Combination therapy including an SOS1 inhibitor and an EGFR inhibitor

Abstract

The present invention relates to combination therapies for treating cancers associated with genetic alterations in the MAPK pathway and / or EGFR. In particular, the present invention relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SOS1 inhibitor and an EGFR inhibitor, pharmaceutical compositions comprising such compositions, kits comprising such compositions, and methods of use thereof.

Description

[Technical field]

[0001] The present invention relates to combination therapies useful in the treatment of cancer. In particular, the present invention relates to therapeutically effective combinations of Son of sevenless homolog 1 (SOS1) inhibitors and EGFR inhibitors, pharmaceutical compositions comprising the inhibitors, kits comprising the compositions, and methods of use thereof. [Background technology]

[0002] SOS1 inhibitors The Ras family includes v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRas), neuroblastoma RAS viral oncogene homolog (NRAS), and Harvey murine sarcoma viral oncogene (HRas), and critically regulates cell division, growth, and function under normal and altered conditions, including cancer (see, e.g., Simanshu et al. Cell, 2017.170(1):p.17-33; Matikas et al., Crit Rev Oncol Hematol, 2017.110:p.1-12). RAS proteins are activated by upstream signals, including receptor tyrosine kinases (RTKs), and transmit signals to several downstream signaling pathways, such as the mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK) pathway. Hyperactivation of RAS signaling is frequently observed in cancer as a result of mutations or alterations in RAS genes or other genes in the RAS pathway. Identification of strategies to inhibit RAS and RAS signaling is predicted to be useful in the treatment of cancer and RAS-regulated disease states.

[0003] RAS proteins are guanosine triphosphate (GTPase) enzymes that cycle between an inactive guanosine diphosphate (GDP)-bound state and an active guanosine triphosphate (GTP)-bound state. RAS proteins exhibit both intrinsic GTP hydrolysis and nucleotide exchange, which is further enhanced by exogenous GTPase activating proteins (GAPs) and guanine exchange factors (GEFs). Son of Sevenless homolog 1 (SOS1) is a GEF that mediates the exchange of GDP for GTP, thereby activating RAS proteins. This regulation through GAPs and GEFs is a mechanism by which activation and deactivation are tightly regulated under normal conditions. Mutations at several residues in all three RAS proteins are frequently observed in cancer, resulting in RAS remaining predominantly in an activated state (see Sanchez-Vega et al., Cell, 2018.173: p.321-337 Li et al., Nature Reviews Cancer, 2018.18: p.767-777). Mutations at codons 12 and 13 disrupt the GTP hydrolysis and exchange rates of the RAS protein set. Recent biochemical analyses have demonstrated that these mutated proteins still require nucleotide cycling for activation based on their intrinsic GTPase activity and may exhibit partial sensitivity to exogenous GAPs and GEFs. Thus, mutated RAS proteins are sensitive to inhibition of upstream factors such as SOS1 GEF (Hillig, 2019; Patricelli, 2016; Lito, 2016; Nichols, 2018).

[0004] Three major RAS-GEF families have been identified in mammalian cells: SOS, RAS-GRF, and RAS-GRP (Rojas, 2011). RAS-GRF and RAS-GRP are expressed in cells of the central nervous system and hematopoietic cells, respectively, while the SOS family is expressed ubiquitously and is involved in transduction of RTK signaling. The SOS family includes SOS1 and SOS2, and these proteins share about 70% sequence identity. SOS1 appears to be much more active than SOS2 due to the rapid degradation of SOS2. Mouse SOS2 knockouts are viable, whereas SOS1 knockouts are embryonic lethal. A tamoxifen-inducible SOS1 knockout mouse model was used to investigate the role of SOS1 and SOS2 in adult mice, demonstrating that SOS1 knockouts were viable, whereas SOS1 / 2 double knockouts were non-viable (Baltanas, 2013), suggesting functional redundancy and that selective inhibition of SOS1 may have a sufficient therapeutic index for the treatment of SOS1-RAS activated diseases.

[0005] SOS proteins are recruited to phosphorylated RTKs through interactions with growth factor receptor bound protein 2 (GRB2). Recruitment to the plasma membrane places SOS in close proximity to RAS, allowing SOS-mediated RAS activation. SOS proteins bind RAS through a catalytic binding site that promotes nucleotide exchange, as well as through an allosteric site that binds GTP-bound RAS family proteins, increasing the catalytic function of SOS (Freedman et al., Proc. Natl. Acad. Sci, USA 2006.103(45):p.16692-97). Binding to the allosteric site relieves steric blockage of the catalytic site and is therefore required for full activation of the catalytic site. Retention of the active conformation at the catalytic site after interaction with the allosteric site is maintained in isolation due to enhanced interactions of key domains in the activated state. SOS1 mutations are found in Noonan syndrome and several cancers, including lung adenocarcinoma, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, and granular cell tumor of the skin (see, e.g., Denayer, E., et al, Genes Chromosomes Cancer, 2010.49(3):p.242-52).

[0006] GTPase-activating proteins (GAPs) are proteins that stimulate the low intrinsic GTPase activity of RAS family members, thus converting active GTP-bound RAS proteins into inactive GDP-bound RAS proteins (see, e.g., Simanshu, DK, Cell, 2017, Ras Proteins and their Regulators in Human Disease). Activating alterations in the phosphatase PTPN11 (SHP2) and the GEF SOS1 occur in cancer, as well as inactivating mutations and loss-of-function alterations in the GAP neurofibromin 1 (NF-1), creating a state in which SOS1 activity is unopposed and downstream activity of pathways through RAS proteins is elevated.

[0007] EGFR inhibitors The epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase of the ErbB receptor family. Upon binding to epidermal growth factor (EGF), the EGFR receptor can homodimerize with another EGFR molecule or heterodimerize with another family member such as ErbB2 (HER2), ErbB 3 (HER3), or ErbB4 (HER4). Homodimerization and / or heterodimerization of ErbB receptors results in phosphorylation of key tyrosine residues in the intracellular domain, leading to the stimulation of multiple intracellular signaling pathways involved in cell proliferation and survival.

[0008] Overexpression of the EGFR gene has been identified in a variety of cancers, including bladder, brain, head and neck, pancreas, lung, breast, ovary, colon, prostate, and kidney. In addition to overexpression, EGFR-activating mutations have been detected in a subset of non-small cell lung cancer (NSCLC) tumors. These mutations tend to occur within EGFR exons 18-21, which encode part of the EGFR kinase domain. Approximately 90% of these mutations are exon 19 deletions or exon 21 L858R point mutations (Ladanyi and Pao (2008) Mod Path. May; 21 Suppl 2: S16-22. doi: 10.1038 / modpathol.3801018). These mutations increase the kinase activity of EGFR, leading to hyperactivation of downstream pro-survival signaling pathways.

[0009] The frequency of overexpression and / or activating mutations of EGFR makes it a desirable target for anti-cancer therapy, and several EGFR inhibitors have been developed and are clinically available.

[0010] The first generation erlotinib and gefitinib inhibit EGFR activity by competitively binding to the ATP-binding site of the EGFR kinase domain; however, further mutations in the EGFR gene, such as the T790M mutation, produce mutant EGFR proteins to which drugs such as erlotinib and gefitinib bind less well. These mutations are associated with resistance to drugs and recurrence in cancer patients with such mutations, leading to the development of second generation EGFR inhibitors that target the T790M mutation.

[0011] Osimertinib is an irreversible third-generation epidermal growth factor receptor (EGFR) inhibitor that is highly selective for EGFR activating mutations as well as EGFR T790M gatekeeper mutations in patients with advanced non-small cell lung cancer (NSCLC) with EGFR oncogene addiction. Despite the demonstrated efficacy of osimertinib in clinical settings, patients inevitably develop resistance. Our data suggest that the combination of MRTX0902 with an EGFR inhibitor, such as osimertinib, can delay the onset of acquired resistance. Here, we demonstrate that the SOS1 inhibitor MRTX0902 can increase the depth of response to osimertinib in an EGFR-dependent NSCLC xenograft model.

[0012] Furthermore, inhibition of the pathway-related enzyme MEK leads to increased expression of ErbB family members, particularly EGFR, which may result in adaptive and acquired resistance to ErbB family inhibitors (Sun et al., (2014) Cell Reports 7:86-93). [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Simanshu et al.Cell,2017.170(1):p.17-33, Matikas et al.,Crit Rev Oncol Hematol,2017.110:p.1-12 [Non-Patent Document 2] Sanchez-Vega et al.,Cell,2018.173:p.321-337 Li et al.,Nature Reviews Cancer,2018.18:p.767-777 [Non-Patent Document 3] Hillig,2019;Patricelli,2016;Lito,2016;Nichols,2018 [Non-Patent Document 4] Rojas, 2011 [Non-Patent Document 5] Baltanas, 2013 [Non-Patent Document 6] Freedman et al., Proc. Natl. Acad. Sci, USA 2006.103(45):p.16692-97 [Non-Patent Document 7] Denayer, E., et al, Genes Chromosomes Cancer, 2010.49(3):p.242-52 [Non-Patent Document 8] Simanshu, DK, Cell, 2017, Ras Proteins and their Regulators in Human Disease [Non-Patent Document 9] Ladanyi and Pao(2008)Mod Path.May;21 Suppl 2:S16-22.doi:10.1038 / modpathol.3801018 [Non-Patent Document 10] Sun et al.,(2014)Cell Reports 7:86-93 Summary of the Invention

[0014] In one aspect, the combination therapy of the present invention synergistically increases the potency of the SOS1 inhibitor, resulting in improved efficacy of the SOS1 inhibitor disclosed herein.In another aspect, the combination therapy of the present invention provides patients with improved clinical benefits compared to treatment with the SOS1 inhibitor disclosed herein as a single agent.

[0015] Thus, in one aspect of the invention, SOS1 inhibitors such as those described in WO 2021 / 127429, WO 2021 / 173524, WO 2022 / 026465, U.S. Provisional Patent Application No. 63 / 213,112 (and corresponding national and international applications and publications), and those described in detail herein, e.g.,

[0016] [ka] (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile,

[0017] [ka] 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile,

[0018] [ka] (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile,

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

[0020] [ka] (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile,

[0021] [ka] (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile,

[0022] [ka] 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile,

[0023] [ka] (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof; Therapeutically effective combinations with EGFR inhibitor compounds, such as osimertinib (TAGRISSO®), gefitinib, erlotinib, afatinib, brigatinib, icotinib, cetuximab, and other small and large molecule EGFR inhibitors, or pharma- ceutically acceptable salts thereof, are provided.

[0024] In another aspect of the present invention, there is provided a therapeutically effective combination of an SOS1 inhibitor, (R-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt thereof, and an EGFR inhibitor selected from osimertinib (TAGRISSO®), gefitinib, erlotinib, afatinib, brigatinib, icotinib, cetuximab, and other small and large molecule EGFR inhibitors, or a pharma- ceutically acceptable salt thereof.

[0025] In another aspect of the invention, there is provided a pharmaceutical composition for use in the method comprising a therapeutically effective amount of the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile or a pharma- ceutically acceptable salt thereof in combination with the EGFR inhibitor compound osimertinib or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0026] In another aspect of the invention, there is provided a pharmaceutical composition for use in the method comprising a therapeutically effective amount of the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile or a pharma- ceutically acceptable salt thereof in combination with the EGFR inhibitor compound gefitinib or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0027] In another aspect of the invention, there is provided a pharmaceutical composition for use in the method comprising a therapeutically effective amount of the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile or a pharma- ceutically acceptable salt thereof in combination with the EGFR inhibitor compound erlotinib or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0028] In another aspect of the invention, there is provided a pharmaceutical composition for use in the method comprising a therapeutically effective amount of the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile or a pharma- ceutically acceptable salt thereof in combination with the EGFR inhibitor compound afatinib or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0029] In another aspect of the invention, a therapeutically effective amount of the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile or a pharma- ceutically acceptable salt thereof, in combination with the EGFR inhibitor compound brigatinib or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, is provided for use in the method.

[0030] In another aspect of the invention, there is provided a pharmaceutical composition for use in the method comprising a therapeutically effective amount of the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile or a pharma- ceutically acceptable salt thereof in combination with the EGFR inhibitor compound icotinib or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0031] In one aspect of the invention, there is provided a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of an SOS1 inhibitor, such as (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2- Methylbenzonitrile, (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido [3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or (R)-3-(1-((6-fluro Provided herein are methods that include administering to a subject a combination of oro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile and an EGFR inhibitor selected from osimertinib (TAGRISSO®), gefitinib, erlotinib, afatinib, brigatinib, icotinib, cetuximab, and other small molecule and large molecule EGFR inhibitors, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0032] In one aspect of the invention, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the EGFR inhibitor osimertinib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0033] In one aspect of the invention, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the EGFR inhibitor gefitinib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0034] In one aspect of the invention, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the EGFR inhibitor erlotinib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0035] In one aspect of the invention, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the EGFR inhibitor afatinib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0036] In one aspect of the invention, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, brigatinib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0037] In one aspect of the invention, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the EGFR inhibitor icotinib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0038] In one embodiment, the cancer is an SOS1-associated cancer.

[0039] In one embodiment, the cancer is a KRas G12C-associated cancer.

[0040] In one embodiment, the cancer is selected from the group consisting of lung cancer, leukemia, colorectal cancer, uterine cancer, and pancreatic cancer.

[0041] In one embodiment, the cancer is selected from the group consisting of lung cancer and leukemia.

[0042] In one embodiment, the lung cancer is lung adenocarcinoma.

[0043] In one embodiment, the lung cancer is non-small cell lung cancer.

[0044] In one embodiment, the leukemia is acute myeloid leukemia (AML).

[0045] In one embodiment, the SOS1 associated cancer is lung cancer.

[0046] In one embodiment, the pancreatic cancer is ductal carcinoma of the pancreas.

[0047] In some aspects of the invention, the EGFR inhibitor and the SOS1 inhibitor are the only active agents in the compositions and methods provided.

[0048] Examples of SOS1 inhibitors suitable for the provided compositions and methods include (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl) Benzonitrile, (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-3-( dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and pharma- ceutically acceptable salts thereof.In yet another aspect, the present invention provides a method for increasing the sensitivity of cancer cells to an SOS1 inhibitor or to an EGFR inhibitor, comprising treating the cancer cells with a therapeutically effective amount of an EGFR inhibitor compound, such as osimertinib (TAGRISSO®), gefitinib, erlotinib, afatinib, brigatinib, icotinib, cetuximab, and other small and large molecule EGFR inhibitors, or pharma- ceutically acceptable salts or pharmaceutical compositions thereof, and an SOS1 inhibitor as described herein, such as (R)-2-methyl-3-(1-((4-methyl- -7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2- Methyl-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 and (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, to synergistically increase sensitivity of the cancer cell to an SOS1 or EGFR inhibitor.In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0049] Also provided herein is a method of treating cancer in a subject in need thereof, the method comprising: (a) determining (e.g., as determined using a regulatory approved, e.g., FDA approved, assay or kit) that the cancer is associated with an SOS1-mediated cancer and / or a genetic alteration in the MAPK pathway (e.g., an SOS1-associated cancer); and (b) administering to the patient a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the EGFR inhibitor synergistically increases the sensitivity of the SOS1-associated cancer to the SOS1 inhibitor, for example, to (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile.

[0050] Also provided herein is a kit comprising an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor compound, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.Also provided is a kit comprising the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the EGFR inhibitor compound osimertinib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, for use in treating SOS1-associated cancer.

[0051] In a related aspect, the present invention provides a kit containing a dose of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor compound, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, in an amount effective to inhibit the proliferation of cancer cells in a subject. The kit optionally includes a package insert containing instructions for administering the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the EGFR inhibitor compound, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof. The package insert may provide the user with a set of instructions for using the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, in combination with the EGFR inhibitor compound, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0052] In some embodiments of any of the methods described herein, prior to treatment with a composition or method of the invention, the patient has been treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, optionally where the previous treatment has been unsuccessful, and / or the patient has been subjected to surgery, optionally where the surgery has been unsuccessful, and / or the patient has been treated with a platinum-based chemotherapy agent, optionally where the patient has been previously determined to be non-responsive to treatment with a platinum-based chemotherapy agent, and / or the patient has been treated with a kinase inhibitor, optionally where the previous treatment with the kinase inhibitor has been unsuccessful, and / or the patient has been treated with one or more other therapeutic agents. [Brief description of the drawings]

[0053] [Figure 1] 1 shows the mean tumor volume (mm3) of NCI-H1975 tumor-bearing mice treated with osimertinib and MRTX0902, both as single agents and in combination. [Diagram 2] 1 shows the mean tumor volume (mm3) of PC-9 tumor-bearing mice treated with osimertinib and MRTX0902, alone and in combination. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0054] The present invention relates to combination therapy for treating SOS1-related cancer. Specifically, the present invention relates to a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, a pharmaceutical composition comprising a therapeutically effective amount of the inhibitor, a kit comprising the composition, and a method of use thereof.

[0055] The combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, with an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, synergistically increases the potency of the SOS1 inhibitor against cancer cells expressing SOS1, thereby increasing the efficacy and therapeutic index of the SOS1 inhibitor or a pharma- ceutically acceptable salt thereof.

[0056] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications mentioned herein are incorporated by reference.

[0057] As used herein, "EGFR" refers to epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans), a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. Epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2 / neu (ErbB-2), Her 3 (ErbB-3), and Her 4 (ErbB-4). In many cancer types, mutations affecting EGFR expression or activity can lead to cancer.

[0058] As used herein, "EGFR inhibitor" refers to compounds such as osimertinib (TAGRISSO®), gefitinib, erlotinib, afatinib, brigatinib, icotinib, cetuximab, and other small and large molecule EGFR inhibitors, or pharma- ceutically acceptable salts thereof. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of EGFR, or mutant EGFR.

[0059] As used herein, an "EGFR-associated disease or disorder" refers to a disease or disorder associated with or mediated by EGFR mutation or overexpression.

[0060] As used herein, "SOS1" refers to the son of sevenless homolog 1 protein encoded by the SOS1 gene, which is involved in signaling through the RAS pathway.

[0061] As used herein, "SOS1 inhibitor" refers to a compound capable of negatively regulating or inhibiting all or part of the interaction between KRAS and SOS1.

[0062] As used herein, "SOS1-associated disease or disorder" refers to a disease or disorder associated with or mediated by SOS1. A non-limiting example of an SOS1-associated disease or disorder is an SOS1-associated cancer.

[0063] As used herein, the terms "subject," "individual," or "patient," used interchangeably, refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with a KRas G12C mutation (e.g., determined using a regulatory approved, e.g., FDA approved, assay or kit). In some embodiments, the subject has a tumor that is positive for the KRas G12C mutation (e.g., determined using a regulatory approved, e.g., FDA approved, assay or kit). The subject can be a subject with a tumor that is positive for the KRas G12C mutation (e.g., identified as positive using a regulatory approved, e.g., FDA approved, assay or kit). The subject may be one whose tumor has a KRas G12C mutation (e.g., where the tumor is identified as such using a regulatory approved, e.g., FDA approved, kit or assay). In some embodiments, the subject is suspected of having a KRas G12C gene-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with a KRas G12C mutation (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0064] The term "pediatric patient" as used herein refers to a patient who is under 16 years of age at the time of diagnosis or treatment. The term "child" can be further divided into various subpopulations, including: neonates (birth to 1 month of age), infants (1 month to 2 years of age), children (2 to 12 years of age), and adolescents (12 to 21 years of age (up to but not including their 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

[0065] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether a patient has SOS1 overexpression using a sample (e.g., a biological sample or a biopsy sample, e.g., a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having an SOS1-associated cancer, a patient having one or more symptoms of an SOS1-associated cancer, and / or a patient at high risk of developing an SOS1-associated cancer), and may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR, quantitative real-time RT-PCR, allele-specific genotyping, or ddPCR). As is well known in the art, the assay is typically performed, for example, using at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0066] The term "regulatory authority" refers to a national agency that approves the medical use of pharmaceutical agents in that country. For example, a non-limiting example of a regulatory authority is the U.S. Food and Drug Administration (FDA).

[0067] As used herein, an "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit the activity of a desired target, i.e., SOS1 or EGFR. Such an amount may be administered as a single dose or according to a regimen whereby it is effective.

[0068] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to ameliorate or in some manner reduce symptoms, or to halt or reverse the progression of a condition, or to negatively regulate or inhibit the activity of SOS1 or EGFR. Such an amount may be administered as a single dose or may be administered according to a regimen whereby it is effective.

[0069] As used herein, a "therapeutically effective amount" of two compounds is an amount that synergistically increases the activity of the combination together, i.e., more than merely additive, compared to the therapeutically effective amount of each compound in the combination. Alternatively, in vivo, a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor compound, or a pharma-ceutically acceptable salt or pharmaceutical composition thereof, results in an increase in overall survival ("OS") time in a subject, compared to treatment with an SOS1 inhibitor alone. In one embodiment, a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma-ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, or a pharma-ceutically acceptable salt or pharmaceutical composition thereof, results in an increase in progression-free survival ("PFS") time in a subject, compared to treatment with an SOS1 inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor regression in a subject compared to treatment with an SOS1 inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor growth inhibition in a subject compared to treatment with an EGFR inhibitor alone. In one embodiment, the combination of a therapeutically effective amount of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in improved stable disease duration in a subject compared to treatment with an SOS1 inhibitor alone or an EGFR inhibitor alone. The amount of each compound in the combination may be the same as or different from the therapeutically effective amount of each compound when administered alone as a monotherapy, so long as the combination is synergistic. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

[0070] As used herein, treatment means any manner in which the symptoms or pathology of a condition, disorder, or disease are ameliorated or otherwise beneficially altered. Treatment also includes any pharmaceutical use of the compositions herein.

[0071] As used herein, "amelioration" of symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, whether permanent or temporary, persistent or transient, that can result from or be associated with administration of the composition.

[0072] As used herein, the term "about", when used to modify a numerically defined parameter (e.g., the dose of an EGFR inhibitor or SOS1 inhibitor, or a pharma- ceutically acceptable salt thereof, or the length of treatment time with a combination therapy described herein), means that the parameter may vary by as much as 10% above or below the numerical value stated for that parameter. For example, a dose of about 5 mg / kg may vary from 4.5 mg / kg to 5.5 mg / kg. When used at the beginning of a list of parameters, "about" is meant to modify the respective parameter. For example, about 0.5 mg, 0.75 mg, or 1.0 mg means about 0.5 mg, about 0.75 mg, or about 1.0 mg. Similarly, about 5% or more, 10% or more, 15% or more, 20% or more, and 25% or more means about 5% or more, about 10% or more, about 15% or more, about 20% or more, and about 25% or more.

[0073] As used herein, the term "contacting" refers to bringing together the indicated moieties in an in vitro or in vivo system. For example, "contacting" a cancer cell includes administering a combination provided herein to an individual or subject (e.g., a human) having KRas G12C, as well as introducing, for example, a combination provided herein into a sample containing a cell or purified preparation containing KRas G12C.

[0074] EGFR inhibitor compounds In one aspect of the present invention, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0075] In one embodiment, the EGFR inhibitor is

[0076] [ka] (also known as gsimertinib or TAGRISSO®), or a pharma- ceutically acceptable salt thereof.

[0077] In one embodiment, the EGFR inhibitor is

[0078] [ka] (also known as gefitinib or IRESSA®), or a pharma- ceutical acceptable salt thereof.

[0079] In one embodiment, the EGFR inhibitor is

[0080] [ka] (also known as erlotinib or TARCEVA®), or a pharma- ceutically acceptable salt thereof.

[0081] In one embodiment, the EGFR inhibitor is

[0082] [ka] (also known as afatinib or GILOTRIF®), or a pharma- ceutical acceptable salt thereof.

[0083] In one embodiment, the EGFR inhibitor is

[0084] [ka] (also known as Icotinib or CONMANA®).

[0085] In one embodiment, the EGFR inhibitor is the monoclonal antibody cetuximab (also known as ERBITUX®).

[0086] The EGFR inhibitors used in the methods of the present invention may have one or more chiral centers and may be synthesized as stereoisomeric mixtures, isomers of the same constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures, or the individual components / isomers may be separated using commercially available reagents and conventional methods for isolating stereoisomers and enantiomers well known to those skilled in the art, for example, using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatography HPLC columns according to the manufacturer's instructions. Alternatively, the compounds of the present invention may be synthesized using optically pure chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Unless otherwise specified, whenever the specification, including the claims, refers to a compound of the present invention, the term "compound" should be understood to include all chiral (enantiomers and diastereomers) and racemic forms.

[0087] In one embodiment, the KRas G12C inhibitor compound adagrasib used in the method includes salts of the above compounds, for example salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like, salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid, and salts formed from quaternary ammonium salts of the formula --NRZ-; where R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzilate, and diphenylacetate).

[0088] Methods for producing the KRas G12C inhibitors disclosed herein are generally known.

[0089] SOS1 inhibitor compounds In one embodiment, the SOS1 inhibitor is (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, (R)-3-(1-((7-(4-ethyl piperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d ]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof, or a compound selected from the compounds described in ____, as described in more detail herein.

[0090] In another embodiment, the SOS1 inhibitor is a compound of the formula

[0091] [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is hydrogen, hydroxy, C1-C6 alkyl, alkoxy, -N(R 6 )2, -NR6 C(O)R 6 , -C(O)N(R 6 )2, -SO2 alkyl, -SO2NR 6 alkyl, cycloalkyl, -Q-heterocyclyl, aryl, or heteroaryl, each of which is optionally represented by one or more R 2 and each Q is independently a bond, O, or NR 6 and X is N or CR 7 And each R 2 are independently hydroxy, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, -N(R 6 )2, -SO2 alkyl, -NR 6 C(O)C1-C3 alkyl, -C(O)cycloalkyl, -C(O)heterocyclyl, or aryl, each of which is optionally represented by one or more R 11 is replaced by R 3 is hydrogen, C1-C6 alkyl, alkoxy, -N(R 10 )2, cycloalkyl, haloalkyl, heterocyclyl, aryl, or heteroaryl, wherein C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally selected from one or more R 9 and Y is a bond or heteroarylene; R 4 Each optionally contains one or more R 5 and each R is an aryl or heteroaryl substituted with 5 are independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C3 alkyl, haloalkyl, -N(R 6 )2, -1-N(R 6 )2, or -SO2 alkyl, L is C1-C3 alkylene, and each R 6 are independently hydrogen, C1-C3 alkyl, haloalkyl, or cycloalkyl; R 7 is hydrogen, cyano, or alkoxy; R 8 is C1-C2 alkyl or halo-C1-C2 alkyl, and each R9 are independently hydroxy, halogen, amino, cyano, alkoxy, or C1-C3 alkyl, and each R 10 are independently hydrogen, C1-C3 alkyl, or cycloalkyl, and each R 11 is independently C1-C3 alkyl or haloalkyl. These compounds include, but are not limited to, all of the exemplary compounds listed in WO 2021 / 127429, WO 2021 / 173524, WO 2022 / 026465, U.S. Provisional Patent Application No. 63 / 213,112 (and corresponding domestic and international applications and publications) and described in more detail herein, including, in particular, (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile.

[0092] In another embodiment, the SOS1 inhibitor is

[0093] [ka] (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile,

[0094] [ka] 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile,

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

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

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

[0098] [ka] (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile,

[0099] [ka] 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and

[0100] [ka] The compound is selected from (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and pharma- ceutically acceptable salts thereof.

[0101] The SOS1 inhibitors used in the methods of the present invention may have one or more chiral centers and may be synthesized as stereoisomeric mixtures, isomers of the same constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures, or the individual components / isomers may be separated using commercially available reagents and conventional methods for isolating stereoisomers and enantiomers well known to those skilled in the art, for example, using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatography HPLC columns according to the manufacturer's instructions. Alternatively, the compounds of the present invention may be synthesized using optically pure chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Unless otherwise specified, whenever the specification, including the claims, refers to a compound of the present invention, the term "compound" should be understood to include all chiral (enantiomers and diastereomers) and racemic forms.

[0102] In one embodiment, the SOS1 inhibitor compound includes salts thereof, for example salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid; and salts formed from quaternary ammonium salts of the formula --NRZ-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzilate, and diphenylacetate).

[0103] Methods for producing the SOS1 inhibitors disclosed herein are known. For example, co-owned applications WO 2021 / 127429, WO 2021 / 173524, WO 2022 / 026465, and U.S. Provisional Patent Application No. 63 / 213,112 (and corresponding domestic and international applications and publications) describe general reaction schemes for preparing compounds, including adagrasib, and also provide detailed synthetic routes for the preparation of these compounds.

[0104] Pharmaceutical Compositions The SOS1 inhibitor and the EGFR compound, or a pharma- ceutically acceptable salt thereof, may be formulated into a pharmaceutical composition.

[0105] In another aspect, the present invention provides a pharmaceutical composition comprising an SOS1 inhibitor, or a pharma- ceutically acceptable salt thereof, an EGFR inhibitor, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, excipient, or diluent that can be used in the methods disclosed herein. The SOS1 inhibitor, or a pharma- ceutically acceptable salt thereof, and the EGFR inhibitor, or a pharma- ceutically acceptable salt thereof, can be independently formulated by any method known in the art and prepared for administration by any route, including, but not limited to, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain embodiments, the SOS1 inhibitor, or a pharma- ceutically acceptable salt thereof, and / or the KRas G12C inhibitor, or a pharma- ceutically acceptable salt thereof, is administered intravenously in a hospital setting.

[0106] In one embodiment, administration of one or both therapeutic components may be by the oral route.

[0107] The characteristics of the carrier depend on the route of administration. As used herein, the term "pharmaceutical acceptable" refers to a non-toxic material that is compatible with a biological system, such as a cell, cell culture, tissue, or organism, and does not interfere with the effectiveness of the biological activity of the active ingredient. Thus, in addition to the inhibitor, the composition may contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutical acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18 th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0108] As used herein, the term "pharmaceutical acceptable salt" refers to a salt that retains the desired biological activity of the above-identified compound and exhibits minimal or no undesired toxicological effects.Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds may also be administered as pharma- ceutically acceptable quaternary salts known to those of skill in the art, specifically including quaternary ammonium salts of the formula -NR+Z-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzilate, and diphenylacetate).

[0109] The active compound is included in a pharma- ceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing serious toxic effects to the patient being treated. In one embodiment, the dose of the active compound for all the above conditions ranges from about 0.01 to 300 mg / kg per day, e.g., 0.1 to 100 mg / kg, and as a further example, 0.5 to about 25 mg per kilogram of recipient body weight per day. A typical topical dose will be in the range of 0.01 to 3% weight / weight in a suitable carrier. The effective dosage range of the pharma- ceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative or by other means known to those skilled in the art.

[0110] A pharmaceutical composition comprising an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, may be used in the methods of use described herein.

[0111] Simultaneous administration SOS1 inhibitor or its pharmaceutically acceptable salt and EGFR inhibitor or its pharmaceutically acceptable salt can be formulated into separate dosage forms or individual dosage forms, and can be co-administered one after the other.Another option is that when the administration route is the same (e.g., oral), the two active compounds can be formulated into a single form for co-administration, but both methods of co-administration are part of the same therapeutic treatment or regimen.

[0112] The pharmaceutical composition for use in the method, comprising an SOS1 inhibitor or a pharma- ceutically acceptable salt thereof, and / or an EGFR inhibitor or a pharma- ceutically acceptable salt thereof, may be for simultaneous, separate, or sequential use. In one embodiment, the SOS1 inhibitor or a pharma- ceutically acceptable salt thereof is administered before the administration of the EGFR inhibitor or a pharma- ceutically acceptable salt thereof. In another embodiment, the SOS1 inhibitor or a pharma- ceutically acceptable salt thereof is administered after the administration of the EGFR inhibitor or a pharma- ceutically acceptable salt thereof. In another embodiment, the SOS1 inhibitor or a pharma- ceutically acceptable salt thereof is administered approximately simultaneously with the administration of the EGFR inhibitor or a pharma- ceutically acceptable salt thereof.

[0113] In some cases, separate administration of each inhibitor at different times and by different routes may be advantageous. Thus, the components of the combination, i.e., the EGFR inhibitor or a pharma- ceutically acceptable salt thereof and the SOS1 inhibitor or a pharma- ceutically acceptable salt thereof, do not necessarily have to be administered essentially simultaneously or in any order.

[0114] Anticancer drugs are typically administered at a maximum tolerated dose ("MTD"), which is the highest dose of a drug that does not cause unacceptable side effects. In one embodiment, the EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are each administered at their respective MTD. In one embodiment, the EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered at its MTD, and the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered in an amount less than its MTD. In one embodiment, the EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered in an amount less than its MTD, and the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered at its MTD. In one embodiment, the EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are each administered at their respective MTD. Administration may be timed so that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.

[0115] In one embodiment, a single dose of the EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered per day (i.e., about 24 hours apart) (i.e., QD). In another embodiment, two doses of the EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are administered per day (i.e., BID). In another embodiment, three doses of the EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are administered per day (i.e., TID).

[0116] In one embodiment, the SOS1 inhibitor, or its pharma- ceutically acceptable salt or pharmaceutical composition, is administered QD. In another embodiment, the SOS1 inhibitor, or its pharma- ceutically acceptable salt or pharmaceutical composition, is administered BID. In another embodiment, the SOS1 inhibitor of the present invention, or its pharma- ceutically acceptable salt or pharmaceutical composition, is administered TID.

[0117] In one embodiment, a single dose of the EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, are each administered once daily.

[0118] Examples of SOS1 inhibitors suitable for the provided compositions and methods include those described herein, such as, for example, (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyridazin- [3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3, 4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile zonitrile, 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, and (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile.

[0119] Combination therapy In one aspect of the present invention, the present invention provides a method for treating cancer in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.In one embodiment, the cancer is an SOS1-associated cancer.In one embodiment, the SOS1-associated cancer is lung cancer.

[0120] In yet another aspect, the present invention provides a method for increasing the sensitivity of a cancer cell to an SOS1 inhibitor, comprising contacting the cancer cell with an effective amount of a combination of an SOS1 inhibitor, such as MRTX0902, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, such as osimertinib, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the EGFR inhibitor synergistically increases the sensitivity of the cancer cell to the SOS1 inhibitor. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0121] In one embodiment, the combination therapy comprises a compound having the formula

[0122] [ka] (also known as MRTX0902), or a pharma- ceutically acceptable salt thereof, in combination with an EGFR inhibitor.

[0123] In one such embodiment, the EGFR inhibitor is osimertinib.

[0124] In one such embodiment, the EGFR inhibitor is gefitinib.

[0125] In one such embodiment, the EGFR inhibitor is erlotinib.

[0126] In one such embodiment, the EGFR inhibitor is afatinib.

[0127] In one such embodiment, the EGFR inhibitor is osimertinib.

[0128] In one such embodiment, the EGFR inhibitor is brigatinib.

[0129] In one such embodiment, the EGFR inhibitor is icotinib.

[0130] In one such embodiment, the EGFR inhibitor is cetuximab.

[0131] In one embodiment, the combination therapy comprises a combination of osimertinib and an SOS1 inhibitor.

[0132] In one such embodiment, the SOS1 inhibitor is

[0133] [ka] (R)-2-Methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile (MRTX0902).

[0134] In another such embodiment, the SOS1 inhibitor is

[0135] [ka] 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile.

[0136] In yet another such embodiment, the SOS1 inhibitor is

[0137] [ka] (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile.

[0138] In yet another such embodiment, the SOS1 inhibitor is

[0139] [ka] (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile.

[0140] In another embodiment, the SOS1 inhibitor is

[0141] [ka] (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile.

[0142] In another embodiment, the SOS1 inhibitor is

[0143] [ka] (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile.

[0144] In another embodiment, the SOS1 inhibitor is

[0145] [ka] 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile.

[0146] In another embodiment, the SOS1 inhibitor is

[0147] [ka] (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile.

[0148] The method described herein is designed to inhibit the unwanted cell proliferation resulting from the enhanced EGFR activity in cells.The degree of inhibitory activity of SOS1 inhibitor-EGFR inhibitor combination in cells can be monitored, for example, by measuring cell viability and the functional inhibition of both RAF / MEK / ERK and PI3K / AKT effector pathway signaling (the amount of phosphorylated ERK and AKT, respectively) to evaluate the effectiveness of treatment, and the dosage can be adjusted by the attending physician accordingly.

[0149] The compositions and methods provided herein may be used for the treatment of SOS1-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, wherein the EGFR inhibitor synergistically increases the sensitivity of the SOS1-associated cancer to the SOS1 inhibitor. In one embodiment, the SOS1-associated cancer is a cancer with a genetic alteration in the MAPK pathway. In one embodiment, the SOS1-associated cancer is a cancer mediated by SOS1. In one embodiment, the SOS1-associated cancer is selected from the group consisting of leukemia, uterine cancer, lung cancer, colorectal cancer, and pancreatic cancer. In one embodiment, the leukemia is acute myeloid leukemia (AML). In one embodiment, the lung cancer is lung adenocarcinoma. In one embodiment, the lung cancer is non-small cell lung cancer. In one embodiment, the pancreatic cancer is pancreatic ductal carcinoma.

[0150] In one embodiment, a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in an increase in overall survival ("OS") in a subject, compared to treatment with an SOS1 inhibitor alone. In one embodiment, a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in an increase in progression-free survival ("PFS") in a subject, compared to treatment with an SOS1 inhibitor alone. In one embodiment, a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in an increase in tumor regression in a subject, compared to treatment with an SOS1 inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor growth inhibition in a subject compared to treatment with an SOS1 inhibitor alone. In one embodiment, a combination of a therapeutically effective amount of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, results in improved stable disease duration in a subject compared to treatment with an SOS1 inhibitor alone.

[0151] In one embodiment, the SOS1 inhibitor is (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl) -2-Methylbenzonitrile, (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl )benzonitrile, (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7 -((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof.

[0152] In another embodiment, an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, is administered in combination with an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, when disease progression is observed with SOS1 monotherapy, and the combination therapy results in enhanced clinical benefit for the patient by increasing OS, PFS, tumor regression, tumor growth inhibition, or stable disease in the patient.

[0153] In one embodiment, the therapeutic combination comprises therapeutically effective amounts of osimertinib and (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt thereof.

[0154] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of osimertinib and 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof.

[0155] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of osimertinib and (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof.

[0156] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of osimertinib and (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt thereof.

[0157] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of osimertinib and (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof.

[0158] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of osimertinib and (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, or a pharma- ceutically acceptable salt thereof.

[0159] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of osimertinib and 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof.

[0160] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of osimertinib and (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof.

[0161] The compositions and methods provided herein may be used to treat a variety of cancers, including tumors such as lung, colon, pancreatic, prostate, breast, brain, skin, cervical, testicular cancer, etc. More specifically, cancers that may be treated by the compositions and methods of the present invention include, but are not limited to, astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid cancers and sarcomas. More specifically, these compounds may be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrohamartoma, mesothelioma; Gastrointestinal: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), Stomach (carcinoma, lymphoma, smooth muscle sarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, cancer, sarcoma); testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder cancer, ampullary carcinoma, cholangiocarcinoma; bone: osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma , osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);Gynecological: uterine cancer (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (cancer); hematological system : Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentigo dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer.;

[0162] Also provided herein is a method of treating cancer in a subject in need of such treatment, the method comprising: (a) determining that the cancer is associated with SOS1 overexpression (e.g., determined using a regulatory agency approved, e.g., FDA approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a combination of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and an EGFR inhibitor, or a pharma-ceutically acceptable salt or pharmaceutical composition thereof, wherein the EGFR inhibitor synergistically increases the sensitivity of the SOS1-associated cancer to the SOS1 inhibitor.In one embodiment, the EGFR inhibitor is selected from osimertinib, gefitinib, erlotinib, afatinib, brigatinib, icotinib, cetuximab, and other small and large molecule EGFR inhibitors, and the SOS1 inhibitor is (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, 3-((R)-1-((7-((S)-hexahydropyrazine (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(4- Methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl) benzonitrile, 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile, or a pharma- ceutically acceptable salt thereof.

[0163] In one embodiment, the therapeutic combination comprises a therapeutically effective amount of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile or a pharma- ceutically acceptable salt thereof.

[0164] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile or a pharma- ceutically acceptable salt thereof.

[0165] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of (R)-3-(1-((7-(3-(dimethylamino)-3-methylazetidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile or a pharma- ceutically acceptable salt thereof.

[0166] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of (R)-2-methyl-3-(1-((4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile or a pharma- ceutically acceptable salt thereof.

[0167] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of (R)-3-(1-((7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile or a pharma- ceutically acceptable salt thereof.

[0168] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of (R)-2-methyl-3-(1-((4-methyl-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile or a pharma- ceutically acceptable salt thereof.

[0169] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of 3-((R)-1-((7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile or a pharma- ceutically acceptable salt thereof.

[0170] In a further embodiment, the therapeutic combination comprises a therapeutically effective amount of (R)-3-(1-((6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile or a pharma- ceutically acceptable salt thereof.

[0171] In one embodiment, the SOS1 inhibitor, the EGFR inhibitor, or both are administered as a tablet or capsule for a period of time. In one embodiment, the tablet or capsule formulation of the SOS1 inhibitor and / or the EGR inhibitor comprises one or more of about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, and about 2000 mg. In one embodiment, the SOS1 inhibitor and / or the EGFR inhibitor is administered orally once daily (QD) every day for a period of time. In one embodiment, the SOS1 inhibitor and / or the EGFR inhibitor is administered orally twice daily (BID) every day for a period of time.

[0172] In one embodiment, the SOS1 inhibitor and / or EGFR inhibitor is administered over a period of time at a dose of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, etc. g, approx. 20 mg to approx. 180 mg, approx. 20 mg to approx. 160 mg, approx. 20 mg to approx. 140 mg, approx. 20 mg to approx. 120 mg, approx. 20 mg to approx. 100 mg, approx. 0mg, 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 40m g~280mg, 40mg~260mg, 40mg~240mg, 40mg~220mg, 40mg~200mg, 40mg~180mg, 40mg~160mg, 40mg~140mg, 40mg~120mg, 40mg~100mg , approx. 40 mg ~ approx. 80 mg, approx. 40 mg ~ approx. 60 mg, approx. 60 mg ~ approx. 500 mg, approx. 60 mg ~ approx. 480 mg, approx. 60 mg ~ approx. 460 mg, approx. 60 mg ~ approx. 440 mg, approx. 0mg, about 60mg to about 340mg, about 60mg to about 320mg, about 60mg to about 300mg, about 60mg to about 280mg, about 60mg to about 260mg, about 60mg to about 240mg, about 60mg to about 220mg, about 60mg to about 200mg, about 60mg to about 180mg, about 60m g ~ about 160mg, about 60mg - about 140mg, about 60mg - about 120mg, about 60mg - about 100mg, about 60mg - about 80mg, about 80mg - about 500mg, about 80mg - about 480mg, about 80mg - about 460mg, about 80mg - about 440mg, about 80mg - about 420mg,about 80 mg to about 400 mg, about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 mg to about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg to about 480 mg, about 100 mg to about 460 mg, about 100 mg to about 440 mg, about 100 mg to about 420 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 mg to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 500 mg, about 120 mg to about 480 mg, about 120 mg to about 460 mg, about 120 mg to about 440 mg, about 120 mg to about 420 mg, about 120 mg to about 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 500 mg, about 140 mg to about 480 mg, about 140 mg to about 460 mg, about 140 mg to about 440 mg, about 140 mg to about 420 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mgAbout 140 mg to about 160 mg, about 160 mg to about 500 mg, about 160 mg to about 480 mg, about 160 mg to about 460 mg, about 160 mg to about 440 mg, about 160 mg to about 420 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 500 mg, about 180 mg to about 480 mg, about 180 mg to about 460 mg, about 180 mg to about 440 mg, about 180 mg to about 420 mg, about 180 mg to about 400 mg, about 180 mg to about 380 mg, about 180 mg to about 360 mg, about 180 mg to about 340 mg, about 180 mg to about 320 mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about 260 mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about 200 mg, about 200 mg to about 500 mg, about 200 mg to about 480 mg, about 200 mg to about 460 mg, about 200 mg to about 440 mg, about 200 mg to about 420 mg, about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about 340 mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about 200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about 220 mg, about 220 mg to about 500 mg, about 220 mg to about 480 mg, about 220 mg to about 460 mg, about 220 mg to about 440 mg, about 220 mg to about 420 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about 280 mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about 500 mg, about 240 mg to about 480 mg, about 240 mg to about 460 mg, about 240 mg to about 440 mg, about 240 mg to about 420 mg, about 240 mg to about 400 mg, about 240 mg to about 380 mg, about 240 mg to about 360 mgAbout 240 mg to about 340 mg, about 240 mg to about 320 mg, about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 500 mg, about 260 mg to about 480 mg, about 260 mg to about 460 mg, about 260 mg to about 440 mg, about 260 mg to about 420 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 500 mg, about 280 mg to about 480 mg, about 280 mg to about 460 mg, about 280 mg to about 440 mg, about 280 mg to about 420 mg, about 280 mg to about 400 mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about 340 mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg, about 300 mg to about 500 mg, about 300 mg to about 480 mg, about 300 mg to about 460 mg, about 300 mg to about 440 mg, about 300 mg to about 420 mg, about 300 mg to about 400 mg, about 300 mg to about 380 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 500 mg, about 320 mg to about 480 mg, about 320 mg to about 460 mg, about 320 mg to about 440 mg, about 320 mg to about 420 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 320 mg to about 340 mg, about 340 mg to about 500 mg, about 340 mg to about 480 mg, about 340 mg to about 460 mg, about 340 mg to about 440 mg, about 340 mg to about 420 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 500 mg, about 360 mg to about 480 mg, about 360 mg to about 460 mg, about 360 mg to about 440 mg, about 360 mg to about 420 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 500 mg, about 380 mg to about 480 mg, about 380 mg to about 460 mg, about 380 mg to about 440 mg, about 380 mg to about 420 mg, about 380 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 480 mg, about 400 mg to about 460 mg,About 400 mg to about 440 mg, about 400 mg to about 420 mg, about 420 mg to about 500 mg, about 420 mg to about 480 mg, about 420 mg to about 460 mg, about 420 mg to about 440 mg, about 440 mg to about 500 mg, about 440 mg to about 480 mg, about 440 mg to about 460 mg, about 460 mg to about 500 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg). In one embodiment, the SOS1 inhibitor and / or EGFR inhibitor is orally administered twice a day (BID) every day for a certain period of time. In one embodiment, adagrasib is administered orally twice daily (BID) every day for a period of time.

[0173] In one embodiment, the combination therapy includes oral administration of an SOS1 inhibitor and / or an EGFR inhibitor, each independently, for example, about 10 mg to about 400 mg (e.g., about 10 mg to about 380 mg, about 10 mg to about 360 mg, about 10 mg to about 340 mg, about 10 mg to about 320 mg, about 10 mg to about 300 mg, about 10 mg to about 280 mg, about 10 mg to about 260 mg, about 10 mg to about 240 mg, about 10 mg to about 220 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, about 10 mg to about 240 mg, about 10 mg to about 26 ...60 mg, about 10 mg to about 240 mg, about 10 mg to about 260 mg, about 10 mg to about 260 mg, about 10 mg to about 260 mg, about 10 mg to about 260 mg, about 10 mg to about 260 mg, about 10 mg to about 260 mg, about 10 mg to about 260 mg, about 10 mg to about mg, approx. 10 mg ~ approx. 100 mg, approx. 10 mg ~ approx. 80 mg, approx. 10 mg ~ approx. 60 mg, approx. 10 mg ~ approx. 40 mg, approx. 10 mg ~ approx. 20 mg, approx. 20 mg ~ approx. 400 mg, approx. 20mg, 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 20 mg ~ about 120mg, about 20mg - about 100mg, about 20mg - about 80mg, about 20mg - about 60mg, about 20mg - about 40mg, about 40mg - about 400mg, about 40mg - about 380mg, about 40mg - about 360mg, about 40mg - about 340mg, about 40mg - about 320mg, About 40mg to about 300mg, about 40mg to about 280mg, about 40mg to about 260mg, about 40mg to about 240mg, about 40mg to about 220mg, about 40mg to about 200mg, about 40mg to about 180mg, about 40mg to about 160mg, about 40mg to about 140mg, about 40mg to about 1 20mg, about 40mg to about 100mg, about 40mg to about 80mg, about 40mg to about 60mg, about 60mg to about 400mg, about 60mg to about 380mg, about 60mg to about 360mg, about 60mg to about 340mg, about 60mg to about 320mg, about 60mg to about 300mg, about 60mg ~280mg, 60mg~260mg, 60mg~240mg, 60mg~220mg, 60mg~200mg, 60mg~180mg, 60mg~160mg, 60mg~140mg, 60mg~120mg, 60mg~100mg,About 60 mg to about 80 mg, about 80 mg to about 400 mg, about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 mg to about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 mg to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mgApproximately 180mg to approximately 400mg, approximately 180mg to approximately 380mg, approximately 180mg to approximately 360mg, approximately 180mg to approximately 340mg, approximately 180mg to approximately 320mg, approximately 180mg to approximately 300mg, approximately 180mg to approximately 280mg, approximately 180mg to approximately 260mg, approximately 180mg to approximately 24 0mg, about 180mg to about 220mg, about 180mg to about 200mg, about 200mg to about 400mg, about 200mg to about 380mg, about 200mg to about 360mg, about 200mg to about 340mg, about 200mg to about 320mg, about 200mg to about 300mg, about 200mg ~280mg, 200mg~260mg, 200~240mg, 200~220mg, 220~400mg, 220~380mg, 220~360mg, 220~340mg, 220~320mg, 2 20mg to about 300mg, about 220mg to about 280mg, about 220mg to about 260mg, about 220mg to about 240mg, about 240mg to about 400mg, about 240mg to about 380mg, about 240mg to about 360mg, about 240mg to about 340mg, about 240mg to about 320mg , about 240 mg to about 300 mg, about 240 mg to about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 3 00mg, about 260mg to about 280mg, about 280mg to about 400mg, about 280mg to about 380mg, about 280mg to about 360mg, about 280mg to about 340mg, about 280mg to about 320mg, about 280mg to about 300mg, about 300mg to about 400mg, about 300m about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 340 mg to about 360 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 400 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg) once or twice a day (during a certain period).The KRas G12C inhibitor adagrasib or a pharma- ceutically acceptable salt or pharmaceutical composition thereof is orally administered once daily. In another embodiment, the KRas G12C inhibitor or a pharma- ceutically acceptable salt or pharmaceutical composition thereof is orally administered twice daily.

[0174] Those of skill in the art will recognize that both in vivo and in vitro tests using suitable, known and generally accepted cellular and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0175] One of ordinary skill in the art will further recognize that human clinical trials, including first-in-human dose ranging and efficacy studies in healthy patients and / or patients afflicted with a given disorder, can be completed according to methods well known in the clinical and medical arts.

[0176] Synergy In one embodiment, the addition of an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, synergistically increases the activity of an SOS1 inhibitor compound, such as MRTX0902, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, against a cancer or cancer cell line that overexpresses SOS1.Any method for determining whether two compounds exhibit synergistic activity can be used to determine the synergistic effect of the combination.

[0177] Several mathematical models have been developed to determine whether two compounds act synergistically, i.e., beyond a mere additive effect. For example, Loewe Additivity (Loewe (1928) Physiol. 27:47-187), Bliss Independence (Bliss (1939) Ann. Appl. Biol. 26:585-615), Best Single Agent, ZIP (Yadav et al (2015) Comput Struct Biotech J 13:504-513) and other models (Chou & Talalay (1984) Adv Enzyme Regul 22:27-55. #6382953, and Greco et al. (1995) Pharmacol Rev 47(2):331-85. #7568331) are well known models in the pharmaceutical industry and can be used to calculate a "synergy score" indicating whether synergy has been detected and the magnitude of such synergy. These synergy scores are combined to provide a composite synergy score that can be used to evaluate and characterize EGFR inhibitors, such as osimertinib, and SOS1 inhibitors, such as MRTX0902.

[0178] Generally, the mathematical model uses data obtained from the single agent values ​​to determine the predicted additive effect of the combination, which is compared to the observed effect for the combination. If the observed effect is greater than the predicted effect, the combination is considered to be synergistic. For example, the Bliss independence model uses the observed combination response (Y O ) to the predicted combination response (Y P ) typically compared with Y O Y P If it is greater, the combined effect is deemed to be synergistic.

[0179] As used herein, "synergy" refers to a combination of an EGFR inhibitor or a pharma- ceutically acceptable salt thereof and an SOS1 inhibitor or a pharma- ceutically acceptable salt thereof that results in any of the beneficial or desired results, including, for example, the clinical outcomes or endpoints described herein, which is greater than the sum of the effects observed when the compounds, for example, the compounds described in the SOS1 patent applications listed herein, for example, MRTX0902, and the EGFR inhibitor or a pharma- ceutically acceptable salt thereof, for example, osimertinib, are administered alone.

[0180] In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile and osimertinib. In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of 3-((R)-1-((7-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile and osimertinib. 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 osimertinib. 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 osimertinib. 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 osimertinib. 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 osimertinib. 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 osimertinib. 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 osimertinib.

[0181] In some embodiments, the methods provided herein provide a method for administering a therapeutically effective amount of a compound to a patient for a period of 1 day to 2 years (e.g., 1 day to 22 months, 1 day to 20 months, 1 day to 18 months, 1 day to 16 months, 1 day to 14 months, 1 day to 12 months, 1 day to 10 months, 1 day to 9 months, 1 day to 8 months, 1 day to 7 months, 1 day to 6 months, 1 day to 5 months, 1 day to 4 months, 1 day to 3 months, 1 day to 2 months, 1 day to 1 month, 1 week to 2 years, 1 week to 22 months, 1 week to 20 months, 1 week to 18 months, 1 week to 16 months, 1 week to 14 months, 1 week to 12 months, 1 week to 10 months, 1 week to 9 months, 1 week to 8 months, 1 week to 7 months, 1 week to 6 months, 1 week to 5 months, 1 week to 5 months, 1 week to 6 months, 1 week to 7 months, 1 week to 5 months, 1 week to 8 months, 1 week to 9 months, 1 week to 8 ... months, 1 week to 4 months, 1 week to 3 months, 1 week to 2 months, 1 week to 1 month, 2 weeks to 2 years, 2 weeks to 22 months, 2 weeks to 20 months, 2 weeks to 18 months, 2 weeks to 16 months, 2 weeks to 14 months, 2 weeks to 12 months, 2 weeks to 10 months, 2 weeks to 9 months, 2 weeks to 8 months, 2 weeks to 7 months, 2 weeks to 6 months, 2 weeks to 5 months, 2 weeks to 4 months, 2 weeks to 3 months, 2 weeks to 2 months, 2 weeks to 1 month, 1 month to 2 years, 1 month to 22 months, 1 month to 20 months, 1 month to 18 months, 1 month to 16 months, 1 month to 14 months, 1 month to 12 months, 1 month to 10 months, 1 month to 9 months, 1 month to 8 months, 1 month to 7 months , 1 month to 6 months, 1 month to 6 months, 1 month to 5 months, 1 month to 4 months, 1 month to 3 months, 1 month to 2 months, 2 months to 2 years, 2 months to 22 months, 2 months to 20 months, 2 months to 18 months, 2 months to 16 months, 2 months to 14 months, 2 months to 12 months, 2 months to 10 months, 2 months to 9 months, 2 months to 8 months, 2 months to 7 months, 2 months to 6 months, or 2 months to 5 months, 2 months to 4 months, 3 months to 2 years, 3 months to 22 months, 3 months to 20 months, 3 months to 18 months, 3 months to 16 months, 3 months to 14 months, 3 months to 12 months, 3 months to 10 months, 3 months to 8 months, 3 months between 1% and 99% (e.g., compared to the size of the patient's one or more solid tumors prior to treatment) of the volume of one or more solid tumors in a patient treated with the combination therapy within a period of 4 months to 6 months, 4 months to 2 years, 4 months to 22 months, 4 months to 20 months, 4 months to 18 months, 4 months to 16 months, 4 months to 14 months, 4 months to 12 months, 4 months to 10 months, 4 months to 8 months, 4 months to 6 months, 6 months to 2 years, 6 months to 22 months, 6 months to 20 months, 6 months to 18 months, 6 months to 16 months, 6 months to 14 months, 6 months to 12 months, 6 months to 10 months, or 6 months to 8 months1%~98%、1%~95%、1%~90%、1~85%、1~80%、1%~75%、1%~70%、1%~65%、1%~60%、1%~55%、1%~50%、1%~45%、1%~40%、1%~35%、1%~30%、1%~25%、1%~20%、1%~15%、1%~10%、1%~5%、2%~99%、2%~90%、2%~85%、2%~80%、2%~75%、2%~70%、2%~65%、2%~60%、2%~55%、2%~50%、2%~45%、2%~40%、2%~35%、2%~30%、2%~25%、2%~20%、2%~15%、2%~10%、2%~5%、4%~99%、4%~95%、4%~90%、4%~85%、4%~80%、4%~75%、4%~70%、4%~65%、4%~60%、4%~55%、4%~50%、4%~45%、4%~40%、4%~35%、4%~30%、4%~25%、4%~20%、4%~15%、4%~10%、6%~99%、6%~95%、6%~90%、6%~85%、6%~80%、6%~75%、6%~70%、6%~65%、6%~60%、6%~55%、6%~50%、6%~45%、6%~40%、6%~35%、6%~30%、6%~25%、6%~20%、6%~15%、6%~10%、8%~99%、8%~95%、8%~90%、8%~85%、8%~80%、8%~75%、8%~70%、8%~65%、8%~60%、8%~55%、8%~50%、8%~45%、8%~40%、8%~35%、8%~30%、8%~25%、8%~20%、8%~15%、10%~99%、10%~95%、10%~90%、10%~85%、10%~80%、10%~75%、10%~70%、10%~65%、10%~60%、10%~55%、10%~50%、10%~45%、10%~40%、10%~35%、10%~30%、10%~25%、10%~20%、10%~15%、15%~99%、15%~95%、15%~90%、15%~85%、15%~80%、15%~75%、15%~70%、15%~65%、15%~60%、15%~55%、15%~50%、15%~55%、15%~50%、15%~45%、15%~40%、15%~35%、15%~30%、15%~25%、15%~20%、20%~99%、20%~95%、20%~90%、20%~85%、20%~80%、20%~75%、20%~70%、20%~65%、20%~60%、20%~55%、20%~50%、20%~45%、20%~40%、20%~35%、20%~30%、20%~25%、25%~99%、25%~95%、25%~90%、25%~85%、25%~80%、25%~75%、25%~70%、25%~65%、25%~60%、25%~55%、25%~50%、25%~45%、25%~40%、25%~35%、25%~30%、30%~99%、30%~95%、30%~90%、30%~85%、30%~80%、30%~75%、30%~70%、30%~65%、30%~60%、30%~55%、30%~50%、30%~45%、30%~40%、30%~35%、35%~99%、35%~95%、35%~90%、35%~85%、35%~80%、35%~75%、35%~70%、35%~65%、35%~60%、35%~55%、35%~50%、35%~45%、35%~40%、40%~99%、40%~95%、40%~90%、40%~85%、40%~80%、40%~75%、40%~70%、40%~65%、40%~60%、40%~55%、40%~60%、40%~55%、40%~50%、40%~45%、45%~99%、45%~95%、45%~95%、45%~90%、45%~85%、45%~80%、45%~75%、45%~70%、45%~65%、45%~60%、45%~55%、45%~50%、50%~99%、50%~95%、50%~90%、50%~85%、50%~80%、50%~75%、50%~70%、50%~65%、50%~60%、50%~55%、55%~99%、55%~95%、55%~90%、55%~85%、55%~80%、55%~75%、55%~70%、55%~65%、55%~60%、60%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、65%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、70%~99%、70%~95%、70%~90%、70%~85%、70%~80%、70%~75%、75%~99%、75%~95%、75%~90%、75%~85%、75%~80%、This may result in a reduction of 80% to 99%, 80% to 95%, 80% to 90%, 80% to 85%, 85% to 99%, 85% to 95%, 85% to 90%, 90% to 99%, 90% to 95%, or 95% to 100%).

[0182] The phrase "survival time" refers to the length of time between the identification or diagnosis of cancer (e.g., any of the cancers described herein) in a mammal by a medical professional and the time of death of the mammal (caused by the cancer). Methods of increasing survival time in a mammal having cancer are described herein.

[0183] In some embodiments, any of the methods described herein provide an improvement or reduction in patient survival (e.g., between 1% and 400%, between 1% and 380%, between 1% and 360%, between 1% and 340%, between 1% and 320%, between 1% and 300%, between 1% and 280%, between 1% and 260%, between 1% and 240%, between 1% and 220%, between 1% and 200%, between 1% and 180%, between 1% and 160%, between 1% and 140%, between 1% and 120%, between 1% and 100%, between 1% and 95%, between 1% and 90%, between 1% and 85%, between 1% and 80%, between 1% and 75%, 1%~70%, 1%~65%, 1%~60%, 1%~55%, 1%~50%, 1%~45%, 1%~40%, 1%~35%, 1%~30%, 1%~25%, 1%~20%, 1%~15%, 1%~10%, 1%~5%, 5%~400%, 5%~380%, 5%~360%, 5%~3 40%, 5%~320%, 5%~300%, 5%~280%, 5%~260%, 5%~240%, 5%~220%, 5%~200%, 5%~180%, 5%~160%, 5%~140%, 5%~120%, 5%~100%, 5%~90%, 5%~80%, 5%~70%, 5%~6 0%, 5%~50%, 5%~40%, 5%~30%, 5%~20%, 5%~10%, 10%~400%, 10%~380%, 10%~360%, 10%~340%, 10%~320%, 10%~300%, 10%~280%, 10%~260%, 10%~240%, 10%~22 0%, 10%~200%, 10%~180%, 10%~160%, 10%~140%, 10%~120%, 10%~100%, 10%~90%, 10%~80%, 10%~70%, 10%~60%, 10%~50%, 10%~40%, 10%~30%, 10%~20%, 20%~ 400%, 20%~380%, 20%~360%, 20%~340%, 20%~320%, 20%~300%, 20%~280%, 20%~260%, 20%~240%, 20%~220%, 20%~200%, 20%~180%, 20%~160%, 20%~140%, 20% ~120%, 20%~100%, 20%~90%, 20%~80%, 20%~70%, 20%~60%, 20%~50%, 20%~40%, 20%~30%, 30%~400%, 30%~380%, 30%~360%, 30%~340%, 30%~320%, 30%~300%,30%~280%、30%~260%、30%~240%、30%~220%、30%~200%、30%~180%、30%~160%、30%~140%、30%~120%、30%~100%、30%~90%、30%~80%、30%~70%、30%~60%、30%~50%、30%~40%、40%~400%、40%~380%、40%~360%、40%~340%、40%~320%、40%~300%、40%~280%、40%~260%、40%~240%、40%~220%、40%~200%、40%~180%、40%~160%、40%~140%、40%~120%、40%~100%、40%~90%、40%~80%、40%~70%、40%~60%、40%~50%、50%~400%、50%~380%、50%~360%、50%~340%、50%~320%、50%~300%、50%~280%、50%~260%、50%~240%、50%~220%、50%~200%、50%~180%、50%~160%、50%~140%、50%~140%、50%~120%、50%~100%、50%~90%、50%~80%、50%~70%、50%~60%、60%~400%、60%~380%、60%~360%、60%~340%、60%~320%、60%~300%、60%~280%、60%~260%、60%~240%、60%~220%、60%~200%、60%~180%、60%~160%、60%~140%、60%~120%、60%~100%、60%~90%、60%~80%、60%~70%、70%~400%、70%~380%、70%~360%、70%~340%、70%~320%、70%~300%、70%~280%、70%~260%、70%~240%、70%~220%、70%~200%、70%~180%、70%~160%、70%~140%、70%~120%,~100%、70%~90%、70%~80%、80%~400%、80%~380%、80%~360%、80%~340%、80%~320%、80%~300%、80%~280%、80%~260%、80%~240%、80%~220%、80%~200%、80%~180%、80%~160%、80%~140%、80%~120%、80%~100%、80%~90%、90%~400%、90%~380%、90%~360%、90%~340%、90%~320%、90%~300%、90%~280%、90%~260%、90%~240%、90%~220%、90%~200%、90%~180%、90%~160%、90%~140%、90%~120%、90%~100%、100%~400%、100%~380%、100%~360%、100%~340%、100%~320%、100%~300%、100%~280%、100%~260%、100%~240%、100%~220%、100%~200%、100%~180%、100%~160%、100%~140%、100%~120%、120%~400%、120%~380%、120%~360%、120%~340%、120%~320%、120%~300%、120%~280%、120%~260%、120%~240%、120%~220%、120%~200%、120%~180%、120%~160%、120%~140%、140%~400%、140%~380%、140%~360%、140%~340%、140%~320%、140%~300%、140%~280%、140%~260%、140%~240%、140%~220%、140%~200%、140%~180%、140%~160%、160%~400%、160%~380%、160%~360%、160%~340%、160%~320%、160%~300%、160%~280%、160%~260%、160%~240%、160%~220%、160%~200%、160%~180%、180%~400%、180%~380%、180%~360%、180%~340%、180%~320%、180%~300%、180%~280%、180%~260%、180%~240%、180%~220%、180%~200%、200%~400%、200%~380%、200%~360%、200%~340%、200%~320%、200%~300%、200%~280%、200%~260%、200%~240%、200%~220%、220%~400%、220%~380%、220%~360%、220%~340%、220%~320%、220%~300%、220%~280%、220%~260%、220%~240%、240%~400%、240%~380%、240%~360%, 240%~340%, 240%~320%, 240%~300%, 240%~280%, 240%~260%, 260%~400%, 260%~380%, 260%~360%, 260%~340%, 260%~320%, 260%~300%, 260%~2 80%, 280% to 400%, 280% to 380%, 280% to 360%, 280% to 340%, 280% to 320%, 280% to 300%, 300% to 400%, 300% to 380%, 300% to 360%, 300% to 340%, or 300% to 320%).

[0184] In some embodiments of any of the methods described herein, prior to treatment with a composition or method of the invention, the patient has been treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, optionally where the previous treatment has been unsuccessful, and / or the patient has been subjected to surgery, optionally where the surgery has been unsuccessful, and / or the patient has been treated with a platinum-based chemotherapy agent, optionally where the patient has been previously determined to be non-responsive to treatment with a platinum-based chemotherapy agent, and / or the patient has been treated with a kinase inhibitor, optionally where the previous treatment with the kinase inhibitor has been unsuccessful, and / or the patient has been treated with one or more other therapeutic agents.

[0185] kit The present invention also relates to a kit comprising an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof (e.g., MRTX0902), and an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof (e.g., osimertinib). Also provided is a kit for use in the treatment of hematological cancer, comprising such an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and such an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0186] In a related aspect, the present invention provides a kit containing a dose of an SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and a dose of an EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, in an amount effective to inhibit the proliferation of cancer cells, particularly SOS1-overexpressing cancer cells, in a subject. The kit optionally includes a package insert containing instructions for administering the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, and the EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof. The package insert may provide the user with a set of instructions for using the SOS1 inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof in combination with the EGFR inhibitor, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof.

[0187] The following examples are intended to illustrate further certain embodiments of the present invention and are not intended to limit the scope of the invention.

[0188] Example A In vivo model to investigate SOS1 inhibitor-EGFR inhibitor combinations Immunocompromised nude / nude mice were inoculated with NCI-H1975 cells harboring the EGFR L585R / T790M mutation in the right hind flank. The size of the tumor volume was 200–400 mm. 3When the tumor reaches a mass index of 100, the mice are divided into four groups of 4-12 mice each. The first group receives vehicle only. The second and third groups receive a single-dose of the EGFR inhibitor osimertinib at a concentration of 2.5 mg / kg or 5 mg / kg, which results in a less than maximal biological effect and does not result in complete tumor regression. The fourth group receives a single-dose of the SOS1 inhibitor MRTX0902 at a concentration of 50 mg / kg, which results in a maximal biological effect but does not result in complete tumor regression. The fourth and fifth groups receive a single-dose of the EGFR inhibitor in combination with a single-dose of the SOS1 inhibitor. The treatment period was 21 days. Tumor volumes are measured every 2-3 days using calipers, and tumor volumes are calculated by the formula: 0.5 x (length x width)2. The greater degree of tumor growth inhibition for the combination in this model demonstrates that combination therapy is more likely to have a clinically meaningful benefit to the treated subjects compared to treatment with an EGFR inhibitor alone.

[0189] 5 × 10 6 NCI-H1975 cells were inoculated into the tumors. 3 When the MC value reached 0 (study day 0), five mice in each of six groups were orally dosed daily for 21 days with: vehicle only (0.5% MC (4000 cps) in water / 0.2% Tween 80), 2.5 mg / kg or 5 mg / kg of the EGFR inhibitor osimertinib (5% DMSO, 45% PEG400, 50% water), 50 mg / kg of the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile (MRTX0902) (0.5% MC (4000 cps) in water / 0.2% Tween 80), or 50 mg / kg of MRTX0902 and either 2.5 mg / kg or 5 mg / kg of osimertinib. Tumor volumes measured on prespecified days for five mice per group were averaged and are reported in Table 1 and FIG. 1 for NCI-H1975 cells.

[0190] [Table 1]

[0191] As shown in Figure 1 and Table 1, administration of osimertinib at 2.5 mg / kg or 5 mg / kg as a single agent resulted in 89% tumor growth and -71% tumor regression, respectively, at day 17. Administration of MRTX0902 at 50 mg / kg BID as a single agent resulted in 26% tumor growth inhibition. The combination of the SOS1 inhibitor MRTX0902 with osimertinib at 2.5 mg / kg or 5 mg / kg resulted in -22.6% and -92.3% tumor regression, respectively, at day 17.

[0192] These results demonstrate that the combination therapy resulted in a greater amount of tumor growth inhibition compared to either single agent alone, demonstrating enhanced in vivo antitumor efficacy of the combination against EGFR L858R T790M-expressing cancers.

[0193] While the invention has been described in relation to particular embodiments thereof, it will be understood that it is capable of further modifications, and this application is intended to cover any variations, uses, or adaptations of the invention in accordance with the principles of the invention generally, within known or customary practice in the art to which the invention pertains, which may be applied to the essential features described above, and which include departures from the present disclosure as follows within the scope of the appended claims.

[0194] Example B In vivo model to investigate SOS1 inhibitor-EGFR inhibitor combinations Immunocompromised NOD / SCID mice were inoculated with PC9 cells carrying the EGFR exon 19del (E746_A750del) mutation into the right hind flank. The tumor volume was 100–150 mm in size. 3When the mice reach a tumor size of 100 mm, the mice are divided into four groups of 4-12 mice each. The first group receives vehicle only. The second and third groups receive a single-dose of the EGFR inhibitor osimertinib at a concentration of 2.5 mg / kg or 5 mg / kg, which results in a less than maximal biological effect and does not result in complete tumor regression. The fourth group receives a single-dose of the SOS1 inhibitor MRTX0902 at a concentration of 50 mg / kg, which results in a maximal biological effect but does not result in complete tumor regression. The fourth and fifth groups receive a single-dose of the EGFR inhibitor in combination with a single-dose of the SOS1 inhibitor. The treatment period was 27 days. Tumor volumes are measured every 2-3 days using calipers, and tumor volumes are calculated by the formula: 0.5 x (length x width)2. The greater degree of tumor growth inhibition for the combination in this model demonstrates that combination therapy is more likely to have a clinically meaningful benefit to the treated subjects compared to treatment with an EGFR inhibitor alone.

[0195] 5 × 10 in the right hind limbs of 30 NOD / SCID mice 6 PC9 cells were inoculated. The tumor volume was approximately 100–150 mm 3 When the baseline serum concentration reached 0.05 mg / kg (study day 0), five mice in each of six groups were orally dosed daily for 27 days with: vehicle alone (0.5% MC (4000 cps) in water / 0.2% Tween 80), 2.5 mg / kg or 5 mg / kg of the EGFR inhibitor osimertinib (5% DMSO, 45% PEG400, 50% water), 50 mg / kg of the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile (MRTX0902) (0.5% MC (4000 cps) in water / 0.2% Tween 80), or 50 mg / kg of MRTX0902 and either 2.5 mg / kg or 5 mg / kg of osimertinib. Tumor volumes measured on prespecified days for five mice per group were averaged and are reported in Table 2 and FIG. 2 for PC9 cells.

[0196] [Table 2]

[0197] As shown in Figure 2 and Table 2, administration of osimertinib at 2.5 mg / kg or 5 mg / kg as a single agent resulted in 92.8% tumor growth and -32.5% tumor regression, respectively, at day 27. Administration of MRTX0902 at 50 mg / kg BID resulted in 54% tumor growth inhibition. The combination of the SOS1 inhibitor MRTX0902 with osimertinib at 2.5 mg / kg or 5 mg / kg resulted in -55.3% and -78% tumor regression, respectively, at day 27.

[0198] These results demonstrate that the combination therapy resulted in a greater amount of tumor growth inhibition compared to either single agent alone, demonstrating enhanced in vivo antitumor efficacy of the combination against EGFR exon 19del (E746_A750del)-expressing cancers.

Claims

1. A pharmaceutical composition for use in a method of treating cancer in a person requiring cancer treatment, The above method involves a therapeutically effective amount of the SOS1 inhibitor: 【Chemistry 1】 The procedure involves administering to the subject a combination of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrid[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile or a pharmaceutically acceptable salt thereof and an EGFR inhibitor. The pharmaceutical composition is the SOS1 inhibitor: 【Chemistry 2】 (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrid[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile or a pharmaceutically acceptable salt thereof, and / or comprising an EGFR inhibitor, Pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the EGFR inhibitor is selected from osimertinib, gefitinib, erlotinib, afatinib, brigatinib, icotinib, cetuximab, or pharmaceutically acceptable salts thereof.

3. The pharmaceutical composition according to claim 1, wherein the EGFR inhibitor is osimertinib.

4. The pharmaceutical composition according to claim 1, wherein the EGFR inhibitor is gefitinib.

5. The pharmaceutical composition according to claim 1, wherein the EGFR inhibitor is erlotinib.

6. The pharmaceutical composition according to claim 1, wherein the EGFR inhibitor is cetuximab.

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

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

9. A pharmaceutical composition comprising a therapeutically effective amount of a combination of an SOS1 inhibitor and an EGFR inhibitor according to any one of claims 1 to 6, and a pharmaceutically acceptable excipient.

10. A pharmaceutical composition for use in a method for increasing the sensitivity of cancer cells to an SOS1 inhibitor, The above method involves an effective amount of the SOS1 inhibitor: 【Chemistry 4】 Or, including administering to subjects receiving treatment with a combination of a pharmaceutically acceptable salt thereof and an EGFR inhibitor, The pharmaceutical composition is the SOS1 inhibitor: 【Transformation 5】 or a pharmaceutically acceptable salt thereof, and / or an EGFR inhibitor, A pharmaceutical composition wherein the EGFR inhibitor synergistically increases the sensitivity of the cancer cells to the SOS1 inhibitor.

11. The aforementioned cancers include: heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: Bronchogenic carcinoma (squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrohammartoma, mesothelioma; Gastrointestinal tract: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); urogenital tract: kidney (adenocarcinoma * Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminocarcinoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder cancer, ampulla cancer, cholangiocarcinoma; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondrodromy (osteochondroma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthomas, malignant lymphomas) Osteitis morphogeneticum), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord (neurofibroma, meningioma, glioma, sarcoma); gynecological system: uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa-capsular cell tumor, A pharmaceutical composition according to any one of claims 1 to 6 and 10, selected from the group consisting of: Sertley-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma; vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, staphylosarcoma (embryonic rhabdomyosarcoma)); fallopian tube (cancer); hematological system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorder, multiple myeloma, myelodysplastic syndrome); Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentigo, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

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

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

14. The pharmaceutical composition according to claim 11, wherein the cancer is selected from the group consisting of lung cancer, leukemia, pancreatic cancer, colorectal cancer, and uterine cancer.

15. The pharmaceutical composition according to claim 14, wherein the lung cancer is lung adenocarcinoma.

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

17. The pharmaceutical composition according to claim 14, wherein the leukemia is acute myeloid leukemia (AML).

Images