DCC-3116 in Combination with a MAPKAP Pathway Inhibitor for Use in the Treatment of Cancer

Abstract

Described herein are compounds that are inhibitors of autophagy and their use in the treatment of disorders such as cancer.

Description

[Technical Field]

[0001] cross reference This application is a continuation of U.S. Provisional Application No. 63 / 403,477 filed September 2, 2022, U.S. Provisional Application No. 63 / 374,451 filed September 2, 2022, U.S. Provisional Application No. 63 / 478,777 filed January 6, 2023, U.S. Provisional Application No. 63 / 478,782 filed January 6, 2023, U.S. Provisional Application No. 63 / 493,825 filed April 3, 2023, U.S. Provisional Application No. 63 / 493,825 filed April 3, 2023, and U.S. Provisional Application No. 63 / 493,825 filed April 3, 2023. This application claims priority to U.S. Provisional Patent Application No. 3,828, filed April 12, 2023, U.S. Provisional Patent Application No. 63 / 495,693, filed April 12, 2023, U.S. Provisional Patent Application No. 63 / 495,694, filed April 12, 2023, U.S. Provisional Patent Application No. 63 / 508,646, filed June 16, 2023, and U.S. Provisional Patent Application No. 63 / 508,652, filed June 16, 2023, the contents of each of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Autophagy (literally meaning "self-eating") is a process that allows cells to recycle organelles, proteins, storage lipids, glucagon, and other substances for the purpose of generating nutrients during periods of stress. These cellular contents are recycled by engulfment in small vesicles called autophagosomes. The autophagosomes then fuse with lysosomes, which degrade the contents of the autophagosomes for cellular nutrient recycling. Tumor cells have high metabolic demands, experience cellular stress, and often live in hypoxic environments with limited blood flow and nutrient supply, which predisposes them to activate autophagy. Furthermore, chemotherapy and targeted anticancer therapies have been shown to induce autophagy as a therapeutic resistance mechanism, and the combination of autophagy inhibition (by genetic loss-of-function mutations in autophagy genes or by pharmacological means) with chemotherapy regimens has been shown to suppress tumor growth and induce tumor cell apoptosis to a greater extent than single-agent chemotherapy.

[0003] Mutant RAS proteins drive approximately 30% of all human cancers, including 95% of pancreatic cancers, 45% of colorectal cancers, and 30% of lung cancers, and treatment of these mutant RAS cancers is currently an area of ​​high unmet medical need. Because mutant RAS cancers are highly proliferative and depend on basal levels of autophagy for survival, inhibiting autophagy in these "autophagy-addicted" cancers has been suggested as an effective therapeutic approach.

[0004] Currently, the most widely used autophagy inhibitors are the well-known antimalarial drugs chloroquine and hydroxychloroquine. These antimalarial drugs are thought to inhibit autophagy by sequestering them in the lysosomal compartment and increasing lysosomal pH, thereby inactivating proteases that degrade and recycle nutrients. These antimalarial drugs have multiple mechanisms of action other than lysosomal inhibition and are known to induce retinopathy in patients. Therefore, more targeted drugs that selectively block autophagy without exhibiting the toxicity of these antimalarial drugs are needed. ULK1 kinase is an autophagy initiator protein and a serine / threonine kinase. The ULK1 kinase complex is activated in response to cellular stresses, including nutrient deprivation and energy depletion. Nutrient deprivation activates ULK kinase activity through inhibition of mTORC1, while energy depletion activates ULK kinase activity through activation by the AMP-activated protein kinase AMPK. Importantly, kinase-dead mutant forms of ULK kinases block the initiation of canonical autophagy, suggesting that small-molecule inhibitors of ULK kinase activity can block autophagy.

[0005] Further mechanistic studies have shown that genetic deletion of ULK1 inhibits autophagy in cancer cells, alleviating FOX3A turnover and upregulation of the pro-apoptotic protein PUMA. In addition to the classical activation of canonical autophagy, ULK1 kinase activity has been shown to be required for Bcl-2-L-13-mediated mitophagy (autophagy of damaged mitochondria). ULK1 and ULK2 kinases have also been demonstrated to reorient glucose metabolism in cancer cells in favor of increased NADPH, a reducing agent that leads to a reduction in toxic reactive oxygen species (ROS). ULK inhibitors may also be useful in blocking these non-canonical tumor-promoting activities of ULK.

[0006] Autophagy is also upregulated in cancer host cells and tissues. Autophagy in pancreatic stellate cells has been demonstrated to support tumor growth. Pancreatic stellate cells have been shown to support tumor metabolism in pancreatic cancer through autophagic alanine secretion. Inhibition of autophagy in host tissues has been demonstrated to result in depletion of circulating arginine (an amino acid required for tumor metabolism and growth) through increased liver-mediated arginase secretion. ULK1 kinase activation has also been shown to inactivate the STING pathway in immune cells through inhibitory phosphorylation of STING, mediating a negative feedback mechanism to limit interferon-mediated innate immune cell responses. Therefore, autophagy is not only activated in tumor cells (cancer cell-autonomous), but also in other cells in the tumor microenvironment or host tissues (cancer cell-nonautonomous), supporting tumor survival and growth.

[0007] Mutant RAS cancers are autophagy-dependent. In pancreatic cancer, mutant RAS signals primarily through the MAPKAP pathway. Mutant RAS activates RAF kinase, which then activates MEK kinase, which ultimately activates ERK kinase: mutant RAS → RAF → MEK → ERK. Despite the fact that mutant RAS signaling is via the MAPKAP pathway, inhibitors of this pathway have provided little or no clinical benefit when used as single agents in clinical trials. Recently, inhibition of the MAPKAP pathway has been reported to induce autophagy as a compensatory adaptive stress response resistance mechanism. Combining a MEK inhibitor with the autophagy inhibitor hydroxychloroquine synergistically resulted in the regression of multiple mutant RAS or mutant BRAF cancers. Similarly, combining an ERK inhibitor with the autophagy inhibitors hydroxychloroquine or chloroquine synergistically resulted in the suppression of mutant RAS pancreatic cancers. It has been demonstrated that genetic depletion of RAF kinases (CRAF and BRAF) results in synergistic antitumor activity in mutant RAS cancer cell lines when autophagy is also genetically depleted. Combined, recent publications highlight that dual inhibition of the RAS / MAPK and autophagy pathways in mutant RAS cancers is a promising therapeutic regimen for patients with mutant RAS cancers. Additionally, other targeted therapeutics and chemotherapeutic agents have been demonstrated to activate tumor autophagy as a resistance mechanism; therefore, there is a rationale for combining such targeted therapeutics or chemotherapeutic agents with autophagy inhibitors.

[0008] It has also been demonstrated that tumor driver receptor tyrosine kinases (RTKs) can regulate autophagy, and that inhibitors of RTKs activate autophagy through the same mTORC1 and AMP kinase pathways as inhibitors of mutant RAS or RAF.

[0009] New targeted therapies are needed that inhibit autophagy and can be used in combination with inhibitors of the RTK / RAS / MAPK pathway, chemotherapeutic agents, and / or other targeted therapeutic agents. Summary of the Invention

[0010] The present disclosure provides, in part, methods of treating disorders with ULK inhibitors in combination therapy. Described herein, in one embodiment, is a method of treating cancer in a patient in need thereof, the method comprising: (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, once or twice daily; and (ii) administering to the patient a therapeutically effective amount of one or more additional therapeutic agents.

[0011] In another embodiment, described herein are methods of treating cancer in a patient in need thereof, the methods comprising: (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, once or twice daily in an amount of about 20 mg to about 600 mg; and (ii) administering a therapeutically effective amount of trametinib to the patient.

[0012] In one embodiment, described herein is a method of treating cancer in a patient in need thereof, the method comprising: (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof at a dose of about 20 mg to about 600 mg once or twice daily; and (ii) orally administering a therapeutically effective amount of binimetinib to the patient.

[0013] In another embodiment, described herein are methods of treating cancer in a patient in need thereof, the methods comprising: (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, once or twice daily in an amount of about 20 mg to about 600 mg; and (ii) administering to the patient a therapeutically effective amount of a KRAS G12C inhibitor.

[0014] In another embodiment, described herein are methods of treating cancer in a patient in need thereof, the methods comprising: (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof at a dose of about 20 mg to about 600 mg once or twice daily; and (ii) administering a therapeutically effective amount of sotorasib to the patient.

[0015] In another embodiment, described herein are methods of treating colon cancer in a patient in need thereof, the method including (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof; and (ii) administering to the patient a therapeutically effective amount of encorafenib.

[0016] In another embodiment, described herein are methods of treating colon cancer in a patient in need thereof, the method including (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof; (ii) administering to the patient a therapeutically effective amount of encorafenib; and (iii) administering to the patient a therapeutically effective amount of cetuximab.

[0017] In another embodiment, described herein are methods for treating gastrointestinal stromal tumors in a patient in need thereof, the methods comprising administering to the patient (i) a therapeutically effective amount of an inhibitor of ULK1 kinase, an inhibitor of ULK2 kinase, or an inhibitor of ULK1 and ULK2 kinases, and (ii) a therapeutically effective amount of ripretinib.

[0018] In another embodiment, described herein are methods of treating advanced gastrointestinal stromal tumors in a patient in need thereof, the methods including (i) administering to the patient a compound of Formula (I): [ka] or a pharmaceutically acceptable salt thereof; and (ii) orally administering to the patient a therapeutically effective amount of ripretinib. [Brief explanation of the drawings]

[0019] [Figure 1] The test protocol of Example 1 is described below. [Figure 2] 1 illustrates the results of treatment duration and response assessment in the monotherapy study of Example 1. [Figure 3] A shows the results of the area under the curve (AUC) of total DCC-3116 on day 5 of cycle 1 (C1D15) in the monotherapy study of Example 1, and B shows the results of the area under the curve (AUC) of unbound DCC-3116. [Figure 4] 1 shows the results of pre-dose trough exposure assessed in patients on cycle 1, day 5 (C1D15) in the monotherapy study of Example 1. [Figure 5A]ULK activation by trametinib and reversal by DCC-3116 in a pancreatic cancer (MiaPaca2) cell line harboring a KRAS G12C mutation. [Figure 5B] 1 shows trametinib activation of autophagy in the MiaPaca2 model and reversal by DCC-3116. [Figure 5C] 1 illustrates the additivity of DCC-3116 in combination with trametinib in the MiaPaca2 pancreatic model. [Figure 6A] ULK activation by trametinib and reversal by DCC-3116 in multiple non-small cell lung cancer (NSCLC) cell lines. [Figure 6B] Activation of autophagy by trametinib and reversal by DCC-3116 in NSCLC lines. [Figure 7A] 1 shows activation of ULK by trametinib and reversal by DCC-3116 in the A549* non-small cell lung cancer (NSCLC) cell line. [Figure 7B] Activation of autophagy by trametinib and reversal by DCC-3116 in NSCLC lines. [Figure 8] Figure 1 depicts results from a study of DCC-3116 in combination with trametinib in an H358 xenograft model demonstrating tumor regression. [Figure 9A] 1 illustrates tumor growth studies of DCC-3116 and binimetinib in SK-MEL-30 rat studies. [Figure 9B] Illustrates tumor growth studies of DCC-3116 and binimetinib in the MiaPaca-2 model. [Figure 10] 1 shows DCC-3116 inhibition of binimetinib- and ripretinib-induced ULK activity in GIST-T1 cell lines. [Figure 11A] We show that DCC-3116 reverses ripretinib-induced ULK activation in multiple GIST cell lines. [Figure 11B]DCC-3116 inhibits riprenib-induced autophagic flux in GIST-T1 cell lines. [Figure 11C] Demonstrating the synergistic effect of DCC-3116 in combination with ripretinib in a GIST-T1 cancer model. [Figure 11D] 1 illustrates the weight change associated with the combination of DCC-3116 and ripretinib in a GIST T1 xenograft model. [Figure 12A] We demonstrate that DCC-3116 reverses ULK activation induced by KRAS G12C inhibitors (sotrasib or adagrasib) in non-small cell lung cancer harboring KRAS G12C mutations. [Figure 12B] DCC-3116 inhibits autophagic flux induced by KRAS G12C inhibitors (adagrasib or sotorasib) in non-small cell lung cancer harboring KRAS G12C mutations. [Figure 12C] 1 shows the additivity of DCC-3116 in combination with sotorasib in the H358 lung cancer model. [Figure 13-1] A, B, C, and D illustrate spaghetti plot analyses showing tumor growth inhibition and / or tumor regression in various combination cohorts at 1 mg / kg (A), 3 mg / kg (B), 10 mg / kg (C), and 30 mg / kg (D) sotorasib. [Figure 13-2] A, B, C, and D illustrate spaghetti plot analyses showing tumor growth inhibition and / or tumor regression in various combination cohorts at 1 mg / kg (A), 3 mg / kg (B), 10 mg / kg (C), and 30 mg / kg (D) sotorasib. [Figure 14A] ULK activation by a KRAS G12C inhibitor in pancreatic cancer (MiaPaca-2) with a KRAS G12C mutation and reversal by DCC-3116 are shown. [Figure 14B] Figure 1 shows activation of autophagy by a KRAS G12C inhibitor and reversal by DCC-3116 in a pancreatic cancer model (MiaPaca-2) harboring a KRAS G12C mutation. [Figure 14C]1 illustrates the additivity of DCC-3116 in combination with sotorasib in the MiaPaca2 pancreatic cancer model. [Figure 15A] 1 shows a tumor growth study of sotorasib in combination with DCC-3116 in a KRAS G12C patient-derived xenograft lung cancer model (LU11554). [Figure 15B] 1 shows a tumor growth study of adagrasib in combination with DCC-3116 in a KRAS G12C patient-derived xenograft lung cancer model (LU11554). [Figure 16A] This shows a combination study of DCC-3116 and sotorasib in a colon cancer cell line (SW1463) with a KRAS G12C mutation. [Figure 16B] This shows a combination study of DCC-3116 and adagrasib in a colon cancer cell line (SW1463) with a KRAS G12C mutation. [Figure 17A] Illustrates a combination study of Compound 1 with MTX-1133, showing induction of ULK activity in the HPAF-II KRAS G12D cell line and inhibition of ULK activity induced by MTX-1133 in the HPAF-II cell line. [Figure 17B] Illustrates a combination study of compound 1 with MTX-1133, showing the inhibition of MRTX1133-induced autophagic flux in HPAF-II cell lines and the stable inhibition of MRTX1133-induced autophagic flux by compound 1 in HPAF-II cell lines. [Figure 18A] Figure 1 shows pATG13 ELISA assay testing of DCC-3116, encorafenib, and cetuximab in a colon cancer cell line (HT-29) harboring the BRAF V600E mutation. [Figure 18B] Autophagy flux assay test of DCC-3116, encorafenib, and cetuximab in a BRAF V600E mutated colon cancer cell line (HT-29). [Figure 19-1] 1 shows the results of DCC-3116 inhibition of encorafenib- and cetuximab-induced pATG13 in HT-29 tumors. [Figure 19-2] Figure 19 continued. [Figure 20-1] A, B, C, and D show the results of a variable tumor burden study of DCC-3116 in combination with encorafenib and cetuximab in HT-29, a colon model harboring the BRAF V600E mutation. [Figure 20-2] A, B, C, and D show the results of a variable tumor burden study of DCC-3116 in combination with encorafenib and cetuximab in HT-29, a colon model harboring the BRAF V600E mutation. [Figure 21] PK results of sotorasib in combination with DCC-3116 in the MiaPaca-2 PK / PD model are shown. [Figure 22A] Figure 1 shows the plasma concentration results of DCC-3116 in combination with adagrasib in female athymic nude mice (0.5% w / v Na CMC, 0.1% v / v Tween®-80 in water). [Figure 22B] Figure 1 shows the results of plasma concentrations of DCC-3116 in combination with adagrasib in female athymic nude mice (10% Captisol®, 50 mM citrate buffer, pH 5.0). [Figure 22C] 1 shows the PK results of adagrasib in combination with DCC-3116 in nude mice 5 days after dosing. [Figure 23] 1 shows induction of ATG13-S318 phosphorylation by encorafenib and cetuximab and dose-dependent inhibition by DCC-3116 in Colo-205 cell line. [Figure 24] 1 shows dose-dependent inhibition of LC3 degradation by DCC-3116 in cells treated with encorafenib and cetuximab. [Figure 25] 1 shows the time course of DCC-3116 inhibition of LC3 degradation in cells treated with encorafenib and cetuximab. [Figure 26] This graph shows tumor growth over time (study day) for encorafenib, cetuximab, and DCC-3116. The drugs were administered from days 6 to 27 (21 days). Tumor volume was measured after administration to assess tumor regrowth. [Figure 27] PK / PD study of DCC-3116 in combination with encorafenib and cetuximab at 2 hours post-dose on Day 7. DETAILED DESCRIPTION OF THE INVENTION

[0020] definition As used herein, "combination therapy" refers to a therapy that includes administering to a patient in need thereof two or more therapeutic agents, e.g., a compound of Formula I and an additional therapeutic agent described herein.

[0021] "RAS / MAPK pathway inhibitors" are inhibitors of the RAS / MAPK signaling pathway. Inhibitors of this pathway include Ras inhibitors (e.g., AMG-510 (sotorasib), MRTX849 (adagrasib), GDC-6036, MRTX-1133, RMS-9805, RMC-6291, and RMC-6236, and pharmaceutically acceptable salts thereof), RAF inhibitors (e.g., LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, KIN-2787, and VS-6766), and the like. and pharmaceutically acceptable salts thereof), MEK inhibitors (e.g., trametinib, selumetinib, cobimetinib, and binimetinib, and pharmaceutically acceptable salts thereof), and ERK inhibitors (e.g., ulixartinib, SCH772984, LY3214996, ravoxartinib, VX-11e, ERAS-007, and ASTX-029, and pharmaceutically acceptable salts thereof). The terms "RAS / MAPK pathway inhibitor" and "RAS / MAPK kinase inhibitor" are used interchangeably herein.

[0022] "RTK pathway inhibitor" refers to an inhibitor of the RTK (receptor tyrosine kinase) signal transduction pathway. Inhibitors of this pathway include KIT inhibitors (e.g., ripretinib, avapritinib, sunitinib, and imatinib, and their pharmaceutically acceptable salts), EGFR inhibitors (e.g., cetuximab, or their pharmaceutically acceptable salts), PDGFRα inhibitors (e.g., JNJ10198409, or their pharmaceutically acceptable salts), VEGFR inhibitors (e.g., regorafenib and pazopanib, and their pharmaceutically acceptable salts), BCR-Abl inhibitors (e.g., imatinib, nilotinib, dasatinib, or their pharmaceutically acceptable salts), and ALK inhibitors (e.g., loralatinib, alectinib, and their pharmaceutically acceptable salts).

[0023] The terms "individual," "patient," or "subject" are used interchangeably herein and include any animal, including mammals, including mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and humans. The compounds described herein can be administered to mammals such as humans, but can also be administered to other mammals, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.), in need of veterinary treatment. The mammal treated by the methods described herein is desirably a mammal in which treatment of a disorder described herein is desired, e.g., a human.

[0024] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the compositions of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, superphosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentianate, fumarate, gluconate, glucuronate, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1-1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

[0025] As used herein, the term "treating" includes any effect that results in the improvement of a condition, disease, disorder, etc., such as diminishment, reduction, modulation, or elimination.

[0026] As used herein, the term "drug holiday" includes a drug holiday for one or more therapeutic agents described herein, e.g., a drug holiday for one therapeutic agent described herein, a drug holiday for two therapeutic agents described herein, or a drug holiday for three therapeutic agents described herein. In some embodiments, the drug holiday is a drug holiday for the compound of Formula (I). In some embodiments, the drug holiday is a drug holiday for the compound of Formula (I) and / or trametinib. In some embodiments, the drug holiday is a drug holiday for the compound of Formula (I) and / or binimetinib. In some embodiments, the drug holiday is a drug holiday for the compound of Formula (I) and / or sotrasib. In some embodiments, the drug holiday is a drug holiday for the compound of Formula (I) and / or adagrasib. In some embodiments, the drug holiday is a drug holiday for the compound of Formula (I), encorafenib, and / or cetuximab. In some embodiments, the drug holiday is a drug holiday of the compound of Formula (I) and / or ripretinib.

[0027] As used herein, "DCC-3116" refers to the compound of formula (I) as defined herein.

[0028] As used herein, "Compound A" refers to a compound of the following structure: [ka]

[0029] A "therapeutically effective amount" includes an amount of a subject compound that elicits the biological or medical response in a tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or other clinician. The compounds described herein, e.g., compounds of Formula (I), are administered in a therapeutically effective amount to treat the conditions described herein. Alternatively, a therapeutically effective amount of a compound is the amount necessary to achieve the desired therapeutic and / or prophylactic effect, such as an amount that results in the prevention or reduction of symptoms associated with a condition.

[0030] The compounds described herein can be formulated into pharmaceutical compositions using pharmaceutically acceptable carriers and administered by various routes. In some embodiments, such compositions are for oral administration. In some embodiments, compositions formulated for oral administration are provided as tablets. In some embodiments, such compositions are for parenteral (by injection) administration. In some embodiments, such compositions are for transdermal administration. In some embodiments, such compositions are for topical administration. In some embodiments, such compositions are for intravenous (IV) administration. In some embodiments, such compositions are for intramuscular (IM) administration. Such pharmaceutical compositions and processes for their preparation are well known in the art. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al., eds., 19th ed., Mack Publishing Co., 1995).

[0031] Treatment methods Combination with one or more additional therapeutic agents Described herein, in one embodiment, is a method of treating cancer in a patient in need thereof, the method comprising: (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, daily; and (ii) administering to the patient a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, the method comprises orally administering the compound to the patient. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 90 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 110 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily.In some embodiments, the method comprises administering to the patient about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 90 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 110 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of an RTK pathway inhibitor, an EGFR inhibitor, a KIT inhibitor, and combinations thereof. In some embodiments, the EGFR inhibitor is cetuximab. In some embodiments, the KIT inhibitor is ripretinib or a pharmaceutically acceptable salt thereof. In some embodiments, the RAS / MAPK pathway inhibitor is selected from the group consisting of a MEK inhibitor, an ERK inhibitor, a RAF inhibitor, a RAS inhibitor, and combinations thereof. In some embodiments, the MEK inhibitor is selected from the group consisting of trametinib, binimetinib, and pharmaceutically acceptable salts thereof. In some embodiments, the RAF inhibitor is encorafenib or a pharmaceutically acceptable salt thereof. In some embodiments, the RAS inhibitor is sotorasib, adagrasib, or a pharmaceutically acceptable salt thereof. In some embodiments, the RAS inhibitor is MRTX-1133 or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of trametinib, binimetinib, sotorasib, adagrasib, cetuximab, encorafenib, ripretinib, and combinations thereof. In some embodiments, the cancer is selected from the group consisting of pancreatic ductal adenocarcinoma, non-small cell lung cancer, colorectal cancer, melanoma, and gastrointestinal stromal tumor.

[0032] Described herein, in one embodiment, is a method of treating cancer in a patient in need thereof, the method comprising: (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, at about 20 mg to about 600 mg once or twice daily; and (ii) administering to the patient a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, the method comprises orally administering the compound to the patient. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 80 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 90 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 110 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 50 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 60 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 70 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 80 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 90 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 110 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of an RTK pathway inhibitor, an EGFR inhibitor, a KIT inhibitor, and combinations thereof. In some embodiments, the EGFR inhibitor is cetuximab. In some embodiments, the KIT inhibitor is ripretinib or a pharmaceutically acceptable salt thereof. In some embodiments, the RAS / MAPK pathway inhibitor is selected from the group consisting of a MEK inhibitor, an ERK inhibitor, a RAF inhibitor, a RAS inhibitor, and combinations thereof. In some embodiments, the MEK inhibitor is selected from the group consisting of trametinib, binimetinib, and pharmaceutically acceptable salts thereof. In some embodiments, the RAF inhibitor is encorafenib or a pharmaceutically acceptable salt thereof. In some embodiments, the RAS inhibitor is sotorasib or a pharmaceutically acceptable salt thereof. In some embodiments, the RAS inhibitor is adagrasib or a pharmaceutically acceptable salt thereof. In some embodiments, the RAS inhibitor is MRTX-1133 or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of trametinib, binimetinib, sotorasib, adagrasib, cetuximab, encorafenib, ripretinib, and combinations thereof. In some embodiments, the cancer is selected from the group consisting of pancreatic ductal adenocarcinoma, non-small cell lung cancer, colorectal cancer, melanoma, and gastrointestinal stromal tumor.

[0033] In combination with trametinib In another embodiment, described herein are methods of treating cancer in a patient in need thereof, the methods comprising: (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, daily; and (ii) administering a therapeutically effective amount of trametinib to the patient. In some embodiments, the method comprises orally administering the compound to the patient. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 90 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily.In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering to the patient about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 650 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the methods comprise administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering about 90 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 110 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 0.5 mg to 2.5 mg of trametinib to the patient once daily. In some embodiments, the method comprises administering about 2 mg of trametinib to the patient once daily. In some embodiments, the method comprises administering about 1.5 mg of trametinib to the patient once daily. In some embodiments, the method comprises administering about 1 mg of trametinib to the patient once daily. In some embodiments, the method comprises administering about 0.5 mg to 2.5 mg of trametinib twice daily. In some embodiments, the method comprises administering about 2 mg of trametinib to the patient once daily. In some embodiments, the method comprises administering about 1.5 mg of trametinib twice daily. In some embodiments, the method comprises administering about 1 mg of trametinib twice daily. In some embodiments, the cancer is selected from the group consisting of pancreatic ductal adenocarcinoma, non-small cell lung cancer, colorectal cancer, and melanoma. In some embodiments, the pancreatic ductal adenocarcinoma has one or more KRAS mutations. In some embodiments, the non-small cell lung cancer has one or more mutations selected from the group consisting of a RAS mutation, an NF1 mutation, a RAF mutation, and combinations thereof.In some embodiments, the non-small cell lung cancer has one or more RAS mutations, wherein the one or more RAS mutations are one or more NRAS mutations, one or more KRAS mutations, one or more HRAS mutations, or a combination thereof. In some embodiments, the non-small cell lung cancer has one or more RAF mutations, wherein the one or more RAF mutations are one or more ARAF mutations, one or more BRAF mutations, one or more CRAF mutations, or a combination thereof. In some embodiments, the colorectal cancer has one or more mutations selected from the group consisting of a RAS mutation, an NF1 mutation, a RAF mutation, and a combination thereof. In some embodiments, the colorectal cancer has one or more RAS mutations, wherein the one or more RAS mutations are one or more NRAS mutations, one or more KRAS mutations, one or more HRAS mutations, or and combinations thereof. In some embodiments, the colorectal cancer has one or more RAF mutations, wherein the one or more RAF mutations are one or more ARAF mutations, one or more BRAF mutations, one or more CRAF mutations, or a combination thereof. In some embodiments, the melanoma has one or more RAS mutations. In some embodiments, the melanoma has one or more RAS mutations, wherein the one or more RAS mutations are one or more NRAS mutations, one or more KRAS mutations, one or more HRAS mutations, or a combination thereof. In some embodiments, the melanoma has one or more NRAS mutations. In some embodiments, the melanoma is unresectable or metastatic melanoma. In some embodiments, the patient with RAF mutant non-small cell lung cancer has previously received at least one prior therapy. In some embodiments, the patient with RAF mutant non-small cell lung cancer has previously received at least three (e.g., 3-5) prior therapies. In some embodiments, the patient with NF1 mutant non-small cell lung cancer has previously received at least one prior therapy. In some embodiments, patients with NF1 mutant non-small cell lung cancer have previously received at least three (e.g., 3-5) prior therapies. In some embodiments, patients with RAS mutant non-small cell lung cancer have previously received at least one prior therapy. In some embodiments, patients with RAS mutant non-small cell lung cancer have previously received at least three (e.g., 3-5) prior therapies. In some embodiments, patients with RAF mutant colon cancer have previously received at least one prior therapy. In some embodiments, patients with RAF mutant colon cancer have previously received at least three (e.g., 3-4) prior therapies. In some embodiments, patients with NF1 mutant colon cancer have previously received at least one prior therapy. In some embodiments, patients with NF1 mutant colon cancer have previously received at least three (e.g., 3-4) prior therapies. In some embodiments, patients with RAS mutant colon cancer have previously received at least one prior therapy. In some embodiments, the patient with RAS mutant colon cancer has previously received at least three (eg, 3-4) prior therapies.In some embodiments, patients with NRAS mutant melanoma have previously received at least one prior therapy, hi some embodiments, patients with NRAS mutant melanoma have previously received at least two (e.g., 2-3) prior therapies.

[0034] In another embodiment, described herein are methods of treating cancer in a patient in need thereof, the methods comprising: (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, at about 20 mg to about 600 mg once or twice daily; and (ii) administering a therapeutically effective amount of trametinib to the patient. In some embodiments, the method comprises orally administering the compound to the patient. In some embodiments, the method comprises administering about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 90 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily.In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering to the patient about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 650 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the methods comprise administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering about 90 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 110 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 600 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 650 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 700 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 0.5 mg to 2.5 mg of trametinib to the patient once daily. In some embodiments, the method comprises administering about 2 mg of trametinib to the patient once daily. In some embodiments, the method comprises administering about 0.5 mg to 2.5 mg of trametinib twice daily to the patient. In some embodiments, the method comprises administering about 2 mg of trametinib once daily to the patient. In some embodiments, the method comprises administering about 1.5 mg of trametinib twice daily to the patient. In some embodiments, the method comprises administering about 1 mg of trametinib twice daily to the patient. In some embodiments, the cancer is selected from the group consisting of pancreatic ductal adenocarcinoma, non-small cell lung cancer, colorectal cancer, and melanoma. In some embodiments, the pancreatic ductal adenocarcinoma has one or more KRAS mutations. In some embodiments, the non-small cell lung cancer has one or more mutations selected from the group consisting of RAS mutations, NF1 mutations, RAF mutations, and combinations thereof. In some embodiments, the non-small cell lung cancer has one or more RAS mutations, wherein the one or more RAS mutations are one or more NRAS mutations, one or more KRAS mutations, one or more HRAS mutations, or a combination thereof. In some embodiments, the non-small cell lung cancer has one or more RAF mutations, wherein the one or more RAF mutations are one or more ARAF mutations, one or more BRAF mutations, one or more CRAF mutations, or a combination thereof. In some embodiments, the colorectal cancer has one or more mutations selected from the group consisting of a RAS mutation, an NF1 mutation, a RAF mutation, or a combination thereof. In some embodiments, the colorectal cancer has one or more RAS mutations, wherein the one or more RAS mutations are one or more NRAS mutations, one or more KRAS mutations, one or more HRAS mutations, or a combination thereof. In some embodiments, the colorectal cancer has one or more RAF mutations, wherein the one or more RAF mutations are one or more ARAF mutations, one or more BRAF mutations, one or more CRAF mutations, or a combination thereof. In some embodiments, the melanoma has one or more RAS mutations. In some embodiments, the melanoma has one or more RAS mutations, wherein the one or more RAS mutations are one or more NRAS mutations, one or more KRAS mutations, one or more HRAS mutations, or a combination thereof. In some embodiments, the melanoma has one or more NRAS mutations. In some embodiments, the melanoma is unresectable or metastatic melanoma.In some embodiments, patients with RAF mutant non-small cell lung cancer have previously received at least one prior therapy. In some embodiments, patients with RAF mutant non-small cell lung cancer have previously received at least three (e.g., 3-5) prior therapies. In some embodiments, patients with NF1 mutant non-small cell lung cancer have previously received at least one prior therapy. In some embodiments, patients with NF1 mutant non-small cell lung cancer have previously received at least three (e.g., 3-5) prior therapies. In some embodiments, patients with RAS mutant non-small cell lung cancer have previously received at least one prior therapy. In some embodiments, patients with RAS mutant non-small cell lung cancer have previously received at least three (e.g., 3-5) prior therapies. In some embodiments, patients with RAF mutant colorectal cancer have previously received at least one prior therapy. In some embodiments, patients with RAF mutant colorectal cancer have previously received at least three (e.g., 3-4) prior therapies. In some embodiments, patients with NF1 mutant colorectal cancer have previously received at least one prior therapy. In some embodiments, patients with NF1 mutant colorectal cancer have previously received at least three (e.g., 3-4) prior therapies. In some embodiments, patients with RAS mutant colorectal cancer have previously received at least one prior therapy. In some embodiments, patients with RAS mutant colorectal cancer have previously received at least three (e.g., 3-4) prior therapies. In some embodiments, patients with NRAS mutant melanoma have previously received at least one prior therapy. In some embodiments, patients with NRAS mutant melanoma have previously received at least two (e.g., 2-3) prior therapies.

[0035] In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and trametinib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to the patient each of the compound of Formula (I) and trametinib for 1 to 30 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and trametinib for 1 to 28 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to the patient each of the compound of Formula (I) and trametinib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and trametinib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to the patient each of the compound of Formula (I) and trametinib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and trametinib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to the patient each of the compound of Formula (I) and trametinib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and trametinib for 1 to 7 consecutive days, followed by a washout period for the compound of Formula (I) and / or trametinib, followed by administering to the patient each of the compound of Formula (I) and trametinib for 1 to 7 consecutive days.

[0036] In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and trametinib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to a patient each of a compound of Formula (I) and said trametinib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and trametinib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to a patient each of a compound of Formula (I) and said trametinib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and trametinib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to a patient each of a compound of Formula (I) and said trametinib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and trametinib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to a patient each of a compound of Formula (I) and said trametinib for 1 to 28 consecutive days.

[0037] In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and trametinib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to a patient each of a compound of Formula (I) and said trametinib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and trametinib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to a patient each of a compound of Formula (I) and said trametinib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and trametinib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to the patient each of the compound of Formula (I) and trametinib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and trametinib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to the patient each of the compound of Formula (I) and trametinib for 1 to 30 consecutive days.

[0038] In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and trametinib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to the patient each of the compound of Formula (I) and trametinib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and trametinib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to the patient each of the compound of Formula (I) and trametinib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and trametinib for 1 to 14 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or trametinib, and then administering to the patient each of the compound of Formula (I) and trametinib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and trametinib for 1 to 14 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or trametinib, and then administering to the patient each of the compound of Formula (I) and trametinib for 1 to 30 consecutive days.

[0039] In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and trametinib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to the patient each of the compound of Formula (I) and trametinib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and trametinib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to the patient each of the compound of Formula (I) and trametinib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and trametinib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to the patient each of the compound of Formula (I) and trametinib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and trametinib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or trametinib, and then administering to the patient each of the compound of Formula (I) and trametinib for 1 to 30 consecutive days.

[0040] In some embodiments, the method includes administering each of the compound of Formula (I) and trametinib to a patient for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days, followed by administration of the compound of Formula (I) and trametinib to a patient for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days, followed by a drug holiday period for the compound of Formula (I) and / or trametinib, and then administering to the patient for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days, respectively, of the compound of Formula (I) and trametinib.

[0041] In some embodiments, the method includes administering each of the compound of Formula (I) and trametinib to a patient for 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days, 15 consecutive days, 16 consecutive days, 17 consecutive days, 18 consecutive days, 19 consecutive days, 20 consecutive days, 21 consecutive days, 22 consecutive days, 23 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, 27 consecutive days, 28 consecutive days, 29 consecutive days, 30 consecutive days, or 31 consecutive days, followed by administration of the compound of Formula (I) and trametinib to a patient for 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days, 15 consecutive days, 16 consecutive days, 17 consecutive days, 18 consecutive days, 19 consecutive days, 20 consecutive days, 21 consecutive days, 22 consecutive days, 23 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, 27 consecutive days, 28 consecutive days, 29 consecutive days, 30 consecutive days, or 31 consecutive days, followed by a drug holiday period for the compound of Formula (I) and / or trametinib, and then administering each of the compound of Formula (I) and trametinib to a patient for 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days, 15 consecutive days, 16 consecutive days, 17 consecutive days, 18 consecutive days, 19 consecutive days, 20 consecutive days, 21 consecutive days, 22 consecutive days, 23 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, 27 consecutive days, 28 consecutive days, 29 consecutive days, 30 consecutive days, or 31 consecutive days.

[0042] In some embodiments, the drug holiday period for the compound of Formula (I) and / or trametinib is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days. In some embodiments, the drug holiday period for the compound of Formula (I) and / or trametinib is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In some embodiments, the drug holiday period is 1 to 6 weeks. In some embodiments, the drug holiday period for the compound of Formula (I) and / or trametinib is 1 to 4 weeks. In some embodiments, the drug holiday period for the compound of Formula (I) and / or trametinib is 1 to 3 weeks in duration, hi some embodiments, the drug holiday period is 1 to 2 weeks in duration.

[0043] In some embodiments, the drug holiday period is about 1 to 2 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 3 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 4 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 5 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 6 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 4 to 5 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 4 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 5 times the half-life of the compound represented by Formula (I) in a patient.

[0044] In some embodiments, the drug holiday is about 1 to 2 half-lives of trametinib in a patient. In some embodiments, the drug holiday is about 1 to 3 half-lives of trametinib in a patient. In some embodiments, the drug holiday is about 1 to 4 half-lives of trametinib in a patient. In some embodiments, the drug holiday is about 1 to 5 half-lives of trametinib in a patient. In some embodiments, the drug holiday is about 1 to 6 half-lives of trametinib in a patient. In some embodiments, the drug holiday is about 4 to 5 half-lives of trametinib in a patient. In some embodiments, the drug holiday is about 4 half-lives of trametinib in a patient. In some embodiments, the drug holiday is about 5 half-lives of trametinib in a patient.

[0045] In combination with binimetinib In one embodiment, described herein is a method of treating cancer in a patient in need thereof, the method comprising: (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, twice daily; and (ii) orally administering a therapeutically effective amount of binimetinib to the patient. In some embodiments, the method comprises orally administering the compound to the patient. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 90 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily.In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering to the patient about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 650 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the methods comprise administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering about 90 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 110 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 600 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 650 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 700 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 20 mg to 50 mg of binimetinib to the patient twice daily. In some embodiments, the method comprises administering about 45 mg of binimetinib to the patient twice daily. In some implementations. In some embodiments, the method comprises administering about 40 mg of binimetinib to the patient twice daily. In some embodiments, the method comprises administering about 35 mg of binimetinib to the patient twice daily. In some embodiments, the method comprises administering about 30 mg of binimetinib to the patient twice daily. In some embodiments, the method comprises administering about 25 mg of binimetinib to the patient twice daily. In some embodiments, the method comprises administering about 20 mg of binimetinib to the patient twice daily. In some embodiments, the method comprises administering about 20 mg to 50 mg of binimetinib once daily. In some embodiments, the method comprises administering about 45 mg of binimetinib to the patient once daily. In some embodiments, the method comprises administering about 40 mg of binimetinib to the patient once daily. In some embodiments, the method comprises administering about 35 mg of binimetinib to the patient once daily. In some embodiments, the method comprises administering about 30 mg of binimetinib to the patient once daily. In some embodiments, the method comprises administering about 25 mg of binimetinib to the patient once daily. In some embodiments, the method comprises administering about 20 mg of binimetinib to the patient once daily. In some embodiments, the cancer is selected from the group consisting of pancreatic ductal adenocarcinoma, non-small cell lung cancer, colorectal cancer, and melanoma. In some embodiments, the pancreatic ductal adenocarcinoma has one or more KRAS mutations. In some embodiments, the non-small cell lung cancer has one or more mutations selected from the group consisting of RAS mutations, NF1 mutations, RAF mutations, and combinations thereof. In some embodiments, the non-small cell lung cancer has one or more RAS mutations, wherein the one or more RAS mutations are one or more NRAS mutations, one or more KRAS mutations, one or more HRAS mutations, or a combination thereof. In some embodiments, the non-small cell lung cancer has one or more RAF mutations, wherein the one or more RAF mutations are one or more ARAF mutations, one or more BRAF mutations, one or more CRAF mutations, or a combination thereof. In some embodiments, the colorectal cancer has one or more mutations selected from the group consisting of a RAS mutation, an NF1 mutation, a RAF mutation, and a combination thereof.In some embodiments, the colorectal cancer has one or more RAS mutations, wherein the one or more RAS mutations are one or more NRAS mutations, one or more KRAS mutations, one or more HRAS mutations, or a combination thereof. In some embodiments, the colorectal cancer has one or more RAF mutations, wherein the one or more RAF mutations are one or more ARAF mutations, one or more BRAF mutations, one or more CRAF mutations, or a combination thereof. In some embodiments, the melanoma has one or more RAS mutations. In some embodiments, the melanoma has one or more RAS mutations, wherein the one or more RAS mutations are one or more NRAS mutations, one or more KRAS mutations, one or more HRAS mutations, or a combination thereof. In some embodiments, the melanoma has one or more NRAS mutations. In some embodiments, the melanoma is unresectable or metastatic melanoma. In some embodiments, the patient with RAF mutant non-small cell lung cancer has previously received at least one prior therapy. In some embodiments, the patient with RAF mutant non-small cell lung cancer has previously received at least three (e.g., 3-5) prior therapies. In some embodiments, patients with NF1 mutant non-small cell lung cancer have previously received at least one prior therapy. In some embodiments, patients with NF1 mutant non-small cell lung cancer have previously received at least three (e.g., 3-5) prior therapies. In some embodiments, patients with RAS mutant non-small cell lung cancer have previously received at least one prior therapy. In some embodiments, patients with RAS mutant non-small cell lung cancer have previously received at least three (e.g., 3-5) prior therapies. In some embodiments, patients with RAF mutant colon cancer have previously received at least one prior therapy. In some embodiments, patients with RAF mutant colon cancer have previously received at least three (e.g., 3-4) prior therapies. In some embodiments, patients with NF1 mutant colon cancer have previously received at least one prior therapy. In some embodiments, patients with NF1 mutant colon cancer have previously received at least three (e.g., 3-4) prior therapies. In some embodiments, the patient with RAS mutant colon cancer has previously received at least one prior therapy.In some embodiments, patients with RAS mutant colorectal cancer have previously received at least three (e.g., 3-4) prior therapies. In some embodiments, patients with NRAS mutant melanoma have previously received at least one prior therapy. In some embodiments, patients with NRAS mutant melanoma have previously received at least two (e.g., 2-3) prior therapies.

[0046] In one embodiment, described herein is a method of treating cancer in a patient in need thereof, the method comprising: (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, at about 20 mg to about 600 mg once or twice daily; and (ii) orally administering a therapeutically effective amount of binimetinib to the patient. In some embodiments, the method comprises orally administering the compound to the patient. In some embodiments, the method comprises administering about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 90 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily.In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering to the patient about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 650 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the methods comprise administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering about 90 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 110 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 600 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 650 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 700 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 20 mg to 50 mg of binimetinib to the patient twice daily. In some embodiments, the method comprises administering about 45 mg of binimetinib to the patient twice daily. In some embodiments, the method comprises administering about 20 mg to 50 mg of binimetinib once daily to the patient. In some embodiments, the method comprises administering about 45 mg of binimetinib once daily to the patient. In some embodiments, the method comprises administering about 40 mg of binimetinib once daily to the patient. In some embodiments, the method comprises administering about 35 mg of binimetinib once daily to the patient. In some embodiments, the method comprises administering about 30 mg of binimetinib once daily to the patient. In some embodiments, the method comprises administering about 25 mg of binimetinib once daily to the patient. In some embodiments, the method comprises administering about 20 mg of binimetinib once daily to the patient. In some embodiments, the cancer is selected from the group consisting of pancreatic ductal adenocarcinoma, non-small cell lung cancer, colorectal cancer, and melanoma. In some embodiments, the pancreatic ductal adenocarcinoma has one or more KRAS mutations. In some embodiments, the non-small cell lung cancer has one or more mutations selected from the group consisting of RAS mutations, NF1 mutations, RAF mutations, and combinations thereof. In some embodiments, the non-small cell lung cancer has one or more RAS mutations, wherein the one or more RAS mutations are one or more NRAS mutations, one or more KRAS mutations, one or more HRAS mutations, or a combination thereof. In some embodiments, the non-small cell lung cancer has one or more RAF mutations, wherein the one or more RAF mutations are one or more ARAF mutations, one or more BRAF mutations, one or more CRAF mutations, or a combination thereof. In some embodiments, the colorectal cancer has one or more mutations selected from the group consisting of RAS mutations, NF1 mutations, RAF mutations, and combinations thereof. In some embodiments, the colorectal cancer has one or more RAS mutations, wherein the one or more RAS mutations are one or more NRAS mutations, one or more KRAS mutations, one or more HRAS mutations, or a combination thereof. In some embodiments, the colorectal cancer has one or more RAF mutations, wherein the one or more RAF mutations are one or more ARAF mutations, one or more BRAF mutations, one or more CRAF mutations, or a combination thereof. In some embodiments, the melanoma has one or more RAS mutations.In some embodiments, the melanoma has one or more RAS mutations, wherein the one or more RAS mutations are one or more NRAS mutations, one or more KRAS mutations, one or more HRAS mutations, or a combination thereof. In some embodiments, the melanoma has one or more NRAS mutations. In some embodiments, the melanoma is unresectable or metastatic melanoma. In some embodiments, the patient with RAF mutant non-small cell lung cancer has previously received at least one prior therapy. In some embodiments, the patient with RAF mutant non-small cell lung cancer has previously received at least three (e.g., 3-5) prior therapies. In some embodiments, the patient with NF1 mutant non-small cell lung cancer has previously received at least one prior therapy. In some embodiments, the patient with NF1 mutant non-small cell lung cancer has previously received at least three (e.g., 3-5) prior therapies. In some embodiments, the patient with RAS mutant non-small cell lung cancer has previously received at least one prior therapy. In some embodiments, the patient with RAS mutant non-small cell lung cancer has previously received at least three (e.g., 3-5) prior therapies. In some embodiments, the patient with RAF mutant colorectal cancer has previously received at least one prior therapy. In some embodiments, the patient with RAF mutant colorectal cancer has previously received at least three (e.g., 3-4) prior therapies. In some embodiments, the patient with NF1 mutant colorectal cancer has previously received at least one prior therapy. In some embodiments, the patient with NF1 mutant colorectal cancer has previously received at least three (e.g., 3-4) prior therapies. In some embodiments, the patient with RAS mutant colorectal cancer has previously received at least one prior therapy. In some embodiments, the patient with RAS mutant colorectal cancer has previously received at least three (e.g., 3-4) prior therapies. In some embodiments, the patient with NRAS mutant melanoma has previously received at least one prior therapy. In some embodiments, patients with NRAS mutant melanoma have previously received at least two (eg, 2-3) prior therapies.

[0047] In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 30 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 28 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and binimetinib for 1 to 7 consecutive days, followed by a washout period for the compound of Formula (I) and / or binimetinib, followed by administering to the patient each of the compound of Formula (I) and binimetinib for 1 to 7 consecutive days.

[0048] In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 28 consecutive days.

[0049] In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 30 consecutive days.

[0050] In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 30 consecutive days.

[0051] In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and binimetinib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or binimetinib, and then administering to a patient each of a compound of Formula (I) and said binimetinib for 1 to 30 consecutive days.

[0052] In some embodiments, the method includes administering each of the compound of Formula (I) and binimetinib to the patient for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days, followed by administration of the compound of Formula (I) and binimetinib to the patient for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days, followed by a drug holiday period for the compound of Formula (I) and / or binimetinib, followed by 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days of administering each of the compound of Formula (I) and binimetinib to a patient.

[0053] In some embodiments, the method includes administering each of a compound of Formula (I) and binimetinib to a patient for 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days, 15 consecutive days, 16 consecutive days, 17 consecutive days, 18 consecutive days, 19 consecutive days, 20 consecutive days, 21 consecutive days, 22 consecutive days, 23 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, 27 consecutive days, 28 consecutive days, 29 consecutive days, 30 consecutive days, or 31 consecutive days, followed by administration of a compound of Formula (I) and binimetinib to a patient for 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days, 15 consecutive days, 16 consecutive days, 17 consecutive days, 18 consecutive days, 19 consecutive days, 20 consecutive days, 21 consecutive days, 22 consecutive days, 23 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, 27 consecutive days, 28 consecutive days, 29 consecutive days, 30 consecutive days, or 31 consecutive days; followed by a drug holiday period for the compound of Formula (I) and / or binimetinib, and then administering each of the compound of Formula (I) and binimetinib to a patient for 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days, 15 consecutive days, 16 consecutive days, 17 consecutive days, 18 consecutive days, 19 consecutive days, 20 consecutive days, 21 consecutive days, 22 consecutive days, 23 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, 27 consecutive days, 28 consecutive days, 29 consecutive days, 30 consecutive days, or 31 consecutive days.

[0054] In some embodiments, the drug holiday period for the compound of Formula (I) and / or binimetinib is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days. In some embodiments, the drug holiday period for the compound of Formula (I) and / or binimetinib is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In some embodiments, the drug holiday period is 1 to 6 weeks. In some embodiments, the drug holiday period for the compound of Formula (I) and / or binimetinib is 1 to 4 weeks. In some embodiments, the drug holiday period for the compound of Formula (I) and / or binimetinib is 1 to 3 weeks in duration, hi some embodiments, the drug holiday period is 1 to 2 weeks in duration.

[0055] In some embodiments, the drug holiday period is about 1 to 2 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 3 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 4 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 5 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 6 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 4 to 5 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 4 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 5 times the half-life of the compound represented by Formula (I) in a patient.

[0056] In some embodiments, the drug holiday is about 1 to 2 half-lives of binimetinib in a patient. In some embodiments, the drug holiday is about 1 to 3 half-lives of binimetinib in a patient. In some embodiments, the drug holiday is about 1 to 4 half-lives of binimetinib in a patient. In some embodiments, the drug holiday is about 1 to 5 half-lives of binimetinib in a patient. In some embodiments, the drug holiday is about 1 to 6 half-lives of binimetinib in a patient. In some embodiments, the drug holiday is about 4 to 5 half-lives of binimetinib in a patient. In some embodiments, the drug holiday is about 4 half-lives of binimetinib in a patient. In some embodiments, the drug holiday is about 5 half-lives of binimetinib in a patient.

[0057] Combination with KRAS G12C inhibitors In another embodiment, described herein are methods of treating cancer in a patient in need thereof, the methods comprising: (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, daily; and (ii) administering to the patient a therapeutically effective amount of a KRAS G12C inhibitor. In some embodiments, the method comprises orally administering the compound to the patient. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 90 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily.In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering to the patient about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 650 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the methods comprise administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering about 90 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 110 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 600 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 650 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 700 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the KRAS G12C inhibitor is sotorasib. In some embodiments, the method comprises administering about 960 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering to the patient between about 100 mg and about 300 mg of sotorasib once daily. In some embodiments, the method comprises administering to the patient about 120 mg of sotorasib once daily. In some embodiments, the method comprises administering to the patient about 140 mg of sotorasib once daily. In some embodiments, the method comprises administering to the patient about 160 mg of sotorasib once daily. In some embodiments, the method comprises administering to the patient about 180 mg of sotorasib once daily. In some embodiments, the method comprises administering to the patient about 200 mg of sotorasib once daily. In some embodiments, the method comprises administering to the patient about 220 mg of sotorasib once daily. In some embodiments, the method comprises administering to the patient about 240 mg of sotorasib once daily. In some embodiments, the method comprises administering to the patient about 260 mg of sotorasib once daily. In some embodiments, the method comprises administering about 280 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 300 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 960 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 100 mg to about 300 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 120 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 140 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 160 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 180 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 200 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 220 mg of sotorasib twice daily to the patient. In some embodiments, the method comprises administering about 240 mg of sotorasib twice daily to the patient. In some embodiments, the method comprises administering about 260 mg of sotorasib twice daily to the patient.In some embodiments, the method comprises administering about 280 mg of sotorasib twice daily to the patient. In some embodiments, the method comprises administering about 300 mg of sotorasib twice daily to the patient. In some embodiments, the KRAS G12C inhibitor is adagrasib. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the non-small cell lung cancer has a KRAS G12C mutation. In some embodiments, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer with a KRAS G12C mutation. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the colorectal cancer is KRAS G12C mutated colorectal cancer. In some embodiments, the pancreatic cancer is KRAS G12C mutated pancreatic cancer. In some embodiments, the pancreatic cancer is selected from the group consisting of locally advanced pancreatic cancer, unresectable pancreatic cancer, and metastatic pancreatic cancer.

[0058] In another embodiment, described herein are methods of treating cancer in a patient in need thereof, the methods comprising: (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, at about 20 mg to about 600 mg once or twice daily; and (ii) administering to the patient a therapeutically effective amount of a KRAS G12C inhibitor. In some embodiments, the method comprises orally administering the compound to the patient. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 90 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily.In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering to the patient about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 650 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the methods comprise administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering about 90 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 110 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 600 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 650 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 700 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the KRAS G12C inhibitor is sotorasib. In some embodiments, the method comprises administering about 960 mg of sotorasib to the patient once daily. In some embodiments, the method. The method comprises administering about 100 mg to about 300 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 120 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 140 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 160 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 180 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 200 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 220 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 240 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 260 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 280 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 300 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 960 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 100 mg to about 300 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 120 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 140 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 160 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 180 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 200 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 220 mg of sotorasib twice daily to the patient. In some embodiments, the method comprises administering about 240 mg of sotorasib twice daily to the patient. In some embodiments, the method comprises administering about 260 mg of sotorasib twice daily to the patient.In some embodiments, the method comprises administering about 280 mg of sotorasib twice daily to the patient. In some embodiments, the method comprises administering about 300 mg of sotorasib twice daily to the patient. In some embodiments, the KRAS G12C inhibitor is adagrasib. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the non-small cell lung cancer has a KRAS G12C mutation. In some embodiments, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer with a KRAS G12C mutation. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the colorectal cancer is KRAS G12C mutated colorectal cancer. In some embodiments, the pancreatic cancer is KRAS G12C mutated pancreatic cancer. In some embodiments, the pancreatic cancer is selected from the group consisting of locally advanced pancreatic cancer, unresectable pancreatic cancer, and metastatic pancreatic cancer.

[0059] In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 30 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 30 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 28 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 21 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 14 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 7 consecutive days, followed by a washout period for the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 7 consecutive days.

[0060] In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 30 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 7 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 30 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 30 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 30 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 28 consecutive days.

[0061] In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 21 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 7 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 21 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 21 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 21 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 30 consecutive days.

[0062] In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 14 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 7 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 14 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 14 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 14 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 30 consecutive days.

[0063] In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 7 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 7 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 7 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 7 consecutive days, followed by a drug holiday from the compound of Formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 to 30 consecutive days.

[0064] In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and a KRAS G12C inhibitor for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days, followed by a washout period for the compound of Formula (I) and / or the KRAS G12C inhibitor, followed by administration of the compound of Formula (I) and / or the KRAS G12C inhibitor to a patient. and administering each of the G12C inhibitors to the patient for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days.

[0065] In some embodiments, the method comprises administering each of a compound of Formula (I) and a KRAS G12C inhibitor to a patient for 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days, 15 consecutive days, 16 consecutive days, 17 consecutive days, 18 consecutive days, 19 consecutive days, 20 consecutive days, 21 consecutive days, 22 consecutive days, 23 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, 27 consecutive days, 28 consecutive days, 29 consecutive days, 30 consecutive days, or 31 consecutive days, followed by a washout period for the compound of Formula (I) and / or the KRAS G12C inhibitor, followed by administration of the compound of Formula (I) and / or the KRAS G12C inhibitor to a patient. and administering each of the G12C inhibitors to a patient for 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days, 15 consecutive days, 16 consecutive days, 17 consecutive days, 18 consecutive days, 19 consecutive days, 20 consecutive days, 21 consecutive days, 22 consecutive days, 23 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, 27 consecutive days, 28 consecutive days, 29 consecutive days, 30 consecutive days, or 31 consecutive days.

[0066] In some embodiments, the drug holiday period for the compound of Formula (I) and / or the KRAS G12C inhibitor is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days. In some embodiments, the drug holiday period for the compound of Formula (I) and / or the KRAS G12C inhibitor is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In some embodiments, the drug holiday period is 1 to 6 weeks in duration. In some embodiments, the drug holiday period for the compound of Formula (I) and / or the KRAS G12C inhibitor is 1 to 4 weeks in duration. In some embodiments, the drug holiday period for the compound of Formula (I) and / or the KRAS G12C inhibitor is 1 to 3 weeks in duration, hi some embodiments, the drug holiday period is 1 to 2 weeks in duration.

[0067] In some embodiments, the drug holiday period is about 1 to 2 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 3 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 4 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 5 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 6 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 4 to 5 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 4 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 5 times the half-life of the compound represented by Formula (I) in a patient.

[0068] In some embodiments, the drug holiday period is about 1 to 2 half-lives of the KRAS G12C inhibitor in the patient. In some embodiments, the drug holiday period is about 1 to 3 half-lives of the KRAS G12C inhibitor in the patient. In some embodiments, the drug holiday period is about 1 to 4 half-lives of the KRAS G12C inhibitor in the patient. In some embodiments, the drug holiday period is about 1 to 5 half-lives of the KRAS G12C inhibitor in the patient. In some embodiments, the drug holiday period is about 1 to 6 half-lives of the KRAS G12C inhibitor in the patient. In some embodiments, the drug holiday period is about 4 to 5 half-lives of the KRAS G12C inhibitor in the patient. In some embodiments, the drug holiday period is about 4 half-lives of the KRAS G12C inhibitor in the patient. In some embodiments, the drug holiday period is about 5 half-lives of the KRAS G12C inhibitor in the patient.

[0069] Combination with sotorasib In another embodiment, described herein are methods of treating cancer in a patient in need thereof, the methods comprising: (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof; and (ii) administering a therapeutically effective amount of sotorasib to the patient. In some embodiments, the method comprises orally administering the compound to the patient. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 90 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily.In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering to the patient about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 650 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the methods comprise administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering about 90 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 110 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering to the patient about 550 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 650 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 960 mg of sotorasib once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of sotorasib once daily. In some embodiments, the method comprises administering about 120 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 140 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 160 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 180 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 200 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 220 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 240 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 260 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 280 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 300 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 960 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 100 mg to about 300 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 120 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 140 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 160 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 180 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 200 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 220 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 240 mg of sotorasib twice daily to the patient. In some embodiments, the method comprises administering about 260 mg of sotorasib twice daily to the patient. In some embodiments, the method comprises administering about 280 mg of sotorasib twice daily to the patient.In some embodiments, the method comprises administering about 300 mg of sotorasib twice daily to the patient. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the non-small cell lung cancer has a KRAS G12C mutation. In some embodiments, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer with a KRAS G12C mutation. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the colorectal cancer is KRAS G12C mutated colorectal cancer. In some embodiments, the pancreatic cancer is KRAS G12C mutated pancreatic cancer. In some embodiments, the pancreatic cancer is selected from the group consisting of locally advanced pancreatic cancer, unresectable pancreatic cancer, and metastatic pancreatic cancer.

[0070] In another embodiment, described herein are methods of treating cancer in a patient in need thereof, the methods comprising: (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, once or twice daily; and (ii) administering a therapeutically effective amount of sotorasib to the patient. In some embodiments, the method comprises orally administering the compound to the patient. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 90 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily.In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering to the patient about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 650 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the methods comprise administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering about 90 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 110 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 600 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 650 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 700 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 960 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 100 mg to about 300 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 120 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 140 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 160 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 180 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 200 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 220 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 240 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 260 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 280 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 300 mg of sotorasib to the patient once daily. In some embodiments, the method comprises administering about 960 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 100 mg to about 300 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 120 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 140 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 160 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 180 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 200 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 220 mg of sotorasib to the patient twice daily. In some embodiments, the method comprises administering about 240 mg of sotorasib twice daily to the patient. In some embodiments, the method comprises administering about 260 mg of sotorasib twice daily to the patient. In some embodiments, the method comprises administering about 280 mg of sotorasib twice daily to the patient.In some embodiments, the method comprises administering about 300 mg of sotorasib twice daily to the patient. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the non-small cell lung cancer has a KRAS G12C mutation. In some embodiments, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer with a KRAS G12C mutation. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the colorectal cancer is KRAS G12C mutated colorectal cancer. In some embodiments, the pancreatic cancer is KRAS G12C mutated pancreatic cancer. In some embodiments, the pancreatic cancer is selected from the group consisting of locally advanced pancreatic cancer, unresectable pancreatic cancer, and metastatic pancreatic cancer.

[0071] In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and sotorasib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of a compound of Formula (I) and sotorasib for 1 to 30 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and sotorasib for 1 to 28 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of a compound of Formula (I) and sotorasib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and sotorasib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of a compound of Formula (I) and sotorasib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and sotorasib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of the compound of Formula (I) and sotorasib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and sotorasib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of the compound of Formula (I) and sotorasib for 1 to 7 consecutive days.

[0072] In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and sotorasib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of a compound of Formula (I) and sotorasib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and sotorasib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of a compound of Formula (I) and sotorasib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and sotorasib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of a compound of Formula (I) and sotorasib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and sotorasib for 1 to 30 consecutive days, followed by a washout period for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of the compound of Formula (I) and sotorasib for 1 to 28 consecutive days.

[0073] In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and sotorasib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of a compound of Formula (I) and sotorasib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and sotorasib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of a compound of Formula (I) and sotorasib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and sotorasib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of a compound of Formula (I) and sotorasib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and sotorasib for 1 to 21 consecutive days, followed by a washout period for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of the compound of Formula (I) and sotorasib for 1 to 30 consecutive days.

[0074] In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and sotorasib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of a compound of Formula (I) and sotorasib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and sotorasib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of a compound of Formula (I) and sotorasib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and sotorasib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of a compound of Formula (I) and sotorasib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and sotorasib for 1 to 14 consecutive days, followed by a washout period for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of the compound of Formula (I) and sotorasib for 1 to 30 consecutive days.

[0075] In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and sotorasib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of a compound of Formula (I) and sotorasib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and sotorasib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of a compound of Formula (I) and sotorasib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to a patient each of a compound of Formula (I) and sotorasib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of a compound of Formula (I) and sotorasib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and sotorasib for 1 to 7 consecutive days, followed by a washout period for the compound of Formula (I) and / or sotorasib, and then administering to the patient each of the compound of Formula (I) and sotorasib for 1 to 30 consecutive days.

[0076] In some embodiments, the method includes administering each of the compound of Formula (I) and sotorasib to a patient for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days, followed by administration of a compound of Formula (I) and sotorasib to a patient for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days. followed by a drug holiday period for the compound and / or sotorasib, followed by 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days of administration of the compound of Formula (I) and sotorasib to the patient, respectively.

[0077] In some embodiments, the method includes administering each of a compound of Formula (I) and binimetinib to a patient for 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days, 15 consecutive days, 16 consecutive days, 17 consecutive days, 18 consecutive days, 19 consecutive days, 20 consecutive days, 21 consecutive days, 22 consecutive days, 23 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, 27 consecutive days, 28 consecutive days, 29 consecutive days, 30 consecutive days, or 31 consecutive days, followed by administration of a compound of Formula (I) and binimetinib to a patient for 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days, 15 consecutive days, 16 consecutive days, 17 consecutive days, 18 consecutive days, 19 consecutive days, 20 consecutive days, 21 consecutive days, 22 consecutive days, 23 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, 27 consecutive days, 28 consecutive days, 29 consecutive days, 30 consecutive days, or 31 consecutive days; and / or binimetinib washout period, followed by administration of each of the compound of Formula (I) and sotorasib to a patient for 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days, 15 consecutive days, 16 consecutive days, 17 consecutive days, 18 consecutive days, 19 consecutive days, 20 consecutive days, 21 consecutive days, 22 consecutive days, 23 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, 27 consecutive days, 28 consecutive days, 29 consecutive days, 30 consecutive days, or 31 consecutive days.

[0078] In some embodiments, the drug holiday period for the compound of Formula (I) and / or sotorasib is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days. In some embodiments, the drug holiday period for the compound of Formula (I) and / or sotorasib is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In some embodiments, the drug holiday period is 1 to 6 weeks in duration. In some embodiments, the drug holiday period for the compound of Formula (I) and / or sotorasib is 1 to 4 weeks in duration. In some embodiments, the drug holiday period for the compound of Formula (I) and / or sotorasib is 1 to 3 weeks in duration, hi some embodiments, the drug holiday period is 1 to 2 weeks in duration.

[0079] In some embodiments, the drug holiday period is about 1 to 2 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 3 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 4 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 5 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 6 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 4 to 5 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 4 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 5 times the half-life of the compound represented by Formula (I) in a patient.

[0080] In some embodiments, the drug holiday period is about 1 to 2 half-lives of sotorasib in the patient. In some embodiments, the drug holiday period is about 1 to 3 half-lives of sotorasib in the patient. In some embodiments, the drug holiday period is about 1 to 4 half-lives of sotorasib in the patient. In some embodiments, the drug holiday period is about 1 to 5 half-lives of sotorasib in the patient. In some embodiments, the drug holiday period is about 1 to 6 half-lives of sotorasib in the patient. In some embodiments, the drug holiday period is about 4 to 5 half-lives of sotorasib in the patient. In some embodiments, the drug holiday period is about 4 half-lives of sotorasib in the patient. In some embodiments, the drug holiday period is about 5 half-lives of sotorasib in the patient.

[0081] In combination with adagrasib In another embodiment, described herein are methods of treating cancer in a patient in need thereof, the methods comprising: (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof; and (ii) administering a therapeutically effective amount of adagrasib to the patient. In some embodiments, the method comprises orally administering the compound to the patient. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 90 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily.In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering to the patient about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 650 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the methods comprise administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering about 90 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 110 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 600 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 650 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 700 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the non-small cell lung cancer has a KRAS G12C mutation. In some embodiments, the non-small cell lung cancer is locally advanced or metastatic with a KRAS G12C mutation. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the colon cancer is KRAS G12C mutated colon cancer. In some embodiments, the pancreatic cancer is KRAS G12C mutated pancreatic cancer. In some embodiments, the pancreatic cancer is selected from the group consisting of locally advanced pancreatic cancer, unresectable pancreatic cancer, and metastatic pancreatic cancer.

[0082] In another embodiment, described herein are methods of treating cancer in a patient in need thereof, the methods comprising: (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, at about 20 mg to about 600 mg once or twice daily; and (ii) administering a therapeutically effective amount of adagrasib to the patient. In some embodiments, the method comprises orally administering the compound to the patient. In some embodiments, the method comprises administering about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 90 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily.In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering to the patient about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 650 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the methods comprise administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering about 90 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 110 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 500 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 550 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 600 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 650 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 700 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the non-small cell lung cancer has a KRAS G12C mutation. In some embodiments, the non-small cell lung cancer is locally advanced and has a KRAS G12C mutation. or metastatic non-small cell lung cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the colon cancer is KRAS G12C mutated colon cancer. In some embodiments, the pancreatic cancer is KRAS G12C mutated pancreatic cancer. In some embodiments, the pancreatic cancer is selected from the group consisting of locally advanced pancreatic cancer, unresectable pancreatic cancer, and metastatic pancreatic cancer.

[0083] In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 30 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 28 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 7 consecutive days, followed by a washout period for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 7 consecutive days.

[0084] In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 28 consecutive days.

[0085] In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 30 consecutive days.

[0086] In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 30 consecutive days.

[0087] In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or adagrasib, and then administering to the patient each of the compound of Formula (I) and adagrasib for 1 to 30 consecutive days.

[0088] In some embodiments, the method includes administering each of the compound of Formula (I) and adagrasib to a patient for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days, thereafter administering the compound of Formula (I) and adagrasib to a patient for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days, followed by a drug holiday period for the compound of Formula (I) and / or adagrasib, and then administering to a patient for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days, respectively, of the compound of Formula (I) and adagrasib.

[0089] In some embodiments, the method includes administering each of the compound of Formula (I) and adagrasib to a patient for 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days, 15 consecutive days, 16 consecutive days, 17 consecutive days, 18 consecutive days, 19 consecutive days, 20 consecutive days, 21 consecutive days, 22 consecutive days, 23 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, 27 consecutive days, 28 consecutive days, 29 consecutive days, 30 consecutive days, or 31 consecutive days, followed by administration of the compound of Formula (I). followed by a drug holiday period for the compound of Formula (I) and / or adamantane, and then administering each of the compound of Formula (I) and adagrasib to a patient for 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days, 15 consecutive days, 16 consecutive days, 17 consecutive days, 18 consecutive days, 19 consecutive days, 20 consecutive days, 21 consecutive days, 22 consecutive days, 23 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, 27 consecutive days, 28 consecutive days, 29 consecutive days, 30 consecutive days, or 31 consecutive days.

[0090] In some embodiments, the drug holiday period for the compound of Formula (I) and / or adagrasib is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days. In some embodiments, the drug holiday period for the compound of Formula (I) and / or adagrasib is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In some embodiments, the drug holiday period is 1 to 6 weeks in duration. In some embodiments, the drug holiday period for the compound of Formula (I) and / or adagrasib is 1 to 4 weeks in duration. In some embodiments, the drug holiday period for the compound of Formula (I) and / or adagrasib is 1 to 3 weeks in duration, hi some embodiments, the drug holiday period is 1 to 2 weeks in duration.

[0091] In some embodiments, the drug holiday period is about 1 to 2 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 3 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 4 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 5 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 6 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 4 to 5 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 4 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 5 times the half-life of the compound represented by Formula (I) in a patient.

[0092] In some embodiments, the drug holiday is about 1 to 2 half-lives of adagrasib in the patient. In some embodiments, the drug holiday is about 1 to 3 half-lives of adagrasib in the patient. In some embodiments, the drug holiday is about 1 to 4 half-lives of adagrasib in the patient. In some embodiments, the drug holiday is about 1 to 5 half-lives of adagrasib in the patient. In some embodiments, the drug holiday is about 1 to 6 half-lives of adagrasib in the patient. In some embodiments, the drug holiday is about 4 to 5 half-lives of adagrasib in the patient. In some embodiments, the drug holiday is about 4 half-lives of adagrasib in the patient. In some embodiments, the drug holiday is about 5 half-lives of adagrasib in the patient.

[0093] In combination with encorafenib In another embodiment, described herein are methods of treating colon cancer in a patient in need thereof, the method including (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof; and (ii) administering to the patient a therapeutically effective amount of encorafenib. In some embodiments, the method comprises orally administering the compound to the patient.

[0094] In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and encorafenib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of a compound of Formula (I) and encorafenib for 1 to 30 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and encorafenib for 1 to 28 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of a compound of Formula (I) and encorafenib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and encorafenib for 1 to 7 consecutive days, followed by a washout period for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of a compound of Formula (I) and encorafenib for 1 to 7 consecutive days.

[0095] In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and encorafenib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of a compound of Formula (I) and encorafenib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and encorafenib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of a compound of Formula (I) and encorafenib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 30 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 28 consecutive days.

[0096] In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 21 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 30 consecutive days.

[0097] In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 14 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 30 consecutive days.

[0098] In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and encorafenib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of a compound of Formula (I) and encorafenib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of a compound of Formula (I) and encorafenib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of a compound of Formula (I) and encorafenib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 7 consecutive days, followed by a drug holiday for the compound of Formula (I) and / or encorafenib, and then administering to the patient each of the compound of Formula (I) and encorafenib for 1 to 30 consecutive days.

[0099] In some embodiments, the method includes administering each of the compound of Formula (I) and encorafenib to a patient for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days, followed by administration of the compound of Formula (I). and / or encorafenib, followed by a drug holiday period, followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days of administering the compound of Formula (I) and encorafenib to a patient, respectively.

[0100] In some embodiments, the method includes administering each of a compound of Formula (I) and encorafenib to a patient for 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days, 15 consecutive days, 16 consecutive days, 17 consecutive days, 18 consecutive days, 19 consecutive days, 20 consecutive days, 21 consecutive days, 22 consecutive days, 23 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, 27 consecutive days, 28 consecutive days, 29 consecutive days, 30 consecutive days, or 31 consecutive days, followed by administration of a compound of Formula (I). and / or encorafenib washout periods, followed by administration of each of the compound of Formula (I) and encorafenib to a patient for 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, 14 consecutive days, 15 consecutive days, 16 consecutive days, 17 consecutive days, 18 consecutive days, 19 consecutive days, 20 consecutive days, 21 consecutive days, 22 consecutive days, 23 consecutive days, 24 consecutive days, 25 consecutive days, 26 consecutive days, 27 consecutive days, 28 consecutive days, 29 consecutive days, 30 consecutive days, or 31 consecutive days. In some embodiments, the drug holiday period for the compound of Formula (I) and / or encorafenib is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days. In some embodiments, the drug holiday period for the compound of Formula (I) and / or encorafenib is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In some embodiments, the drug holiday period is 1 to 6 weeks. In some embodiments, the drug holiday period for the compound of Formula (I) and / or encorafenib is 1 to 4 weeks. In some embodiments, the drug holiday period for the compound of Formula (I) and / or encorafenib is 1 to 3 weeks in duration, hi some embodiments, the drug holiday period is 1 to 2 weeks in duration.

[0101] In some embodiments, the drug holiday period is about 1 to 2 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 3 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 4 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 5 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 1 to 6 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 4 to 5 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 4 times the half-life of the compound represented by Formula (I) in a patient. In some embodiments, the drug holiday period is about 5 times the half-life of the compound represented by Formula (I) in a patient.

[0102] In some embodiments, the drug holiday period is about 1 to 2 half-lives of encorafenib in the patient. In some embodiments, the drug holiday period is about 1 to 3 half-lives of encorafenib in the patient. In some embodiments, the drug holiday period is about 1 to 4 half-lives of encorafenib in the patient. In some embodiments, the drug holiday period is about 1 to 5 half-lives of encorafenib in the patient. In some embodiments, the drug holiday period is about 1 to 6 half-lives of encorafenib in the patient. In some embodiments, the drug holiday period is about 4 to 5 half-lives of encorafenib in the patient. In some embodiments, the drug holiday period is about 4 half-lives of encorafenib in the patient. In some embodiments, the drug holiday period is about 5 half-lives of encorafenib in the patient.

[0103] In combination with encorafenib and cetuximab In another embodiment, described herein are methods of treating colon cancer in a patient in need thereof, the method including (i) administering to the patient a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof; (ii) administering a therapeutically effective amount of encorafenib to the patient; and (iii) administering a therapeutically effective amount of cetuximab to the patient. In some embodiments, the method comprises orally administering the compound to the patient. In some embodiments, the method comprises administering about 20 mg to about 1200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient daily. In some embodiments, the method comprises administering about 20 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once or twice daily. In some embodiments, the method comprises administering about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering about 90 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 110 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the methods comprise administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily.In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 200 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 250 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 300 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 350 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 400 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering about 450 mg of the compound or a pharmaceutically acceptable salt thereof to the patient twice daily. In some embodiments, the method comprises administering to the patient about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 550 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 650 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the methods comprise administering to the patient about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering about 70 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 80 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily.In some embodiments, the method comprises administering about 90 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 100 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 110 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 120 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 130 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 140 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 150 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 160 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 170 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 180 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering about 190 mg of the compound or a pharmaceutically acceptable salt thereof to the patient once daily. In some embodiments, the method comprises administering abo...

Claims

1. 1. A method of treating cancer in a patient in need thereof, comprising: (i) administering to the patient a dose of formula (I): 【Chemical Formula 1】 or a pharmaceutically acceptable salt thereof, in a dose of about 20 mg to about 600 mg, once or twice daily; (ii) administering to said patient a therapeutically effective amount of one or more additional therapeutic agents.

2. 10. The method of claim 1, comprising administering to said patient about 20 mg to about 400 mg of said compound or a pharmaceutically acceptable salt thereof twice daily.

3. 3. The method of claim 1 or 2, comprising administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.

4. 4. The method of any one of claims 1 to 3, wherein the one or more additional therapeutic agents are selected from the group consisting of a MAPKAP pathway inhibitor, an EGFR inhibitor, a KIT inhibitor, and combinations thereof.

5. 5. The method of claim 4, wherein the MAPKAP pathway inhibitor is selected from the group consisting of a MEK inhibitor, an ERK inhibitor, a RAF inhibitor, a Ras inhibitor, and combinations thereof.

6. 6. The method of claim 5, wherein the MEK inhibitor is selected from the group consisting of trametinib, binimetinib, and pharmaceutically acceptable salts thereof.

7. 6. The method of claim 5, wherein the RAF inhibitor is encorafenib, or a pharmaceutically acceptable salt thereof.

8. 6. The method of claim 5, wherein the Ras inhibitor is sotorasib, or a pharmaceutically acceptable salt thereof.

9. 5. The method of claim 4, wherein the EGFR inhibitor is cetuximab.

10. 5. The method of claim 4, wherein the KIT inhibitor is ripretinib, or a pharmaceutically acceptable salt thereof.

11. 4. The method of any one of claims 1 to 3, wherein the one or more additional therapeutic agents are selected from the group consisting of trametinib, binimetinib, sotorasib, adagrasib, cetuximab, encorafenib, ripretinib, and combinations thereof.

12. The method of any one of claims 1 to 11, wherein the cancer is selected from the group consisting of pancreatic ductal adenocarcinoma, non-small cell lung cancer, colorectal cancer, melanoma, and gastrointestinal stromal tumor.

13. 1. A method of treating cancer in a patient in need thereof, comprising: (i) administering to the patient a dose of formula (I): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof in an amount of about 20 mg to about 600 mg, once or twice daily; (ii) administering to said patient a therapeutically effective amount of trametinib.

14. 14. The method of claim 13, comprising administering to the patient from about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.

15. 15. The method of claim 13 or 14, comprising administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.

16. 16. The method of any one of claims 13 to 15, comprising administering to the patient about 0.5 mg to about 2.5 mg of trametinib once daily.

17. 17. The method of any one of claims 13 to 16, comprising administering about 2 mg of trametinib once daily to the patient.

18. The method of any one of claims 13 to 17, wherein the cancer is selected from the group consisting of pancreatic ductal adenocarcinoma, non-small cell lung cancer, colorectal cancer, and melanoma.

19. 19. The method of claim 18, wherein the pancreatic ductal adenocarcinoma has one or more KRAS mutations.

20. 19. The method of claim 18, wherein the non-small cell lung cancer has one or more mutations selected from the group consisting of a RAS mutation, an NRAS mutation, an NF1 mutation, and a RAF mutation.

21. 19. The method of claim 18, wherein the colon cancer has one or more mutations selected from the group consisting of a RAS mutation, an NRAS mutation, an NF1 mutation, and a RAF mutation.

22. 19. The method of claim 18, wherein the melanoma has one or more NRAS mutations.

23. 23. The method of claim 18 or 22, wherein the melanoma is unresectable or metastatic melanoma.

24. 1. A method of treating cancer in a patient in need thereof, comprising: (i) administering to the patient a dose of formula (I): 【Chemistry 3】 or a pharmaceutically acceptable salt thereof in an amount of about 20 mg to about 600 mg, once or twice daily; (ii) administering to said patient a therapeutically effective amount of binimetinib.

25. 25. The method of claim 24, comprising administering to the patient from about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.

26. 26. The method of claim 24 or 25, comprising administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.

27. 27. The method of any one of claims 24-26, comprising administering to the patient about 20 mg to about 50 mg of binimetinib twice daily.

28. 28. The method of any one of claims 24 to 27, comprising administering to the patient about 45 mg of binimetinib twice daily.

29. The method of any one of claims 24 to 28, wherein the cancer is selected from the group consisting of pancreatic ductal adenocarcinoma, non-small cell lung cancer, colorectal cancer, and melanoma.

30. 30. The method of claim 29, wherein the pancreatic ductal adenocarcinoma has one or more KRAS mutations.

31. 30. The method of claim 29, wherein the non-small cell lung cancer has one or more mutations selected from the group consisting of a RAS mutation, an NRAS mutation, an NF1 mutation, and a RAF mutation.

32. 30. The method of claim 29, wherein the colon cancer has one or more mutations selected from the group consisting of a RAS mutation, an NRAS mutation, an NF1 mutation, and a RAF mutation.

33. 30. The method of claim 29, wherein the melanoma has one or more NRAS mutations.

34. 30. The method of claim 29, wherein the melanoma is unresectable or metastatic melanoma.

35. 1. A method of treating cancer in a patient in need thereof, comprising: (i) administering to the patient a dose of formula (I): 【Chemistry 4】 or a pharmaceutically acceptable salt thereof in an amount of about 20 mg to about 600 mg, once or twice daily; (ii) administering to said patient a therapeutically effective amount of a KRAS G12C inhibitor.

36. 36. The method of claim 35, comprising administering to the patient from about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.

37. 37. The method of claim 35 or 36, comprising administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.

38. 38. The method of any one of claims 35 to 37, wherein the cancer is non-small cell lung cancer.

39. 39. The method of claim 38, wherein the non-small cell lung cancer has a KRAS G12C mutation.

40. 40. The method of claim 38 or 39, wherein the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer with a KRAS G12C mutation.

41. 1. A method of treating cancer in a patient in need thereof, comprising: (i) administering to the patient a dose of formula (I): 【Chemistry 5】 or a pharmaceutically acceptable salt thereof in an amount of about 20 mg to about 600 mg, once or twice daily; (ii) administering to said patient a therapeutically effective amount of sotorasib.

42. 42. The method of claim 41, comprising administering to the patient from about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.

43. 43. The method of claim 41 or 42, comprising administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.

44. 44. The method of any one of claims 41 to 43, comprising administering about 960 mg of sotorasib once daily to the patient.

45. 44. The method of any one of claims 41-43, comprising administering to the patient about 100 mg to about 300 mg of sotorasib once daily.

46. 44. The method of any one of claims 41 to 43, comprising administering about 120 mg of sotorasib once daily to the patient.

47. 44. The method of any one of claims 41 to 43, comprising administering about 240 mg of sotorasib once daily to the patient.

48. 48. The method of any one of claims 41 to 47, wherein the cancer is non-small cell lung cancer.

49. 49. The method of claim 48, wherein the non-small cell lung cancer has a KRAS G12C mutation.

50. 50. The method of claim 48 or 49, wherein the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer with a KRAS G12C mutation.

51. 1. A method of treating colon cancer in a patient in need thereof, comprising: (i) a therapeutically effective amount of a compound of formula (I): 【Chemistry 6】 orally administering to said patient a compound represented by the formula: (ii) administering to said patient a therapeutically effective amount of encorafenib.

52. 1. A method of treating colon cancer in a patient in need thereof, comprising: (i) a therapeutically effective amount of a compound of formula (I): 【Chemistry 7】 orally administering to said patient a compound represented by the formula: (ii) administering to said patient a therapeutically effective amount of encorafenib; (iii) administering to said patient a therapeutically effective amount of cetuximab.

53. 53. The method of claim 51 or 52, comprising administering to the patient from about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.

54. 54. The method of any one of claims 51 to 53, comprising administering to the patient from about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.

55. 55. The method of any one of claims 51-54, comprising administering to the patient about 250 mg to about 350 mg of encorafenib once daily.

56. 56. The method of any one of claims 51-55, comprising administering to the patient about 300 mg of encorafenib once daily.

57. Approximately 250mg / m ２ ~Approx. 550mg / m ２ of cetuximab to said patient every two weeks.

58. Approximately 500mg / m ２ of cetuximab to said patient every two weeks.

59. The method of any one of claims 51 to 58, wherein the colon cancer is metastatic colon cancer.

60. 60. The method of any one of claims 51 to 59, wherein the colon cancer has a BRAF V600E mutation.

61. 61. The method of any one of claims 51 to 60, wherein the patient has previously been treated with at least one previous therapy.

62. 1. A method of treating gastrointestinal stromal tumors in a patient in need thereof, comprising administering to said patient (i) a therapeutically effective amount of a ULK1 kinase inhibitor, a ULK2 kinase inhibitor, or an inhibitor of ULK1 kinase and ULK2 kinase; and, (ii) administering a therapeutically effective amount of ripretinib.

63. 1. A method of treating advanced gastrointestinal stromal tumor in a patient in need thereof, comprising: (i) a therapeutically effective amount of a compound of formula (I): 【Chemistry 8】 orally administering to said patient a compound represented by the formula: (ii) orally administering to said patient a therapeutically effective amount of ripretinib.

64. 64. The method of claim 63, comprising administering to the patient from about 20 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once or twice daily.

65. 65. The method of any one of claims 63 or 64, comprising administering to the patient from about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once or twice daily.

66. 66. The method of any one of claims 63-65, comprising administering to said patient from about 50 mg to about 300 mg of said compound or a pharmaceutically acceptable salt thereof twice daily.

67. 67. The method of any one of claims 63-66, comprising administering to the patient about 150 mg of ripretinib once daily.

68. 67. The method of any one of claims 63-66, comprising administering to the patient about 150 mg of ripretinib twice daily.

69. 69. The method of any one of claims 63 to 68, wherein the gastrointestinal stromal tumor is selected from the group consisting of NF-1-deficient gastrointestinal stromal tumor, succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor, KIT-positive gastrointestinal stromal tumor, and PDGFRA-positive gastrointestinal stromal tumor.

70. The method of any one of claims 63 to 69, wherein the gastrointestinal stromal tumor has a mutation in exon 11 of KIT.

71. The method of any one of claims 63 to 70, wherein the gastrointestinal stromal tumor has a mutation in exon 9 of KIT, a mutation in exon 18 of PDGFRA, a mutation in exon 12 of PDGFRA, or an activation loop mutation in exon 18 of PDGFRA.

72. 72. The method of any one of claims 63-71, wherein the patient has previously been administered at least one tyrosine kinase inhibitor prior to administration of ripretinib.

73. The method of any one of claims 61 to 72, wherein the patient's gastrointestinal stromal tumor has progressed from or the patient has been intolerant to first-line administration of imatinib, second-line administration of sunitinib, and third-line administration of regorafenib, or the patient has documented intolerance to one or more of imatinib, sunitinib, and / or regorafenib.

Images