

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

(R) -3- (1- ((6-fluoro-4-methyl-7- (4-methylpiperazin-1-yl) phthalazin-1-yl) amino) ethyl) -2-methylbenzonitrile and pharmaceutically acceptable salts thereof.

SOS1 inhibitors used in the methods of the invention may have one or more chiral centers and may be synthesized as stereoisomeric mixtures, i.e., isomers that constitute the same, spatially diverse arrangements of atoms. The compounds may be used as mixtures, or the individual components/isomers may be used according to manufacturer's instructions for separation of stereoisomers as is well known to those skilled in the art Commercially available reagents and conventional methods for isomers and enantiomers, for example, using(Sigma-Aldrich) or +.>Chiral chromatographic HPLC column (celluloid Corp). Alternatively, the compounds of the invention may be synthesized using optically pure chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Unless otherwise indicated, whenever the specification including the claims refers to a compound of the present invention, the term "compound" is understood to encompass all chiral (enantiomeric and diastereomeric) and racemic forms.

In one embodiment, SOS1 inhibitor compounds include salts thereof, for example salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, salts with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and polygalacturonic acid, and salts formed from quaternary amines of the formula —nr+z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, — O-alkyl, tosylate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzyl, and diphenylacetate).

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

Pharmaceutical composition

SOS1 inhibitors and KRAS G12C compound Aldaglazeb or pharmaceutically acceptable salts thereof can be formulated into pharmaceutical compositions.

In another aspect, the invention provides a pharmaceutical composition comprising an SOS1 inhibitor or a pharmaceutically acceptable salt thereof and a KRas G12C inhibitor adaglazeb or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent useful in the methods disclosed herein. The SOS1 inhibitor or pharmaceutically acceptable salt thereof and the KRas G12C inhibitor or pharmaceutically acceptable salt thereof may be formulated independently by any method well known in the art and may be 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 pharmaceutically acceptable salt thereof and the KRas G12C inhibitor or a pharmaceutically acceptable salt thereof are administered intravenously in a hospital setting. In one embodiment, administration may be by the oral route.

The vehicle characteristics will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" refers to a non-toxic material that is compatible with biological systems such as cells, cell cultures, tissues or organisms and that does not interfere with the effectiveness of the biological activity of one or more active ingredients. Thus, in addition to inhibitors, the compositions may contain diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in the university of pharmaceutical Remington's Pharmaceutical Sciences, 18 th edition, editors A. Gennaro, mark Publishing Co., easton, pa., 1990.

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

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

Pharmaceutical compositions comprising an SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof may be used in the methods of use described herein.

Co-administration of

The SOS1 inhibitor or a pharmaceutically acceptable salt thereof and the KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof may be formulated into separate or individual dosage forms which may be co-administered one after the other. Another option is that if the route of administration is the same (e.g., oral), the two active compounds may be formulated in a single form for co-administration, however, both methods of co-administration are part of the same therapeutic treatment or regimen.

The pharmaceutical composition comprising the SOS1 inhibitor or a pharmaceutically acceptable salt thereof and/or the KRas G12C inhibitor or a pharmaceutically acceptable salt thereof for use in the method may be for simultaneous, separate or sequential use. In one embodiment, the SOS1 inhibitor or a pharmaceutically acceptable salt thereof is administered prior to the administration of the KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt thereof. In another embodiment, the SOS1 inhibitor or a pharmaceutically acceptable salt thereof is administered after administration of the KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt thereof. In another embodiment, the SOS1 inhibitor or a pharmaceutically acceptable salt thereof is administered at about the same time as the KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt thereof is administered.

In some cases, it will be advantageous to administer each inhibitor separately at different times and by different routes. Thus, the components of the combination, i.e., the KRas G12C inhibitor compound adagransie or a pharmaceutically acceptable salt thereof, and the SOS1 inhibitor or a pharmaceutically acceptable salt thereof, need not necessarily be administered at substantially the same time or in any order.

Oncology drugs are typically administered at a maximum tolerated dose ("MTD"), which is the highest drug dose that does not cause unacceptable side effects. In one embodiment, the KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and the SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof are each administered at their corresponding MTD. In one embodiment, the KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered at its MTD, and the SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered in an amount less than its MTD. In one embodiment, the KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered in an amount less than its MTD, and the SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered at its MTD. In one embodiment, the KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and the SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof are each administered at less than their corresponding MTD. Administration may be timed such that the peak pharmacokinetic effect of one compound is consistent with the peak pharmacokinetic effect of another compound.

In one embodiment, a single dose of the KRas G12C inhibitor compound adaglazeb or pharmaceutically acceptable salt or pharmaceutical composition thereof is administered daily (i.e., at about 24 hour intervals) (i.e., QDs). In another embodiment, the two doses of the KRas G12C inhibitor compound adaglazeb or pharmaceutically acceptable salt or pharmaceutical composition thereof are administered daily (i.e., BID). In another embodiment, three doses of the KRas G12C inhibitor compound adaglazeb or pharmaceutically acceptable salt or pharmaceutical composition thereof are administered daily (i.e., TID).

In one embodiment, the SOS1 inhibitor or pharmaceutically acceptable salt or pharmaceutical composition thereof is QD administration. In another embodiment, the SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is BID administration. In another embodiment, the SOS1 inhibitor of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered as TID.

In one embodiment, a single dose of the KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof and the SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof are each administered once daily.

Examples of SOS1 inhibitors suitable for use in the provided compositions and methods include those mentioned herein, such as (R) -2-methyl-3- (1- ((4-methyl-7-morpholinopyridao [3,4-d ] pyridazin-1-yl) amino) ethyl) benzonitrile, 3- ((R) -1- ((7- ((S) -hexahydropyrazin [2,1-c ] [1,4] oxazin-8 (1H) -yl) -4-methylpyridazin-1-yl) amino) ethyl) -2-methylbenzonitrile, (R) -3- (1- ((7- (3- (dimethylamino) -3-methylazetidin-1-yl) -4-methylpyridazin-1-yl) amino) ethyl) -2-methylbenzonitrile, (R) -2-methyl-3- (1- ((4-methyl-7- (4-methylpiperazin-1-yl) pyrido-1-yl) amino) ethyl) benzonitrile, (R) -3- (1- ((7- (4-ethylpiperazin-1-yl) -4-methylpyridazin-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-methylpyridazo [3,4-d ] pyridazin-1-yl) amino) ethyl) -2-methylbenzonitrile and (R) -3- (1- ((6-fluoro-4-methyl-7- (4-methylpiperazin-1-yl) amino) ethyl) -2-methylbenzonitrile,

or a pharmaceutically acceptable salt thereof or an SOS1 inhibitor such as BI1701963.

Combination therapy

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 SOS1 inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in combination with the KRasKRas G12C inhibitor compound adaxazepine, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In one embodiment, the cancer is a KRas G12C-associated cancer. In one embodiment, the KRas G12C-associated cancer is lung cancer.

or a pharmaceutically acceptable salt thereof, and an SOS1 inhibitor.

In one embodiment, the SOS1 inhibitor has the following structure:

or a pharmaceutically acceptable salt thereof.

In yet another aspect, the invention provides a method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor, the method comprising contacting the cancer cell with an effective amount of the KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof in combination with a SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor. In one embodiment, the contacting is performed ex vivo. In one embodiment, the contacting is performed in vivo. In one embodiment, the method comprises administering to a subject undergoing KRas G12C treatment an effective amount of a combination of the KRas G12C inhibitor adaglazeb or a pharmaceutically acceptable salt thereof and an SOS1 inhibitor, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cells to the KRas G12C inhibitor.

or a pharmaceutically acceptable salt thereof.

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

(adaglazeb) or a pharmaceutically acceptable salt thereof in combination with an SOS1 inhibitor.

In one such embodiment, the SOS1 inhibitor is:

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

In another such embodiment, the SOS1 inhibitor is:

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

In yet another such embodiment, the SOS1 inhibitor is:

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

In yet another such embodiment, the SOS1 inhibitor is:

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

In another embodiment, the SOS1 inhibitor is:

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

In another embodiment, the SOS1 inhibitor is:

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

In another embodiment, the SOS1 inhibitor is:

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

In another embodiment, the SOS1 inhibitor is:

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

In yet another embodiment, the SOS1 inhibitor is BI1701963.

In yet another embodiment, the invention provides a therapeutically effective combination of:

SOS1 inhibitors of the formula (R) -2-methyl-3- (1- ((4-methyl-7-morpholinopyrimido [3, 4-d)]Pyridazin-1-yl) amino) ethyl) benzonitrile (also known as MRTX 0902):or a pharmaceutically acceptable salt thereof

In another embodiment, the invention provides a therapeutically effective combination of:

or a pharmaceutically acceptable salt thereof,

Or a pharmaceutically acceptable salt thereof.

The term "contacting" as used herein refers to bringing together designated portions of an in vitro system or an in vivo system. For example, "contacting" cancer cells includes administering a combination provided herein to an individual, e.g., a human, having KRas G12C, and, e.g., introducing a combination provided herein into a sample containing KRas G12C-containing cells or a purified preparation.

By down regulating KRas G12C activity, the methods described herein are designed to inhibit undesired cell proliferation resulting from enhanced KRas G12C activity within the cell. The extent of covalent modification of KRas G12C can be monitored in vitro using well known methods including those described in published international PCT applications nos. WO2017201161 and WO 2019099524. In addition, the inhibitory activity of the combination in the cell may be monitored, for example, by measuring the inhibition of KRas G12C activity by an amount of phosphorylated ERK to assess the effectiveness of the treatment, and thus the dose may be adjusted by the attending physician.

The compositions and methods provided herein can be used to treat KRas G12C-related cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SOS1 inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in combination with a KRas G12C inhibitor compound adaglazepan or a pharmaceutically acceptable salt thereof or a pharmaceutical composition, wherein the SOS1 inhibitor synergistically increases the sensitivity of the KRas G12C-related cancer to the KRas G12C inhibitor. In one embodiment, the KRas G12C-associated cancer is lung cancer.

In one embodiment, a combination of a therapeutically effective amount of an SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and an inhibitor compound of formula KRas G12C, adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an overall survival ("OS") duration of the subject that is prolonged relative to treatment with the KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and an inhibitor compound of formula KRas G12C, adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an extended progression free survival ("PFS") duration in a subject relative to treatment with the KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof causes increased tumor regression in a subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof causes an increase in tumor growth inhibition in a subject relative to treatment with a KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof results in an extended duration of disease stabilization in a subject as compared to treatment with the KRas G12C inhibitor adaglazeb alone. In one embodiment, the SOS1 inhibitor is selected from (R) -2-methyl-3- (1- ((4-methyl-7-morpholinopyridazin-1-yl) amino) ethyl) benzonitrile, 3- ((R) -1- ((7- ((S) -hexahydropyrazin [2,1-c ] [1,4] oxazin-8 (1H) -yl) -4-methylpyridazo [3,4-d ] pyridazin-1-yl) amino) ethyl) -2-methylbenzonitrile, (R) -3- (1- ((7- (3- (dimethylamino) -3-methylazetidin-1-yl) -4-methylpyridazo [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-methylpyridazin-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-methylpyridazo [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 pharmaceutically acceptable salt thereof. In another embodiment, the SOS1 inhibitor is BI1701963.

In another embodiment, for KRas G12C monotherapy, once disease progression has been observed, SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered in combination with KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the combination therapy causes an increase in clinical benefit in the patient by extending OS, extending PFS, increasing tumor regression, increasing tumor growth inhibition, or extending the duration of disease stabilization in the patient. In one embodiment, the KRas G12C inhibitor is a compound selected from compounds No. 1-678 (numbered in WO 2019099524) or a pharmaceutically acceptable salt thereof (e.g., example No. 234, 359, 478, or 507 or a pharmaceutically acceptable salt thereof).

In one embodiment, the SOS1 inhibitor is selected from (R) -2-methyl-3- (1- ((4-methyl-7-morpholinopyridazin-1-yl) amino) ethyl) benzonitrile, 3- ((R) -1- ((7- ((S) -hexahydropyrazin [2,1-c ] [1,4] oxazin-8 (1H) -yl) -4-methylpyridazo [3,4-d ] pyridazin-1-yl) amino) ethyl) -2-methylbenzonitrile, (R) -3- (1- ((7- (3- (dimethylamino) -3-methylazetidin-1-yl) -4-methylpyridazo [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-methylpyridazin-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-methylpyridazo [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 pharmaceutically acceptable salt thereof. In another embodiment, the SOS1 inhibitor is BI1701963.

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

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

In another embodiment, the therapeutic combination comprises a therapeutically effective amount of adaglazepan 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 pharmaceutically acceptable salt thereof.

In another embodiment, the therapeutic combination comprises a therapeutically effective amount of adaglazeb 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 pharmaceutically acceptable salt thereof.

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

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

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

In another embodiment, the therapeutic combination comprises a therapeutically effective amount of adaglazeb and (R) -3- (1- ((6-fluoro-4-methyl-7- (4-methylpiperazin-1-yl) phthalazin-1-yl) amino) ethyl) -2-methylbenzonitrile or a pharmaceutically acceptable salt thereof.

In another embodiment, the therapeutic combination comprises a therapeutically effective amount of adaglazeb and the SOS1 inhibitor is BI1701963.

The compositions and methods provided herein are useful for treating a wide variety of cancers, including tumors, such as lung tumors, colorectal tumors, pancreatic tumors, prostate tumors, breast tumors, brain tumors, skin tumors, cervical cancer, testicular cancer, and the like. More specifically, cancers treatable by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytes, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocytes, laryngeal, pulmonary, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds are useful in the treatment of: and (3) heart: sarcomas (hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromisstructured tumor, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagon tumor, gastrinoma, carcinoid tumor, schuz bowel peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); urogenital 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, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gall bladder cancer, ampulla cancer, bile duct cancer; bone: osteogenic sarcomas (osteosarcoma), fibrosarcomas, malignant fibrous histiocytomas, chondrosarcomas, ewing's sarcoma, malignant lymphomas (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondral tumors (osteochondral exotoses), benign chondrias, chondroblastomas, chondromucoid fibromas, osteoid osteomas and giant cell tumors; the nervous system: skull (bone tumor, hemangioma, granuloma, xanthoma, malformed osteomyelitis), meninges (meningioma, glioblastoma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); gynaecology: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-neoplastic cervical dysplasia), ovary (ovarian carcinoma (serous cystic adenocarcinoma, mucinous cystic adenocarcinoma, unclassified carcinoma), granulosa cell carcinoma, support-stromal cell carcinoma, anaplastic cell carcinoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative diseases, 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, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloids, psoriasis, and adrenal gland neuroblastoma in certain embodiments, cancer is non-small cell lung carcinoma.

Also provided herein are methods for treating cancer in a subject in need thereof, the methods comprising: (a) Determining that the cancer is associated with a KRas G12C mutation (e.g., KRas G12C-associated cancer) (e.g., determined using regulatory agency-approved (e.g., FDA-approved) assays or kits); and (b) administering to the patient a therapeutically effective amount of a combination of a SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the SOS1 inhibitor synergistically increases the sensitivity of the KRas G12C-related cancer to the KRas G12C inhibitor. In one embodiment, the KRas G12C inhibitor is a compound selected from compounds No. 1-678 (as numbered in WO 2019099524) or a pharmaceutically acceptable salt thereof (e.g., one of embodiments No. 234, 359, 478, or 507 or a pharmaceutically acceptable salt thereof). In one embodiment, the SOS1 inhibitor is selected from the group consisting of: (R) -2-methyl-3- (1- ((4-methyl-7-morpholinopyridazin-1-yl) amino) ethyl) benzonitrile, 3- ((R) -1- ((7- ((S) -hexahydropyrazine [2,1-c ] [1,4] oxazin-8 (1H) -yl) -4-methylpyridazin-1-yl) amino) ethyl) -2-methylbenzonitrile, (R) -3- (1- ((7- (3- (dimethylamino) -3-methylazetidin-1-yl) -4-methylpyridazin-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-methylpyridazin-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-methylpyridazo [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 pharmaceutically acceptable salt thereof; or SOS1 inhibitor is BI1701963.

In one embodiment, the therapeutic combination comprises a therapeutically effective amount of (R) -2-methyl-3- (1- ((4-methyl-7-morpholinopyridazin-1-yl) amino) ethyl) benzonitrile, or a pharmaceutically acceptable salt thereof.

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

In further embodiments, 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 pharmaceutically acceptable salt thereof.

In further embodiments, 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 pharmaceutically acceptable salt thereof.

In further embodiments, 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 pharmaceutically acceptable salt thereof.

In further embodiments, 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 pharmaceutically acceptable salt thereof.

In further embodiments, 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 pharmaceutically acceptable salt thereof.

In further embodiments, 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 pharmaceutically acceptable salt thereof.

In further embodiments, the therapeutic combination comprises a therapeutically effective amount of BI1701963.

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

In one embodiment, the SOS1 compound is administered orally in the following amounts: about 20mg to about 500mg (e.g., about 20mg to about 480mg, about 20mg to about 460mg, about 20mg to about 440mg, about 20mg to about 420mg, about 20mg to about 400mg, about 20mg to about 380mg, about 20mg to about 360mg, about 20mg to about 340mg, about 20mg to about 320mg, about 20mg to about 300mg, about 20mg to about 280mg, about 20mg to about 260mg, about 20mg to about 240mg, about 20mg to about 220mg, about 20mg to about 200mg, about 20mg to about 180mg, about 20mg to about 160mg, about 20mg to about 140mg, about 20mg to about 120mg, about 20mg to about 100mg, about 20mg to about 80mg about 20mg to about 60mg, about 20mg to about 40mg, about 40mg to about 500mg, about 40mg to about 480mg, about 40mg to about 460mg, about 40mg to about 440mg, about 40mg to about 420mg, about 40mg to about 400mg, about 40mg to about 380mg, about 40mg to about 360mg, about 40mg to about 340mg, about 40mg to about 320mg, about 40mg to about 300mg, about 40mg to about 280mg, about 40mg to about 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 20mg to about 60mg, about 20mg to about 40mg, about 40mg to about 500mg, about 40mg to about 480mg, about 40mg to about 460mg, about 40mg to about 440mg, about 40mg to about 420mg, about 40mg to about 400mg, about 40mg to about 380mg, about 40mg to about 360mg, about 40mg to about 340mg about 40mg to about 320mg, about 40mg to about 300mg, about 40mg to about 280mg, about 40mg to about 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 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 100mg 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

180mg, about 120mg to about 160mg, 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 180mg, 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 220mg 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 500mg, 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 340mg 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 400mg to about 440mg, about 400mg to about 420mg, about 420mg to about 500mg, about 420mg to about 480mg, about 420mg to about 460mg, about 420mg to about 440mg, about 440mg to about 500mg, about 440mg to about 480mg, about 440mg to about 460mg, about 460mg to about 500mg, about 460mg to about 480mg, about 480mg to about 500mg, about 25mg, about 50mg, about 75mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, or about 500 mg) for a certain period of time. In one embodiment, the SOS1 compound is administered orally twice a day (BID) on a daily basis during a period of time. In one embodiment, adaglazeb is administered orally twice a day (BID) on a daily basis during a period of time.

In one embodiment, the combination therapy comprises orally administering adaglazeb (during a period of time) on a daily basis, for example, once or twice a day, in the following amounts: about 10mg to about 400mg (e.g., about 10mg to about 380mg, about 10mg to about 360mg, about 10mg to about 340mg, about 10mg to about 320mg, about 10mg to about 300mg, about 10mg to about 280mg, about 10mg to about 260mg, about 10mg to about 240mg, about 10mg to about 220mg, about 10mg to about 200mg, about 10mg to about 180mg, about 10mg to about 160mg, about 10mg to about 140mg, about 10mg to about 120mg, about 10mg to about 100mg, about 10mg to about 80mg, about 10mg to about 60mg, about 10mg to about 40mg, about 10mg to about 20mg, about 20mg to about 400mg, about 20mg to about 380mg about 20mg to about 360mg, about 20mg to about 340mg, about 20mg to about 320mg, about 20mg to about 300mg, about 20mg to about 280mg, about 20mg to about 260mg, about 20mg to about 240mg, about 20mg to about 220mg, about 20mg to about 200mg, about 20mg to about 180mg, about 20mg to about 160mg, about 20mg to about 140mg, about 20mg to about 120mg, about 20mg to about 100mg, about 20mg to about 80mg, about 20mg to about 60mg, about 20mg to about 40mg, about 40mg to about 400mg, about 40mg to about 380mg, about 40mg to about 360mg, about 40mg to about 340mg about 20mg to about 360mg, about 20mg to about 340mg, about 20mg to about 320mg, about 20mg to about 300mg, about 20mg to about 280mg, about 20mg to about 260mg, about 20mg to about 240mg, about 20mg to about 220mg, about 20mg to about 200mg, about 20mg to about 180mg, about 20mg to about 160mg about 20mg to about 140mg, about 20mg to about 120mg, about 20mg to about 100mg, about 20mg to about 80mg, about 20mg to about 60mg, about 20mg to about 40mg, about 40mg to about 400mg, about 40mg to about 380mg, about 40mg to about 360mg, about 40mg to about 340mg, 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 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 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 400mg, about 160mg to about

380mg, about 160mg to about 360mg

340mg, about 160mg to about 320mg, about 160mg to about 300mg, about 160mg to about

280mg, about 160mg to about 260mg, about 160mg to about 240mg, about 160mg to about

220mg, about 160mg to about 200mg, about 160mg to about 180mg, about 180mg to about

400mg, about 180mg to about 380mg, about 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 400mg, about 200mg to about

400mg, about 220mg to about 380mg, about 220mg to about 360mg, about 220mg to about

340mg, about 220mg to about 320mg, about 220mg to about 300mg, about 220mg to about

280mg, about 220mg to about 260mg, about 220mg to about 240mg, about 240mg to about

400mg, about 240mg to about 380mg, about 240mg to about 360mg, about 240mg to about 340mg, about 240mg to about 320mg, about 240mg to about 300mg, about 240mg to about 280mg, about 240mg to about 260mg, about 260mg to about 400mg, about 260mg to about 380mg, about 260mg to about 360mg, about 260mg to about 340mg, about 260mg to about 320mg, about 260mg to about 300mg, 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 to about 380mg, about 300mg to about 360mg, about 300mg to about 340mg, about 300mg to about 320mg, about 320mg to about 400mg, about 320mg to about 380mg, about 320mg to about 360mg, about 340mg to about 400mg, about 340mg to about 380mg, about 340mg to about 360mg, about 360mg to about 400mg, about 360mg to about 380mg, about 380mg to about 400mg, about 100mg, about 200mg, about 300 or about 400 mg) orally administering a SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, it is administered once a day (during a period of time) on a daily basis. In one embodiment, the KRas G12C inhibitor adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered orally once daily. In another embodiment, the KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered orally twice daily.

Those of skill in the art will recognize that both in vivo and in vitro assays using suitable, known and commonly accepted cell and/or animal models predict the ability of the test compound of the combination or the combination to treat or prevent a given disorder.

Those of skill in the art will further recognize that human clinical trials, including first human trials, dose ranges and efficacy trials, may be completed in healthy patients and/or patients suffering from established conditions according to methods well known in the clinical and medical arts.

Synergistic effect

In one embodiment, the addition of the SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof synergistically increases the activity of the KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof against KRas G12C expressing cancer cells or cancer cell lines. Any method for determining whether two compounds exhibit synergy may be used to determine the synergy of the combination.

Several mathematical models have been developed to determine whether two compounds act synergistically, i.e. not just additive. For example, the Loewe addition model (Loewe (1928); physiology (physiol.)) 27:47-187, the Bliss independent model (Bliss (1939); applied biology annual book (Ann. Appl. Biol.)) 26:585-615, the highest single agent model (Highest Single Agent), the ZIP model (Yadav et al, (2015); journal of computing and structural biotechnology (Comput Struct Biotech J); 13:504-513), and other models (Chou and Talalay, (1984); enzyme regulatory progress (Adv Enzyme Regul); 22:27-55.# 6382953), and Greco et al, (1995); pharmacological review (Phacol Rev); 47 (2); 331-85.# 7568331) are well known models in the pharmaceutical industry and can be used to compute a "synergy score" indicating whether synergy is detected or not and the magnitude of the synergy. Combining these synergy scores results in a combined synergy score that can be used to evaluate and characterize the KRas G12C inhibitor compound adaglazeb in combination with the SOS1 inhibitor.

In general, the mathematical model uses data obtained from a single agent value to determine a predicted additive effect of the combination compared to the observed effect of the combination. If the observed effect is greater than the predicted effect, the combination is considered synergistic. For example, the BLISS independent model will observe a combined response (Y _O ) Combined response with prediction (Y _P ) The predicted combined response was obtained based on the assumption that drug-drug interactions were not affected. In general, if Y _O Greater than Y _P The combined effect is shown to be synergistic.

In some embodiments, "synergistic effect" as used herein refers to the effect produced by a combination of a KRasKRas inhibitor or a pharmaceutically acceptable salt thereof and a SOS1 inhibitor or a pharmaceutically acceptable salt thereof, e.g., any one of the beneficial or desired results, including clinical results or endpoints as described herein, that is greater than the sum of the effects observed when a compound (such as a compound described in WO2019099524 numbered 1-678, e.g., adaglazecloth) is administered alone with the SOS1 inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the KRas G12C inhibitor is adaglazeb (example 478 in MRTX-849, wo 2019099524) or a pharmaceutically acceptable salt thereof. In one embodiment, the SOS1 inhibitor is selected from (R) -2-methyl-3- (1- ((4-methyl-7-morpholinopyridazin-1-yl) amino) ethyl) benzonitrile, 3- ((R) -1- ((7- ((S) -hexahydropyrazin [2,1-c ] [1,4] oxazin-8 (1H) -yl) -4-methylpyridazo [3,4-d ] pyridazin-1-yl) amino) ethyl) -2-methylbenzonitrile, (R) -3- (1- ((7- (3- (dimethylamino) -3-methylazetidin-1-yl) -4-methylpyridazo [3,4-d ] pyridazin-1-yl) amino) ethyl) -2-methylbenzonitrile, (R) -2-methyl-3- (1- ((4-methyl-7- (4-methylpiperazin-1-yl) pyrido [3,4-d ] pyridazin-1-yl) amino) ethyl) benzonitrile, (R) -3- (1- ((6-fluoro-4-methyl-7- (4-methylpiperazin-1-yl) phthalazin-1-yl) amino) ethyl) -2-methylbenzonitrile, or a pharmaceutically acceptable salt thereof, or an SOS1 inhibitor such as BI1701963.

In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of (R) -2-methyl-3- (1- ((4-methyl-7-morpholinopyridao [3,4-d ] pyridazin-1-yl) amino) ethyl) benzonitrile and adaglazeb. In one embodiment, the synergistic therapeutic combination comprises a therapeutically effective amount of 3- ((R) -1- ((7- ((S) -hexahydropyrazine [2,1-c ] [1,4] oxazin-8 (1H) -yl) -4-methylpyrido [3,4-d ] pyridazin-1-yl) amino) ethyl) -2-methylbenzonitrile and adaglazecloth. 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 adaglazecloth. 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 adaglazeb. 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 adaglazeb. 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 adaglazecloth. 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 adaglazecloth. 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 adaglazeb.

In one embodiment, the therapeutic combination comprises a therapeutically effective amount of BI1701963 and adaglazeb.

In some embodiments, the methods provided herein may be such that, during a period of between 1 day and 2 years of treatment with the combination therapy (e.g., between 1 day and 22 months, between 1 day and 20 months, between 1 day and 18 months, between 1 day and 16 months, between 1 day and 14 months, between 1 day and 12 months, between 1 day and 10 months, between 1 day and 9 months, between 1 day and 8 months, between 1 day and 7 months, between 1 day and 6 months, between 1 day and 5 months, between 1 day and 4 months, between 1 day and 3 months, between 1 day and 2 months, between 1 day and 1 month, between one week and 2 years, between 1 week and 22 months, between 1 week and 20 months, between 1 week and 18 months, between 1 week and 16 months, between 1 week and 14 months, between 1 week and 12 months, between 1 week and 10 months, between 1 week and 9 months, between 1 week and 8 months, between 1 week and 2 weeks and 2 months, between 1 week and 10 weeks between 1 week and 7 months, between 1 week and 6 months, between 1 week and 5 months, between 1 week and 4 months, between 1 week and 3 months, between 1 week and 2 months, between 1 week and 1 month, between 2 weeks and 2 years, between 2 weeks and 22 months, between 2 weeks and 20 months, between 2 weeks and 18 months, between 2 weeks and 16 months, between 2 weeks and 14 months, between 2 weeks and 12 months, between 2 weeks and 10 months, between 2 weeks and 9 months, between 2 weeks and 8 months, between 2 weeks and 7 months, between 2 weeks and 6 months, between 2 weeks and 5 months, between 2 weeks and 4 months, between 2 weeks and 3 months, between 2 weeks and 2 months, between 2 weeks and 1 month, between 1 month and 2 years, between 1 month and 22 months, between 2 weeks and 10 months, between 2 weeks and 8 months, between 2 weeks and 7 months, between 2 weeks and 6 months, between 2 weeks and 4 months, between 2 weeks and 3 months, between 2 weeks and 2 months, between 1 year, between 2 weeks and 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 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 to 6 months or 2 to 5 months, 2 to 4 months, 3 to 2 years, 3 to 22 months, 3 to 20 months, 3 to 18 months, 3 to 16 months, 3 to 14 months, 3 to 12 months, 3 to 10 months, 3 to 8 months, 3 to 6 months, 4 to 2 years, 4 to 22 months, 4 to 20 months, 4 to 18 months, 4 to 16 months, 4 to 14 months, 4 to 12 months, 4 to 10 months, 4 to 6 months, 6 to 22 months, 6 to 20 months The volume of the one or more solid tumors in the patient is reduced by 1% to 99% after between 6 months and 18 months, between 6 months and 16 months, between 6 months and 14 months, between 6 months and 12 months, between 6 months and 10 months or between 6 months and 8 months (e.g., 1% to 98%, 1% to 95%, 1% to 90%, 1% to 85%, 1% to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 2% to 99%, 2% to 90%, 2% to 85%, 2% to 80%, 2% to 75%, 2% to 70%, 2% to 65%, 2% to 60%, 2% to 55%, 2% to 50%, 2% to 45%, 2% to 40%, 2% to 35%, 2% to 30%, 2% to 25%, 2% to 20%, 1% to 10%, 1% to 5%, 2% to 99%, 2% to 90%, 2% to 85%, 2% to 80%, 2% to 75%, 2% to 65%, 2% to 60%, 2% to 55%, 2% to 50%, 2% to 45%, 2% to 40%, 2% to 35%, 2% to 30%, 2% to 25%. 2% to 15%, 2% to 10%, 2% to 5%, 4% to 99%, 4% to 95%, 4% to 90%, 4% to 85%, 4% to 80%, 4% to 75%, 4% to 70%, 4% to 65%, 4% to 60%, 4% to 55%, 4% to 50%, 4% to 45%, 4% to 40%, 4% to 35%, 4% to 30%, 4% to 25%, 4% to 20%, 4% to 15%, 4% to 10%, 6% to 99%, 6% to 95%, 6% to 90%, 6% to 85%, 6% to 80%, 6% to 75%, 6% to 70%, 6% to 65%, 6% to 60%, 6% to 55%, 6% to 50%, 6% to 45%, 6% to 40% 6% to 35%, 6% to 30%, 6% to 25%, 6% to 20%, 6% to 15%, 6% to 10%, 8% to 99%, 8% to 95%, 8% to 90%, 8% to 85%, 8% to 80%, 8% to 75%, 8% to 70%, 8% to 65%, 8% to 60%, 8% to 55%, 8% to 50%, 8% to 45%, 8% to 40%, 8% to 35%, 8% to 30%, 8% to 25%, 8% to 20%, 8% to 15%, 10% to 99%, 10% to 95%, 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 10% to 15%, 15% to 99%, 15% to 95%, 10% to 99%, 10% to 95%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%. 15% to 90%, 15% to 85%, 15% to 80%, 15% to 75%, 15% to 70%, 15% to 65%, 15% to 60%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 15% to 20%, 20% to 99%, 20% to 95%, 20% to 90%, 20% to 85%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 20% to 20%, 20% to 99%, 20% to 95%, 20% to 90%, 20% to 85%, and 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 35%, 20% to 30%, 20% to 25%, 25% to 99%, 25% to 95%, 25% to 90%, 25% to 85%, 25% to 80%, 25% to 75%, 25% to 70%, 25% to 65%, 25% to 60%, and, 25% to 55%, 25% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 25% to 30%, 30% to 99%, 30% to 95%, 30% to 90%, 30% to 85%, 30% to 80%, 30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 30% to 45%, 30% to 40%, 30% to 35%, 35% to 99%, 35% to 95%, 35% to 90%, 35% to 85%, 35% to 80%, 35% to 75%, 35% to 70%, 35% to 65%, 35% to 60%, 35% to 55%, 35% to 50%, 35% to 45%, 35% to 40%, 40% to 99%, 40% to 95%, 40% to 90%, 40% to 85%, 40% to 80%, 40% to 75%, 40% to 70%, 40% to 65%, 40% to 60%, 40% to 55%, 35% to 85%, 35% to 80%, 35% to 70%, 35% and 35% to 45%. 40% to 60%, 40% to 55%, 40% to 50%, 40% to 45%, 45% to 99%, 45% to 95%, 45% to 90%, 45% to 85%, 45% to 80%, 45% to 75%, 45% to 70%, 45% to 65%, 45% to 60%, 45% to 55%, 45% to 50%, 50% to 99%, 50% to 95%, 50% to 90%, 50% to 85%, 50% to 80%, 50% to 75%, and 50% to 70%, 50% to 65%, 50% to 60%, 50% to 55%, 55% to 99%, 55% to 95%, 55% to 90%, 55% to 85%, 55% to 80%, 55% to 75%, 55% to 70%, 55% to 65%, 55% to 60%, 60% to 99%, 60% to 95%, 60% to 90%, 60% to 85%, 60% to 80%, 60% to 75%, 60% to 70%, 60% to 65%, and, 65% to 99%, 60% to 95%, 60% to 90%, 60% to 85%, 60% to 80%, 60% to 75%, 60% to 70%, 60% to 65%, 70% to 99%, 70% to 95%, 70% to 90%, 70% to 85%, 70% to 80%, 70% to 75%, 75% to 99%, 75% to 95%, 75% to 90%, 75% to 85%, 75% to 80%, 80% to 99%, 80% to 95%, 80% to 90%, 80% to 85%, 85% to 99%, 85% to 95%, 85% to 90%, 90% to 99%, 90% to 95%, or 95% to 100%) (e.g., as compared to the size of one or more solid tumors in a patient prior to treatment.

The phrase "time to live" means the period of time between the identification or diagnosis of a cancer (e.g., any of the cancers described herein) of a mammal by medical personnel and the time of death (caused by the cancer) of the mammal. Described herein are methods of prolonging survival of a mammal having cancer.

In some embodiments of the present invention, in some embodiments, any of the methods described herein can result in an increase in survival time of the patient (e.g., 1% to 400%, 1% to 380%, 1% to 360%, 1% to 340%, 1% to 320%, 1% to 300%, 1% to 280%, 1% to 260%, 1% to 240%, 1% to 220%, 1% to 200%, 1% to 180%, 1% to 160%, 1% to 140%, 1% to 120%, 1% to 100%, 1% to 95%, 1% to 90%, 1% to 85%, 1% to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 400%, 5% to 380%, 5% to 360%, 1% to 45%, 1% to 40%, 1% to 30% of the patient 5% to 340%, 5% to 320%, 5% to 300%, 5% to 280%, 5% to 260%, 5% to 240%, 5% to 220%, 5% to 200%, 5% to 180%, 5% to 160%, 5% to 140%, 5% to 120%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 10%, 10% to 400%, 10% to 380%, 10% to 360%, 10% to 340%, 10% to 320%, 10% to 300%, 10% to 280%, 10% to 260%, 10% to 240%, 10% to 220%, 10% to 200%, 10% to 180%, 10% to 160%, 10% to 140%, 10% to 120%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 360%, and the like, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 20% to 400%, 20% to 380%, 20% to 360%, 20% to 340%, 20% to 320%, 20% to 300%, 20% to 280%, 20% to 260%, 20% to 240%, 20% to 220%, 20% to 200%, 20% to 180%, 20% to 160%, 20% to 140%, 20% to 120%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 400%, 30% to 380%, 30% to 360%, 30% to 340%, 30% to 320%, 30% to 300%, 30% to 280%, 30% to 260%, 30% to 240%, 30% to 220%, 30% to 200%, 30% to 180%, 30% to 160%, 30% to 140%, 30% to 120%, 30% to 100%, 30% to 220%, 30% to 100% and 30% to 340%, 30% to 320% and 30% to 320% of the composition. 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 400%, 40% to 380%, 40% to 360%, 40% to 340%, 40% to 320%, 40% to 300%, 40% to 280%, 40% to 260%, 40% to 240%, 40% to 220%, 40% to 200%, 40% to 180%, 40% to 160%, 40% to 140%, 40% to 120%, 40% to 100% >. 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 400%, 50% to 380%, 50% to 360%, 50% to 340%, 50% to 320%, 50% to 300%, 50% to 280%, 50% to 260%, 50% to 240%, 50% to 220%, 50% to 200%, 50% to 180%, 50% to 160%, 50% to 140%, 50% to 120%, and, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 400%, 60% to 380%, 60% to 360%, 60% to 340%, 60% to 320%, 60% to 300%, 60% to 280%, 60% to 260%, 60% to 240%, 60% to 220%, 60% to 200%, 60% to 180%, 60% to 160%, 60% to 140%, 60% to 120%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 400%, 70% to 380%, 70% to 360%, 70% to 340%, 70% to 320%, 70% to 300%, 70% to 280%, 70% to 260%, 70% to 240%, 70% to 220%, 70% to 200%, 70% to 180%, 70% to 160%, 70% to 140%, 70% to 120%, 100%, 70% to 90%, 70% to 80%, 80% to 400%, 80% to 380%, 70% to 70%, 70% to 400%, 70% to 70% and 60% to 380% of the composition 80% to 360%, 80% to 340%, 80% to 320%, 80% to 300%, 80% to 280%, 80% to 260%, 80% to 240%, 80% to 220%, 80% to 200%, 80% to 180%, 80% to 160%, 80% to 140%, 80% to 120%, 80% to 100%, 80% to 90%, 90% to 400%, 90% to 380%, 90% to 360%, 90% to 340%, 90% to 320%, 90% to 300%, 90% to 280%, and 90% to 260%, 90% to 240%, 90% to 220%, 90% to 200%, 90% to 180%, 90% to 160%, 90% to 140%, 90% to 120%, 90% to 100%, 100% to 400%, 100% to 380%, 100% to 360%, 100% to 340%, 100% to 320%, 100% to 300%, 100% to 280%, 100% to 260%, 100% to 240%, 100% to 220%, 100% to 200%, and, 100% to 180%, 100% to 160%, 100% to 140%, 100% to 120%, 120% to 400%, 120% to 380%, 120% to 360%, 120% to 340%, 120% to 320%, 120% to 300%, 120% to 280%, 120% to 260%, 120% to 240%, 120% to 220%, 120% to 200%, 120% to 180%, 120% to 160%, 120% to 140%, 140% to 400%, 140% to 380%, 140% to 360%, 140% to 340%, and 140% to 320%, 140% to 300%, 140% to 280%, 140% to 260%, 140% to 240%, 140% to 220%, 140% to 200%, 140% to 180%, 140% to 160%, 160% to 400%, 160% to 380%, 160% to 360%, 160% to 340%, 160% to 320%, 160% to 300%, 160% to 280%, 160% to 260%, 160% to 240%, 160% to 220%, 160% to 200%, 160% to 180%, and 180% to 400%, 180% to 380%, 180% to 360%, 180% to 340%, 180% to 320%, 180% to 300%, 180% to 280%, 180% to 260%, 180% to 240%, 180% to 220%, 180% to 200%, 200% to 400%, 200% to 380%, 200% to 360%, 200% to 340%, 200% to 320%, 200% to 300%, 200% to 280%, 200% to 260%, 200% to 240%, 200% to 220%, 220% to 400%, and 220% to 380%, 220% to 360%, 220% to 340%, 220% to 320%, 220% to 300%, 220% to 280%, 220% to 260%, 220% to 240%, 240% to 400%, 240% to 380%, 240% to 360%, 240% to 340%, 240% to 320%, 240% to 300%, 240% to 280%, 240% to 260%, 260% to 400%, 260% to 380%, 260% to 360%, 260% to 340%, 260% to 320%, and, 260% to 300%, 260% to 280%, 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%) (e.g., as compared to a patient with a similar cancer and administered a different treatment or not).

In some embodiments of any of the methods described herein, the patient received treatment with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery prior to treatment with the compositions or methods of the invention, and optionally, prior treatment was unsuccessful; and/or a surgical procedure has been performed on the patient, and optionally, the surgical procedure is unsuccessful; and/or the patient has received treatment with a platinum-based chemotherapeutic agent, and optionally, the patient has been previously determined to be non-responsive to treatment with the platinum-based chemotherapeutic agent; and/or the patient has received treatment with a kinase inhibitor, and optionally, prior treatment with a kinase inhibitor has been unsuccessful; and/or the patient has received treatment with one or more other therapeutic agents.

Kit for detecting a substance in a sample

The invention also relates to a kit comprising an SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and the KRAS G12C inhibitor compound adagransie or a pharmaceutically acceptable salt or pharmaceutical composition thereof. Also provided are kits comprising an SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in the treatment of hematological cancer.

In a related aspect, the invention provides a kit comprising a dose of an SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a dose of the KRas G12C inhibitor compound adagransieb or a pharmaceutically acceptable salt or pharmaceutical composition thereof in an amount effective to inhibit proliferation of cancer cells, particularly cancer cells expressing KRas G12C, in a subject. In some cases, the kit includes instructions for administering the SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and the KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof. The instructions may provide the user with a set of instructions for using the SOS1 inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof in combination with the KRas G12C inhibitor compound adaglazeb or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

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

Example A

In vivo models for testing KRAS G12C inhibitor-SOS 1 inhibitor combinations

The right posterior flank of immunocompromised nude mice (nude/nude mice) were vaccinated with cells having KRas G12C mutations or patient-derived tumor samples. When the tumor volume reaches 200mm ³ -400mm ³ Between sizes, the mice were divided into four groups of 4-12 mice each. Administration of vehicle only to the first group. Depending on the cell line and single agent activity, the administration of a single agent dose of KRas G12C inhibitor to the second group at a concentration that produces the greatest biological effect or less than the greatest biological effect does not cause complete tumor regression. Depending on the cell line and single agent activity, administration of a single agent dose of SOS1 inhibitor to the third group at a concentration that produces the greatest biological effect or less than the greatest biological effect also does not cause complete tumor regression. The optional group is administered a single dose of a MEK inhibitor (VS-6766) that produces less than the maximum biological effect. The last group was administered a single dose of KRas G12C inhibitor in combination with a single dose of SOS1 inhibitor, or a single dose of KRas G12C inhibitor in combination with a single dose of SOS1 inhibitor and a single dose of VS-6766. The treatment cycle varies from cell line to cell line, but is typically between 20-42 days. Tumor volumes were measured every two-three days using calipers and calculated by the following formula: 0.5× (length×width) ² . The higher degree of tumor growth inhibition of the combination in this model suggests that combination therapy may have clinically significant benefit to the treated individual relative to treatment with KRas G12C inhibitor alone.

16-32 nude mice/nude mice, balb/c nude mice or NOD/SCID mice per study were vaccinated 5X 10 in the right hind limb ⁶ Indicated cell lines or tumor fragments. When the tumor volume reaches about 200mm ³ -400mm ³ At time (study day 0), 4 or more mice in each of four to six groups were orally administered daily for 20-42 days: vehicle alone (0.5% MC (4000 cps)/0.2% Tween80 in water), 10mg/kg, 30mg/kg or 100mg/kg of KRAS G12C inhibitor adagransie (10% Captisol in 50mM citrate buffer, pH 5.0), 0.3mg/kg of MEK inhibitor VS-6766 (5% DMSO with 10% hydroxypropyl-beta-cyclodextrin in water), 50mg/kg or 100mg/kg of SOS1 inhibitor (R) -2-methyl-3- (1- ((4-methyl-7-morpholinopyrimido [3, 4-d)]Pyridazin-1-yl) amino) ethyl) benzonitrile (MRTX-0902) (0.5% MC (4000 cps)/0.2% Tween80 in water), 3- ((R) -1- ((7- ((S) -hexahydropyrazine [2, 1-c)][1,4]Oxazin-8 (1H) -yl) -4-methylpyrido [3,4-d]Pyridazin-1-yl) amino) ethyl) -2-methylBenzonitrile (MRTX-2006) (20% SBE-. Beta. -CD/50mM citric acid pH 5), or (R) -2-methyl-3- (1- ((4-methyl-7- (4-methylpiperazin-1-yl) pyrido [3, 4-d)]Pyridazin-1-yl) amino) ethyl) benzonitrile (MRTX-4197) (20% SBE-. Beta. -CD/50mM citric acid pH 5), or 10mg/kg, 30mg/kg or 100mg/kg of the KRAS G12C inhibitor adaglazeb and 50mg/kg or 100mg/kg of MRTX-0902, MRTX-2006 or MRTX-4197. For the triple combination study, an additional combination set with 0.3mg/kg MEK inhibitor VS-6766 was included. Tumor volumes of 4-8 mice/group measured on a predetermined day were averaged and reported in tables 1, 2, 3 and 4 for MIA PaCa-2 cells; reported in table 5 for LU99 cells; report in tables 6 and 7 for NCI-H2122 cells; tumors derived for CR6256 colorectal patients are reported in table 8.

TABLE 1

³ Average tumor volume (mm) of MIA PaCA-2 tumor-bearing mice treated with single and combination agents

Study days	Vehicle agent	Adaglazecloth	MRTX-0902	Adaglazeb+mrtx-0902 combination
					0	254	252	255	252
2	337	263	293	201
					6	560	212	452	101
9	643	192	497	35
					13	882	219	524	17
16	955	286	584	22
					20	1091	344	688	24
23	1139	410	793	53
					27	1263	493	884	67

As shown in fig. 1 and table 1, administration of adaglazeb or MRTX-0902 as a single agent showed 76.3% and 37.5% tumor growth on day 27, respectively. The combination of SOS1 inhibitor MRTX-0902 with adaglazeb caused-73.4% tumor regression on day 27.

TABLE 2

As shown in FIGS. 2 and Table 2, administration of single agents adaglazeb or 25mg/kg and 50mg/kg BID MRTX-0902 showed 93.5%, 41.2% and 52.9% tumor growth on day 25, respectively. The combination of SOS1 inhibitor MRTX-0902 (25 mg/kg and 50mg/kg BID) and adaglazeb caused-54.1% and-92.1% tumor regression on day 25, respectively.

TABLE 3 Table 3

Study days	Vehicle agent	Adaglazecloth	MRTX-2006	Adaglazeb+mrtx-2006 combination
					0	165	159	158	152
4	286	125	218	103
					7	381	95	255	67
11	551	119	359	72
					15	710	153	493	105
18	710	191	549	128
					21	816	210	623	112
25	909	282	710	169
					27	966	346	728	197

As shown in fig. 3 and table 3, administration of adaglazeb or MRTX-2006 as a single agent showed 77.4% and 29.7% tumor growth on day 27, respectively. The combination of SOS1 inhibitor MRTX-2006 with adaglazeb caused 96.0% tumor growth inhibition on day 27.

TABLE 4 Table 4

Study days	Vehicle agent	Adaglazecloth	MRTX-4197	adaglazeb+MRTX-4197 combination
					0	254	252	251	248
2	337	263	279	151
					6	560	212	332	94
9	643	192	405	43
					13	882	219	397	40
16	955	286	461	53
					20	1091	344	438	67

As shown in fig. 4 and table 4, administration of adaglazeb or MRTX-4197 as a single agent showed 89.2% and 78.0% tumor growth on day 20, respectively. The combination of SOS1 inhibitor MRTX-4197 with adaglazeb caused-73.0% tumor regression on day 28.

TABLE 5

³ Average tumor volume (mm) of LU99 tumor-bearing mice treated with single and combination agents

Study days	Vehicle agent	Adaglazecloth	MRTX-0902	Adaglazeb+mrtx-0902 combination
					0	152	154	153	153
5	180	142	186	110
					8	304	117	224	85
12	545	87	290	36
					15	718	81	433	17
20	1140	84	770	10
					22	1237	103	976	10
26	1548	171	1249	14

As shown in fig. 5 and table 5, administration of adaglazeb or MRTX-0902 as a single agent showed 98.6% and 21.4% tumor growth on day 28, respectively. The combination of SOS1 inhibitor MRTX-0902 with adaglazeb caused-90.9% tumor regression on day 26.

TABLE 6

³ Average tumor volume (mm) of mice bearing H2122 tumors treated with single and combination agents

Study days	Vehicle agent	Adaglazecloth	MRTX-0902	Adaglazeb+mrtx-0902 combination
					1	166	169	167	169
7	818	377	724	339
					10	1077	350	937	248
13	1514	320	1284	223
					16	1790	335	1471	219
20	1916	405	1754	246

As shown in fig. 6 and table 6, administration of adaglazeb or MRTX-0902 as a single agent showed 86.3% and 9.2% tumor growth on day 28, respectively. The combination of SOS1 inhibitor MRTX-0902 with adaglazeb caused a 95.4% tumor growth inhibition on day 20.

TABLE 7

As shown in fig. 7 and table 7, administration of adaglazeb, MRTX-0902, or VS-6766 as single agents showed 86.9%, 13.7%, and 81.1% tumor growth on day 23, respectively. The combination of SOS1 inhibitors MRTX-0902, VS-6766 and adaglazeb caused a-61.9% regression on day 23.

TABLE 8

³ Average tumor volume (mm) of CR6256 tumor-bearing mice treated with single and combined agents

Study days	Vehicle agent	Adaglazecloth	MRTX-0902	Adaglazeb+mrtx-0902 combination
					0	254	254	254	254
4	455	276	429	241
					7	565	216	579	153
11	727	189	684	108
					14	837	140	849	74
18	1063	152	1059	60
					21	1303	168	1306	73
25	1503	164	1500	76
					28	1572	160	1577	72
32	1688	156	1697	43
					35	1750	178	1579	38
39	2109	220	1871	62
					42	2308	276	2182	50

As shown in fig. 8 and table 8, administration of adaglazeb or MRTX-0902 as a single agent showed 99.0% and 6.1% tumor growth on day 42, respectively. The combination of SOS1 inhibitor MRTX-0902 with adaglazeb caused a-80.4% regression on day 42.

As shown in fig. 9, administration of MRTX-0902 with adaglazeb resulted in a broad range of anti-tumor activity in KRASG12C mutant human tumor cell line-derived and patient-derived xenograft models from pancreatic, non-small cell lung, colorectal, and esophageal cancers. These results demonstrate that combination therapy results in a greater amount of tumor growth inhibition than single agents alone, demonstrating enhanced in vivo anti-tumor efficacy of the combination against KRas G12C expressing cancers.

While the invention has been described in connection with specific 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 following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

Claims

1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the KRAS G12C inhibitor adaglazepine,

or a pharmaceutically acceptable salt thereof, in combination with an SOS1 inhibitor.

2. The method of claim 1, wherein the SOS1 inhibitor is selected from the group consisting of:

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, and pharmaceutically acceptable salts thereof.

3. The method of claim 1, wherein the SOS1 inhibitor is

Or a pharmaceutically acceptable salt thereof.

4. The method of claim 3, wherein the method further comprises administering to a subject in need thereof a compound having the structure:

or a pharmaceutically acceptable salt thereof.

5. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of:

-KRas G12C inhibitor adaglazeb:

or a pharmaceutically acceptable salt thereof,

SOS1 inhibitor:or a pharmaceutically acceptable salt thereof

-MEK inhibitors:

or a pharmaceutically acceptable salt thereof.

6. The method of claim 1, wherein the SOS1 inhibitor compound is BI1701963.

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

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

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

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

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

12. The method of any one of claims 1 to 8, wherein the KRas G12C inhibitor is administered at a lower than maximum tolerated dose.

13. The method of any one of claims 1 to 8, wherein the SOS1 inhibitor is administered at a lower than maximum tolerated dose.

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

15. The method of any one of claims 1 to 14, wherein the combination of the therapeutically effective amount of the SOS1 inhibitor and the KRas G12C inhibitor results in an increase in total survival duration, an increase in progression free survival duration, an increase in tumor growth regression, an increase in tumor growth inhibition, or an increase in disease stability duration of the subject relative to treatment with the KRas G12C inhibitor alone.

16. The method of any one of claims 1 to 14, wherein the combination of the therapeutically effective amount of the SOS1 inhibitor and the KRas G12C inhibitor results in an increase in total survival duration, an increase in progression free survival duration, an increase in tumor growth regression, an increase in tumor growth inhibition, or an increase in disease stability duration of the subject relative to treatment with the SOS1 inhibitor alone.

17. A pharmaceutical composition comprising a therapeutically effective amount of a combination of the SOS1 inhibitor of any one of claims 1 to 14 and the KRas G12C inhibitor adaxazepine, and a pharmaceutically acceptable excipient.

18. A method for inhibiting KRas G12C activity in a cell, the method comprising contacting a cell in which inhibition of KRas G12C activity is desired with an effective amount of a combination of: the KRas G12C inhibitor adaglazeb:

or a pharmaceutically acceptable salt thereof, and an SOS1 inhibitor.

19. The method of claim 18, wherein the SOS1 inhibitor is selected from the group consisting of:

20. The method of claim 18, wherein the SOS1 inhibitor is

Or a pharmaceutically acceptable salt thereof.

21. The method of claim 20, further comprising contacting the cell with a compound having the structure:

or a pharmaceutically acceptable salt thereof.

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

23. A method for increasing the sensitivity of a cancer cell to the KRas G12C inhibitor, the method comprising administering an effective amount of the KRas G12C inhibitor adaglazeb to a subject undergoing KRas G12C treatment:

or a pharmaceutically acceptable salt thereof, in combination with a SOS1 inhibitor, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor.

24. The method of claim 23, wherein the SOS inhibitor is

Or a pharmaceutically acceptable salt thereof.

25. The method of claim 24, wherein the method further comprises administering to a subject in need thereof a compound having the structure:

or a pharmaceutically acceptable salt thereof.

26. The method of any one of claims 1 to 16 or 18 to 25, wherein the therapeutically effective amount of the KRas G12C inhibitor in the combination is between about 0.01 mg/kg/day and 100 mg/kg/day.

27. The method of claim 26, wherein the therapeutically effective amount of the KRas G12C inhibitor in the combination is between about 0.1 mg/kg/day and 50 mg/kg/day.

28. The method of any one of claims 1 to 16 or 18 to 27, wherein the therapeutically effective amount of the SOS1 inhibitor in the combination is between about 0.01 mg/kg/day and 100 mg/kg/day.

29. The method of claim 28, wherein the therapeutically effective amount of the SOS1 inhibitor in the combination is between about 0.1 mg/kg/day and 50 mg/kg/day.

30. The method of any one of claims 1 to 16 and 18 to 29, wherein the cancer is selected from the group consisting of: and (3) heart: sarcomas (hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromisstructured tumor, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagon tumor, gastrinoma, carcinoid tumor, schuz bowel peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); urogenital 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, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gall bladder cancer, ampulla cancer, bile duct cancer; bone: osteogenic sarcomas (osteosarcoma), fibrosarcomas, malignant fibrous histiocytomas, chondrosarcomas, ewing's sarcoma, malignant lymphomas (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondral tumors (osteochondral exotoses), benign chondrias, chondroblastomas, chondromucoid fibromas, osteoid osteomas and giant cell tumors; the nervous system: skull (bone tumor, hemangioma, granuloma, xanthoma, malformed osteomyelitis), meninges (meningioma, glioblastoma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); gynaecology: uterus (endometrial carcinoma (serous cystic adenocarcinoma, mucinous cystic adenocarcinoma, unclassified carcinoma), granulosa follicular cytoma, support-stromal cytoma, anaplastic cytoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, 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, dysplasia, lipoma, hemangioma, skin fibroma, keloids, psoriasis, adrenal gland: neuroblastoma.

31. The method of claim 30, wherein the cancer is KRas G12C-associated cancer.

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

33. A kit comprising the pharmaceutical composition of claim 17 for treating KRas G12C cancer in a subject.

34. The kit of claim 33, further comprising instructions for administering the pharmaceutical composition.