TW202317123A - Erk1/2 and cdk4/6 inhibitors combination therapy - Google Patents

Abstract

The present disclosure relates generally to the use of an ERK1/2 inhibitor in combination with a CDK4/6 inhibitor for treating cancer, specifically solid tumors.

Description

Combination therapy of ERK1/2 and CDK4/6 inhibitors

ERK1 and ERK2 (collectively "ERK1/2") are serine/threonine-related proteins involved in, inter alia, the Ras-Raf-MEK-ERK signal transduction pathway, sometimes referred to as the mitogen-activated protein kinase (MAPK) pathway acid kinase. This pathway is thought to play a key role in the regulation of several important cellular processes including one or more of cell proliferation, survival, adhesion, cycle progression, migration, differentiation, metabolism and transcription. Activation of the MAPK pathway has been reported in various tumor types including lung, colorectal, pancreatic, renal and ovarian cancers. Substances that can reduce activation are therefore interesting potential therapeutic approaches.

ERK1/2 appears to be activated by MEK phosphorylation at both threonine and tyrosine residues, ie at Tyr204/187 and Thr202/185. Upon activation, ERK1/2 catalyzes the phosphorylation of over 100 substrate serine/threonine residues and activates cytoplasmic and nuclear proteins associated with cell growth, proliferation, survival, angiogenesis, and differentiation (cancer All hallmarks of the phenotype). Therefore, it may be beneficial to target ERK 1 and ERK 2 to develop and use ERK1/2 inhibitors as a way to inhibit tumor growth.

In addition, ERK inhibitors may work in combination with other kinase inhibitors, such as MAPK inhibitors. Recently, researchers reported that the dual inhibition of MEK and ERK by small molecule inhibitors is synergistic and used to address acquired resistance to MEK inhibitors. See Hatzivassiliou et al., ERK Inhibition Overcomes Acquired Resistance to MEK Inhibition, Mol. Cancer Ther . 2012, 11, 1143-1154.

In addition to ERK1/2, CDK4/6 plays a key role in the regulation of cell proliferation and transformation, as well as in the occurrence and progression of various malignant tumors. Inhibition of CDK4/6 has been shown to provide antitumor activity and manageable toxicity in HR+/HER2- breast cancer patients. In addition, CDK4/6-related proteins have been shown to co-express with canonical tumor signaling pathways, such as RAS, PI3K and MYC pathways.

，或其醫藥學上可接受之鹽，及 (ii)   CDK4/6抑制劑。 Disclosed herein is a method of treating cancer in an individual in need thereof, the method comprising: administering to the individual in need a therapeutically effective amount of (i) Compound 1:

, or a pharmaceutically acceptable salt thereof, and (ii) a CDK4/6 inhibitor.

In some embodiments, the CDK4/6 inhibitor is palbociclib, ribociclib, abemaciclib, FCN-437c, or alvociclib.

In some embodiments, the CDK4/6 inhibitor is palbocoxib.

In some embodiments, palbocoxib is administered in an amount between about 50 mg/day and about 500 mg/day.

In some embodiments, palbocoxib is administered in an amount of about 75 mg/day, 100 mg/day, 125 mg/day, or 150 mg/day.

In some embodiments, palbocoxib is administered in an amount between about 50 mg once a week and about 650 mg once a week.

In some embodiments, palbocoxib is administered in an amount of about 200 mg once a week, 300 mg once a week, 400 mg once a week, 500 mg once a week, or 600 mg once a week.

，或其醫藥學上可接受之鹽，及 (ii)   帕泊昔布。 Also disclosed herein is a method of treating cancer in an individual in need thereof, the method comprising: administering to the individual in need a therapeutically effective amount of (i) Compound 1:

, or a pharmaceutically acceptable salt thereof, and (ii) palbocoxib.

In some embodiments, the pharmaceutically acceptable salt of Compound 1 is mandelate.

In some embodiments, the cancer is a mitogen-activated protein kinase (MAPK) pathway driven cancer.

In some embodiments, the cancer is a BRAF-driven cancer, a HRAS-driven cancer, or an NRAS-driven cancer.

In some embodiments, the cancer comprises at least one cancer cell driven by deregulated ERK.

In some embodiments, the cancer has at least one RAS mutation. In some embodiments, the cancer has at least one RAF mutation. In some embodiments, the cancer has at least one MEK mutation.

In some embodiments, the cancer has a G12C KRAS mutation. In some embodiments, the cancer has a G12D KRAS mutation. In some embodiments, the cancer has a G12S KRAS mutation. In some embodiments, the cancer has a G12V KRAS mutation. In some embodiments, the cancer has a G13D KRAS mutation. In some embodiments, the cancer has a Q16H KRAS mutation. In some embodiments, the cancer has a Q16K KRAS mutation. In some embodiments, the cancer has a Q61R NRAS mutation.

In some embodiments, the cancer is a BRAF V600E or V600K mutant tumor.

In some embodiments, the cancer is MAPKm/MAPKi untreated pancreatic cancer or PDAC.

In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of increased EGFR gene duplication, EGFR gene amplification, chromosome 7 polychromosome, L858R, exon 19 deletion/insertion, L861Q, G719C , G719S, G719A, V765A, T783A, exon 20 insertion, EGFR splice variants (Viii, Vvi, and Vii), A289D, A289T, A289V, G598A, G598V, T790M, and C797S.

In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of L858R, exon 19 deletion, and T790M.

In some embodiments, the cancer is a solid tumor.

In some embodiments, the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, salivary gland tumors, thyroid cancer, colorectal cancer (CRC), or esophageal cancer.

In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is EGFR mutant NSCLC. In some embodiments, the NSCLC is KRAS ^G12C mutant NSCLC. In some embodiments, the NSCLC is KRAS ^G12D mutant NSCLC. In some embodiments, the NSCLC is KRAS ^G12S mutant NSCLC. In some embodiments, the NSCLC is KRAS ^G12V mutant NSCLC. In some embodiments, the NSCLC is KRAS ^G13D mutant NSCLC. In some embodiments, the NSCLC is KRAS ^Q61H mutant NSCLC. In some embodiments, the NSCLC is KRAS ^Q61K mutant NSCLC. In some embodiments, the NSCLC is NRAS ^Q61R mutant NSCLC. In some embodiments, the cancer is MAPKm/MAPKi-naïve NSCLC. In some embodiments, the cancer is BRAFi-treated V600 NSCLC. In some embodiments, the cancer is KRAS-treated G12C NSCLC. In some embodiments, the cancer is KRAS-treated G12D NSCLC. In some embodiments, the cancer is KRAS-treated G12S NSCLC. In some embodiments, the cancer is KRAS-treated G12V NSCLC. In some embodiments, the cancer is KRAS-treated G13D NSCLC. In some embodiments, the cancer is KRAS-treated Q61H NSCLC. In some embodiments, the cancer is KRAS-treated Q61K NSCLC. In some embodiments, the cancer is NRAS-treated Q61R NSCLC.

In some embodiments, the cancer is pancreatic cancer.

In some embodiments, the cancer is MAPKm/MAPKi untreated pancreatic cancer or PDAC.

In some embodiments, the cancer is melanoma.

In some embodiments, the melanoma is a BRAF V600E or V600K mutant tumor.

In some embodiments, the cancer is BRAFi-treated V600 melanoma.

In some embodiments, the cancer is a salivary gland tumor.

In some embodiments, the cancer is thyroid cancer.

In some embodiments, the cancer is colorectal cancer (CRC).

In some embodiments, the CRC is a BRAF V600E CRC.

In some embodiments, the CRC is KRAS mutant CRC. In some embodiments, the CRC is KRAS ^G12C mutant CRC. In some embodiments, the CRC is KRAS ^G12D mutant CRC. In some embodiments, the CRC is KRAS ^G12S mutant CRC. In some embodiments, the CRC is KRAS ^G12V mutant CRC. In some embodiments, the CRC is KRAS ^G13D mutant CRC. In some embodiments, the CRC is KRAS ^Q61H mutant CRC. In some embodiments, the CRC is KRAS ^Q61K mutant CRC. In some embodiments, the CRC is NRAS mutant CRC. In some embodiments, the CRC is NRAS ^Q61R mutant CRC.

In some embodiments, the cancer is esophageal cancer.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount between about 25 mg/day and about 300 mg/day.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount between 25 mg/day and 150 mg/day.

In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is dosed at about 25 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 125 mg/day, about 150 mg/day Administered in an amount of mg/day, about 175 mg/day, about 200 mg/day, about 225 mg/day, or about 250 mg/day.

In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 25 mg/day, about 50 mg/day, about 100 mg/day, or about 150 mg/day.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 250 mg/day.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a day (QD). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day (BID). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered three times a day (TID).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a week.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 25 mg and about 300 mg twice a day (BID-QW).

In some embodiments, Compound 1 , or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 25 mg and about 250 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 25 mg and about 150 mg twice a day (BID-QW).

In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is about 25 mg, 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg once a week or twice a day (BID-QW) , about 175 mg, about 200 mg, about 225 mg, or about 250 mg.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount of about 25 mg, 50 mg, about 100 mg, about 125 mg, or about 150 mg twice a day (BID-QW) .

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount of about 125 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day cycle.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on Day 1, Day 8, and Day 15 of a 28-day cycle.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

In some embodiments, the method further comprises administering an additional MAPK pathway inhibitor. In some embodiments, the additional MAPK pathway inhibitor is a KRAS inhibitor, NRAS inhibitor, HRAS inhibitor, PDGFRA inhibitor, PDGFRB inhibitor, MET inhibitor, FGFR inhibitor, ALK inhibitor, ROS1 inhibitor, TRKA inhibitor Agents, TRKB inhibitors, TRKC inhibitors, EGFR inhibitors, IGFR1R inhibitors, GRB2 inhibitors, SOS inhibitors, ARAF inhibitors, BRAF inhibitors, RAF1 inhibitors, MEK1 inhibitors, MEK2 inhibitors, c-Mycv, A CDK2 inhibitor, FLT3 inhibitor, or ERK1/2 inhibitor. In some embodiments, the additional MAPK pathway inhibitor is a KRAS inhibitor. In some embodiments, the additional MAPK pathway inhibitor is a BRAF inhibitor. In some embodiments, the additional MAPK pathway inhibitor is an EGFR inhibitor. In some embodiments, the additional MAPK pathway inhibitor is CDK4/6. In some embodiments, the additional MAPK pathway inhibitor is a FLT3 inhibitor. In some embodiments, the additional MAPK pathway inhibitor is adagrasib, afatinib, ASTX029, binimetinib, cetuximab, corbitinib Cobimetinib, dabrafenib, dacomitinib, encorafenib, erlotinib, gefitinib, gefitinib ( gilteritinib, lapatinib, LTT462, LY3214996, necitumumab, neratinib, nimotuzumab, osimertinib, panitumumab Panitumumab, selumetinib, sotorasib, trametinib, ulixertinib, vandetanib, or vemurafenib ). In some embodiments, the additional MAPK pathway inhibitor is adagracib. In some embodiments, the additional MAPK pathway inhibitor is cetuximab. In some embodiments, the additional MAPK pathway inhibitor is dabrafenib. In some embodiments, the additional MAPK pathway inhibitor is enrafenib. In some embodiments, the additional MAPK pathway inhibitor is gilteritinib. In some embodiments, the additional MAPK pathway inhibitor is panitumumab. In some embodiments, the additional MAPK pathway inhibitor is sotocoxib.

cross reference

This application asserts U.S. Provisional Application No. 63/214,768 filed on June 24, 2021, U.S. Provisional Application No. 63/236,636 filed on August 24, 2021, U.S. Provisional Application No. 63/236,636 filed on November 16, 2021 Benefit of Application No. 63/279,880, U.S. Provisional Application No. 63/314,832, filed February 28, 2022, U.S. Provisional Application No. 63/321,610, filed March 18, 2022, the provisional applications The case is incorporated herein by reference in its entirety. incorporated by reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference way into the general.

As used herein and in the appended claims, the singular forms "a(a)", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents and reference to "the cell" includes reference to one or more cells (or a plurality of cells) and others known to those skilled in the art. effects etc. When ranges are used herein for a physical property such as molecular weight or a chemical property such as a chemical formula, all combinations and subcombinations of ranges and specific embodiments herein are intended to be included. The term "about" when referring to a number or numerical range means that the referenced number or numerical range is an approximation within experimental variability (or within statistical experimental error), so that in some cases the number or numerical range will be within Vary between 1% and 15% of stated values or ranges of values. The term "comprising" (and related terms such as "comprise/comprises" or "has" or "including") is not intended to exclude that in certain other embodiments, such as any described herein Embodiments of a composition of matter, composition, method, or process, or the like, "consist of" or "consist essentially of" the stated features.

Unless stated to the contrary, as used in the specification and appended claims, the following terms have the meanings indicated below.

As used herein, the term "therapeutic agent" means an agent for treating, combating, ameliorating, preventing or ameliorating an undesirable condition or disease in a patient. In some embodiments, a therapeutic agent such as Compound 1 is directed towards the treatment and/or amelioration of cancer.

"Administering" when used in conjunction with a therapeutic agent means administering the therapeutic agent directly into or onto a target tissue, systemically or locally, or administering the therapeutic agent to a patient, whereby the therapeutic agent positively affects its target organization. Thus, as used herein, the term "administering" when used in conjunction with a composition described herein may include, but is not limited to, providing the composition into or onto a target tissue; by, for example, oral administration The composition is provided systemically to the patient whereby the therapeutic agent reaches the target tissue or cell. "Administering" compositions can be accomplished by injection, topical administration, and oral administration or by other methods alone or in combination with other known techniques.

As used herein, the term "animal" includes, but is not limited to, humans and non-human vertebrates, such as wild animals, domestic animals, and farm animals. As used herein, the terms "patient" and "subject/individual" are intended to include living organisms that may develop certain pathologies as described herein. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In a preferred embodiment, the patient is a primate. In certain embodiments, the primate or individual is a human. In some cases, the human is an adult. In some cases, the human is a child. In other cases, the humans were under the age of 12. In some cases, the human is an elderly person. In other cases, the human is 60 years or older. Other examples of subjects include laboratory animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. Experimental animals can be animal models of disorders, such as transgenic mice with hypertensive lesions.

"Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The term "pharmaceutical composition" shall mean a composition comprising at least one active ingredient, wherein the composition is suitable for studying a given effective result in a mammal such as, but not limited to, a human. Those of ordinary skill will know and appreciate techniques suitable for determining whether an active ingredient has the desired effective result based on the needs of the skilled artisan.

As used herein, a "therapeutically effective amount" or "effective amount" means that the active compound or agent elicits in a tissue, system, animal, individual, or human the biological or medical effect being sought by the researcher, veterinarian, physician, or other clinician. Quantity of a response that includes one or more of: (1) prevention of a disease; for example, prevention of a disease, condition, or condition in an individual who may be predisposed to a disease, condition, or disorder but has not yet experienced or exhibited a lesion or symptom of the disease (2) inhibiting a disease; for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting a lesion or symptom of a disease, condition, or disorder (i.e., arresting the further development of the lesion and/or symptoms), and (3) Ameliorating a disease; eg, ameliorating a disease, condition, or disorder (ie, reversing the pathology and/or symptoms) in an individual who is experiencing or exhibiting a lesion or symptom of the disease, condition, or disorder.

The terms "treat", "treated", "treatment" or "treating" as used herein refer to therapeutic treatment in some embodiments and prophylactic in other embodiments. Or preventive measures, in which the objective is to prevent or slow down (lessen) an undesired physical condition, disorder or disease, or to obtain a beneficial or desired clinical outcome. For the purposes described herein, a beneficial or desired clinical outcome includes, but is not limited to, relief of symptoms; reduction in the extent of a condition, disorder, or disease; stabilization of the state of the condition, disorder, or disease (i.e., not worsening); , delay in the onset or slowing of progression of a disorder or disease; amelioration of a condition, disorder or disease state; and remission (whether partial or complete) or improvement or improvement (whether detectable or undetectable) of a condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. The prophylactic benefit of treatment includes preventing the condition, delaying progression of the condition, stabilizing the condition, or reducing the likelihood of occurrence of the condition. As used herein, "treat," "treated," "treatment," or "treating" includes, in some embodiments, prophylaxis.

As used herein, the term "substantially the same" when considered by one of ordinary skill means that the powder x-ray diffraction pattern or differential scanning calorimetry pattern is the same as those depicted herein. Patterns were determined to be inconsistent, but within the limits of experimental error. Compound 1

，或其醫藥學上可接受之鹽。 This paper discloses that (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran -4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide:

, or a pharmaceutically acceptable salt thereof.

In some embodiments, the salt of Compound 1 is mandelate. In some embodiments, the salt of Compound 1 is besylate. In some embodiments, the salt of Compound 1 is hydrochloride. In some embodiments, the salt of Compound 1 is p-toluenesulfonate. CDK4/6 inhibitors

CDK4/6 inhibitors work at the G ₁ to S cell cycle checkpoint _, which is tightly controlled by the D-type cyclins CDK4 and CDK6. When CDK4 and CDK6 are activated by D-type cyclins, they phosphorylate retinoblastoma-associated protein (pRb), which releases pRb's repression of the E2F family of transcription factors and allows cells to proceed through the cell cycle. In HR+ cancers, D-type cyclin overexpression is common and loss of pRb is rare, making the _G1 to S checkpoint an ideal therapeutic agent.

In some embodiments, the CDK4/6 inhibitor is palbocoxib, ribociclib, abeciclib, FCN-437c, or avocilib.

In some embodiments, the CDK4/6 inhibitor is palbocoxib. palbocoxib

係一種用於治療HR+/HER2-晚期或轉移性乳癌之激酶抑制劑。帕泊昔布由Pfizer以Ibrance®出售。 組合 palbocoxib

It is a kinase inhibitor for the treatment of HR+/HER2- advanced or metastatic breast cancer. Palbocoxib is sold as Ibrance® by Pfizer. combination

，或其醫藥學上可接受之鹽，及 (ii)   CDK4/6抑制劑。 Disclosed herein is a method of treating cancer in an individual in need thereof, the method comprising administering to the individual in need a therapeutically effective amount of (i) Compound 1:

, or a pharmaceutically acceptable salt thereof, and (ii) a CDK4/6 inhibitor.

In some embodiments, the CDK4/6 inhibitor is palbocoxib, ribociclib, abeciclib, FCN-437c, or avocilib.

In some embodiments, the CDK4/6 inhibitor is palbocoxib.

，或其醫藥學上可接受之鹽，及 (ii)   帕泊昔布。 其他組合 Disclosed herein is a method of treating cancer in an individual in need thereof, the method comprising administering to the individual in need a therapeutically effective amount of (i) Compound 1:

, or a pharmaceutically acceptable salt thereof, and (ii) palbocoxib. other combinations

In some embodiments, the methods comprise administering additional MAPK pathway inhibitors. Without being bound by theory, inhibition of MAPK signaling in cancer cells can lead to downregulation of PD-L1 expression and increase the likelihood of cancer cells being detected by the immune system. Such third MAPK pathway inhibitors may be based on other mutations in proteins in the MAPK pathway. In some embodiments, additional MAPK pathway inhibitors inhibit proteins in the MAPK pathway. In some embodiments, additional MAPK pathway inhibitors inhibit proteins other than the MAPK pathway. In some embodiments, the additional MAPK pathway inhibitor is a KRAS inhibitor, NRAS inhibitor, HRAS inhibitor, PDGFRA inhibitor, PDGFRB inhibitor, MET inhibitor, FGFR inhibitor, ALK inhibitor, ROS1 inhibitor, TRKA inhibitor Agents, TRKB inhibitors, TRKC inhibitors, EGFR inhibitors, IGFR1R inhibitors, GRB2 inhibitors, SOS inhibitors, ARAF inhibitors, BRAF inhibitors, RAF1 inhibitors, MEK1 inhibitors, MEK2 inhibitors, c-Mycv, CDK4/6 inhibitors, CDK2 inhibitors, FLT3 inhibitors, or ERK1/2 inhibitors. Exemplary MAPK pathway inhibitors include, but are not limited to, adagracib, afatinib, ASTX029, bemetinib, cetuximab, cobimetinib, dabrafenib, dacomitinib, enla Fini, Erlotinib, Gefitinib, Gelicitinib, Lapatinib, LTT462, LY3214996, Laximab, Neratinib, Nimotuzumab, Osimertinib, Panitumumab anti, selumetinib, sutocoxib, trametinib, uritinib, vandetanib and vemurafenib.

In some embodiments, the additional MAPK pathway inhibitor is adagracib. In some embodiments, the additional MAPK pathway inhibitor is afatinib. In some embodiments, the additional MAPK pathway inhibitor is Bametinib. In some embodiments, the additional MAPK pathway inhibitor is cetuximab. In some embodiments, the additional MAPK pathway inhibitor is cobimetinib. In some embodiments, the additional MAPK pathway inhibitor is dabrafenib. In some embodiments, the additional MAPK pathway inhibitor is dacomitinib. In some embodiments, the additional MAPK pathway inhibitor is enrafenib. In some embodiments, the additional MAPK pathway inhibitor is erlotinib. In some embodiments, the additional MAPK pathway inhibitor is gefitinib. In some embodiments, the additional MAPK pathway inhibitor is gilteritinib. In some embodiments, the additional MAPK pathway inhibitor is lapatinib. In some embodiments, the additional MAPK pathway inhibitor is LTT462. In some embodiments, the additional MAPK pathway inhibitor is LY3214996. In some embodiments, the additional MAPK pathway inhibitor is lesximab. In some embodiments, the additional MAPK pathway inhibitor is neratinib. In some embodiments, the additional MAPK pathway inhibitor is nimotuzumab. In some embodiments, the additional MAPK pathway inhibitor is osimertinib. In some embodiments, the additional MAPK pathway inhibitor is panitumumab. In some embodiments, the additional MAPK pathway inhibitor is selumetinib. In some embodiments, the additional MAPK pathway inhibitor is sotocoxib. In some embodiments, the additional MAPK pathway inhibitor is Trametinib. In some embodiments, the additional MAPK pathway inhibitor is uritinib. In some embodiments, the additional MAPK pathway inhibitor is vandetanib. cancer

Disclosed herein are methods of treating cancer using the combinations disclosed herein.

"Cancer" refers to all types of cancers, neoplasms or malignancies found in mammals such as humans, including but not limited to leukemias, lymphomas, myelomas, carcinomas and sarcomas. Exemplary cancers that can be treated with the compounds or methods provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer (such as pancreatic cancer, PDAC), Medulloblastoma, Melanoma, Cervical Cancer, Stomach Cancer, Ovarian Cancer, Lung Cancer, Head Cancer, Hodgkin's Disease and Non-Hodgkin's Lymphoma. Exemplary cancers that can be treated with the compounds or methods provided herein include blood, thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, ovary, pancreas, rectum, stomach, and uterus of cancer. Additional examples include thyroid cancer, cholangiocarcinoma, pancreatic cancer, skin melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, invasive breast cancer, lung adenocarcinoma, lung squamous cell carcinoma carcinoma, non-small cell lung cancer, mesothelioma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, primary giant Globulinemia, primary brain tumor, malignant insulinoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia cancer, endometrial cancer, adrenocortical cancer, endocrine or exocrine pancreatic neoplasm, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

In some embodiments, the cancer has a class 1 B-Raf mutation.

In some embodiments, the cancer carries at least one of EGFR, KRAS, BRAF (eg, BRAF class III), and/or NF1 (eg, loss-of-function) mutations.

In some embodiments, the mutant B-Raf comprises a V600 mutation. In some embodiments, the mutant of B-Raf comprises the mutation V600E. In some embodiments, the mutation is V600K. In some embodiments, the mutation is V600D. In some embodiments, the mutation is V600L. In some embodiments, the mutation is V600R. In some embodiments, the cancer is a BRAF V600E or V600K mutant tumor.

In some embodiments, the cancer is a mitogen-activated protein kinase (MAPK) pathway driven cancer.

In some embodiments, the cancer is a BRAF-driven cancer, a HRAS-driven cancer, or an NRAS-driven cancer.

In some embodiments, the cancer comprises at least one cancer cell driven by deregulated ERK.

In some embodiments, the cancer has at least one RAS mutation. In some embodiments, the cancer has at least one RAF mutation. In some embodiments, the cancer has at least one MEK mutation.

In some embodiments, the cancer has a G12C KRAS mutation. In some embodiments, the cancer has a G12D KRAS mutation. In some embodiments, the cancer has a G12S KRAS mutation. In some embodiments, the cancer has a G12V KRAS mutation. In some embodiments, the cancer has a G13D KRAS mutation. In some embodiments, the cancer has a Q16H KRAS mutation. In some embodiments, the cancer has a Q16K KRAS mutation. In some embodiments, the cancer has a Q61R NRAS mutation.

In some embodiments, the cancer is pancreatic cancer that has not been treated with MAPKm/MAPKi. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, PDAC is indicated by a KRAS G12V mutation.

In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of increased EGFR gene duplication, EGFR gene amplification, chromosome 7 polychromosome, L858R, exon 19 deletion/insertion, L861Q, G719C , G719S, G719A, V765A, T783A, exon 20 insertion, EGFR splice variants (Viii, Vvi, and Vii), A289D, A289T, A289V, G598A, G598V, T790M, and C797S. In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of L858R, exon 19 deletion, and T790M.

In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is an advanced or metastatic solid tumor.

In some embodiments, the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, salivary gland tumors, thyroid cancer, colorectal cancer (CRC), or esophageal cancer.

In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is EGFR mutant NSCLC. In some embodiments, the NSCLC is KRAS ^G12C mutant NSCLC. In some embodiments, the NSCLC is KRAS ^G12D mutant NSCLC. In some embodiments, the NSCLC is KRAS ^G12S mutant NSCLC. In some embodiments, the NSCLC is KRAS ^G12V mutant NSCLC. In some embodiments, the NSCLC is KRAS ^G13D mutant NSCLC. In some embodiments, the NSCLC is KRAS ^Q61H mutant NSCLC. In some embodiments, the NSCLC is KRAS ^Q61K mutant NSCLC.

In some embodiments, the NSCLC is NRAS ^Q61R mutant NSCLC. In some embodiments, the cancer is MAPKm/MAPKi-naïve NSCLC. In some embodiments, the cancer is BRAFi-treated V600 NSCLC. In some embodiments, the cancer is KRAS-treated G12C NSCLC. In some embodiments, the cancer is KRAS-treated G12D NSCLC. In some embodiments, the cancer is KRAS-treated G12S NSCLC. In some embodiments, the cancer is KRAS-treated G12V NSCLC. In some embodiments, the cancer is KRAS-treated G13D NSCLC. In some embodiments, the cancer is KRAS-treated Q61H NSCLC. In some embodiments, the cancer is KRAS-treated Q61K NSCLC. In some embodiments, the cancer is NRAS-treated Q61R NSCLC.

In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is pancreatic cancer that has not been treated with MAPKm/MAPKi. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, PDAC is indicated by a KRAS G12V mutation.

In some embodiments, the cancer is melanoma. In some embodiments, the melanoma is a BRAF V600E or V600K mutant tumor. In some embodiments, the cancer is BRAFi-treated V600 melanoma.

In some embodiments, the cancer is a salivary gland tumor.

In some embodiments, the cancer is thyroid cancer.

In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the CRC is a BRAF V600E CRC. In some embodiments, the CRC is KRAS mutant CRC.

In some embodiments, the CRC is KRAS ^G12C mutant CRC. In some embodiments, the CRC is KRAS ^G12D mutant CRC. In some embodiments, the CRC is KRAS ^G12S mutant CRC. In some embodiments, the CRC is KRAS ^G12V mutant CRC. In some embodiments, the CRC is KRAS ^G13D mutant CRC. In some embodiments, the CRC is KRAS ^Q61H mutant CRC. In some embodiments, the CRC is KRAS ^Q61K mutant CRC. In some embodiments, the CRC is NRAS mutant CRC. In some embodiments, the CRC is NRAS ^Q61R mutant CRC.

In some embodiments, the cancer is esophageal cancer.

In some embodiments, the cancer is colorectal cancer (CRC), pancreatic duct adenocarcinoma (PDAC), bile duct cancer, appendix cancer, gastric cancer, esophageal cancer, non-small cell lung cancer (NSCLC), head and neck cancer, ovarian cancer, uterine cancer , acute myeloid leukemia (AML), or melanoma.

In some embodiments, the cancer is gastrointestinal cancer. In some embodiments, the gastrointestinal cancer is anal cancer, bile duct cancer, colorectal cancer, rectal cancer, esophageal cancer, gallbladder cancer, liver cancer, pancreatic cancer, small bowel cancer, or gastric cancer (stomach cancer). medication

In one aspect, the compositions described herein are used to treat the diseases and conditions described herein. Additionally, methods for treating any of the diseases or conditions described herein in a subject in need of such treatment involve administering to the subject a therapeutically effective amount of the composition.

Dosages of the compositions described herein can be determined by any suitable method. The maximum tolerated dose (MTD) and maximum responsive dose (MRD) of Compound 1, or a pharmaceutically acceptable salt thereof, can be determined through established animal and human experimental protocols and in the Examples described herein. For example, the toxicity and therapeutic efficacy of Compound 1 or a pharmaceutically acceptable salt thereof can be determined by standard medical procedures in cell culture or experimental animals, including (but not limited to) determination of LD50 (50% population lethal dose) and ED50 (50% of the population therapeutically effective dose) to determine. The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. The information obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range, depending upon the dosage form employed and the route of administration utilized. Additional relative doses (expressed as a percentage of maximum response or maximum tolerated dose) are readily obtained via such protocols.

In some embodiments, the amount corresponding to such amount of a given formulation comprising Compound 1 or a pharmaceutically acceptable salt thereof varies depending on factors such as the molecular weight of the particular salt or form, the disease condition and its Severity, attributes of the individual or host requiring treatment (e.g. age, weight, sex), but may depend on the specific circumstances surrounding the case including, for example, the specific agent administered, the type of fluid formulation, the condition being treated, and the treatment being administered The individual or host is determined.

In some embodiments, palbocoxib is administered in an amount between about 50 mg/day and about 500 mg/day. In some embodiments, palbocoxib is administered in an amount of about 75 mg/day. In some embodiments, palbocoxib is administered in an amount of about 100 mg/day. In some embodiments, palbocoxib is administered in an amount of about 125 mg/day. In some embodiments, palbocoxib is administered in an amount of about 150 mg/day.

In some embodiments, palbocoxib is administered in an amount between about 50 mg once weekly and about 650 mg once weekly. In some embodiments, palbocoxib is administered in an amount of about 200 mg once a week. In some embodiments, palbocoxib is administered in an amount of about 300 mg once a week. In some embodiments, palbocoxib is administered in an amount of about 400 mg once a week. In some embodiments, palbocoxib is administered in an amount of about 500 mg once a week. In some embodiments, palbocoxib is administered in an amount of about 600 mg once a week.

In some embodiments, the amount of Compound 1 , or a pharmaceutically acceptable salt thereof, as described herein is relative to the free base equivalent of Compound 1 .

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount between about 25 mg/day and about 300 mg/day.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount between 25 mg/day and 150 mg/day.

In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is dosed at about 25 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 125 mg/day, about 150 mg/day Administered in an amount of mg/day, about 175 mg/day, about 200 mg/day, about 225 mg/day, or about 250 mg/day.

In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 25 mg/day, about 50 mg/day, about 100 mg/day, or about 150 mg/day.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 25 mg to about 300 mg twice a day (BID-QW).

In some embodiments, Compound 1 , or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 25 mg and about 250 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 25 mg and about 200 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 25 mg and about 150 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 25 mg and about 100 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 25 mg and about 50 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 50 mg to about 300 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 50 mg and about 250 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 50 mg and about 200 mg twice a day (BID-QW).

In some embodiments, Compound 1 , or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 50 mg and about 150 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 50 mg and about 100 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 100 mg and about 300 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 100 mg and about 250 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 100 mg and about 200 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 100 mg and about 150 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 150 mg and about 300 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 150 mg and about 250 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 150 mg and about 200 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 175 mg and about 300 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 175 mg and about 250 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 175 mg and about 200 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 200 mg and about 300 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 200 mg and about 250 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 225 mg and about 300 mg twice a day (BID-QW).

In some embodiments, Compound 1 , or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 225 mg and about 250 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount between about 25 mg and about 300 mg once a week (QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount between about 50 mg and about 250 mg once a week (QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount between about 100 mg and about 300 mg once a week (QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount between about 100 mg and about 250 mg once a week (QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount between about 150 mg and about 300 mg once a week (QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount between about 150 mg and about 250 mg once a week (QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100 mg once a week (QW). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 150 mg once a week (QW). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 200 mg once a week (QW). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 250 mg once a week (QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 25 mg and about 300 mg twice a day (BID-QW).

In some embodiments, Compound 1 , or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 25 mg and about 250 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount between about 25 mg and about 150 mg twice a day (BID-QW).

In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is about 25 mg, 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg once a week or twice a day (BID-QW) , about 175 mg, about 200 mg, about 225 mg, or about 250 mg.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount of about 25 mg, 50 mg, about 100 mg, about 125 mg, or about 150 mg twice a day (BID-QW) .

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount of about 125 mg twice a day (BID-QW).

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week in an amount of about 250 mg once a day.

In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is dosed at about 25 mg, 30 mg, 40 mg, 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg , about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg , about 280 mg, about 290 mg, or about 300 mg.

In some embodiments, each of the above amounts can be administered QD, QW, BID, BID-QD, or BID-QW. dosing

Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, are administered at the dosages described herein or at other dosages and compositions as determined and considered by a medical practitioner. In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered for prophylactic and/or therapeutic treatment. In certain therapeutic applications, Compound 1 , or pharmaceutically acceptable salts and combination partners thereof, described herein is administered to a patient already suffering from a disease in an amount sufficient to cure the disease or at least partially arrest or ameliorate symptoms. Amounts effective for this use will depend on the patient's age, severity of disease, previous therapy, patient's health, weight, and response to the composition, and the judgment of the treating physician. A therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation clinical trials.

In prophylactic applications, a composition described herein is administered to a patient predisposed to or otherwise at risk of a particular disease, such as cancer. Such amount is defined as a "prophylactically effective amount or dose". In this use, the precise amount will also depend on the patient's age, health, weight, and the like. When used in a patient, amounts effective for this use will depend on the apparent risk or susceptibility to the particular disease, previous therapy, the patient's health status and response to the compositions, and the judgment of the treating physician.

In certain embodiments in which the patient's condition does not improve, the administration of the compositions described herein is chronic, that is, for a prolonged period of time, including throughout the duration of the patient's life, in the judgment of the physician, so that Ameliorate or otherwise manage or limit the symptoms of the patient's disease. In other embodiments, the composition is administered until a complete or partial disease response.

In some embodiments, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, is administered once a day. In some embodiments, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, is administered twice a day. In some embodiments, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, is administered three times a day.

In some embodiments, palbocoxib is administered once daily. In some embodiments, palbocoxib is administered twice daily. In some embodiments, palbocoxib is administered three times daily.

In some embodiments, palbocoxib is administered weekly. In some embodiments, palbocoxib is administered twice weekly. In some embodiments, palbocoxib is administered three times per week.

In some embodiments, palbocoxib is administered once daily for 21 days, followed by 7 days of discontinuation of treatment.

In some embodiments, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, are administered to a subject in a fasted state. The fasted state means that the individual has fasted or fasted for a certain period of time. Typical fasting periods include at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours and at least 16 hours without food. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to an individual who has been in a fasted state for at least 8 hours. In other embodiments, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, is administered to an individual who has been in a fasted state for at least 10 hours. In other embodiments, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, is administered to a subject in a fasted state for at least 12 hours. In other embodiments, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, is administered to an overnight fasted subject.

In other embodiments, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, are administered to a subject in a fed state. The fed state means that the individual has eaten or eaten a meal. In certain embodiments, 5 minutes after a meal, 10 minutes after a meal, 15 minutes after a meal, 20 minutes after a meal, 30 minutes after a meal, 40 minutes after a meal, 50 minutes after a meal, 1 hour after a meal, or 2 minutes after a meal The composition is administered to the individual in the fed state every hour. In certain instances, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject in a fed state 30 minutes after a meal. In other instances, Compound 1 , or pharmaceutically acceptable salts and combination partners thereof, described herein is administered to a subject in a fed state 1 hour after a meal. In other embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to an individual with food.

The length of the treatment cycle depends on the treatment given. In some embodiments, the length of the treatment cycle ranges from two weeks to six weeks. In some embodiments, the length of the treatment cycle ranges from three weeks to six weeks. In some embodiments, the length of the treatment cycle ranges from three weeks to four weeks. In some embodiments, the treatment cycle is three weeks (or 21 days) in length. In some embodiments, the treatment cycle is four weeks (28 days) in length. In some embodiments, the treatment cycle is five weeks (35 days) in length. In some embodiments, the treatment cycle is 56 days in length. In some embodiments, the treatment cycle lasts one, two, three, four, or five weeks. In some embodiments, the treatment cycle lasts three weeks. In some embodiments, the treatment cycle lasts four weeks. In some embodiments, the treatment cycle lasts five weeks. The number of therapeutic doses scheduled within each cycle will also vary depending on the drug administered.

In some embodiments of the methods of treating cancer, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, is administered in a 28-day cycle. In some embodiments of the methods of treating cancer, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, is administered for multiple 28-day cycles. In some embodiments of the methods of treating cancer, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, is administered for at least one 28-day cycle. In some embodiments of the methods of treating cancer, Compound 1 , or pharmaceutically acceptable salts and combination partners thereof, described herein is administered for at least two 28-day cycles. In some embodiments of the methods of treating cancer, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, is administered for at least three 28-day cycles. In some embodiments of the methods of treating cancer, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, is administered for at least four 28-day cycles. In some embodiments of the methods of treating cancer, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, is administered for at least five 28-day cycles. In some embodiments of the methods of treating cancer, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, is administered for at least six 28-day cycles.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-7 of each 28-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-14 of each 28-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-21 of each 28-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-28 of each 28-day cycle.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day on Day 1 of a 28-day cycle. In some embodiments of the method of treating cancer, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 8 of a 28-day cycle. In some embodiments of the method of treating cancer, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 15 of a 28-day cycle. In some embodiments of the method of treating cancer, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 22 of a 28-day cycle. In some embodiments of the method of treating cancer, Compound 1 or a pharmaceutically acceptable salt thereof is not administered twice a day on day 22 of a 28-day cycle.

In some embodiments of the method of treating cancer, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on days 1, 8, and 15 of a 28-day cycle.

In some embodiments of the method of treating cancer, Compound 1 or a pharmaceutically acceptable salt thereof is not on days 2-7, days 9-14, days 16-21, or days 23-28 of a 28-day cycle vote with.

In some embodiments of the methods of treating cancer, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, is administered in a 35-day cycle. In some embodiments of the methods of treating cancer, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, is administered for multiple 35-day cycles. In some embodiments of the methods of treating cancer, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, is administered for at least one 35-day cycle. In some embodiments of the methods of treating cancer, Compound 1 described herein, or pharmaceutically acceptable salts and combination partners thereof, is administered for at least two 35-day cycles. In some embodiments of the methods of treating cancer, Compound 1 , or pharmaceutically acceptable salts and combination partners thereof, described herein is administered for at least three 35-day cycles. In some embodiments of the methods of treating cancer, Compound 1 , or pharmaceutically acceptable salts and combination partners thereof, described herein is administered for at least four 35-day cycles. In some embodiments of the methods of treating cancer, Compound 1 , or pharmaceutically acceptable salts and combination partners thereof, described herein is administered for at least five 35-day cycles. In some embodiments of the methods of treating cancer, Compound 1 , or pharmaceutically acceptable salts and combination partners thereof, described herein is administered for at least six 35-day cycles.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-7 of each 35-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-14 of each 35-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-21 of each 35-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-28 of each 35-day cycle. In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-35 of each 35-day cycle.

In some embodiments of the method of treating cancer, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice a day on Day 1 of a 35-day cycle. In some embodiments of the method of treating cancer, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 8 of a 35-day cycle. In some embodiments of the method of treating cancer, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 15 of a 35-day cycle. In some embodiments of the method of treating cancer, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 22 of a 35-day cycle. In some embodiments of the method of treating cancer, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 29 of a 35-day cycle. In some embodiments of the method of treating cancer, Compound 1 or a pharmaceutically acceptable salt thereof is not administered twice a day on day 29 of a 35-day cycle.

In some embodiments of the method of treating cancer, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on days 1, 8, 15, and 22 of a 35-day cycle.

In some embodiments of the method of treating cancer, Compound 1 or a pharmaceutically acceptable salt thereof is not on days 2-7, 9-14, 16-21, or 23-28 of a 35-day cycle and administration on day 30-35. patient selection

In some embodiments of the method of treating cancer, the individual is 18 years old. In another embodiment, the individual is 18 years or older. In another embodiment, the individual is no more than 99 years old.

In some embodiments of the method of treating cancer, the subject is willing and able to provide written informed consent.

In some embodiments of the method of treating cancer, the individual has histologically or cytologically confirmed metastatic CRC carrying the applicable mutation based on analytically validated analysis of tumor tissue performed in a certified laboratory. In some embodiments, the individual has a BRAFm V600E mutation. In some embodiments, the individual has a KRAS mutation. In some embodiments, the individual has an NRAS mutation.

In some embodiments of the method of treating cancer, the individual has sufficient bone marrow and organ function.

In some embodiments of the method of treating cancer, the individual has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

In some embodiments of the method of treating cancer, the subject is willing to comply with all protocol-required visits, evaluations, and procedures.

In some embodiments of the method of treating cancer, the individual is able to swallow the oral medication.

In some embodiments of the methods of treating cancer, the individual has not received prior therapy with a RAS, MEK or ERK inhibitor.

In some embodiments of the method of treating cancer, the subject has not received anticancer therapy < 21 days prior to the first dose of the study drug or drug combination.

In some embodiments of the method of treating cancer, the subject has not received anticancer therapy for 4 half-lives prior to the first dose of the study drug or drug combination.

In some embodiments of the method of treating cancer, the subject has not received palliative radiation <7 days prior to the first dose of the study drug or drug combination.

In some embodiments of the method of treating cancer, the individual does not have or has not been diagnosed with symptomatic brain cancer metastasis or leptomeningeal disease.

In some embodiments of the method of treating cancer, the subject does not have or has not been diagnosed with a gastrointestinal condition that might affect the absorption of the oral drug.

In some embodiments of the method of treating cancer, the individual does not have or has not been diagnosed with an active infection requiring systemic therapy or a history of HIV infection, hepatitis B virus, or hepatitis C virus.

In some embodiments of the method of treating cancer, the subject does not have chronic inflammatory bowel disease or chronic inflammatory bowel disease requiring medical intervention (such as immunomodulatory, immunosuppressive drugs, or surgery) ≤ 12 months prior to the first dose of the study drug or drug combination History of Crohn's disease.

In some embodiments of the method of treating cancer, the subject does not have active and clinically significant interstitial lung disease or pneumonia.

In some embodiments of the method of treating cancer, the subject does not have compromised cardiovascular function or clinically significant cardiovascular disease.

In some embodiments of the method of treating cancer, the subject does not have a history of thromboembolic or cerebrovascular events < 6 months prior to the first dose of the study drug or drug combination.

In some embodiments of the method of treating cancer, the subject has not had major surgery within 28 days of study enrollment, or is not expected to have major surgery during study treatment.

In some embodiments of the method of treating cancer, the subject has no known intolerance or contraindication to enrafenib, cetuximab, or palbocoxib.

In some embodiments of the method of treating cancer, the individual is not pregnant or breastfeeding.

In some embodiments of the method of treating cancer, the subject does not have any signs of severe or uncontrolled systemic disease or any other significant clinical condition or laboratory finding that would render the patient unsuitable for participation in a study. Examples Example 1 : In vitro cell population analysis

Cells were plated in 12-well dishes at the indicated densities and allowed to adhere overnight (see table below). The next day, vehicle or compound was added to the wells in 1 mL of media. After 7 days of incubation, the medium was replaced with fresh medium containing vehicle or compound. After 14 days of incubation, cells were washed twice in 1×PBS, fixed in 4% formaldehyde for 30 minutes, and then washed twice with 1×PBS. Cells were stained with 0.1% crystal violet for 60 minutes and then washed five times with 1×PBS. Plates were dried at room temperature for 2 hours and imaged. Subsequently, cells were destained with 10% acetic acid and absorbance was measured using the BCA protocol or absorbance at 560 nm. picture cell line Spreading density ( per hole; 12 holes ) Figure 1A LS180 4,000 Figure 1B NCI-H727 8,000 Figure 1C A549 2,000 Figure 1D SW-620 4,000 Figure 1E HCT-116 3,000 Figure 1F LoVo 6,000 Figure 1G HCT-15 3,000 Figure 1H NCI-H1944 6,000 Figure 1I NCI-H460 3,000 Figure 1J SK-MEL-2 5,000 Figure 1K Calu-6 3,000 result

Compound 1 and palbocoxib demonstrated combined benefit in vitro in a mutant RAS cell model. Cell population analysis was performed in RAS mutation-bearing cell lines with Compound 1 alone, palbocoxib alone or in combination in the tumor types as indicated (Figure 1A-K). Example 2 : Phase 1b/2 study design of the combination of compound 1 and palbocoxib targeting the MAPK pathway in patients with advanced gastrointestinal malignancies

This Phase 1b/2 study will evaluate Compound 1 administered weekly (QW) versus once daily (QD) or once weekly (QW) in patients with previously treated KRASm or NRASm colorectal cancer Safety, clinical pharmacology and preliminary efficacy of Chengzhi's palbocoxib combination.

Part 1 will determine the recommended dose (RD) for Compound 1 QW + Pabocoxib QD, and Part 3 will determine the recommended dose (RD) for Compound 1 QW + Pabocoxib QW. Only RDs were selected from Part 1 and Part 3, respectively, for expansion in larger patient cohorts in Part 2 or Part 4. RD selection will be based on comparison of safety, tolerability, PK, PD and preliminary efficacy. This extension was designed to test the hypothesis that the combination of Compound 1 and palbocoxib has antitumor activity superior to the current standard of care in patients with previously treated KRASm or NRASm CRC.

Up to approximately 252 patients will be enrolled in this study, with up to approximately 58 and 82 safety evaluable patients enrolled in Part 1 and Part 3, respectively. Patients who withdrew from the study during the 28-day DLT evaluation period for reasons unrelated to treatment-emergent toxicity were replaced. Following RD and schedule selection, up to approximately 112 patients will be enrolled in Part 2 or Part 4, assuming that 10% of patients receiving at least 1 dose of Compound 1 withdraw from the study prior to first post-dose tumor assessment, The target is 100 efficacy-evaluable patients. part 1

Part 1 will determine the recommended dose (RD) for Compound 1 QW + palbocoxib QD. Part 1 will evaluate compound 1 QW + palbocoxib QD in a 28-day cycle using a Bayesian optimal interval (BOIN) design with 21 days of palbocoxib administered in multiple doses and 7 days off (or QD [3/1]).

The first dose cohort in Part 1 was Compound 1 100 mg QW + palbocoxib 75 mg QD (3/1). The Safety Review Committee (SRC) will use the safety, PK and PD data from this QD sentinel cohort to inform decisions regarding: 1) when this combination is further evaluated at higher doses in the QD dose escalation matrix and 2) initial assessment of Compound 1 100 mg QW + palbocoxib 200 mg QW in the QW sentinel cohort. QD dose escalation

A total of 9 possible doses can be explored in the compound 1 QW + palbocoxib QD (3/1) time course, where compound 1 is 100, 150, 200 or 250 mg QW and palbocoxib is 75, 100 or 125 mg QD. part 3

The first dose cohort in Part 3 (QW sentinel cohort) was Compound 1 100 mg QW + palbocoxib 200 mg QW. The decision to open this cohort will be based on the assessment of safety data and available PK and PD data from the QD sentinel cohort in Part 1, or from additional cohorts in the QD dose escalation matrix if deemed necessary by the SRC. QW dose escalation

A total of 15 possible doses can be explored in the compound 1 QW + palbocoxib QW time course, where compound 1 is 100 mg, 150, 200 or 250 mg QW and palbocoxib is 200, 300, 400, 500 or 600 mg QW. Research Objectives Part 1

The primary objectives of Part 1 are to assess the safety and tolerability of escalating doses of Compound 1 QW + Pabocoxib QD in patients with previously treated KRASm/NRASm CRC and to determine the safety and tolerability of Compound 1 (QW) + Pabocoxib QD Maximum tolerated dose (MTD) and/or recommended dose (RD) of coxib (QD).

Secondary objectives of Part 1 were to assess the antitumor activity of Compound 1 QW + Pabocoxib QD in patients with previously treated KRASm/NRASm CRC, and to assess the PK of Compound 1 and Pabocoxib administered in combination profile. part 2

The primary objective of Part 2 is to evaluate the antitumor activity of Compound 1 QW + palbocoxib QD at the RD established in Part 1 in patients with previously treated KRASm/NRASm CRC.

The secondary objective of Part 2 was to evaluate the durability of antitumor activity of Compound 1 QW + Pabocoxib QD at the RD established in Part 1 in previously treated KRASm/NRASm CRC patients, evaluating Compound 1 QW + Pabocoxib Safety and tolerability of QDs, and assessment of the PK profile of Compound 1 QW and palbocoxib QD administered in combination. part 3

The primary objectives of Part 3 are to evaluate the safety and tolerability of escalating doses of palbocoxib monotherapy and Compound 1 QW + palbocoxib QW in patients with previously treated KRASm/NRASm CRC and to identify compound 1 (QW) + MTD and/or RD of palbocoxib (QW).

Secondary objectives of Part 3 were to evaluate the antitumor activity of Compound 1 QW + Pabocoxib QW in patients with previously treated KRASm/NRASm CRC, and to evaluate Compound 1 administered as pabocoxib monotherapy and in combination PK profile of QW and palbocoxib QW. part 4

The primary objective of Part 4 was to evaluate the antitumor activity of Compound 1 QW + palbocoxib QW at the RD established in Part 3 in patients with previously treated KRASm/NRASm CRC.

The secondary objective of Part 4 was to evaluate the durability of antitumor activity of Compound 1 QW + Pabocoxib QW at the RD established in Part 4 in patients with previously treated KRASm/NRASm CRC. Safety and tolerability of QW, and assessment of the PK profile of Compound 1 QW and palbocoxib QW administered in combination. Dosing schedule Compound 1 + palbocoxib in KRASm/NRASm CRC or KRASm PDAC Compound 1 QW ^a + Pabocoxib QD ^b Compound 1 QW ^a + Pabocoxib QW ^c Compound 1 BID-QW ^d + palbocoxib QD ^b Compound 1 BID-QW ^d + palbocoxib QW ^b dose escalation Compound 1 100 mg QW + Pabocoxib QD Compound 1 100 mg QW + Pabocoxib QW Compound 1 50 mg BID-QW + Pabocoxib QD Compound 1 50 mg BID-QW + Pabocoxib QW Compound 1 150 mg QW + Pabocoxib QD Compound 1 150 mg QW + Pabocoxib QW Compound 1 75 mg BID-QW + Pabocoxib QD Compound 1 75 mg BID-QW + Pabocoxib QW Compound 1 200 mg QW + Pabocoxib QD Compound 1 200 mg QW + Pabocoxib QW Compound 1 100 mg BID-QW + Pabocoxib QD Compound 1 100 mg BID-QW + Pabocoxib QW Compound 1 250 mg QW + Pabocoxib QD Compound 1 250 mg QW + Pabocoxib QW Compound 1 125 mg BID-QW + Pabocoxib QD Compound 1 125 mg BID-QW + Pabocoxib QW dose escalation Compound 1 QW + Pabocoxib QD (RD) Compound 1 QW + Pabocoxib QW (RD) Compound 1 BID-QW + Pabocoxib QD (RD) Compound 1 BID-QW + Pabocoxib QW (RD) ^a Compound 1 QW - Compound 1 orally once ^{a weekbPabocoxib} QD - Pabocoxib orally once a day for 21 consecutive days in a 28-day cycle, followed by 7 days off ^cPabocoxib QW - Pabocoxib orally once a week ^d Compound 1 BID-QW: Compound 1 orally twice a day on a single day per week Inclusion criteria :

Age ≥ 18 years old.

Willing and able to provide written informed consent.

With histologically or cytologically confirmed metastatic CRC carrying applicable mutations (eg, BRAFm V600E; KRAS or NRAS mutations) based on analytically validated analysis of tumor tissue performed in a certified laboratory.

Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Adequate bone marrow and organ function.

Has an ECOG performance status of 0 or 1.

Willingness to comply with all protocol-required visits, assessments, and procedures.

Able to swallow oral medications. Exclusion criteria :

Prior therapy with RAS, MEK or ERK inhibitors. Depending on the treatment arm to which the patient is assigned, other therapies may also be prohibited.

Anticancer therapy ≤ 21 days or 4 half-lives (whichever is shorter) prior to the first dose of study drug.

Palliative radiation ≤ 7 days prior to first dose of study drug.

Symptomatic brain metastases or leptomeningeal disease.

Gastrointestinal conditions that may affect the absorption of oral medications.

Active infection requiring systemic therapy or history of HIV infection, hepatitis B virus, or hepatitis C virus.

History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (such as immunomodulatory or immunosuppressive drugs or surgery) ≤ 12 months prior to the first study drug dose.

Active, clinically significant interstitial lung disease or pneumonia.

Decreased cardiovascular function or clinically significant cardiovascular disease.

History of thromboembolic or cerebrovascular events ≤ 6 months prior to first dose.

No major surgery within 28 days of enrollment, or anticipated major surgery during study treatment.

Known intolerance or contraindication to enrafenib, cetuximab, or palbociclib.

Women who are pregnant or breastfeeding.

Any sign of severe or uncontrolled systemic disease or any other significant clinical condition or laboratory finding that would render the patient unsuitable for study participation. Example 3 : In Vivo Study of Compound 1 Alone , Pabocoxib Alone, and Compound 1 + Pabocoxib Combination in the LoVo KRAS Mutant CRC Model

A vehicle/control article of Compound 1 was prepared containing 0.5% methylcellulose (MC) and 0.1% Tween 80 in deionized water and stored at ambient conditions throughout the 28-day mouse administration.

Test article Compound 1 was prepared weekly in a vehicle of 0.5% methylcellulose (MC) and 0.1% Tween 80 solution and stored at ambient conditions. Combination doses of palbocoxib were prepared weekly in a vehicle of 50 mM sodium lactate buffer pH 3.8-4.0 and stored at 2-8°C.

Female Balb/c nude mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Mice were housed in a special pathogen-free (SPF) environment in a housing facility and allowed to acclimate to the new environment for at least 3 days before starting any experiments. Mice were between 6-8 weeks old at implantation. All procedures related to animal handling, care and handling in this study were performed according to protocols and guidelines approved by GenenDesign's Institutional Animal Care and Use Committee (IACUC). Animal institutions and programs were operated in accordance with the guidelines for the care and use of laboratory animals (National Research Council (National Research Council), 2011) and were accredited by the Assessment and Accreditation Committee for Laboratory Animal Care (AAALAC). Specifically, all parts of this study were conducted at GenenDesign following a study protocol and applicable standard operating procedures (SOPs) reviewed and approved by IACUC. Preparation of PDX

LoVo is a human CRC cell line carrying the KRAS ^G13D mutation. LoVo cell lines were purchased from the American Type Culture Collection (ATCC® CCL-229™). LoVo cells were cultured in F12K medium containing 10% fetal bovine serum (FBS) at 37°C in an atmosphere of 5% CO ₂ in air. Medium was refreshed every 2 to 3 days and tumor cells were usually subcultured at 80-90% confluency. Cells growing in exponential phase were harvested using trypsin-EDTA, counted for inoculation, and then implanted subcutaneously into mice. 200 µL of cell suspension containing 2×10 ⁶ tumor cells mixed with 50% Matrigel was subcutaneously implanted into the right flank of mice using a syringe. Animal health and tumor growth were monitored daily. Tumor volume was measured by caliper twice a week when the tumor was palpable and measurable. When tumor volumes reached a mean of 190 ^mm3 (150-259 ^mm3 range), tumor-bearing mice were randomized into different groups of 8 mice each. The day of randomization is denoted as treatment day 0. deal with

Treatment began on the day of randomization. The treatment start day was indicated as treatment day 0. Mice were dosed by oral administration of vehicle control solution, 25 mg/kg QD palbocoxib or 30 mg/kg QD Compound 1 monotherapy. An additional group received compound 1 in combination with palbocoxib at 30 mg/kg QD and palbocoxib at 25 mg/kg QD. In the combination treatment group, the Compound 1 dose was reduced from its maximum effective monotherapy dose of 30 mg/kg/dose BID to 30 mg/kg QD based on a previously performed tolerability study. The dosing volume of each compound was 5 mL/kg and the time interval of the BID regimen was 8 hours. Compound 1 was administered one hour after palbocoxib in the combination group. The study was terminated on treatment day 28 as defined in the study protocol.

As shown in Figure 2A , compound 1 and palbocoxib demonstrated combined benefit in vivo in the LoVo KRAS mutant CRC model. Example 4 : In Vivo Study of Compound 1 Alone , Pabocoxib Alone, and Compound 1 + Pabocoxib Combination in the SW-620 KRAS Mutant CRC Model

A vehicle/control article of Compound 1 was prepared containing 0.5% methylcellulose (MC) and 0.1% Tween 80 in deionized water and stored at ambient conditions throughout the 28-day mouse administration.

Test article Compound 1 was prepared weekly in a vehicle of 0.5% methylcellulose (MC) and 0.1% Tween 80 solution and stored at ambient conditions. Combination doses of palbocoxib were prepared weekly in a vehicle of 50 mM sodium lactate buffer pH 3.8-4.0 and stored at 2-8°C.

Female Balb/c nude mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Mice were housed in a special pathogen-free (SPF) environment in a housing facility and allowed to acclimate to the new environment for at least 3 days before starting any experiments. Mice were between 6-8 weeks old at implantation. All procedures related to animal handling, care and handling in this study were performed according to protocols and guidelines approved by GenenDesign's Institutional Animal Care and Use Committee (IACUC). Animal institutions and programs were operated in accordance with the Guidelines for the Care and Use of Laboratory Animals (National Research Council, 2011) and were accredited by the Assessment and Accreditation Committee for Laboratory Animal Care (AAALAC). Specifically, all parts of this study were conducted at GenenDesign following a study protocol and applicable standard operating procedures (SOPs) reviewed and approved by IACUC. Preparation of PDX

SW-620 is a human CRC cell line carrying KRAS ^G12V mutation. The SW-620 cell line was purchased from the American Type Culture Collection (ATCC® CCL-227). SW-620 cells were cultured in L-15 medium + 10% fetal bovine serum (FBS) at 37°C in 100% air atmosphere. Medium was refreshed every 2 to 3 days and tumor cells were usually subcultured at 80-90% confluency. Cells growing in exponential phase were harvested using trypsin-EDTA, counted for inoculation, and then implanted subcutaneously into mice. 200 µL of cell suspension containing 5×10 ⁶ tumor cells mixed with 50% Matrigel was subcutaneously implanted into the right flank of mice using a syringe. Animal health and tumor growth were monitored daily. Tumor volume was measured by caliper twice a week when the tumor was palpable and measurable. When tumor volumes reached a mean of 210 mm ³ (150-271 mm ³ range), tumor-bearing mice were randomized into different groups of 8 mice each. The day of randomization is denoted as treatment day 0. deal with

Treatment began on the day of randomization. The treatment start day was indicated as treatment day 0. Mice were dosed by oral administration of vehicle control solution, 25 mg/kg QD palbocoxib or 30 mg/kg QD Compound 1 monotherapy. An additional group received compound 1 in combination with palbocoxib at 30 mg/kg QD and palbocoxib at 25 mg/kg QD. In the combination treatment group, the Compound 1 dose was reduced from its maximum effective monotherapy dose of 30 mg/kg/dose BID to 30 mg/kg QD based on a previously performed tolerability study. The dosing volume of each compound was 5 mL/kg and the time interval of the BID regimen was 8 hours. Compound 1 was administered one hour after palbocoxib in the combination group. The study was terminated on treatment day 28 as defined in the study protocol.

As shown in Figure 2B , compound 1 and palbocoxib demonstrated combined benefit in vivo in the SW-620 KRAS mutant CRC model. Example 5 : In Vivo Study Vehicle / Control Articles for Pabocoxib Alone, Compound 1 Alone , and Compound 1 + Pabocoxib Combination in KRAS ^G12D Mutant PDAC PDX Model PAN092

A vehicle/control article of Compound 1 was prepared containing 0.5% methylcellulose (MC) and 0.1% Tween 80 in deionized water and stored at ambient conditions throughout the 28-day mouse administration. Deployment of test items

Test article Compound 1 was freshly prepared once a week in a vehicle of 0.5% methylcellulose (MC) and 0.1% Tween 80 solution and stored at ambient conditions. Combination agent palbocoxib was prepared fresh weekly in a vehicle of 50 mM sodium lactate buffer pH 3.8-4.0 and stored at 2-8°C. animal

Female Balb/c nude mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Mice were between 6-8 weeks old at implantation. Mice were housed in a special pathogen-free (SPF) environment in a breeding facility and allowed to acclimate to the new environment for at least 3 days before starting any experiments according to the IACUC protocol.

All procedures related to animal handling, care and handling in this study were performed according to protocols and guidelines approved by GenenDesign's Institutional Animal Care and Use Committee (IACUC). Animal institutions and programs were operated in accordance with the Guidelines for the Care and Use of Laboratory Animals (National Research Council, 2011) and were accredited by the Assessment and Accreditation Committee for Laboratory Animal Care (AAALAC). Specifically, all parts of this study were conducted at GenenDesign following a study protocol and applicable standard operating procedures (SOPs) reviewed and approved by IACUC. Preparation of PDX

The PAN092 model was established for nonclinical efficacy studies at GenenDesign (Shanghai, China). The PDX model was derived from a 65-year-old Chinese male PDAC patient with KRASG12D mutation. KRASG12D mutation in PDX model PAN092 was confirmed by whole exome sequencing and PCR sequencing. Tumor fragments harvested from PDX models were implanted subcutaneously in the right flank of female Balb/c nude mice. Mice were anesthetized with isoflurane and maintained throughout the implantation procedure. Sterilize the right flank of the mouse with appropriate surgical scrub and alcohol, and use aseptic surgical procedures. A small skin incision was made using the tip of the trocar and along the right chest wall a 1.5 cm subcutaneous pocket was created by blunt dissection with the probe of a 10-12 g trocar. A tumor fragment (15-30 mm ³ ) was placed in a trocar and advanced into a subcutaneous pocket on the right flank. The trocar incision is closed with sutures or clips and removed after one week of closure. When the volumetric tumor size reached an average of 204 mm ³ (150-250 mm ³ range), tumor-bearing mice were randomly divided into study groups, with 8 mice in each group. The day of randomization is denoted as treatment day 0. deal with

Treatment began on the day of randomization. The treatment start day was indicated as treatment day 0. Mice were dosed by oral administration of vehicle control solution, 25 mg/kg QD palbocoxib, 30 mg/kg/dose BID Compound 1 or 30 mg/kg QD Compound 1 as monotherapy treatment. An additional group received compound 1 in combination with palbocoxib at 30 mg/kg QD and palbocoxib at 25 mg/kg QD. In the combination treatment group, the Compound 1 dose was reduced from its maximum effective monotherapy dose of 30 mg/kg/dose BID to 30 mg/kg QD based on a previously performed tolerability study. The dosing volume of each compound was 5 mL/kg and the time interval of the BID regimen was 8 hours. Compound 1 was administered one hour after palbocoxib in the combination group. As a routine practice, DietGel (ClearH2O, US) was added to cages in which at least two mice in the treatment groups showed a BWL > 10%, in addition to the regular food and water supply. According to this practice, mice in the 30 mg/kg/dose BID Compound 1 monotherapy-treated group and mice in the combination-treated group were supplied with DietGel food starting on day 10 and day 21 of treatment, respectively, and for the remainder of the study period Continue to supply. The study was terminated on treatment day 28 as defined in the study protocol.

Compound 1 and palbocoxib demonstrate combined benefit in vivo in the KRAS ^G12D mutant PDAC PDX model PAN092. Example 6 : In Vivo Study of Pabocoxib Alone, Compound 1 Alone , and Compound 1 + Pabocoxib Combination in KRAS ^G12D Mutant PDAC PDX Model PAN026

A vehicle/control article of Compound 1 was prepared containing 0.5% methylcellulose (MC) and 0.1% Tween 80 in deionized water and stored at ambient conditions throughout the 28-day mouse administration. Deployment of test items

Test article Compound 1 was freshly prepared once a week in a vehicle of 0.5% methylcellulose (MC) and 0.1% Tween 80 solution and stored at ambient conditions. Combination agent palbocoxib was prepared fresh weekly in a vehicle of 50 mM sodium lactate buffer pH 3.8-4.0 and stored at 2-8°C. animal

Female Balb/c nude mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Mice were between 6-8 weeks old at implantation. Mice were housed in a special pathogen-free (SPF) environment in a breeding facility and allowed to acclimate to the new environment for at least 3 days before starting any experiments according to the IACUC protocol.

All procedures related to animal handling, care and handling in this study were performed according to protocols and guidelines approved by GenenDesign's Institutional Animal Care and Use Committee (IACUC). Animal institutions and programs were operated in accordance with the Guidelines for the Care and Use of Laboratory Animals (National Research Council, 2011) and were accredited by the Assessment and Accreditation Committee for Laboratory Animal Care (AAALAC). Specifically, all parts of this study were conducted at GenenDesign following a study protocol and applicable standard operating procedures (SOPs) reviewed and approved by IACUC. Preparation of PDX

The PAN026 model was established for nonclinical efficacy studies at GenenDesign (Shanghai, China). The PDX model was derived from a 58-year-old Chinese male PDAC patient with KRAS ^G12D mutation. The KRAS ^G12D mutation in PDX model PAN026 was confirmed by whole exome sequencing and PCR sequencing. Tumor fragments harvested from PDX models were implanted subcutaneously in the right flank of female Balb/c nude mice. Mice were anesthetized with isoflurane and maintained throughout the implantation procedure. Sterilize the right flank of the mouse with appropriate surgical scrub and alcohol, and use aseptic surgical procedures. A small skin incision was made using the tip of the trocar and along the right chest wall a 1.5 cm subcutaneous pocket was created by blunt dissection with the probe of a 10-12 g trocar. A tumor fragment (15-30 mm ³ ) was placed in a trocar and advanced into a subcutaneous pocket on the right flank. The trocar incision is closed with sutures or clips and removed after one week of closure. When the volumetric tumor size reached an average of 190 mm ³ (140-269 mm ³ range), the tumor-bearing mice were randomly divided into study groups, with 8 mice in each group. The day of randomization is denoted as treatment day 0. deal with

Treatment began on the day of randomization. The treatment start day was indicated as treatment day 0. Mice were dosed by oral administration of vehicle control solution, 25 mg/kg QD palbocoxib, 30 mg/kg QD Compound 1 or 30 mg/kg/dose BID Compound 1 as monotherapy treatment. An additional group received compound 1 in combination with palbocoxib at 30 mg/kg QD and palbocoxib at 25 mg/kg QD. In the combination treatment group, the Compound 1 dose was reduced from its maximum effective monotherapy dose of 30 mg/kg/dose BID to 30 mg/kg QD based on a previously performed tolerability study. The dosing volume of each compound was 5 mL/kg and the time interval of the BID regimen was 8 hours. Compound 1 was administered one hour after palbocoxib administration in the combination group. As a routine practice, DietGel (ClearH2O, US) was added to cages in which at least two mice in the treatment group showed a BWL > 10%, in addition to the regular food and water supply. In accordance with this practice, mice in the 30 mg/kg/dose BID Compound 1 monotherapy treatment group were fed DietGel chow beginning on day 23 of treatment and continued for the remainder of the study period. The study was terminated on treatment day 28 as defined in the study protocol.

Compound 1 and palbocoxib demonstrate combined benefit in vivo in the KRAS ^G12D mutant PDAC PDX model PAN026. Example 7 : In Vivo Study of Compound 1 Alone, Pabocoxib Alone, and Compound 1+ Pabocoxib Combination in Mutant KRAS ^G12V Cell Model SW-480 Materials and Methods Cell Plating and Treatment

Cells were plated in 12-well flat-bottomed cell culture dishes at 3,000 cells/well. Cells were allowed to adhere overnight at 37°C, 0% or 5% CO2, 95% air, and 100% relative humidity.

The next day, compounds were dissolved to generate 10 mM stocks in DMSO. To prepare compound stock plates (1000x), 10 mM stocks were serially diluted in DMSO from highest to lowest according to the plate diagram. To treat cells, compounds were prepared as follows: (1). Preparation of 20× concentrated compound culture plate: Add 196 μL of assay medium to each well of the V-bottom culture plate; then transfer 4 μL of stock compound solutions of each concentration from the stock solution culture plate. Add 4 μL DMSO to control wells. Pipette up and down to mix well. This V-plate is indicated as a 20X concentrated compound plate. (2). Compound treatment: Add 50 μL Compound-A-medium and 50 μL Compound-B-medium from each well of the 20× concentrated compound culture plate to the cells in the 12-well assay plate according to the plate diagram. For the vehicle group, 100 μL of DMSO-medium was added to the wells. The final DMSO concentration was 0.2%. (3). The assay plate was returned to the incubator and incubated for 7 days.

After 7 days of cultivation, the medium was replaced with freshly prepared compounds and incubated for an additional 7 days. cell staining

On day 14, cells were washed with 1 mL of PBS and then fixed by adding 1 mL of 100% methanol to each well for 10-15 minutes at room temperature. After removal of methanol, cells were stained with 0.1% crystal violet for 60 minutes at room temperature. Cells were then washed 4-6 times with water and dried at room temperature for 2 hours before imaging. Crystal violet decolorization and OD measurement

Cells were destained by incubation with 10% acetic acid and absorbance was measured using the conventional BCA protocol. The absorbance of each well was tested in duplicate.

As shown in Figure 4 , the combination of compound 1 and palbocoxib caused a greater reduction in relative population numbers and demonstrated the benefit of the combination in vitro in the KRAS ^G12V mutant cell model SW-480. Example 8 : Analysis of NRAS ^Q61K mutant melanoma CDX model WM3268 in vivo

A vehicle/control article of Compound 1 was prepared containing 0.5% methylcellulose (MC) and 0.1% Tween 80 in deionized water and stored at ambient conditions throughout the 36-day mouse administration.

Test article Compound 1 was prepared weekly in a vehicle of 0.5% methylcellulose (MC) and 0.1% Tween 80 solution and stored at ambient conditions. Combination doses of palbocoxib were prepared weekly in a vehicle of 50 mM sodium lactate buffer pH 3.8-4.0 and stored at 2-8°C. Female Balb/c nude mice were between 6-8 weeks of age at implantation. Mice were housed in a special pathogen-free (SPF) environment in a breeding facility and allowed to acclimate to the new environment for at least 3 days before starting any experiments according to the IACUC protocol.

WM3268 is a human melanoma cell line carrying NRAS ^Q61K mutation.

WM3268 cells were cultured in tumor-specific medium (80% MCDB153, 20% Leibovitz's L-15, 1.68 mM CaCl ₂ ) + 2% FBS + Pen/Strep at 37°C in an atmosphere of 5% CO ₂ in air. The medium was refreshed every 2 to 3 days and tumor cells were subcultured by trypsin-EDTA usually at 80-90% confluency. Cells growing in exponential growth phase were harvested and counted for inoculation. WM3268 tumor cells were implanted subcutaneously into mice. 200 µL of cell suspension containing 10×10 ⁶ tumor cells mixed with 50% Matrigel was subcutaneously implanted into the right flank of mice using a syringe. Eighty-four mice were implanted in this study. Animal health and tumor growth were monitored daily. Tumor volume was measured by caliper twice a week when the tumor was palpable and measurable. When the tumor volume reached a mean of 144 mm ³ (range 117-198 mm ³ ) on day 22 after subcutaneous implantation, tumor-bearing mice were randomized into different groups of 8 mice each. The day of randomization is denoted as treatment day 0. deal with

Treatment started the day after randomization. The treatment start day was indicated as treatment day 1. Mice were dosed by oral administration of vehicle control solution or monotherapy treatment with 30 mg/kg/dose QD of Compound 1 or 25 mg/kg QD of Sotocoxib. An additional group received a combination of 30 mg/kg/dose QD of Compound 1 or 25 mg/kg QD of palbocoxib. In the combination group, palbocoxib was administered first and compound 1 was administered one hour later. The study was terminated on Day 36 of treatment as defined in the study protocol. The results are shown in Figure 5. Compound 1 and palbocoxib demonstrate combined benefit in vivo in the NRAS ^Q61K mutant melanoma CDX model WM3268. Tumor growth curve of WM3268 PDX model. Example 9 : Analysis of NRAS ^Q61K mutant melanoma CDX model WM3456 in vivo

A vehicle/control article of Compound 1 was prepared containing 0.5% methylcellulose (MC) and 0.1% Tween 80 in deionized water and stored at ambient conditions throughout the 28-day mouse administration.

Test article Compound 1 was prepared weekly in a vehicle of 0.5% methylcellulose (MC) and 0.1% Tween 80 solution and stored at ambient conditions. Combination doses of palbocoxib were prepared weekly in a vehicle of 50 mM sodium lactate buffer pH 3.8-4.0 and stored at 2-8°C.

Female Balb/c nude mice were between 6-8 weeks of age at implantation. Mice were housed in a special pathogen-free (SPF) environment in a breeding facility and allowed to acclimate to the new environment for at least 3 days before starting any experiments according to the IACUC protocol.

WM3456 is a human melanoma cell line carrying NRAS ^Q61K mutation.

WM3456 cells were cultured in tumor-specific medium (80% MCDB153, 20% Leibovitz's L-15, 1.68 mM CaCl ₂ ) + 2% FBS + Pen/Strep at 37°C in an atmosphere of 5% CO ₂ in air. The medium was refreshed every 2 to 3 days and tumor cells were subcultured by trypsin-EDTA usually at 80-90% confluency. Cells growing in exponential growth phase were harvested and counted for inoculation. WM3456 tumor cells were implanted subcutaneously into mice. 200 µL of cell suspension containing 10×10 ⁶ tumor cells mixed with 50% Matrigel was subcutaneously implanted into the right flank of mice using a syringe. Eighty-four mice were implanted in this study. Animal health and tumor growth were monitored daily. Tumor volume was measured by caliper twice a week when the tumor was palpable and measurable. When tumor volume reached a mean of 149 ^mm3 (range 136-180 ^mm3 ) on day 16 after subcutaneous implantation, tumor-bearing mice were randomized into different groups of 8 mice each. The day of randomization is denoted as treatment day 0. deal with

Treatment started the day after randomization. The treatment start day was indicated as treatment day 1. Mice were dosed by oral administration of vehicle control solution or monotherapy treatment with 30 mg/kg/dose QD of Compound 1 or 25 mg/kg QD of Sotocoxib. An additional group received a combination of 30 mg/kg/dose QD of Compound 1 or 25 mg/kg QD of palbocoxib. In the combination group, palbocoxib was administered first and compound 1 was administered one hour later. The study was terminated on Day 36 of treatment as defined in the study protocol. The results are shown in Figure 6. Compound 1 and palbocoxib demonstrate combined benefit in vivo in the NRAS ^Q61K mutant melanoma CDX model WM3456. Tumor growth curve of WM3456 PDX model.

The novel features of the invention are set forth in detail in the appended claims. A better understanding of the features and advantages of the invention will be obtained by reference to the following detailed description and accompanying drawings which illustrate illustrative embodiments utilizing the principles of the invention:

Figure 1A shows the results of cell population analysis with Compound 1 alone, palbocoxib alone, and Compound 1 + palbocoxib in LS180 cells.

Figure IB shows the results of cell population analysis with Compound 1 alone, palbocoxib alone, and Compound 1 + palbocoxib in NCI-H727 cells.

Figure 1C shows the results of cell population analysis with Compound 1 alone, palbocoxib alone, and Compound 1 + palbocoxib in A549 cells.

Figure ID shows the results of cell population analysis in SW-620 cells with Compound 1 alone, palbocoxib alone, and Compound 1 + palbocoxib.

Figure IE shows the results of cell population analysis in HCT-116 cells with Compound 1 alone, palbocoxib alone, and Compound 1 + palbocoxib.

Figure IF shows the results of cell population analysis in LoVo cells with Compound 1 alone, palbocoxib alone, and Compound 1 + palbocoxib.

Figure 1G shows the results of cell population analysis in HCT-15 cells with Compound 1 alone, palbocoxib alone, and Compound 1 + palbocoxib.

Figure 1H shows the results of cell population analysis with Compound 1 alone, palbocoxib alone, and Compound 1 + palbocoxib in NCI-H1944 cells.

Figure II shows the results of cell population analysis with Compound 1 alone, palbocoxib alone, and Compound 1 + palbocoxib in NCI-H460 cells.

Figure 1J shows the results of cell population analysis in SK-MEL-2 cells with Compound 1 alone, palbocoxib alone, and Compound 1 + palbocoxib.

Figure IK shows the results of cell population analysis in Calu-6 cells with Compound 1 alone, palbocoxib alone, and Compound 1 + palbocoxib.

Figure 2A shows in vivo data for Compound 1 alone, palbocoxib alone, and Compound 1 + palbocoxib in the LoVo KRAS ^G13D CDX model.

Figure 2B shows in vivo data for Compound 1 alone, palbocoxib alone, and Compound 1 + palbocoxib in the SW-620 KRAS ^G12V CDX model.

Figure 3A shows the in vivo tumor growth inhibition (TGI) of palbocoxib alone, Compound 1 alone, and Compound 1 + palbocoxib in the KRAS ^G12D mutant PDAC PDX model PAN092.

Figure 3B shows the in vivo tumor growth inhibition (TGI) of palbocoxib alone, Compound 1 alone, and Compound 1 + palbocoxib in the KRAS ^G12D mutant PDAC PDX model PAN026.

Figure 4 shows the in vitro data of compound 1 alone, palbocoxib alone and compound 1 + palbocoxib in the mutant KRAS ^G12V cell model SW-480.

Figure 5 shows in vitro data for Compound 1 alone, palbocoxib alone, and Compound 1 + palbocoxib in the mutant NRAS ^Q61K cell model WM3268.

Figure 6 shows in vitro data for Compound 1 alone, palbocoxib alone, and Compound 1 + palbocoxib in the mutant NRAS ^Q61K cell model WM3456.

Claims (104)

A method of treating cancer in an individual in need, the method comprising: administering a therapeutically effective amount of (i) Compound 1 to the individual in need:

, or a pharmaceutically acceptable salt thereof, and (ii) a CDK4/6 inhibitor. The method according to claim 1, wherein the CDK4/6 inhibitor is palbociclib, ribociclib, abemaciclib, FCN-437c or alvociclib. The method according to claim 1 or 2, wherein the CDK4/6 inhibitor is palbocoxib. The method of claim 3, wherein palbocoxib is administered in an amount between about 50 mg/day and about 500 mg/day. The method according to claim 4, wherein palbocoxib is administered in an amount of about 75 mg/day, 100 mg/day, 125 mg/day or 150 mg/day. The method of claim 3, wherein palbocoxib is administered in an amount between about 50 mg once a week and about 650 mg once a week. The method according to claim 6, wherein palbocoxib is administered in an amount of about 200 mg once a week, 300 mg once a week, 400 mg once a week, 500 mg once a week or 600 mg once a week. A method of treating cancer in an individual in need, the method comprising: administering a therapeutically effective amount of (i) Compound 1 to the individual in need:

, or a pharmaceutically acceptable salt thereof, and (ii) palbocoxib. The method according to any one of claims 1 to 8, wherein the pharmaceutically acceptable salt of compound 1 is mandelate. The method according to any one of claims 1 to 9, wherein the cancer is a mitogen-activated protein kinase (MAPK) pathway-driven cancer. The method according to any one of claims 1 to 9, wherein the cancer is a BRAF driven cancer, a HRAS driven cancer or an NRAS driven cancer. The method according to any one of claims 1 to 9, wherein the cancer comprises at least one cancer cell driven by dysregulated ERK. The method of any one of claims 1 to 9, wherein the cancer has at least one RAS mutation. The method of any one of claims 1 to 9, wherein the cancer has at least one RAF mutation. The method of any one of claims 1 to 9, wherein the cancer has at least one MEK mutation. The method of any one of claims 1 to 9, wherein the cancer has a G12C KRAS mutation. The method of any one of claims 1 to 9, wherein the cancer has a G12D KRAS mutation. The method of any one of claims 1 to 9, wherein the cancer has a G12S KRAS mutation. The method of any one of claims 1 to 9, wherein the cancer has a G12V KRAS mutation. The method of any one of claims 1 to 9, wherein the cancer has a G13D KRAS mutation. The method of any one of claims 1 to 9, wherein the cancer has a Q16H KRAS mutation. The method of any one of claims 1 to 9, wherein the cancer has a Q16K KRAS mutation. The method of any one of claims 1 to 9, wherein the cancer has a Q61R NRAS mutation. The method according to any one of claims 1 to 9, wherein the cancer is a BRAF V600E or V600K mutant tumor. The method according to any one of claims 1 to 9, wherein the cancer is pancreatic cancer or PDAC not treated with MAPKm/MAPKi. The method according to any one of claims 1 to 9, wherein the cancer comprises one or more EGFR mutations selected from the group consisting of increased EGFR gene duplication, EGFR gene amplification, chromosome 7 polychromosomal, L858R, penetrance Exon 19 deletion/insertion, L861Q, G719C, G719S, G719A, V765A, T783A, exon 20 insertion, EGFR splice variants (Viii, Vvi, and Vii), A289D, A289T, A289V, G598A, G598V, T790M, and C797S. The method of any one of claims 1 to 9, wherein the cancer comprises one or more EGFR mutations selected from the group consisting of: L858R, exon 19 deletion, and T790M. The method according to any one of claims 1 to 27, wherein the cancer is a solid tumor. The method according to any one of claims 1 to 28, wherein the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, salivary gland tumor, thyroid cancer, colorectal cancer (CRC) or esophageal cancer. The method according to any one of claims 1 to 28, wherein the cancer is non-small cell lung cancer (NSCLC). The method according to claim 30, wherein the NSCLC is EGFR mutant NSCLC. The method according to claim 30, wherein the NSCLC is KRAS ^G12C mutant NSCLC. The method according to claim 30, wherein the NSCLC is KRAS ^G12D mutant NSCLC. The method according to claim 30, wherein the NSCLC is KRAS ^G12S mutant NSCLC. The method according to claim 30, wherein the NSCLC is KRAS ^G12V mutant NSCLC. The method according to claim 30, wherein the NSCLC is KRAS ^G13D mutant NSCLC. The method according to claim 30, wherein the NSCLC is KRAS ^Q61H mutant NSCLC. The method according to claim 30, wherein the NSCLC is KRAS ^Q61K mutant NSCLC. The method according to claim 30, wherein the NSCLC is NRAS ^Q61R mutant NSCLC. The method according to claim 30, wherein the cancer is NSCLC not treated with MAPKm/MAPKi. The method according to claim 30, wherein the cancer is V600 NSCLC treated with BRAFi. The method according to claim 30, wherein the cancer is G12C NSCLC treated with KRAS. The method according to claim 30, wherein the cancer is G12D NSCLC treated with KRAS. The method according to claim 30, wherein the cancer is G12S NSCLC treated with KRAS. The method according to claim 30, wherein the cancer is G12V NSCLC treated with KRAS. The method according to claim 30, wherein the cancer is G13D NSCLC treated with KRAS. The method according to claim 30, wherein the cancer is Q61H NSCLC treated with KRAS. The method according to claim 30, wherein the cancer is Q61K NSCLC treated with KRAS. The method according to claim 30, wherein the cancer is Q61R NSCLC treated with NRAS. The method according to any one of claims 1 to 28, wherein the cancer is pancreatic cancer. The method according to claim 50, wherein the cancer is pancreatic cancer or PDAC not treated with MAPKm/MAPKi. The method according to any one of claims 1 to 28, wherein the cancer is melanoma. The method according to claim 52, wherein the melanoma is a BRAF V600E or V600K mutant tumor. The method of claim 52, wherein the cancer is V600 melanoma treated with BRAFi. The method according to any one of claims 1 to 28, wherein the cancer is a salivary gland tumor. The method according to any one of claims 1 to 28, wherein the cancer is thyroid cancer. The method according to any one of claims 1 to 28, wherein the cancer is colorectal cancer (CRC). The method according to claim 57, wherein the CRC is a BRAF V600E CRC. The method according to claim 57, wherein the CRC is a KRAS mutant CRC. The method according to claim 59, wherein the CRC is a KRAS ^G12C mutant CRC. The method according to claim 59, wherein the CRC is KRAS ^G12D mutant CRC. The method according to claim 59, wherein the CRC is KRAS ^G12S mutant CRC. The method according to claim 59, wherein the CRC is KRAS ^G12V mutant CRC. The method according to claim 59, wherein the CRC is KRAS ^G13D mutant CRC. The method according to claim 59, wherein the CRC is KRAS ^Q61H mutant CRC. The method according to claim 59, wherein the CRC is KRAS ^Q61K mutant CRC. The method according to claim 59, wherein the CRC is NRAS mutant CRC. The method according to claim 67, wherein the CRC is NRAS ^Q61R mutant CRC. The method according to any one of claims 1 to 28, wherein the cancer is esophageal cancer. The method according to any one of claims 1 to 69, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount between about 25 mg/day and about 300 mg/day. The method according to any one of claims 1 to 70, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount between 25 mg/day and 150 mg/day. The method according to any one of claims 1 to 71, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered at about 25 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, It is administered in an amount of about 125 mg/day, about 150 mg/day, about 175 mg/day, about 200 mg/day, about 225 mg/day, or about 250 mg/day. The method as claimed in any one of items 1 to 72, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered at about 25 mg/day, about 50 mg/day, about 100 mg/day or about 150 mg/day Quantitative investment. The method according to any one of claims 1 to 72, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered at an amount of about 250 mg/day. The method according to any one of claims 1 to 74, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day (QD). The method according to any one of claims 1 to 74, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day (BID). The method according to any one of claims 1 to 74, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered three times a day (TID). The method according to any one of claims 1 to 77, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered once a week. The method according to any one of claims 1 to 77, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered twice a week. The method of any one of claims 1 to 69, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered once a week in an amount between about 25 mg and about 300 mg twice a day (BID-QW). The method of any one of claims 1 to 69, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered once a week in an amount between about 25 mg and about 250 mg twice a day (BID-QW). The method of any one of claims 1 to 69, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered once a week in an amount between about 25 mg and about 150 mg twice a day (BID-QW). The method according to any one of claims 1 to 69, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered once a week or twice a day (BID-QW) about 25 mg, 50 mg, about 75 mg, about 100 mg , about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg. The method according to any one of claims 1 to 69, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered once a week or twice a day (BID-QW) about 25 mg, 50 mg, about 100 mg, about 125 mg or about 150 mg. The method according to any one of claims 1 to 69, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 125 mg twice a day (BID-QW) once a week. The method of any one of claims 1 to 85, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered for at least one 28-day cycle. The method according to any one of claims 1 to 86, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered on day 1, day 8, day 15 and day 22 of a 28-day cycle. The method according to any one of claims 1 to 86, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered on day 1, day 8, and day 15 of a 28-day cycle. The method according to any one of claims 1 to 88, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered orally. The method of any one of claims 1 to 89, wherein the method further comprises administering an additional MAPK pathway inhibitor. The method of claim 90, wherein the additional MAPK pathway inhibitor is a KRAS inhibitor, NRAS inhibitor, HRAS inhibitor, PDGFRA inhibitor, PDGFRB inhibitor, MET inhibitor, FGFR inhibitor, ALK inhibitor, ROS1 inhibitor , TRKA inhibitor, TRKB inhibitor, TRKC inhibitor, EGFR inhibitor, IGFR1R inhibitor, GRB2 inhibitor, SOS inhibitor, ARAF inhibitor, BRAF inhibitor, RAF1 inhibitor, MEK1 inhibitor, MEK2 inhibitor, c - Mycv, CDK2 inhibitors, FLT3 inhibitors or ERK1/2 inhibitors. The method according to claim 91, wherein the additional MAPK pathway inhibitor is a KRAS inhibitor. The method of claim 91, wherein the additional MAPK pathway inhibitor is a BRAF inhibitor. The method of claim 91, wherein the additional MAPK pathway inhibitor is an EGFR inhibitor. The method according to claim 91, wherein the additional MAPK pathway inhibitor is CDK4/6. The method according to claim 91, wherein the additional MAPK pathway inhibitor is a FLT3 inhibitor. The method of claim item 91, wherein the additional MAPK pathway inhibitor is adagrasib (adagrasib), afatinib (afatinib), ASTX029, bemetinib (binimetinib), cetuximab (cetuximab), Cobimetinib, dabrafenib, dacomitinib, encorafenib, erlotinib, gefitinib, Gillette Gilteritinib, lapatinib, LTT462, LY3214996, necitumumab, neratinib, nimotuzumab, osimertinib, panitumumab, selumetinib, sotorasib, trametinib, ulixertinib, vandetanib, or vemurafi Ni (vemurafenib). The method according to claim 91, wherein the additional MAPK pathway inhibitor is adagracib. The method according to claim 91, wherein the additional MAPK pathway inhibitor is cetuximab. The method according to claim 91, wherein the additional MAPK pathway inhibitor is dabrafenib. The method according to claim 91, wherein the additional MAPK pathway inhibitor is enrafenib. The method according to claim 91, wherein the additional MAPK pathway inhibitor is gilteritinib. The method of claim 91, wherein the additional MAPK pathway inhibitor is panitumumab. The method according to claim 91, wherein the additional MAPK pathway inhibitor is sotocoxib.

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