Combination of DCC-3116 and MAPKAP pathway inhibitors for treatment of disorders

Abstract

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

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 403,477, filed on September 2, 2022; U.S. Provisional Application No. 63 / 374,451, filed on September 2, 2022; U.S. Provisional Application No. 63 / 478,777, filed on January 6, 2023; U.S. Provisional Application No. 63 / 478,782, filed on January 6, 2023; U.S. Provisional Application No. 63 / 493,825, filed on April 3, 2023; U.S. Provisional Application No. 63 / 493,828, filed on April 3, 2023; U.S. Provisional Application No. 63 / 495,693, filed on April 12, 2023; U.S. Provisional Application No. 63 / 495,694, filed on April 12, 2023; U.S. Provisional Application No. 63 / 508,646, filed on June 16, 2023; and U.S. Provisional Application No. 63 / 508,652, filed on June 16, 2023, the respective contents of which are incorporated herein by reference in their entireties. Background of the Invention

[0003] Autophagy (literally “self - eating”) is a process by which cells can recycle organelles, proteins, stored lipids, glucagon, and other substances for the purpose of generating nutrients during periods of stress. These cellular contents are recycled by engulfing them in vesicles called autophagosomes. Subsequently, the autophagosomes fuse with lysosomes that degrade the autophagosome contents to recycle the nutrients back to the cell. Tumor cells are prone to activating autophagy because these cells have high metabolic demands, experience cellular stress, and are often in a hypoxic environment with limited blood flow and nutrient supply. In addition, chemotherapy and targeted anti - cancer therapies have been shown to induce autophagy as a mechanism of treatment resistance, and it has been shown that the combination of autophagy inhibition (either through loss - of - function mutations in autophagy genes or by pharmacological means) with chemotherapy regimens inhibits tumor growth and triggers tumor cell apoptosis to a greater extent than single - agent chemotherapy.

[0004] 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 the treatment of these mutant Ras cancers is a currently highly unmet area of medical need. Mutant Ras cancers are highly proliferative and depend on the basal amount of autophagy for survival, suggesting that autophagy inhibition is a viable treatment approach in these “autophagy - addicted cancers”.

[0005] Currently, the most widely used autophagy inhibitors are chloroquine and hydroxychloroquine, which are well-known antimalarial agents. It has been thought that these antimalarial drugs block autophagy by being chelated in the lysosomal compartment, raising the pH of these lysosomes and thus inactivating the proteases that degrade and recycle nutrients. These antimalarial agents also have multiple mechanisms of action in addition to inhibiting lysosomes and are known to induce retinopathy in patients. Therefore, there is a need for more targeted agents that selectively block autophagy and do not exhibit the toxicity of these antimalarial agents. The ULK1 kinase is an initiating protein of autophagy and is a serine / threonine kinase. The ULK1 kinase complex is activated in response to cellular stress including nutrient deprivation and energy depletion. Nutrient deprivation activates ULK kinase activity via inhibition of mTORC1, and energy depletion activates ULK kinase activity via activation by the AMP-activated protein kinase AMPK. Importantly, the kinase-dead mutant of the ULK kinase blocks the initiation of canonical autophagy, indicating that small molecule inhibitors with ULK kinase activity should be able to block autophagy.

[0006] Additional mechanistic studies have shown that deletion of the ULK1 gene inhibits autophagy in cancer cells, alleviating FOX3A conversion 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). It has also been demonstrated that ULK1 and ULK2 kinases remodel cancer cell glucose metabolism, which is beneficial for an increase in the reducing agent NADPH, resulting in a decrease in toxic reactive oxygen species (ROS). ULK inhibitors may also find utility in blocking these non-canonical pro-tumor activities of ULK.

[0007] Autophagy is also upregulated in cancer host cells and tissues. It has been confirmed that autophagy in pancreatic tissue stellate cells supports tumor growth. It has been shown that pancreatic stellate cells support pancreatic cancer tumor metabolism via autophagic alanine secretion. Inhibition of host tissue autophagy has been confirmed to cause depletion of circulating arginine (an amino acid required for tumor metabolism and growth) via an increase in liver-mediated arginase secretion. It has also been shown that activation of the ULK1 kinase inactivates the STING pathway in immune cells via STING inhibitory phosphorylation, regulating a negative feedback mechanism to limit interferon-mediated innate immune cell responses. Therefore, autophagy is activated not only in tumor cells (spontaneously in cancer cells), but also in other cells in the tumor microenvironment or host tissues (non-spontaneously in cancer cells) to support tumor survival and growth.

[0008] Mutant Ras cancers are addicted to autophagy. In pancreatic cancer, mutant Ras signaling mainly occurs through the MAPKAP pathway. Mutant Ras activates the RAF kinase, which then activates the MEK kinase, and finally activates the ERK kinase: mutant Ras → RAF → MEK → ERK. Although mutant Ras signaling occurs through the MAPKAP pathway, inhibitors of this pathway do not provide or provide very little clinical benefit when used as single agents in clinical trials. It has recently been reported that inhibition of the MAPKAP pathway induces autophagy as a compensatory adaptive stress response resistance mechanism. When a MEK inhibitor is combined with the autophagy inhibitor hydroxychloroquine, it has synergistic activity that causes regression of various mutant Ras cancers or mutant BRAF cancers. Similarly, when an ERK inhibitor is combined with the autophagy inhibitor hydroxychloroquine or chloroquine, it has synergistic activity that causes inhibition of mutant Ras pancreatic cancer. It has been demonstrated that genetic depletion of the RAF kinases (CRAF and BRAF) causes synergistic anti-tumor activity in mutant Ras cancer cell lines when autophagy is also genetically depleted. Collectively, recent publications have emphasized that dual inhibition of the RAS / MAPK pathway and the autophagy pathway in mutant Ras cancers is a promising treatment option for patients with mutant Ras cancers. It has also been demonstrated that other targeted therapies and chemotherapeutic agents activate tumor autophagy as a drug resistance mechanism; thus, there is a theoretical basis for combining such targeted therapeutic agents or chemotherapeutic agents with autophagy inhibitors.

[0009] It has also been demonstrated that the tumor driver receptor tyrosine kinase (RTK) can regulate autophagy, and inhibitors of RTK also activate autophagy via the same mTORC1 and AMP kinase pathways as mutant RAS or RAF inhibitors.

[0010] There is a need for novel targeted therapies that inhibit autophagy and can be used in combination with RTK / RAS / MAPK pathway inhibitors, chemotherapeutic agents, and / or other targeted therapeutic agents. SUMMARY OF THE INVENTION

[0011] The present invention provides, in part, methods of treating a disorder with a ULK inhibitor in a combination therapy. In one specific embodiment, a method of treating cancer in a patient in need thereof is described herein, which comprises: (i) administering to the patient about 20 mg to about 600 mg of a compound represented by formula (I) once or twice daily:

[0012]

[0013] or a pharmaceutically acceptable salt thereof; and (ii) administering to the patient a therapeutically effective amount of one or more additional therapeutic agents.

[0014] In another specific embodiment, a method for treating cancer in a patient in need thereof is described herein, which comprises: (i) administering to the patient about 20 mg to about 600 mg of a compound represented by formula (I) once or twice a day:

[0015]

[0016] or a pharmaceutically acceptable salt thereof; and (ii) orally administering to the patient a therapeutically effective amount of trametinib.

[0017] In one specific embodiment, a method for treating cancer in a patient in need thereof is described herein, which comprises: (i) administering to the patient about 20 mg to about 600 mg of a compound represented by formula (I) once or twice a day:

[0018]

[0019] or a pharmaceutically acceptable salt thereof; and (ii) orally administering to the patient a therapeutically effective amount of binimetinib.

[0020] In another specific embodiment, a method for treating cancer in a patient in need thereof is described herein, which comprises administering to the patient: (i) about 20 mg to about 600 mg of a compound represented by formula (I) once or twice a day to the patient:

[0021]

[0022] or a pharmaceutically acceptable salt thereof; and (ii) orally administering to the patient a therapeutically effective amount of a KRAS G12C inhibitor.

[0023] In another specific embodiment, a method for treating cancer in a patient in need thereof is described herein, which comprises administering to the patient: (i) orally administering to the patient about 20 mg to about 600 mg of a compound represented by formula (I) once or twice a day:

[0024]

[0025] or a pharmaceutically acceptable salt thereof; and (ii) administering to the patient a therapeutically effective amount of sotorasib.

[0026] In another specific embodiment, a method for treating colorectal cancer in a patient in need thereof is described herein, which comprises: (i) administering to the patient a therapeutically effective amount of a compound represented by formula (I):

[0027]

[0028] or a pharmaceutically acceptable salt thereof; and (ii) administering to the patient a therapeutically effective amount of encorafenib.

[0029] In another embodiment, described herein is a method of treating a patient in need of treating colorectal cancer, comprising: (i) administering to the patient a therapeutically effective amount of a compound represented by formula (I):

[0030]

[0031] or a pharmaceutically acceptable salt thereof; and (ii) administering to the patient a therapeutically effective amount of encorafenib, and (iii) administering to the patient a therapeutically effective amount of cetuximab.

[0032] In another embodiment, described herein is a method of treating a patient in need of treating gastrointestinal stromal tumor, 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.

[0033] In another embodiment, described herein is a method of treating a patient in need of treating advanced gastrointestinal stromal tumor, comprising: (i) administering to the patient a therapeutically effective amount of a compound represented by formula (I):

[0034]

[0035] or a pharmaceutically acceptable salt thereof; and (ii) orally administering to the patient a therapeutically effective amount of ripretinib. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 Describe the study protocol of Example 1.

[0037] Figure 2 Depict the treatment duration and response evaluation results in the monotherapy study of Example 1.

[0038] Figure 3A Depict the total area under the curve (AUC) results on Day 5 of Cycle 1 (C1D15) in the monotherapy study of Example 1, and Figure 3B Depict the area under the curve (AUC) results of unbound DCC-3116.

[0039] Figure 4 Depict the pre-dose trough exposure results of the patients evaluated on Day 5 of Cycle 1 (C1D15) in the monotherapy study of Example 1.

[0040] Figure 5ADepict the activation of ULK by trametinib and its reversal by DCC-3116 in pancreatic cancer (MiaPaca2) cell lines harboring the KRAS G12C mutation. Figure 5B Depict the activation of autophagy by trametinib and its reversal by DCC-3116 in the MiaPaca2 model. Figure 5C Depict the additivity of the combination of DCC-3116 and trametinib in the MiaPaca2 pancreatic model.

[0041] Figure 6A Depict the activation of ULK by trametinib and its reversal by DCC-3116 in multiple non-small cell lung cancer (NSCLC) cell lines. Figure 6B Depict the activation of autophagy by trametinib and its reversal by DCC-3116 in NSCLC cell lines.

[0042] Figure 7A Depict the activation of ULK by trametinib and its reversal by DCC-3116 in the A549* non-small cell lung cancer (NSCLC) cell line. Figure 7B Depict the activation of autophagy by trametinib and its reversal by DCC-3116 in NSCLC cell lines.

[0043] Figure 8 Depict the results of the study on the combination of DCC-3116 and trametinib in the H358 xenograft model, which shows tumor regression.

[0044] Figure 9A Depict the tumor growth study of DCC-3116 and binimetinib in the SK-MEL-30 rat study. Figure 9B Depict the tumor growth study of DCC-3116 and binimetinib in the MiaPaca-2 model.

[0045] Figure 10 Depict DCC-3116 inhibiting binimetinib- and ripretinib-induced ULK activity in the GIST-T1 cell line.

[0046] Figure 11A Depict DCC-3116 reversing ripretinib-induced ULK activation in multiple GIST cell lines. Figure 11B Depict DCC-3116 inhibiting ripretinib-induced autophagic flux in the GIST-T1 cell line. Figure 11C Depict the synergistic effect of the combination of DCC-3116 and ripretinib in the GIST-T1 cancer model. Figure 11D Depict the body weight changes related to the combination of DCC-3116 and ripretinib in the GIST T1 xenograft model.

[0047] Figure 12A Depict DCC-3116 reversing KRAS G12CKRAS in mutant non-small cell lung cancer G12C ULK activation induced by inhibitors (sotorasib or adagrasib). Figure 12B Depiction of DCC-3116 inhibiting KRAS G12C KRAS in mutant non-small cell lung cancer G12C Autophagic flux induced by inhibitors (adagrasib or sotorasib). Figure 12C Depiction of the additivity of the combination of DCC-3116 and sotorasib in the H358 lung cancer model.

[0048] Figure 13A 、 13B Figures 13C and 13D depict spaghetti plot analyses showing tumor growth inhibition and / or regression in various combination groups of sotorasib at 1 mg / kg ( Figure 13A ), 3 mg / kg ( Figure 13B ), 10 mg / kg ( Figure 13C ), and 30 mg / kg ( Figure 13D ).

[0049] Figure 14A Depiction of KRAS G12C Activation of ULK by KRAS inhibitors in mutant pancreatic cancer (MiaPaCa-2) and reversal by DCC-3116. G12C Figure 14B Depiction of KRAS G12C Activation of autophagy by KRAS inhibitors in a mutant pancreatic cancer model (MiaPaCa-2) and reversal by DCC-3116. G12C Figure 14C Depiction of the additivity of the combination of DCC-3116 and sotorasib in the MiaPaca2 pancreatic cancer model.

[0050] Figure 15A Tumor growth study of the combination of sotorasib and DCC-3116 in a xenograft lung cancer model (LU11554) derived from a KRAS G12C patient. Figure 15B Tumor growth study of the combination of adagrasib and DCC-3116 in a xenograft lung cancer model (LU11554) derived from a patient.

[0051] Figure 16A Depiction of KRAS G12C Combination study of DCC-3116 and sotorasib in mutant colorectal cancer cell line (SW1463). Figure 16B Depiction of KRAS G12C Combination study of DCC-3116 and adagrasib in mutant colorectal cancer cell line (SW1463). ​​

[0052] Figure 17A Describes the combination study of Compound 1 and MTX-1133, which shows induction of ULK activity in the HPAF-II KRAS G12D cell line and inhibition of MRTX-1133-induced ULK activity in the HPAF-II cell line. Figure 17B Describes the combination study of Compound 1 and MTX-1133, which shows inhibition of MRTX1133-induced autophagic flux in the HPAF-II cell line and stable inhibition of MRTX1133-induced autophagic flux in the HPAF-II cell line by Compound 1.

[0053] Figure 18A Describes BRAF V600E pATG13 ELISA analysis study of DCC-3116, encorafenib, and cetuximab in BRAF Figure 18B Describes BRAF V600E Autophagic flux analysis study of DCC-3116, encorafenib, and cetuximab in BRAF

[0054] Figure 19 Describes the results of DCC-3116 inhibiting encorafenib- and cetuximab-induced pATG13 in HT-29 tumors.

[0055] Figure 20A 、 20B 、20C and 20D describe the results of various tumor burden studies of the combination of DCC-3116 with encorafenib and cetuximab in the BRAF V600E mutant colorectal model HT-29.

[0056] Figure 21 Describes the PK results of the combination of sotorasib and DCC-3116 in the MiaPaca-2 PK / PD model.

[0057] Figure 22A Describes the plasma concentration results of the combination of DCC-3116 and adagrasib in female athymic nude mice (0.5% w / v Na CMC, 0.1% v / v -80 aqueous solution). Figure 22B Describes the plasma concentration results of the combination of DCC-3116 and adagrasib in female athymic nude mice (10% 50 mM citrate buffer, pH 5.0).

[0058] Figure 22C Describes the PK results of the combination of adagrasib and DCC-3116 in nude mice 5 days after dosing.

[0059] Figure 23Depiction of the induction of ATG13-S phosphorylation and dose-dependent inhibition of DCC-3116 in the Colo-205 cell line by encorafenib and cetuximab 318 phosphorylation and dose-dependent inhibition of DCC-3116.

[0060] Figure 24 Depiction of the dose-dependent inhibition of LC3 degradation in cells treated with encorafenib and cetuximab by DCC-3116.

[0061] Figure 25 Depiction of the time course of the inhibition of LC3 degradation in cells treated with encorafenib and cetuximab by DCC-3116.

[0062] Figure 26 Graph depicting tumor growth over time (study days) using encorafenib and cetuximab and DCC-3116. Drugs were administered on days 6 - 27 (21 days). Tumor volume was measured after the end of dosing to measure tumor regrowth.

[0063] Figure 27 Depiction of the PK / PD study of the combination of DCC-3116 with encorafenib and cetuximab 2 hours after dosing on day 7. DETAILED DESCRIPTION

[0064] DEFINITIONS

[0065] As used herein, "combination therapy" is a treatment that includes administering to a patient in need two or more therapeutic agents, such as a compound of formula I and additional therapeutic agents described herein.

[0066] "RAS / MAPK pathway inhibitor" refers to an inhibitor of the RAS / MAPK signaling pathway. Inhibitors of this pathway include Ras inhibitors (such as AMG-510 (sotorasib), MRTX849 (adagrasib), GDC-6036, MRTX-1133, RMS-9805, RMC-6291, and RMC-6236, and their pharmaceutically acceptable salts), RAF inhibitors (such as LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, belvarafenib, KIN-2787, and VS-6766, and their pharmaceutically acceptable salts), MEK inhibitors (such as trametinib, selumetinib, cobimetinib, and binimetinib, and their pharmaceutically acceptable salts), and ERK inhibitors (such as ulixertinib, SCH772984, LY3214996, ravoxertinib, VX-11e, ERAS-007, and ASTX-029, and their pharmaceutically acceptable salts). The terms "RAS / MAPK pathway inhibitor" and "RAS / MAPK kinase inhibitor" are used interchangeably herein.

[0067] "RTK pathway inhibitor" refers to an inhibitor of the RTK (receptor tyrosine kinase) signaling pathway. Inhibitors of this pathway include KIT inhibitors (such as ripretinib, avapritinib, sunitinib, and imatinib, and their pharmaceutically acceptable salts), EGFR inhibitors (such as cetuximab or its pharmaceutically acceptable salt), PDGFRα inhibitors (such as JNJ10198409 or its pharmaceutically acceptable salt), VEGFR inhibitors (such as regorafenib and pazopanib, and their pharmaceutically acceptable salts), BCR-Abl inhibitors (such as imatinib, nilotinib, dasatinib, or their pharmaceutically acceptable salts), and ALK inhibitors (such as loralatinb and alectinib, and their pharmaceutically acceptable salts).

[0068] "Individual", "patient", or "subject" are used interchangeably herein and include any animal comprising a mammal, which mammals include mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and humans. The compounds described herein can be administered not only to mammals such as humans, but also to other mammals such as animals in need of veterinary treatment, for example, domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammals to be treated by the methods described herein are preferably mammals in need of treatment for the disorders described herein, such as humans.

[0069] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts having acidic or basic groups that may be present in the compounds used in the compositions. Compounds included in the compositions of the present invention that are inherently basic are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can 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: malates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, bisulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbates, succinates, maleates, gentisates, fumarates, gluconates, glucuronates, galacturonates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoates)).

[0070] As used herein, "treatment" includes any action that causes an improvement in a condition, disease, disorder, etc., such as alleviation, reduction, modulation, or elimination.

[0071] As used herein, the term "drug holiday" includes a drug holiday of one or more therapeutic agents described herein, such as a drug holiday of one therapeutic agent described herein, a drug holiday of two therapeutic agents described herein, or a drug holiday of three therapeutic agents described herein. In some embodiments, the drug holiday is a drug holiday of the compound represented by formula (I). In some embodiments, the drug holiday is a drug holiday of the compound represented by formula (I) and / or trametinib. In some embodiments, the drug holiday is a drug holiday of the compound represented by formula (I) and / or binimetinib. In some embodiments, the drug holiday is a drug holiday of the compound represented by formula (I) and / or sotorasib. In some embodiments, the drug holiday is a drug holiday of the compound represented by formula (I) and / or adagrasib. In some embodiments, the drug holiday is a drug holiday of the compound represented by formula (I), encorafenib, and / or cetuximab. In some embodiments, the drug holiday is a drug holiday of the compound represented by formula (I) and / or ripretinib.

[0072] As used herein, "DCC-3116" refers to the compound of formula (I) as defined herein.

[0073] As used herein, "Compound A" refers to the compound having the following structure:

[0074]

[0075] "Therapeutically effective amount" includes the amount of a compound of the present invention that will elicit a biological or medical response of a tissue, system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician. The compounds described herein are administered in a therapeutically effective amount, such as a compound of formula (I) to treat the conditions described herein. Alternatively, a therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and / or prophylactic effect, such as the amount to prevent or reduce the symptoms associated with a condition.

[0076] The compounds described herein can be formulated into pharmaceutical compositions using pharmaceutically acceptable carriers and administered by a variety of routes. In some embodiments, such compositions are for oral administration. In some embodiments, the formulated compositions 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 their preparation processes are well known in the art. See, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro et al., eds., 19th ed., Mack Publishing Co., 1995).

[0077] Method of treatment

[0078] Combination with one or more additional therapeutic agents

[0079] In one embodiment, a method of treating cancer in a patient in need thereof is described herein, comprising: (i) administering to the patient about 20 mg to about 1200 mg of a compound represented by formula (I) per day:

[0080]

[0081] or a pharmaceutically acceptable salt thereof; 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 certain 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 certain 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 certain 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 to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 150 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 of the compound or a pharmaceutically acceptable salt thereof 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 to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 150 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 of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 300 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of RTK pathway inhibitors, EGFR inhibitors, KIT inhibitors, 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 inhibitors are selected from the group consisting of MEK inhibitors, ERK inhibitors, RAF inhibitors, Ras inhibitors, and combinations thereof. In some embodiments, the MEK inhibitors are 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.

[0082] In one embodiment, a method of treating cancer in a patient in need thereof is described herein, comprising: (i) administering to the patient about 20 mg to about 600 mg of a compound represented by formula (I) once or twice daily:

[0083]

[0084] or a pharmaceutically acceptable salt thereof; 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 from 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 from 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 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 to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof twice daily.

[0085] In some embodiments, the method comprises administering to the patient about 200 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient from about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient from about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 90 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 200 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 300 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of RTK pathway inhibitors, EGFR inhibitors, KIT inhibitors, 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 inhibitors are selected from the group consisting of MEK inhibitors, ERK inhibitors, RAF inhibitors, Ras inhibitors, and combinations thereof. In some embodiments, the MEK inhibitors are selected from 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.

[0086] In combination with trametinib

[0087] In another embodiment, provided herein is a method of treating cancer in a patient in need thereof, comprising: (i) administering to the patient from about 20 mg to about 1200 mg per day of a compound represented by formula (I):

[0088]

[0089] or a pharmaceutically acceptable salt thereof; and (ii) orally administering to the patient a therapeutically effective amount of trametinib. 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 to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof 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 350 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 to the patient about 90 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 of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 150 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 of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 0.5 mg to about 2.5 mg of trametinib once daily. In some embodiments, the method comprises administering to the patient about 2 mg of trametinib once daily. In some embodiments, the method comprises administering to the patient about 1.5 mg of trametinib once daily. In some embodiments, the method comprises administering to the patient about 1 mg of trametinib once daily. In some embodiments, the method comprises administering to the patient about 0.5 mg to about 2.5 mg of trametinib twice daily. In some embodiments, the method comprises administering to the patient about 2 mg of trametinib once daily. In some embodiments, the method comprises administering to the patient about 1.5 mg of trametinib twice daily. In some embodiments, the method comprises administering to the patient 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 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 combinations 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 combinations 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, 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, 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, melanoma has one or more RAS mutations. In some embodiments, 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, melanoma has one or more NRAS mutations. In some embodiments, melanoma is unresectable melanoma or metastatic melanoma. In some embodiments, at least one prior therapy has been administered to a patient with RAF-mutated non-small cell lung cancer. In some embodiments, at least three (e.g., three to five) prior therapies have been administered to a patient with RAF-mutated non-small cell lung cancer. In some embodiments, at least one prior therapy has been administered to a patient with NF1-mutated non-small cell lung cancer. In some embodiments, at least three (e.g., three to five) prior therapies have been administered to a patient with NF1-mutated non-small cell lung cancer. In some embodiments, at least one prior therapy has been administered to a patient with RAS-mutated non-small cell lung cancer. In some embodiments, at least three (e.g., three to five) prior therapies have been administered to a patient with RAS-mutated non-small cell lung cancer. In some embodiments, at least one prior therapy has been administered to a patient with RAF-mutated colorectal cancer. In some embodiments, at least three (e.g., three to four) prior therapies have been administered to a patient with RAF-mutated colorectal cancer. In some embodiments, at least one prior therapy has been administered to a patient with NF1-mutated colorectal cancer. In some embodiments, at least three (e.g., three to four) prior therapies have been administered to a patient with NF1-mutated colorectal cancer. In some embodiments, at least one prior therapy has been administered to a patient with RAS-mutated colorectal cancer. In some embodiments, at least three (e.g., three to four) prior therapies have been administered to a patient with RAS-mutated colorectal cancer. In some embodiments, at least one prior therapy has been administered to a patient with NRAS-mutated melanoma. In some embodiments, at least two (e.g., two to three) prior therapies have been administered to a patient with NRAS-mutated melanoma.

[0090] In another embodiment, a method of treating cancer in a patient in need thereof is described herein, which comprises: (i) administering to the patient, once or twice daily, from about 20 mg to about 600 mg of a compound represented by formula (I):

[0091]

[0092] or a pharmaceutically acceptable salt thereof; and (ii) orally administering to the patient a therapeutically effective amount of trametinib. 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 to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof 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 350 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof 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 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 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 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 to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 350 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 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 0.5 mg to about 2.5 mg of trametinib once daily. In some embodiments, the method comprises administering to the patient about 2 mg of trametinib once daily.In some embodiments, the method comprises administering to the patient about 0.5 mg to about 2.5 mg of trametinib twice a day. In some embodiments, the method comprises administering to the patient about 2 mg of trametinib once a day. In some embodiments, the method comprises administering to the patient about 1.5 mg of trametinib twice a day. In some embodiments, the method comprises administering to the patient about 1 mg of trametinib twice a day. 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 combinations 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 combinations thereof. In some embodiments, the colorectal cancer has one or more mutations selected from the group consisting of RAS mutations, NF1 mutations, RAF mutations, or 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 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 combinations 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 combinations thereof. In some embodiments, the melanoma has one or more NRAS mutations. In some embodiments, the melanoma is unresectable melanoma or metastatic melanoma. In some embodiments, at least one prior therapy has been administered to a patient with RAF-mutated non-small cell lung cancer. In some embodiments, at least three (e.g., three to five) prior therapies have been administered to a patient with RAF-mutated non-small cell lung cancer. In some embodiments, at least one prior therapy has been administered to a patient with NF1-mutated non-small cell lung cancer. In some embodiments, at least three (e.g., three to five) prior therapies have been administered to a patient with NF1-mutated non-small cell lung cancer.In some embodiments, at least one prior therapy has been administered to a patient with RAS-mutated non-small cell lung cancer. In some embodiments, at least three (e.g., three to five) prior therapies have been administered to a patient with RAS-mutated non-small cell lung cancer. In some embodiments, at least one prior therapy has been administered to a patient with RAF-mutated colorectal cancer. In some embodiments, at least three (e.g., three to four) prior therapies have been administered to a patient with RAF-mutated colorectal cancer. In some embodiments, at least one prior therapy has been administered to a patient with NF1-mutated colorectal cancer. In some embodiments, at least three (e.g., three to four) prior therapies have been administered to a patient with NF1-mutated colorectal cancer. In some embodiments, at least one prior therapy has been administered to a patient with RAS-mutated colorectal cancer. In some embodiments, at least three (e.g., three to four) prior therapies have been administered to a patient with RAS-mutated colorectal cancer. In some embodiments, at least one prior therapy has been administered to a patient with NRAS-mutated melanoma. In some embodiments, at least two (e.g., two to three) prior therapies have been administered to a patient with NRAS-mutated melanoma.

[0093] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and trametinib for each of 1 to 30 consecutive days, followed by a drug holiday from the compound represented by formula (I) and / or trametinib, and then administering to the patient each of the compound represented by formula (I) and trametinib for each of 1 to 30 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and trametinib for each of 1 to 28 consecutive days, followed by a drug holiday from the compound represented by formula (I) and / or trametinib, and then administering to the patient each of the compound represented by formula (I) and trametinib for each of 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and trametinib for each of 1 to 21 consecutive days, followed by a drug holiday from the compound represented by formula (I) and / or trametinib, and then administering to the patient each of the compound represented by formula (I) and trametinib for each of 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and trametinib for each of 1 to 14 consecutive days, followed by a drug holiday from the compound represented by formula (I) and / or trametinib, and then administering to the patient each of the compound represented by formula (I) and trametinib for each of 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and trametinib for each of 1 to 7 consecutive days, followed by a drug holiday from the compound represented by formula (I) and / or trametinib, and then administering to the patient each of the compound represented by formula (I) and trametinib for each of 1 to 7 consecutive days.

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

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

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

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

[0098] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and trametinib for 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, followed by a drug holiday for the compound represented by formula (I) and / or trametinib, and then administering to the patient each of the compound represented by formula (I) and trametinib for 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.

[0099] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and trametinib for 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 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or trametinib, and then administering to the patient each of the compound represented by formula (I) and trametinib for 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 consecutive days.

[0100] In some embodiments, the drug holiday of the compound represented by formula (I) and / or trametinib is a period of 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 of the compound represented by formula (I) and / or trametinib is a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 weeks. In some embodiments, the drug holiday is a period of 1 - 6 weeks. In some embodiments, the drug holiday of the compound represented by formula (I) and / or trametinib is a period of 1 - 4 weeks. In some embodiments, the drug holiday of the compound represented by formula (I) and / or trametinib is a period of 1 - 3 weeks. In some embodiments, the drug holiday is a period of 1 - 2 weeks.

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

[0102] In some embodiments, the drug holiday is about 1 - 2 times the half - life of trametinib in the patient's body. In some embodiments, the drug holiday is about 1 - 3 times the half - life of trametinib in the patient's body. In some embodiments, the drug holiday is about 1 - 4 times the half - life of trametinib in the patient's body. In some embodiments, the drug holiday is about 1 - 5 times the half - life of trametinib in the patient's body. In some embodiments, the drug holiday is about 1 - 6 times the half - life of trametinib in the patient's body. In some embodiments, the drug holiday is about 4 - 5 times the half - life of trametinib in the patient's body. In some embodiments, the drug holiday is about 4 times the half - life of trametinib in the patient's body. In some embodiments, the drug holiday is about 5 times the half - life of trametinib in the patient's body.

[0103] In combination with binimetinib

[0104] In one embodiment, described herein is a method of treating cancer in a patient in need thereof, comprising: (i) administering to the patient about 20 mg to about 1200 mg of a compound represented by formula (I) per day:

[0105]

[0106] or a pharmaceutically acceptable salt thereof; and (ii) orally administering to the patient a therapeutically effective amount of binimetinib. 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 to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof 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 350 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 to the patient about 90 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 of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 350 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 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 20 mg to about 50 mg of binimetinib twice daily. In some embodiments, the method comprises administering to the patient about 45 mg of binimetinib twice daily.In some embodiments, the method comprises administering to the patient about 40 mg of binimetinib twice daily. In some embodiments, the method comprises administering to the patient about 35 mg of binimetinib twice daily. In some embodiments, the method comprises administering to the patient about 30 mg of binimetinib twice daily. In some embodiments, the method comprises administering to the patient about 25 mg of binimetinib twice daily. In some embodiments, the method comprises administering to the patient about 20 mg of binimetinib twice daily. In some embodiments, the method comprises administering to the patient about 20 mg to about 50 mg of binimetinib once daily. In some embodiments, the method comprises administering to the patient about 45 mg of binimetinib once daily. In some embodiments, the method comprises administering to the patient about 40 mg of binimetinib once daily. In some embodiments, the method comprises administering to the patient about 35 mg of binimetinib once daily. In some embodiments, the method comprises administering to the patient about 30 mg of binimetinib once daily. In some embodiments, the method comprises administering to the patient about 25 mg of binimetinib once daily. In some embodiments, the method comprises administering to the patient about 20 mg of binimetinib 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 combinations 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 combinations 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 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 combinations 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 an unresectable melanoma or a metastatic melanoma. In some embodiments, at least one prior therapy has been administered to a patient with RAF-mutated non-small cell lung cancer. In some embodiments, at least three (e.g., three to five) prior therapies have been administered to a patient with RAF-mutated non-small cell lung cancer. In some embodiments, at least one prior therapy has been administered to a patient with NF1-mutated non-small cell lung cancer. In some embodiments, at least three (e.g., three to five) prior therapies have been administered to a patient with NF1-mutated non-small cell lung cancer. In some embodiments, at least one prior therapy has been administered to a patient with RAS-mutated non-small cell lung cancer. In some embodiments, at least three (e.g., three to five) prior therapies have been administered to a patient with RAS-mutated non-small cell lung cancer. In some embodiments, at least one prior therapy has been administered to a patient with RAF-mutated colorectal cancer. In some embodiments, at least three (e.g., three to four) prior therapies have been administered to a patient with RAF-mutated colorectal cancer. In some embodiments, at least one prior therapy has been administered to a patient with NF1-mutated colorectal cancer. In some embodiments, at least three (e.g., three to four) prior therapies have been administered to a patient with NF1-mutated colorectal cancer. In some embodiments, at least one prior therapy has been administered to a patient with RAS-mutated colorectal cancer. In some embodiments, at least three (e.g., three to four) prior therapies have been administered to a patient with RAS-mutated colorectal cancer. In some embodiments, at least one prior therapy has been administered to a patient with NRAS-mutated melanoma. In some embodiments, at least two (e.g., two to three) prior therapies have been administered to a patient with NRAS-mutated melanoma.

[0107] In one embodiment, described herein is a method of treating cancer in a patient in need thereof, comprising: (i) administering to the patient, once or twice daily, from about 20 mg to about 600 mg of a compound represented by formula (I):

[0108]

[0109] or a pharmaceutically acceptable salt thereof; and (ii) orally administering to the patient a therapeutically effective amount of binimetinib. 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 a day. In some embodiments, the method comprises administering to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 190 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 200 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 350 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 450 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 550 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 650 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice a day.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 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 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 to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 350 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 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 20 mg to about 50 mg of binimetinib twice daily. In some embodiments, the method comprises administering to the patient about 45 mg of binimetinib twice daily.In some embodiments, the method comprises administering to the patient from about 20 mg to about 50 mg of binimetinib once daily. In some embodiments, the method comprises administering to the patient about 45 mg of binimetinib once daily. In some embodiments, the method comprises administering to the patient about 40 mg of binimetinib once daily. In some embodiments, the method comprises administering to the patient about 35 mg of binimetinib once daily. In some embodiments, the method comprises administering to the patient about 30 mg of binimetinib once daily. In some embodiments, the method comprises administering to the patient about 25 mg of binimetinib once daily. In some embodiments, the method comprises administering to the patient about 20 mg of binimetinib 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 combinations 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 combinations 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 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 combinations 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 combinations thereof. In some embodiments, the melanoma has one or more NRAS mutations. In some embodiments, the melanoma is unresectable melanoma or metastatic melanoma. In some embodiments, at least one prior therapy has been administered to a patient with RAF-mutant non-small cell lung cancer. In some embodiments, at least three (e.g., three to five) prior therapies have been administered to a patient with RAF-mutant non-small cell lung cancer.In some embodiments, at least one prior therapy has been administered to a patient with NF1-mutated non-small cell lung cancer. In some embodiments, at least three (e.g., three to five) prior therapies have been administered to a patient with NF1-mutated non-small cell lung cancer. In some embodiments, at least one prior therapy has been administered to a patient with RAS-mutated non-small cell lung cancer. In some embodiments, at least three (e.g., three to five) prior therapies have been administered to a patient with RAS-mutated non-small cell lung cancer. In some embodiments, at least one prior therapy has been administered to a patient with RAF-mutated colorectal cancer. In some embodiments, at least three (e.g., three to four) prior therapies have been administered to a patient with RAF-mutated colorectal cancer. In some embodiments, at least one prior therapy has been administered to a patient with NF1-mutated colorectal cancer. In some embodiments, at least three (e.g., three to four) prior therapies have been administered to a patient with NF1-mutated colorectal cancer. In some embodiments, at least one prior therapy has been administered to a patient with RAS-mutated colorectal cancer. In some embodiments, at least three (e.g., three to four) prior therapies have been administered to a patient with RAS-mutated colorectal cancer. In some embodiments, at least one prior therapy has been administered to a patient with NRAS-mutated melanoma. In some embodiments, at least two (e.g., two to three) prior therapies have been administered to a patient with NRAS-mutated melanoma.

[0110] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib for each of 1 to 30 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib for each of 1 to 30 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib for each of 1 to 28 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib for each of 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib for each of 1 to 21 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib for each of 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib for each of 1 to 14 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib for each of 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib for each of 1 to 7 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib for each of 1 to 7 consecutive days.

[0111] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 30 days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 7 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 30 days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 14 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 30 days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 21 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 30 days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 28 days.

[0112] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 21 days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 7 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 21 days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 14 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 21 days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 28 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 21 days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 30 days.

[0113] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 14 days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 7 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 14 days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 21 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 14 days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 28 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 14 days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 30 days.

[0114] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 7 days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 14 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 7 days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 21 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 7 days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 28 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 7 days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib continuously for 1 to 30 days.

[0115] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib for 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, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib for 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.

[0116] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and binimetinib for 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 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or binimetinib, and then administering to the patient each of the compound represented by formula (I) and binimetinib for 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 consecutive days.

[0117] In some embodiments, the drug holiday for the compound represented by formula (I) and / or binimetinib is a period of 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 for the compound represented by formula (I) and / or binimetinib is a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In some embodiments, the drug holiday is a period of 1 - 6 weeks. In some embodiments, the drug holiday for the compound represented by formula (I) and / or binimetinib is a period of 1 - 4 weeks. In some embodiments, the drug holiday for the compound represented by formula (I) and / or binimetinib is a period of 1 - 3 weeks. In some embodiments, the drug holiday is a period of 1 - 2 weeks.

[0118] In some embodiments, the drug holiday is about 1 - 2 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 1 - 3 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 1 - 4 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 1 - 5 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 1 - 6 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 4 - 5 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 4 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 5 times the half-life of the compound represented by formula (I) in the patient's body.

[0119] In some embodiments, the drug holiday is about 1 - 2 times the half-life of binimetinib in the patient's body. In some embodiments, the drug holiday is about 1 - 3 times the half-life of binimetinib in the patient's body. In some embodiments, the drug holiday is about 1 - 4 times the half-life of binimetinib in the patient's body. In some embodiments, the drug holiday is about 1 - 5 times the half-life of binimetinib in the patient's body. In some embodiments, the drug holiday is about 1 - 6 times the half-life of binimetinib in the patient's body. In some embodiments, the drug holiday is about 4 - 5 times the half-life of binimetinib in the patient's body. In some embodiments, the drug holiday is about 4 times the half-life of binimetinib in the patient's body. In some embodiments, the drug holiday is about 5 times the half-life of binimetinib in the patient's body.

[0120] Combination with a KRAS G12C inhibitor

[0121] In another embodiment, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient: (i) from about 20 mg to about 1200 mg per day of a compound represented by formula (I):

[0122]

[0123] or a pharmaceutically acceptable salt thereof; and (ii) orally 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof twice a day.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 to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof 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 350 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 90 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof once a day.In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 350 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 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 KRAS G12C inhibitor is sotorasib. 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 from about 100 mg to 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 to the patient about 280 mg of sotorasib once daily. In some embodiments, the method comprises administering to the patient about 300 mg of sotorasib once daily. In some embodiments, the method comprises administering to the patient about 960 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient from about 100 mg to about 300 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 120 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 140 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 160 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 180 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 200 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 220 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 240 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 260 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 280 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 300 mg of sotorasib twice daily. 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 mutant colorectal cancer. In some embodiments, the pancreatic cancer is KRAS G12C mutant 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.

[0124] In another embodiment, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient: (i) administering to the patient from about 20 mg to about 600 mg of a compound represented by formula (I) once or twice daily:

[0125]

[0126] or a pharmaceutically acceptable salt thereof; and (ii) orally 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 to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof 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 350 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof 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 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 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 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 to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 350 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 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 KRAS G12C inhibitor is sotorasib. 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 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 to the patient about 280 mg of sotorasib once daily. In some embodiments, the method comprises administering to the patient about 300 mg of sotorasib once daily. In some embodiments, the method comprises administering to the patient about 960 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 120 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 140 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 160 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 180 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 200 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 220 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 240 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 260 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 280 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 300 mg of sotorasib twice daily. 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 mutant colorectal cancer. In some embodiments, the pancreatic cancer is KRAS G12C mutant 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.

[0127] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 30 days, followed by a drug holiday from the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 30 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 28 days, followed by a drug holiday from the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 28 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 21 days, followed by a drug holiday from the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 21 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 14 days, followed by a drug holiday from the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 14 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 7 days, followed by a drug holiday from the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 7 days.

[0128] In some embodiments, the method includes administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 30 days, followed by a drug holiday from the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 7 days. In some embodiments, the method includes administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 30 days, followed by a drug holiday from the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 14 days. In some embodiments, the method includes administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 30 days, followed by a drug holiday from the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 21 days. In some embodiments, the method includes administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 30 days, followed by a drug holiday from the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 28 days.

[0129] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 21 days, followed by a drug holiday from the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 7 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 21 days, followed by a drug holiday from the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 14 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 21 days, followed by a drug holiday from the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 28 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 21 days, followed by a drug holiday from the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 30 days.

[0130] In some embodiments, the method includes administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 14 days, followed by a drug holiday for the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 7 days. In some embodiments, the method includes administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 14 days, followed by a drug holiday for the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 21 days. In some embodiments, the method includes administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 14 days, followed by a drug holiday for the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 28 days. In some embodiments, the method includes administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 14 days, followed by a drug holiday for the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 30 days.

[0131] In some embodiments, the method includes administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 7 days, followed by a drug holiday for the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 14 days. In some embodiments, the method includes administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 7 days, followed by a drug holiday for the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 21 days. In some embodiments, the method includes administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 7 days, followed by a drug holiday for the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 28 days. In some embodiments, the method includes administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor continuously for 1 to 7 days, followed by a drug holiday for the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor continuously for 1 to 30 days.

[0132] In some embodiments, the method includes administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor for 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, followed by a drug holiday for the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor for 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.

[0133] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and a KRAS G12C inhibitor for 1 day, for 2 consecutive days, for 3 consecutive days, for 4 consecutive days, for 5 consecutive days, for 6 consecutive days, for 7 consecutive days, for 8 consecutive days, for 9 consecutive days, for 10 consecutive days, for 11 consecutive days, for 12 consecutive days, for 13 consecutive days, for 14 consecutive days, for 15 consecutive days, for 16 consecutive days, for 17 consecutive days, for 18 consecutive days, for 19 consecutive days, for 20 consecutive days, for 21 consecutive days, for 22 consecutive days, for 23 consecutive days, for 24 consecutive days, for 25 consecutive days, for 26 consecutive days, for 27 consecutive days, for 28 consecutive days, for 29 consecutive days, for 30 consecutive days, or for 31 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or the KRAS G12C inhibitor, and then administering to the patient each of the compound represented by formula (I) and the KRAS G12C inhibitor for 1 day, for 2 consecutive days, for 3 consecutive days, for 4 consecutive days, for 5 consecutive days, for 6 consecutive days, for 7 consecutive days, for 8 consecutive days, for 9 consecutive days, for 10 consecutive days, for 11 consecutive days, for 12 consecutive days, for 13 consecutive days, for 14 consecutive days, for 15 consecutive days, for 16 consecutive days, for 17 consecutive days, for 18 consecutive days, for 19 consecutive days, for 20 consecutive days, for 21 consecutive days, for 22 consecutive days, for 23 consecutive days, for 24 consecutive days, for 25 consecutive days, for 26 consecutive days, for 27 consecutive days, for 28 consecutive days, for 29 consecutive days, for 30 consecutive days, or for 31 consecutive days.

[0134] In some embodiments, the drug holiday for the compound represented by formula (I) and / or the KRAS G12C inhibitor is a period of 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 for the compound represented by formula (I) and / or the KRAS G12C inhibitor is a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In some embodiments, the drug holiday is a period of 1 - 6 weeks. In some embodiments, the drug holiday for the compound represented by formula (I) and / or the KRAS G12C inhibitor is a period of 1 - 4 weeks. In some embodiments, the drug holiday for the compound represented by formula (I) and / or the KRAS G12C inhibitor is a period of 1 - 3 weeks. In some embodiments, the drug holiday is a period of 1 - 2 weeks.

[0135] In some embodiments, the drug holiday is about 1 to 2 times the half-life of the compound represented by formula (I) in the patient. In some embodiments, the drug holiday is about 1 to 3 times the half-life of the compound represented by formula (I) in the patient. In some embodiments, the drug holiday is about 1 to 4 times the half-life of the compound represented by formula (I) in the patient. In some embodiments, the drug holiday is about 1 to 5 times the half-life of the compound represented by formula (I) in the patient. In some embodiments, the drug holiday is about 1 to 6 times the half-life of the compound represented by formula (I) in the patient. In some embodiments, the drug holiday is about 4 to 5 times the half-life of the compound represented by formula (I) in the patient. In some embodiments, the drug holiday is about 4 times the half-life of the compound represented by formula (I) in the patient. In some embodiments, the drug holiday is about 5 times the half-life of the compound represented by formula (I) in the patient.

[0136] In some embodiments, the drug holiday is about 1 to 2 times the half-life of the KRAS G12C inhibitor in the patient. In some embodiments, the drug holiday is about 1 to 3 times the half-life of the KRAS G12C inhibitor in the patient. In some embodiments, the drug holiday is about 1 to 4 times the half-life of the KRAS G12C inhibitor in the patient. In some embodiments, the drug holiday is about 1 to 5 times the half-life of the KRAS G12C inhibitor in the patient. In some embodiments, the drug holiday is about 1 to 6 times the half-life of the KRAS G12C inhibitor in the patient. In some embodiments, the drug holiday is about 4 to 5 times the half-life of the KRAS G12C inhibitor in the patient. In some embodiments, the drug holiday is about 4 times the half-life of the KRAS G12C inhibitor in the patient. In some embodiments, the drug holiday is about 5 times the half-life of the KRAS G12C inhibitor in the patient.

[0137] In combination with sotorasib

[0138] In another embodiment, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient: (i) orally administering to the patient from about 20 mg to about 1200 mg of the compound represented by formula (I) per day:

[0139]

[0140] or a pharmaceutically acceptable salt thereof; and (ii) administering to the patient a therapeutically effective amount of sotorasib. 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 to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 150 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 160 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof 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 350 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 to the patient about 90 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 of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 350 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 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 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 to the patient about 280 mg of sotorasib once daily. In some embodiments, the method comprises administering to the patient about 300 mg of sotorasib once daily. In some embodiments, the method comprises administering to the patient about 960 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient from about 100 mg to about 300 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 120 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 140 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 160 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 180 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 200 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 220 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 240 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 260 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 280 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 300 mg of sotorasib twice 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 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, pancreatic cancer is selected from the group consisting of: locally advanced pancreatic cancer, unresectable pancreatic cancer, and metastatic pancreatic cancer.

[0141] In another embodiment, a method of treating cancer in a patient in need thereof is described herein, which comprises administering to the patient: (i) orally administering to the patient from about 20 mg to about 600 mg of a compound represented by formula (I) once or twice daily:

[0142]

[0143] or a pharmaceutically acceptable salt thereof; and (ii) administering to the patient a therapeutically effective amount of sotorasib. 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 to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof 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 350 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof 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 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 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 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 to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 350 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 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 from about 100 mg to 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 to the patient about 280 mg of sotorasib once daily. In some embodiments, the method comprises administering to the patient about 300 mg of sotorasib once daily. In some embodiments, the method comprises administering to the patient about 960 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient from about 100 mg to about 300 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 120 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 140 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 160 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 180 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 200 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 220 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 240 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 260 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 280 mg of sotorasib twice daily. In some embodiments, the method comprises administering to the patient about 300 mg of sotorasib twice 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 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.

[0144] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib for each of 1 to 30 consecutive days, followed by a drug holiday from the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib for each of 1 to 30 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib for each of 1 to 28 consecutive days, followed by a drug holiday from the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib for each of 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib for each of 1 to 21 consecutive days, followed by a drug holiday from the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib for each of 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib for each of 1 to 14 consecutive days, followed by a drug holiday from the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib for each of 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib for each of 1 to 7 consecutive days, followed by a drug holiday from the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib for each of 1 to 7 consecutive days.

[0145] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib continuously for 1 to 30 days, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib continuously for 1 to 7 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib continuously for 1 to 30 days, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib continuously for 1 to 14 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib continuously for 1 to 30 days, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib continuously for 1 to 21 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib continuously for 1 to 30 days, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib continuously for 1 to 28 days.

[0146] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib continuously for 1 to 21 days, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib continuously for 1 to 7 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib continuously for 1 to 21 days, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib continuously for 1 to 14 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib continuously for 1 to 21 days, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib continuously for 1 to 28 days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib continuously for 1 to 21 days, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib continuously for 1 to 30 days.

[0147] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib for 1 to 14 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib for 1 to 14 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib for 1 to 14 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib for 1 to 14 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib for 1 to 30 consecutive days.

[0148] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib for 1 to 7 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib for 1 to 7 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib for 1 to 7 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib for 1 to 7 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib for 1 to 30 consecutive days.

[0149] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib for 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, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib for 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.

[0150] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and sotorasib for 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 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or sotorasib, and then administering to the patient each of the compound represented by formula (I) and sotorasib for 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 consecutive days.

[0151] In some embodiments, the drug holiday of the compound represented by formula (I) and / or sotorasib is a period of 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 of the compound represented by formula (I) and / or sotorasib is a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 weeks. In some embodiments, the drug holiday is a period of 1 - 6 weeks. In some embodiments, the drug holiday of the compound represented by formula (I) and / or sotorasib is a period of 1 - 4 weeks. In some embodiments, the drug holiday of the compound represented by formula (I) and / or sotorasib is a period of 1 - 3 weeks. In some embodiments, the drug holiday is a period of 1 - 2 weeks.

[0152] In some embodiments, the drug holiday is about 1 - 2 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 1 - 3 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 1 - 4 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 1 - 5 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 1 - 6 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 4 - 5 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 4 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 5 times the half-life of the compound represented by formula (I) in the patient's body.

[0153] In some embodiments, the drug holiday is about 1 - 2 times the half-life of sotorasib in the patient's body. In some embodiments, the drug holiday is about 1 - 3 times the half-life of sotorasib in the patient's body. In some embodiments, the drug holiday is about 1 - 4 times the half-life of sotorasib in the patient's body. In some embodiments, the drug holiday is about 1 - 5 times the half-life of sotorasib in the patient's body. In some embodiments, the drug holiday is about 1 - 6 times the half-life of sotorasib in the patient's body. In some embodiments, the drug holiday is about 4 - 5 times the half-life of sotorasib in the patient's body. In some embodiments, the drug holiday is about 4 times the half-life of sotorasib in the patient's body. In some embodiments, the drug holiday is about 5 times the half-life of sotorasib in the patient's body.

[0154] In combination with adagrasib

[0155] In another embodiment, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient: (i) from about 20 mg to about 1200 mg per day of a compound represented by formula (I) orally to the patient:

[0156]

[0157] or a pharmaceutically acceptable salt thereof; and (ii) administering to the patient a therapeutically effective amount of adagrasib. 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 a day. In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 190 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 200 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 350 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 450 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 550 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 650 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice a day.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 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 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 to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 350 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 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 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 mutant colorectal cancer. In some embodiments, the pancreatic cancer is KRAS G12C mutant 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.

[0158] In another embodiment, a method of treating cancer in a patient in need thereof is described herein, which comprises administering to the patient: (i) orally administering to the patient from about 20 mg to about 600 mg of a compound represented by formula (I) once or twice daily:

[0159]

[0160] or a pharmaceutically acceptable salt thereof; and (ii) administering to the patient a therapeutically effective amount of adagrasib. 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 to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof 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 350 mg of the compound or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 from 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 to the patient about 90 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 of the compound or a pharmaceutically acceptable salt thereof once daily.In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 350 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 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 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 mutant colorectal cancer. In some embodiments, the pancreatic cancer is KRAS G12C mutant 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.

[0161] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for each of 1 to 30 consecutive days, followed by a drug holiday of the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for each of 1 to 30 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for each of 1 to 28 consecutive days, followed by a drug holiday of the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for each of 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for each of 1 to 21 consecutive days, followed by a drug holiday of the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for each of 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for each of 1 to 14 consecutive days, followed by a drug holiday of the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for each of 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for each of 1 to 7 consecutive days, followed by a drug holiday of the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for each of 1 to 7 consecutive days.

[0162] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 30 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 30 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 30 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 30 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 28 consecutive days.

[0163] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 21 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 21 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 21 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 21 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 30 consecutive days.

[0164] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 14 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 14 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 14 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 14 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 30 consecutive days.

[0165] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 7 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 7 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 7 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 7 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib for 1 to 30 consecutive days.

[0166] In some embodiments, the method includes administering to the patient each of the compound represented by formula (I) and adagrasib 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 for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib 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.

[0167] In some embodiments, the method includes administering to the patient each of the compound represented by formula (I) and adagrasib 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 for the compound represented by formula (I) and / or adagrasib, and then administering to the patient each of the compound represented by formula (I) and adagrasib 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.

[0168] In some embodiments, the drug holiday of the compound represented by formula (I) and / or adagrasib is a period of 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 of the compound represented by formula (I) and / or adagrasib is a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 weeks. In some embodiments, the drug holiday is a period of 1 - 6 weeks. In some embodiments, the drug holiday of the compound represented by formula (I) and / or adagrasib is a period of 1 - 4 weeks. In some embodiments, the drug holiday of the compound represented by formula (I) and / or adagrasib is a period of 1 - 3 weeks. In some embodiments, the drug holiday is a period of 1 - 2 weeks.

[0169] In some embodiments, the drug holiday is about 1 - 2 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 1 - 3 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 1 - 4 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 1 - 5 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 1 - 6 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 4 - 5 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 4 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 5 times the half-life of the compound represented by formula (I) in the patient's body.

[0170] In some embodiments, the drug holiday is about 1 to 2 times the half-life of adagrasib in the patient. In some embodiments, the drug holiday is about 1 to 3 times the half-life of adagrasib in the patient. In some embodiments, the drug holiday is about 1 to 4 times the half-life of adagrasib in the patient. In some embodiments, the drug holiday is about 1 to 5 times the half-life of adagrasib in the patient. In some embodiments, the drug holiday is about 1 to 6 times the half-life of adagrasib in the patient. In some embodiments, the drug holiday is about 4 to 5 times the half-life of adagrasib in the patient. In some embodiments, the drug holiday is about 4 times the half-life of adagrasib in the patient. In some embodiments, the drug holiday is about 5 times the half-life of adagrasib in the patient.

[0171] In combination with encorafenib

[0172] In another embodiment, described herein is a method of treating colorectal cancer in a patient in need thereof, comprising: (i) administering to the patient a therapeutically effective amount of a compound represented by formula (I):

[0173]

[0174] 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.

[0175] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 30 consecutive days, followed by a drug holiday from the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 30 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 28 consecutive days, followed by a drug holiday from the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 21 consecutive days, followed by a drug holiday from the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 14 consecutive days, followed by a drug holiday from the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 7 consecutive days, followed by a drug holiday from the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 7 consecutive days.

[0176] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 30 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 30 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 30 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 30 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 28 consecutive days.

[0177] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 21 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 21 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 21 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 21 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 30 consecutive days.

[0178] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 14 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 7 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 14 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 14 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 14 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 30 consecutive days.

[0179] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 7 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 14 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 7 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 21 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 7 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 28 consecutive days. In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 7 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 1 to 30 consecutive days.

[0180] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 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, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 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.

[0181] In some embodiments, the method comprises administering to the patient each of the compound represented by formula (I) and encorafenib for 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 consecutive days, followed by a drug holiday for the compound represented by formula (I) and / or encorafenib, and then administering to the patient each of the compound represented by formula (I) and encorafenib for 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 consecutive days.

[0182] In some embodiments, the drug holiday of the compound represented by formula (I) and / or encorafenib is a period of 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 of the compound represented by formula (I) and / or encorafenib is a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 weeks. In some embodiments, the drug holiday is a period of 1 - 6 weeks. In some embodiments, the drug holiday of the compound represented by formula (I) and / or encorafenib is a period of 1 - 4 weeks. In some embodiments, the drug holiday of the compound represented by formula (I) and / or encorafenib is a period of 1 - 3 weeks. In some embodiments, the drug holiday is a period of 1 - 2 weeks.

[0183] In some embodiments, the drug holiday is about 1 - 2 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 1 - 3 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 1 - 4 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 1 - 5 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 1 - 6 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 4 - 5 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 4 times the half-life of the compound represented by formula (I) in the patient's body. In some embodiments, the drug holiday is about 5 times the half-life of the compound represented by formula (I) in the patient's body.

[0184] In some embodiments, the drug holiday is about 1 - 2 times the half-life of encorafenib in the patient's body. In some embodiments, the drug holiday is about 1 - 3 times the half-life of encorafenib in the patient's body. In some embodiments, the drug holiday is about 1 - 4 times the half-life of encorafenib in the patient's body. In some embodiments, the drug holiday is about 1 - 5 times the half-life of encorafenib in the patient's body. In some embodiments, the drug holiday is about 1 - 6 times the half-life of encorafenib in the patient's body. In some embodiments, the drug holiday is about 4 - 5 times the half-life of encorafenib in the patient's body. In some embodiments, the drug holiday is about 4 times the half-life of encorafenib in the patient's body. In some embodiments, the drug holiday is about 5 times the half-life of encorafenib in the patient's body.

[0185] Combination with encorafenib and cetuximab

[0186] In another embodiment, described herein is a method of treating a patient in need of treatment for colorectal cancer, comprising: (i) administering to the patient a therapeutically effective amount of a compound represented by formula (I):

[0187]

[0188] or a pharmaceutically acceptable salt thereof; and (ii) administering to the patient a therapeutically effective amount of encorafenib, and (iii) administering to the patient a therapeutically effective amount of cetuximab. In some embodiments, the method comprises orally administering the compound to the patient. In some embodiments, the method comprises administering to the patient from about 20 mg to about 1200 mg of the compound or a pharmaceutically acceptable salt thereof per day. In some embodiments, the method comprises administering to the patient from about 20 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof once or twice a day. In some embodiments, the method comprises administering to the patient from about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient from about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient from about 100 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient from about 100 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient from about 100 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient from about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient from about 100 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient from about 100 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient from about 100 mg to about 200 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient from about 200 mg to about 800 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient from about 200 mg to about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient from about 200 mg to about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient from about 200 mg to about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient from about 200 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof twice a day.In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 80 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 90 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 190 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 200 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 350 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 450 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 500 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 550 mg of the compound or a pharmaceutically acceptable salt thereof twice a day.In some embodiments, the method comprises administering to the patient about 600 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 650 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the method comprises administering to the patient about 700 mg of the compound or a pharmaceutically acceptable salt thereof twice a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. 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 a day. In some embodiments, the method comprises administering to the patient about 50 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 60 mg of the compound or a pharmaceutically acceptable salt thereof once a day. In some embodiments, the method comprises administering to the patient about 70 mg of the compound or a pharmaceutically acceptable salt thereof once a day.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 to the patient about 100 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 110 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 120 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 130 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 140 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 150 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 160 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 170 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 180 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 190 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 of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient about 250 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 350 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering to the patient 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 450 mg of the compound or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the method comprises administering...

Claims

1. A method for treating cancer in a patient in need thereof, comprising: (i) administering to the patient once or twice a day about 20 mg to about 600 mg of a compound represented by formula (I): or a pharmaceutically acceptable salt thereof; and (ii) administering to the patient a therapeutically effective amount of one or more additional therapeutic agents.

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

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

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

5. The method according to claim 4, wherein, The MAPKAP pathway inhibitors are selected from the group consisting of MEK inhibitors, ERK inhibitors, RAF inhibitors, Ras inhibitors, and combinations thereof.

6. The method according to claim 5, wherein, The MEK inhibitors are selected from the group consisting of trametinib, binimetinib, and pharmaceutically acceptable salts thereof.

7. The method according to claim 5, wherein The RAF inhibitor is encorafenib or a pharmaceutically acceptable salt thereof.

8. The method according to claim 5, wherein The Ras inhibitor is sotorasib or a pharmaceutically acceptable salt thereof.

9. The method according to claim 4, wherein The EGFR inhibitor is cetuximab.

10. The method according to claim 4, wherein, The KIT inhibitor is ripretinib or a pharmaceutically acceptable salt thereof.

11. The method according to 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 according to 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. A method for treating cancer in a patient in need thereof, comprising: (i) administering orally to the patient once or twice a day about 20 mg to about 600 mg of a compound represented by formula (I): or a pharmaceutically acceptable salt thereof; and (ii) administering orally to the patient a therapeutically effective amount of trametinib.

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

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

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

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

18. The method according to 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. The method according to claim 18, wherein, The pancreatic ductal adenocarcinoma has one or more KRAS mutations.

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

21. The method according to claim 18, wherein, The colorectal cancer has one or more mutations selected from the group consisting of: RAS mutation, NRAS mutation, NF1 mutation, and RAF mutation.

22. The method according to claim 18, wherein The melanoma has one or more NRAS mutations.

23. The method according to claim 18 or 22, wherein The melanoma is unresectable melanoma or metastatic melanoma.

24. A method for treating cancer in a patient in need thereof, comprising: (i) orally administering to the patient about 20 mg to about 600 mg of a compound represented by formula (I) once or twice a day: or a pharmaceutically acceptable salt thereof; and (ii) orally administering to the patient a therapeutically effective amount of binimetinib.

25. The method according to claim 24, which comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice a day.

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

27. The method according to any one of claims 24 to 26, which comprises administering to the patient about 20 mg to about 50 mg of binimetinib twice a day.

28. The method according to any one of claims 24 to 27, which comprises administering to the patient about 45 mg of binimetinib twice a day.

29. The method according to 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. The method according to claim 29, wherein, The pancreatic ductal adenocarcinoma has one or more KRAS mutations.

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

32. The method according to claim 29, wherein, The colorectal cancer has one or more mutations selected from the group consisting of: RAS mutation, NRAS mutation, NF1 mutation, and RAF mutation.

33. The method according to claim 29, wherein, The melanoma has one or more NRAS mutations.

34. The method according to claim 29, wherein, The melanoma is unresectable melanoma or metastatic melanoma.

35. A method for treating cancer in a patient in need thereof, comprising administering to the patient: (i) orally administering to the patient about 20 mg to about 600 mg of a compound represented by formula (I) once or twice a day: or a pharmaceutically acceptable salt thereof; and (ii) orally administering to the patient a therapeutically effective amount of a KRAS G12C inhibitor.

36. The method according to claim 35, which comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice a day.

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

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

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

40. The method according to 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. A method for treating cancer in a patient in need thereof, comprising administering to the patient: (i) orally administering to the patient about 20 mg to about 600 mg of a compound represented by formula (I) once or twice a day: or a pharmaceutically acceptable salt thereof; and (ii) Administering to the patient an orally administered therapeutically effective amount of sotorasib.

42. The method according to claim 41, which comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice a day.

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

44. The method according to any one of claims 41 to 43, which comprises administering to the patient about 960 mg of sotorasib once a day.

45. The method according to any one of claims 41 to 43, which comprises administering to the patient about 100 mg to about 300 mg of sotorasib once a day.

46. The method according to any one of claims 41 to 43, which comprises administering to the patient about 120 mg of sotorasib once a day.

47. The method according to any one of claims 41 to 43, which comprises administering to the patient about 240 mg of sotorasib once a day.

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

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

50. The method according to 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. A method for treating a patient in need of colorectal cancer, which comprises: (i) Administering to the patient an orally administered therapeutically effective amount of a compound represented by formula (I): or a pharmaceutically acceptable salt thereof; and (ii) Administering to the patient a therapeutically effective amount of encorafenib.

52. A method for treating a patient in need of colorectal cancer, which comprises: (i) Administering to the patient an orally administered therapeutically effective amount of a compound represented by formula (I): or a pharmaceutically acceptable salt thereof; and (ii) Administering to the patient a therapeutically effective amount of encorafenib, and (iii) Administering to the patient a therapeutically effective amount of cetuximab.

53. The method according to claim 51 or 52, which comprises administering to the patient about 20 mg to about 400 mg of the compound or a pharmaceutically acceptable salt thereof twice a day.

54. The method according to any one of claims 51 to 53, which comprises administering to the patient about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof twice a day.

55. The method according to any one of claims 51 to 54, which comprises administering to the patient about 250 mg to about 350 mg of encorafenib once a day.

56. The method according to any one of claims 51 to 55, which comprises administering to the patient about 300 mg of encorafenib once a day.

57. The method according to any one of claims 51 to 56, which comprises administering to the patient about 250 mg / m 2 to about 550 mg / m 2 of cetuximab every two weeks.

58. The method according to any one of claims 51 to 57, which comprises administering to the patient about 500 mg / m every two weeks 2 Cetuximab.

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

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

61. The method according to any one of claims 51 to 60, wherein, At least one prior therapy has been administered to the patient previously.

62. A method for treating a patient in need of gastrointestinal stromal tumor, which comprises administering to the patient: (i) A therapeutically effective amount of an inhibitor of ULK1 kinase, an inhibitor of ULK2 kinase, or an inhibitor of both ULK1 kinase and ULK2 kinase; and (ii) A therapeutically effective amount of ripretinib.

63. A method for treating a patient in need thereof for advanced gastrointestinal stromal tumors, comprising: (i) Orally administering to the patient a therapeutically effective amount of a compound represented by formula (I): Or a pharmaceutically acceptable salt thereof; and (ii) Orally administering to the patient a therapeutically effective amount of ripretinib.

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

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

66. The method according to any one of claims 63 to 65, comprising administering to the patient twice a day about 50 mg to about 300 mg of the compound or a pharmaceutically acceptable salt thereof.

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

68. The method according to any one of claims 63 to 66, comprising administering to the patient twice a day about 150 mg of ripretinib.

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

70. The method according to any one of claims 63 to 69, wherein, The gastrointestinal stromal tumors have a KIT exon 11 mutation.

71. The method according to any one of claims 63 to 70, wherein, The gastrointestinal stromal tumors have a KIT exon 9 mutation, a PDGFRA exon 18 mutation, a PDGFRA exon 12 mutation, or a PDGFRA exon 18 activation loop mutation.

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

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

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