ERK1 / 2 inhibitor combination therapy

Abstract

The present invention relates generally to the combination of an ERK1 / 2 inhibitor with a B-Raf inhibitor, encorafenib or dabrafenib, for the treatment of cancer, specifically solid tumors.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 214,764, filed June 24, 2021, which is incorporated by reference in its entirety herein. [Background technology]

[0002] ERK1 and ERK2 (collectively "ERK1 / 2") are related protein-serine / threonine kinases that are involved in, among others, the Ras-Raf-MEK-ERK signaling pathway, which is sometimes referred to as the mitogen-activated protein kinase (MAPK) pathway. This pathway is believed to play a central role in regulating many fundamental 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 many tumor types, including lung, colon, pancreatic, renal, and ovarian cancers. Thus, substances that can attenuate activation may be of interest as viable treatments. Summary of the Invention

[0003] ERK1 / 2 is believed to be activated by MEK through phosphorylation of both threonine and tyrosine residues, namely Tyr204 / 187 and Thr202 / 185. Once activated, ERK1 / 2 catalyzes the phosphorylation of over 100 substrates at serine / threonine residues, activating both cytosolic and nuclear proteins associated with cell growth, proliferation, survival, angiogenesis, and differentiation, all of which are phenotypic hallmarks of cancer. Thus, it may be beneficial to target ERK1 and ERK2 in order to develop and use ERK1 / 2 inhibitors as a method to inhibit tumor growth.

[0004] In addition, ERK inhibitors may be useful in combination with other kinases, such as MAPK inhibitors. Recently, researchers have reported that dual inhibition of MEK and ERK with small molecule inhibitors was synergistic and acted to overcome acquired resistance to MEK inhibitors. See Hatzivassiliou et al., ERK Inhibition Overcomes Acquired Resistance to MEK Inhibition, Mol. Cancer Ther. 2012, 11, 1143-1154.

[0005] In addition to ERK1 / 2, the RAS-MAPK signaling pathway includes the Raf family of proteins. This family consists of three related kinases (A-Raf, B-Raf, and C-Raf) that function as downstream effectors of Ras. Among them, B-Raf is a serine / threonine protein kinase that activates the MAP kinase / ERK-signaling pathway. It is commonly known that constitutively active B-Raf mutations cause cancer by over-transmitting signaling that causes cells to proliferate. For example, activating mutations of the B-Raf V600E kinase occur in about 7% of human malignancies and about 50-60% of melanomas. The opportunity to target the signaling pathway from multiple angles and potentially improve the feedback loop upstream of Ras via ERK1 / 2 and BRAF offers the possibility of developing methods using combination therapies.

[0006] The present embodiments disclosed herein generally relate to compositions and methods relating to combination therapies for treating cancer that employ an ERK1 / 2 inhibitor in combination with a B-Raf inhibitor, encorafenib or dabrafenib, providing an unexpected degree of synergy.

[0007] In a first aspect, the disclosure provides a method of treating cancer in a subject in need thereof, the method comprising: (i) Compound 1

[0008] [ka] or a pharma- ceutically acceptable salt thereof, and (ii) a BRAF inhibitor that is encorafenib or dabrafenib to the subject in a therapeutically effective amount.

[0009] In a second aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising: (i) Compound 1

[0010] [ka] or a pharma- ceutically acceptable salt thereof; (ii) a BRAF inhibitor that is encorafenib or dabrafenib, and (iii) panitumumab to the subject in a therapeutically effective amount.

[0011] In a third aspect, the disclosure provides a method of treating cancer in a subject in need thereof, the method comprising: (i) Compound 1

[0012] [ka] or a pharma- ceutically acceptable salt thereof, and (ii) Panitumumab to the subject in a therapeutically effective amount.

[0013] In some embodiments, the BRAF inhibitor is encorafenib. In some embodiments, the encorafenib is administered in an amount of about 450 mg / day.

[0014] In some embodiments, the BRAF inhibitor is dabrafenib. In some embodiments, the dabrafenib is administered in an amount of about 150 mg / day.

[0015] In some embodiments, the method further comprises administering panitumumab. In some embodiments, panitumumab is administered in an amount of about 6 mg / kg.

[0016] In some embodiments, the pharma- ceutically acceptable salt of Compound 1 is a mandelate salt.

[0017] 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, an HRAS-driven cancer, or an NRAS-driven cancer.

[0018] In some embodiments, the cancer comprises at least one cancer cell driven by deregulated ERK.

[0019] In some embodiments, the cancer has at least one mutation in RAS. In some embodiments, the cancer has at least one mutation in RAF. In some embodiments, the cancer has at least one mutation in MEK.

[0020] In some embodiments, the cancer has a G12C KRAS 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 G12C 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.

[0021] In some embodiments, the cancer has a Q61R NRAS mutation.

[0022] In some embodiments, the cancer is a BRAF V600E or V600K mutant tumor.

[0023] In some embodiments, the cancer is a MAPKm / MAPKi naive pan-cancer.

[0024] In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of EGFR gene copy number gain, EGFR gene amplification, chromosome 7 polysomy, 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.

[0025] In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of L858R, exon 19 deletion, and T790M.

[0026] 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 tumor, thyroid cancer, colorectal cancer (CRC), or esophageal cancer.

[0027] In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is EGFR mutated NSCLC. In some embodiments, the NSCLC is KRAS G12C mutated NSCLC. In some embodiments, the NSCLC is KRAS G12D mutated NSCLC. In some embodiments, the NSCLC is KRAS G12S mutated NSCLC. In some embodiments, the NSCLC is KRAS G12V mutated NSCLC. In some embodiments, the NSCLC is KRAS G13D mutated NSCLC. In some embodiments, the NSCLC is KRAS Q61H mutated NSCLC. In some embodiments, the NSCLC is KRAS Q61K mutated NSCLC.

[0028] In some embodiments, the NSCLC is NRAS Q61R mutant NSCLC.

[0029] In some embodiments, the cancer is MAPKm / MAPKi naive NSCLC.

[0030] In some embodiments, the cancer is V600 NSCLC treated with BRAFi.

[0031] 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.

[0032] In some embodiments, the cancer is NRAS-treated Q61R NSCLC.

[0033] In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is MAPKm / MAPKi naive pancreatic cancer.

[0034] 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 a V600 melanoma treated with BRAFi.

[0035] In some embodiments, the cancer is a salivary gland tumor.

[0036] In some embodiments, the cancer is thyroid cancer.

[0037] In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the CRC is BRAF V600E CRC.

[0038] In some embodiments, the CRC is a KRAS mutated CRC. In some embodiments, the CRC is a KRAS G12C mutated CRC. In some embodiments, the CRC is a KRAS G12D mutated CRC. In some embodiments, the CRC is a KRAS G12S mutated CRC. In some embodiments, the CRC is a KRAS G12V mutated CRC. In some embodiments, the CRC is a KRAS G13D mutated CRC. In some embodiments, the CRC is a KRAS Q61H mutated CRC. In some embodiments, the CRC is a KRAS Q61K mutated CRC.

[0039] In some embodiments, the CRC is NRAS mutated CRC. In some embodiments, the CRC is NRAS Q61R mutated CRC.

[0040] In some embodiments, the cancer is esophageal cancer.

[0041] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 25 mg / day to about 300 mg / day. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered in an amount of 25 mg / day to 150 mg / day.

[0042] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 25 mg / day, about 50 mg / day, about 75 mg / day, about 100 mg / day, about 150 mg / day, about 175 mg / day, about 200 mg / day, about 225 mg / day, or about 250 mg / day.

[0043] In some embodiments, Compound 1, or a pharma- ceutically 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.

[0044] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered once a day (QD). In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered twice a day (BID). In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered three times a day (TID).

[0045] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered once a week. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered twice a week.

[0046] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 50 mg once per week to about 400 mg once per week. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 50 mg twice per week to about 400 mg twice per week.

[0047] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered for at least one 28-day cycle. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered on days 1, 8, 15, and 22 of the 28-day cycle. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered on days 1, 8, and 15 of the 28-day cycle.

[0048] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered for at least one 21-day cycle.

[0049] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered orally.

[0050] Citation 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. [Brief description of the drawings]

[0051] The novel features of the invention are set forth with particularity in the appended claims. The features and advantages of the present invention will be better understood by reference to the following detailed description that sets forth illustrative embodiments in which the principles of the invention are utilized and the accompanying drawings of which: [Figure 1A] 1 shows cell viability assay data for Compound 1 and Encorafenib in RKO cells. [Figure 1B] 1 shows cell viability assay data for Compound 1 and Encorafenib in HT-29 cells. [Figure 1C] 1 shows cell viability assay data for Compound 1 and Encorafenib in WiDr cells. [Figure 1D] 1 shows cell viability assay data for Compound 1 and Encorafenib in MDST8 cells. [Figure 1E] 1 shows cell viability assay data for Compound 1 and Encorafenib in LIM2405 cells. [Figure 2A] Shown is in vivo data for compound 1 plus encorafenib in the encorafenib-refractory BRAFV600E RKO CDX model. [Figure 2B] Shown is in vivo data for compound 1 plus encorafenib in the encorafenib-refractory BRAFV600E WiDr CDX model. [Figure 3A] Western blot gels illustrating phosphorylation of RSK (P-RSK) and ERK (P-ERK) using two BRAF V600E mutant CRC cell lines, RKO (top) and HT-29 (bottom), with encorafenib in combination with binimetinib. [Figure 3B] 1 shows a Western blot gel illustrating phosphorylation of RSK (P-RSK) and ERK (P-ERK) using two BRAF V600E mutant CRC cell lines, RKO (top) and HT-29 (bottom), with compound 1 in combination with encorafenib. [Figure 3C] Western blot gels illustrating phosphorylation of RSK (P-RSK) and ERK (P-ERK) using two BRAF V600E mutant CRC cell lines, RKO (top) and HT-29 (bottom), with LY3214996 in combination with encorafenib. [Figure 3D] Western blot gels illustrating phosphorylation of RSK (P-RSK) and ERK (P-ERK) using two BRAF V600E mutant CRC cell lines, RKO (top) and HT-29 (bottom), with ravoxartinib in combination with encorafenib. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0052] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to an "agent" includes a plurality of such agents, a reference to a "cell" includes a reference to one or more cells (or cells) and equivalents thereof known to those of skill in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, it is intended to include all combinations and subcombinations of the ranges and specific embodiments within the ranges. The term "about" when referring to a numerical value or numerical range means that the stated numerical value or numerical range is an approximation within experimental variation (or within statistical experimental error), and thus the numerical value or numerical range may vary, in some cases, between 1% and 15% of the stated numerical value or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude certain other embodiments, such as embodiments of any substance, composition, method, or process described herein, from "consisting of" or "consist essentially of" the recited features.

[0053] As used in this specification and the appended claims, unless specifically stated otherwise, the following terms have the following meanings.

[0054] As used herein, the term "therapeutics" refers to agents utilized to treat, inhibit, mitigate, prevent, or ameliorate an undesirable disease or disorder in a patient. In some embodiments, therapeutic agents, such as Compound 1, are directed to the treatment and / or amelioration of cancer.

[0055] "Administering" when used in conjunction with a therapeutic agent means administering the therapeutic agent systemically or locally, e.g., administering directly into or onto a target tissue, or administering the therapeutic agent to a patient so that the therapeutic agent positively affects the targeted tissue. Thus, as used herein, the term "administration" when used in conjunction with the compositions described herein can include, but is not limited to, providing the composition into or onto a target tissue, e.g., by oral administration, providing the composition throughout the patient's systemic life so that the therapeutic agent reaches the target tissue or cell. "Administering" the composition can be by injection, topical administration, oral administration, or other methods, alone or in combination with other known techniques.

[0056] As used herein, the term "animal" includes, but is not limited to, humans and non-human vertebrates such as wild, domestic, and livestock animals. As used herein, the terms "patient," "subject," and "individual" are intended to include living organisms in which a particular disease may occur 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 a particular embodiment, the primate, i.e., the subject, is a human. In a particular example, the human is an adult. In a particular example, the human is a child. In a further example, the human is under the age of 12. In a particular example, the human is an elderly person. In other examples, the human is over the age of 60. Other examples of subjects include laboratory animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The laboratory animal can be an animal model of a disorder, e.g., a transgenic mouse with a hypertensive condition.

[0057] By "pharmacologically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0058] The term "pharmaceutical composition" means a composition that includes at least one active ingredient, such that the composition can be studied to obtain a particular efficacious result in a mammal (such as, but not limited to, a human). Those of skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacy based on the needs of the artisan.

[0059] A "therapeutically effective amount" or "effective amount," as used herein, refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual, or human that a researcher, veterinarian, physician, or other clinician seeks to obtain, including one or more of the following: (1) disease prevention, e.g., preventing a disease, illness, or disorder in an individual who is predisposed to the disease, illness, or disorder but has not yet experienced or manifested a pathology or symptom of the disease, (2) disease inhibition, e.g., inhibiting the disease, illness, or disorder (i.e., inhibiting further development of the pathology and / or symptoms) in an individual who is experiencing or manifesting a pathology or symptom of the disease, illness, or disorder, and (3) disease amelioration, e.g., alleviating the disease, illness, or disorder (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or manifesting a pathology or symptom of the disease, illness, or disorder.

[0060] As used herein, the terms "treat," "treated," "treatment," or "treating" refer to both therapeutic treatment in some embodiments and preventative or prophylactic measures in other embodiments, the purpose of which is to prevent or slow (alleviate) an undesirable physiological disease, disorder, or condition, or to obtain a beneficial or desired clinical outcome. For purposes described herein, a beneficial or desired clinical outcome includes, but is not limited to, alleviation of symptoms, attenuation of the severity of the disease, disorder, or condition, stabilization (i.e., not worsening) of the disease, disorder, or condition, delay in onset or slowing of progression of the disease, disorder, or condition, improvement of the disease, disorder, or condition, and remission, whether detectable or undetectable (whether partial or total), or improvement or amelioration of the disease, disorder, or condition. Treatment includes eliciting a clinically significant response without undue side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Prophylactic benefits of treatment include preventing a disease, inhibiting the progression of a disease, stabilizing a disease, or reducing the likelihood of development of a disease. As used herein, "treat," "treated," "treatment" or "treating" includes, in some embodiments, prevention.

[0061] The term "substantially the same" as used herein refers to a powder X-ray diffraction pattern or a differential scanning calorimetry pattern that is not identical to that depicted herein, but falls within the limits of experimental error as would be considered by one of ordinary skill in the art.

[0062] compound 1 As used herein, (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

[0063] [ka] or a pharma- ceutically acceptable salt thereof is disclosed.

[0064] In some embodiments, the salt of Compound 1 is a mandelate salt. In some embodiments, the salt of Compound 1 is a benzenesulfonate salt. In some embodiments, the salt of Compound 1 is a hydrochloride salt. In some embodiments, the salt of Compound 1 is a p-toluenesulfonate salt.

[0065] Encorafenib Encorafenib

[0066] [ka] is a drug for the treatment of certain melanomas. Encorafenib is a small molecule BRAF inhibitor that targets a key enzyme in the MAPK signaling pathway. This pathway occurs in many different cancers, including melanoma and colorectal cancer. Encorafenib was approved by the FDA in June 2018 in combination with binimetinib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma. Encorafenib is marketed by Pfizer as Braftovi®.

[0067] Dabrafenib Dabrafenib

[0068] [ka] Dabrafenib is a treatment for cancers associated with mutated forms of the BRAF gene. Dabrafenib acts as an inhibitor of the associated B-Raf enzyme, which affects the control of cell proliferation. Dabrafenib has clinical activity with a manageable safety profile in phase I and II clinical trials in patients with BRAF(V600)-mutated, metastatic melanoma. Dabrafenib is marketed by Novartis as Tafinlar®.

[0069] Panitumumab Panitumumab, formerly known as ABX-EGF, is a fully human monoclonal antibody specific for the epidermal growth factor receptor (also known as the EGF receptor, EGFR, ErbB-1, and HER1 in humans).

[0070] Panitumumab is an epidermal growth factor receptor (EGFR) antagonist indicated for the treatment of wild-type KRAS (exon 2) metastatic colorectal cancer (mCRC) for first-line treatment following disease progression after conditioning with a chemotherapy containing fluoropyrimidine, oxaliplatin, and irinotecan, or in combination with FOLFOX as monotherapy, as determined by FDA-approved trials. Panitumumab is marketed by Amgen as Vectibix®.

[0071] Use in combination Provided herein is a method of treating cancer in a subject in need thereof, comprising: (i) Compound 1

[0072] [ka] or a pharma- ceutically acceptable salt thereof; (ii) a BRA inhibitor that is encorafenib or dabrafenib; The method includes administering to the subject a therapeutically effective amount of. In some embodiments, compound 1 is combined with encorafenib. In some embodiments, compound 1 is combined with dabrafenib.

[0073] Provided herein is a method of treating cancer in a subject in need thereof, comprising: (i) Compound 1

[0074] [ka] or a pharma- ceutically acceptable salt thereof; (ii) a BRA inhibitor, encorafenib; to said subject in a therapeutically effective amount.

[0075] Provided herein is a method of treating cancer in a subject in need thereof, comprising: (i) Compound 1

[0076] [ka] or a pharma- ceutically acceptable salt thereof; (ii) a BRAF inhibitor, dabrafenib; to said subject in a therapeutically effective amount.

[0077] Provided herein is a method of treating cancer in a subject in need thereof, comprising: (i) Compound 1

[0078] [ka] or a pharma- ceutically acceptable salt thereof; (ii) a BRAF inhibitor that is encorafenib or dabrafenib; and (iii) panitumumab to said subject in a therapeutically effective amount.

[0079] Provided herein is a method of treating cancer in a subject in need thereof, comprising: (i) Compound 1

[0080] [ka] or a pharma- ceutically acceptable salt thereof; (ii) a BRAF inhibitor, which is encorafenib; and (iii) panitumumab to said subject in a therapeutically effective amount.

[0081] Provided herein is a method of treating cancer in a subject in need thereof, comprising: (i) Compound 1

[0082] [ka] or a pharma- ceutically acceptable salt thereof; (ii) a BRAF inhibitor, which is dabrafenib; and (iii) panitumumab to said subject in a therapeutically effective amount.

[0083] Provided herein is a method of treating cancer in a subject in need thereof, comprising: (i) Compound 1

[0084] [ka] or a pharma- ceutically acceptable salt thereof; (iii) panitumumab to said subject in a therapeutically effective amount.

[0085] cancer Disclosed herein are methods of treating cancer using the combinations disclosed herein.

[0086] "Cancer" refers to any type of cancer, neoplasm or malignant tumor found in a mammal (e.g., human), including, but not limited to, leukemia, lymphoma, myeloma, carcinoma, and sarcoma. Examples of cancers that can be treated with the compounds or methods provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colon cancer, pancreatic cancer (such as pancreatic adenocarcinoma, PDAC), medulloblastoma, melanoma, cervical cancer, gastric cancer, ovarian cancer, lung cancer, head cancer, Hodgkin's disease, and non-Hodgkin's lymphoma. Examples of cancers that can be treated with the compounds or methods provided herein include cancers of the blood, thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, ovary, pancreas, rectum, stomach, and uterus. Further examples include thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, squamous cell carcinoma of the head and neck, invasive breast cancer, lung adenocarcinoma, squamous cell carcinoma of the lung, non-small cell lung cancer, mesothelioma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, precancerous skin lesion, testicular cancer, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical carcinoma, pancreatic endocrine or exocrine neoplasms, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, or prostate cancer.

[0087] In some embodiments, the cancer has a class 1 B-Raf mutation.

[0088] In some embodiments, the cancer has at least one of an EGFR mutation, a KRAS mutation, a BRAF (e.g., BRAF class 3) mutation, and / or an NF1 (e.g., loss of function) mutation.

[0089] In some embodiments, the mutant B-Raf comprises a V600 mutation. In some embodiments, the mutant B-Raf comprises a V600E mutation. 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.

[0090] In some embodiments, the cancer is a mitogen-activated protein kinase (MAPK) pathway-driven cancer.

[0091] In some embodiments, the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer. In some embodiments, the cancer comprises at least one cancer cell driven by deregulated ERK.

[0092] In some embodiments, the cancer has at least one mutation in RAS.

[0093] In some embodiments, the cancer has at least one mutation in RAF, hi some embodiments, the cancer has at least one mutation in MEK.

[0094] 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.

[0095] In some embodiments, the cancer is a BRAF V600E or V600K mutant tumor.

[0096] In some embodiments, the cancer is a MAPKm / MAPKi naive pan-cancer.

[0097] In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of EGFR gene copy number gain, EGFR gene amplification, chromosome 7 polysomy, 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.

[0098] In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is a solid tumor with progression or distant metastasis.

[0099] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, salivary gland tumor, thyroid cancer, colorectal cancer (CRC), or esophageal cancer.

[0100] In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is EGFR mutated NSCLC. In some embodiments, the NSCLC is KRAS G12C mutated NSCLC. In some embodiments, the NSCLC is KRAS G12D mutated NSCLC. In some embodiments, the NSCLC is KRAS G12S mutated NSCLC. In some embodiments, the NSCLC is KRAS G12V mutated NSCLC. In some embodiments, the NSCLC is KRAS G13D mutated NSCLC. In some embodiments, the NSCLC is KRAS Q61H mutated NSCLC. In some embodiments, the NSCLC is KRAS Q61K mutated NSCLC.

[0101] In some embodiments, the NSCLC is NRAS Q61R mutant NSCLC. In some embodiments, the cancer is MAPKm / MAPKi naive 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.

[0102] In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is MAPKm / MAPKi naive pancreatic cancer. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, PDAC is indicated by KRAS G12V mutation.

[0103] 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 a V600 melanoma treated with BRAFi.

[0104] In some embodiments, the cancer is a salivary gland tumor.

[0105] In some embodiments, the cancer is thyroid cancer.

[0106] In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the CRC is BRAF V600E CRC. In some embodiments, the CRC is KRAS mutant CRC.

[0107] In some embodiments, the CRC is a KRAS G12C mutated CRC. In some embodiments, the CRC is a KRAS G12D mutated CRC. In some embodiments, the CRC is a KRAS G12S mutated CRC. In some embodiments, the CRC is a KRAS G12V mutated CRC. In some embodiments, the CRC is a KRAS G13D mutated CRC. In some embodiments, the CRC is a KRAS Q61H mutated CRC. In some embodiments, the CRC is a KRAS Q61K mutated CRC. In some embodiments, the CRC is an NRAS mutated CRC. In some embodiments, the CRC is an NRAS Q61R mutated CRC.

[0108] In some embodiments, the cancer is esophageal cancer.

[0109] In some embodiments, the cancer is colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), cholangiocarcinoma, 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.

[0110] In some embodiments, the cancer is a gastrointestinal cancer. In some embodiments, the gastrointestinal cancer is anal cancer, bile duct cancer, colon cancer, rectal cancer, esophageal cancer, liver cancer, pancreatic cancer, small intestine cancer, or stomach cancer (gastric cancer).

[0111] In some embodiments, the cancer is colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), cholangiocarcinoma, 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.

[0112] In some embodiments, the cancer is a gastrointestinal cancer. In some embodiments, the gastrointestinal cancer is anal cancer, bile duct cancer, colon cancer, rectal cancer, esophageal cancer, liver cancer, pancreatic cancer, small intestine cancer, or stomach cancer (gastric cancer).

[0113] Administration In one aspect, the compositions described herein are used to treat the diseases and disorders described herein. Furthermore, a method for treating any of the diseases or disorders described herein in a subject in need of such treatment comprises administering to the subject a therapeutically effective amount of the composition.

[0114] The dosage of the compositions described herein can be determined by any suitable method. The maximum tolerated dose (MTD) and maximum response dose (MRD) of Compound 1 or its pharmaceutically acceptable salts can be determined through established animal and human experimental protocols, as well as the examples described herein. For example, the toxicity and therapeutic efficacy of Compound 1 or its pharmaceutically acceptable salts can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to those for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio of LD50 to ED50. The data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dosage of such compounds is preferably within a range of circulating concentrations that includes the ED50 with minimal toxicity. The dosage may vary within this range depending on the dosage form used and the route of administration utilized. Further relative dosages, expressed as a percentage of the maximum response or maximum tolerated dose, are readily available from the protocols.

[0115] In some embodiments, the amount of a given formulation containing Compound 1 or a pharma- ceutically acceptable salt thereof that corresponds to such an amount can be determined by the particular circumstances surrounding the case, including, for example, the particular formulation being administered, the type of liquid formulation, the disease being treated, and the subject or host being treated, although this will vary depending on factors such as the particular salt or form, the condition and its severity, the identity of the subject or host requiring treatment (e.g., age, weight, sex), and the like.

[0116] In some embodiments, encorafenib is administered in an amount of about 100 mg / day to 500 mg / day. In some embodiments, encorafenib is administered in an amount of about 450 mg / day.

[0117] In some embodiments, dabrafenib is administered in an amount of about 50 mg / day to 200 mg / day. In some embodiments, dabrafenib is administered in an amount of about 150 mg / day.

[0118] In some embodiments, panitumumab is administered in an amount of 6 mg / kg. In some embodiments, panitumumab is administered every 14 days. In some embodiments, panitumumab is administered as an intravenous infusion over 60 minutes (up to 1000 mg) or 90 minutes (greater than 1000 mg).

[0119] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered orally.

[0120] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 25 mg / day to about 300 mg / day.

[0121] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 25 mg / day to 150 mg / day.

[0122] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 25 mg / day, about 50 mg / day, about 75 mg / day, about 100 mg / day, about 150 mg / day, about 175 mg / day, about 200 mg / day, about 225 mg / day, or about 250 mg / day.

[0123] In some embodiments, Compound 1, or a pharma- ceutically 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.

[0124] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 300 mg.

[0125] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 250 mg.

[0126] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 200 mg.

[0127] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 150 mg.

[0128] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 100 mg.

[0129] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 25 mg to about 50 mg.

[0130] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 50 mg to about 300 mg.

[0131] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 50 mg to about 250 mg.

[0132] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 50 mg to about 200 mg.

[0133] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 50 mg to about 150 mg.

[0134] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 50 mg to about 100 mg.

[0135] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 100 mg to about 300 mg.

[0136] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 100 mg to about 250 mg.

[0137] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 100 mg to about 200 mg.

[0138] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 100 mg to about 150 mg.

[0139] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 150 mg to about 300 mg.

[0140] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 150 mg to about 250 mg.

[0141] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 150 mg to about 200 mg.

[0142] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 175 mg to about 300 mg.

[0143] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 175 mg to about 250 mg.

[0144] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 175 mg to about 200 mg.

[0145] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 200 mg to about 300 mg.

[0146] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 200 mg to about 250 mg.

[0147] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 225 mg to about 300 mg.

[0148] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily, once weekly (BID-QW) in an amount of about 225 mg to about 250 mg.

[0149] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered once a day, once a week, in an amount of about 250 mg.

[0150] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 25 mg, 30 mg, 40 mg, 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 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.

[0151] Administration The administration of compound 1 or its pharmaceutically acceptable salt and combination partner described herein is carried out in the dosage amounts described herein or other dosage levels and compositions determined and contemplated by a physician. In certain embodiments, compound 1 or its pharmaceutically acceptable salt is administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, compound 1 or its pharmaceutically acceptable salt and combination partner described herein are administered to a patient already suffering from a disease in an amount sufficient to cure the disease or at least partially suppress or ameliorate symptoms. The amount effective for this use depends on the age of the patient, the severity of the disease, previous treatments, the patient's health condition, weight, and response to the composition, as well as the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation clinical trials.

[0152] In prophylactic applications, the compositions described herein are administered to patients who are susceptible to or otherwise at risk of developing a particular disease, such as cancer. Such an amount is defined as a "prophylactically effective amount or dose." In this use, the exact amount also depends on the patient's age, health, weight, etc. When used in patients, the effective amount for this use will depend on the risk or susceptibility of developing a particular disease, previous treatments, the patient's health and response to the composition, and the judgment of the treating physician.

[0153] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compositions described herein is chronic, i.e., for an extended period of time, including the entire life of the patient, to improve or otherwise control or limit the symptoms of the patient's disease. In other embodiments, administration of the compositions is continued until complete or partial response of the disease.

[0154] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof described herein and combination partners are administered once a day. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof described herein and combination partners are administered twice a day. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof described herein and combination partners are administered three times a day.

[0155] In some embodiments, encorafenib is administered in an amount of about 450 mg / day. In some embodiments, encorafenib is administered once daily. In some embodiments, encorafenib is administered twice daily. In some embodiments, encorafenib is administered three times daily.

[0156] In some embodiments, dabrafenib is administered once daily. In some embodiments, dabrafenib is administered twice daily. In some embodiments, dabrafenib is administered three times daily.

[0157] In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered to a subject in a fasting state. Fasting state refers to a subject who has not consumed food or has fasted for a 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 pharma- ceutically acceptable salt thereof as described herein is administered to a subject in a fasting state for at least 8 hours. In other embodiments, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered to a subject in a fasting state for at least 10 hours. In still other embodiments, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered to a subject in a fasting state for at least 12 hours. In other embodiments, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered to a subject who has fasted overnight.

[0158] In other embodiments, compound 1 or its pharmaceutically acceptable salt and combination partner described herein are administered to a subject in a fed state. Fed state refers to a subject who has consumed food or eaten a meal. In certain embodiments, the composition is administered to a subject in a fed state 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 hours after a meal. In certain examples, compound 1 or its pharmaceutically acceptable salt is administered to a subject in a fed state 30 minutes after a meal. In other examples, compound 1 or its pharmaceutically acceptable salt and combination partner described herein are administered to a subject in a fed state 1 hour after a meal. In still further embodiments, compound 1 or its pharmaceutically acceptable salt is administered to a subject with food.

[0159] The length of the treatment cycle depends on the treatment being administered. In some embodiments, the length of the treatment cycle ranges from 2 to 6 weeks. In some embodiments, the length of the treatment cycle ranges from 3 to 6 weeks. In some embodiments, the length of the treatment cycle ranges from 3 to 4 weeks. In some embodiments, the length of the treatment cycle is 3 weeks (i.e., 21 days). In some embodiments, the length of the treatment cycle is 4 weeks (28 days). In some embodiments, the length of the treatment cycle is 5 weeks (35 days). In some embodiments, the length of the treatment cycle is 56 days. In some embodiments, the treatment cycle lasts 1, 2, 3, 4, or 5 weeks. In some embodiments, the treatment cycle lasts 3 weeks. In some embodiments, the treatment cycle lasts 4 weeks. In some embodiments, the treatment cycle lasts 5 weeks. The number of treatment doses scheduled within each cycle also varies depending on the drug being administered. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and the combination partner are administered in a 21-day cycle.

[0160] In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered over multiple 21-day cycles. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered over at least one 21-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered over at least two 21-day cycles. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered over at least three 21-day cycles. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered over at least four 21-day cycles. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered over at least five 21-day cycles. In some embodiments of the methods of treating cancer, Compound 1, or a pharma- ceutically acceptable salt thereof, and a combination partner described herein are administered for at least six 21-day cycles.

[0161] In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered in a 28-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered over multiple 28-day cycles. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered over at least one 28-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered over at least two 28-day cycles. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered over at least three 28-day cycles. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered over at least four 28-day cycles. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered for at least five 28-day cycles. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered for at least six 28-day cycles.

[0162] In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically acceptable salt thereof is administered on days 1-28 of each 28 day cycle.

[0163] In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof is administered twice daily on day 1 of a 28-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof is administered twice daily on day 8 of a 28-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof is administered twice daily on day 15 of a 28-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof is administered twice daily on day 22 of a 28-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof is not administered twice daily on day 22 of a 28-day cycle.

[0164] In some embodiments of the methods of treating cancer, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily on days 1, 8, and 15 of a 28 day cycle.

[0165] In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof is not administered on days 2-7, 9-14, 16-21, or 23-28 of a 28-day cycle.

[0166] In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered in a 35-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered over multiple 35-day cycles. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered over at least one 35-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered over at least two 35-day cycles. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered over at least three 35-day cycles. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered over at least four 35-day cycles. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered for at least five 35-day cycles. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof as described herein and combination partner are administered for at least six 35-day cycles.

[0167] In some embodiments of the method of treating cancer, Compound 1 or a pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically acceptable salt thereof is administered on days 1 through 28 of each 35-day cycle. In some embodiments of the method of treating cancer, Compound 1 or a pharma- ceutically acceptable salt thereof is administered on days 1 through 35 of each 35-day cycle.

[0168] In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof is administered twice daily on day 1 of a 35-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof is administered twice daily on day 8 of a 35-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof is administered twice daily on day 15 of a 35-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof is administered twice daily on day 22 of a 35-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof is administered twice daily on day 29 of a 35-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof is not administered twice daily on day 29 of a 35-day cycle.

[0169] In some embodiments of the methods of treating cancer, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered twice daily on days 1, 8, 15, and 22 of a 35-day cycle.

[0170] In some embodiments of the methods of treating cancer, compound 1 or a pharma- ceutically acceptable salt thereof is not administered on days 2-7, 9-14, 16-21, 23-28, and 30-35 of a 28-day cycle.

[0171] Working Example Example 1. In Vitro Survival Assay Cells were plated at a density of 1,000 (RKO, HT-29, WiDr, MDST8) or 5,000 (LIM2405) cells per well in 96-well plates (Corning #3903). Cells were allowed to adhere overnight and compounds were added in a matrix format using an HP Tecan D300e digital dispenser (Switzerland). Compound 1 was added from bottom to top of the plate (rows B-H) in a 1:3 dilution series (8-point dose response) and encorafenib was added from right to left (columns 2-11) in a 1:3 dilution series (11-point dose response). Final DMSO concentrations were normalized across the plate. Cell viability was assessed 5 days after treatment using Promega CellTiter-Glo 3D Cell Viability Assay reagent (#G9683) according to the manufacturer's protocol. Luminescence was assessed using a SpectraMax M3e (Molecular Devices, San Jose, CA) and the effect of the combination was assessed using the BLISS model in Combenefit software (Cancer Research UK Cambridge Institute).

[0172] [Table 1]

[0173] RKO cells (Figure 1A), HT-29 cells (Figure 1B), WiDr cells (Figure 1C), MDST8 cells (Figure 1D), and LIM2405 (Figure 1E) were treated with a dilution matrix of compound 1 versus encorafenib in a 3D cell viability assay. Cell viability, expressed as the percentage of viable cells relative to vehicle-treated controls, is shown within the matrix. Compound 1 and encorafenib inhibit BRAF V600E The combination effect has been demonstrated in vitro in cell lines carrying the mutation.

[0174] Example 2. In-Vivo Assay Vehicle / Control Vehicle / control, 0.5% methylcellulose and 0.1% Tween 80 or 100 mM acetic acid in deionized water adjusted to pH 4.8-5.0, was prepared and stored under ambient conditions throughout the study period.

[0175] Test substance composition The test article, Compound 1, was prepared fresh weekly in a vehicle of 0.5% methylcellulose and 0.1% Tween 80 and stored under ambient conditions. The co-agent, encorafenib, was prepared fresh weekly in a vehicle of 0.5% CMC and 0.5% Tween 80 and stored at 2-8°C.

[0176] animal Female Balb / c nude mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Mice were housed in a specific pathogen-free (SPF) environment in the animal facility and were allowed to acclimate to the new environment for at least 3 days prior to the start of any experiment. Mice were 6-8 weeks old at the time of transplantation.

[0177] All procedures related to the handling, care, and treatment of animals in this study were performed in accordance with protocols and guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of GenenDesign and WuXi AppTec. The animal facility and program are operated under the standards of the Guide for the Care and Use of Laboratory Animals (NRC, 2011) and are accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Specifically, all parts of this study performed at GenenDesign and WuXi AppTec adhered to the study protocol and applicable standard operating procedures (SOPs) reviewed and approved by the IACUC.

[0178] Preparation of xenograft models RKO, BRAF V600EThe RKO cell line is a human CRC tumor cell line carrying a mutation. The RKO cell line was purchased from the American Type Culture Collection (ATCC® CRL-2577™). RKO cells were cultured at 37°C in an atmosphere of 5% CO2 in air in medium containing EMEM supplemented with 10% fetal bovine serum (FBS) supplemented with non-essential amino acids. 2 × 10 6 RKO cells in 200 μL of cell suspension containing 10 cells were implanted subcutaneously into mice. Tumor volumes averaged 200 mm 3 When the tumor-bearing mice reached 100% CI, they were randomized into different groups with 8 mice in each group and treatment was started on the day of randomization.

[0179] WiDr is a BRAF V600E The WiDr cell line is a human CRC tumor cell line carrying a mutation. The WiDr cell line was purchased from the European Collection of Authenticated Cell Cultures (ECACC, 85111501). WiDr cells were cultured at 37°C in an atmosphere of 5% CO2 in air in medium containing EMEM supplemented with 10% fetal bovine serum (FBS), 2 mM glutamine, and 1% non-essential amino acids (NEAAs) (EBSS). 5 × 10 6 WiDr cells in 200 μL of cell suspension containing 10 cells were implanted subcutaneously in mice. Tumor volumes averaged 190 mm 3 When the tumor-bearing mice reached 100% CI, they were randomized into different groups with 8 mice in each group and treatment was started on the day of randomization.

[0180] treatment In the monotherapy treatment groups, mice were administered vehicle control solution, compound 1, or encorafenib by oral administration. Combinations containing compound 1 and encorafenib were administered to mice by oral administration. The dose was 5 mL / kg for each compound, with an interval of 8 hours for the BID regimen. In the combination of compound 1 and encorafenib, compound 1 was administered 1 hour after encorafenib administration. In addition to regular food and water supplies, DietGel (ClearH2O, US) was added to cages in which at least two mice showed BWL >10%. The study was completed at the end of 4 weeks of treatment or when tumor volumes in the vehicle control group reached 2,000 mm 3 It ended when it reached

[0181] result Compound 1 and encorafenib are candidates for the treatment of encorafenib-refractory BRAF V600E The combination efficacy is demonstrated in vivo in the CDX model. Tumor growth curves in the RKO model in Fig. 2A and the WiDr CDX model in Fig. 2B.

[0182] Example 3. Treatment of BRAF V600E Mutated CRC Cell Lines (RKO and HT-29) with Encorafenib in Combination with MEK and ERK Inhibitors Treatment of two BRAF V600E mutant CRC cell lines, RKO and HT-29, with encorafenib in combination with the MEK inhibitor binimetinib, the ERK inhibitor compound 1, the ERK inhibitor LY3214996, and the ERK inhibitor lavoxertinib. Western blot gels show phosphorylation of RSK (P-RSK) and ERK (P-ERK). Higher levels of phosphorylation are represented by higher (i.e., darker) band intensity. Total GAPDH protein (GAPDH) serves as a loading control. ERK signaling activity is represented by the phosphorylation status of RSK (P-RSK), a downstream target of ERK. Column values ​​indicate compound incubation times up to 72 h. Figure 3A-D.

[0183] In BRAF V600E colon cell lines, compound 1 blocked the feedback reactivation of the RAS / MAPK pathway observed with MEK or other ERK and BRAF inhibitor combinations at one-tenth the concentrations used for MEK and other ERK inhibitors. These results further support that inhibition of ERK with compound 1, alone or in combination, may lead to a more complete and sustained blockade of the RAS / MAPK pathway compared to other inhibitors of ERK or MEK.

Claims

1. Use in the manufacture of a medicament for treating cancer in a subject in need of cancer treatment, (i) Compound 1 【Chemical 1】 or a pharmaceutically acceptable salt thereof, and (ii) a BRAF inhibitor which is encorafenib or dabrafenib wherein the medicament is administered in a therapeutically effective amount to the subject in need of cancer treatment.

2. The use according to claim 1, wherein the medicament further comprises panitumumab.

3. The use according to claim 1, wherein the pharmaceutically acceptable salt of Compound 1 is mandelate.

4. The use according to claim 1, wherein the cancer is a mitogen-activated protein kinase (MAPK) pathway-driven cancer.

5. The use according to claim 1, wherein the cancer is a BRAF-driven cancer, an HRAS-driven cancer, or an NRAS-driven cancer.

6. The use according to claim 1, wherein the cancer comprises at least one cancer cell driven by deregulated ERK.

7. The use according to claim 1, wherein the cancer has at least one mutation in RAS, RAF, or MEK.

8. The use according to claim 1, wherein the cancer has a G12C KRAS mutation, a G12D KRAS mutation, a G12S KRAS mutation, a G12V KRAS mutation, a G13D KRAS mutation, a Q16H KRAS mutation, a Q16K KRAS mutation, or a Q61R NRAS mutation.

9. The use according to claim 1, wherein the cancer is a BRAF V600E or V600K mutant tumor.

10. The use according to claim 1, wherein the cancer is MAPKm / MAPKi-naïve pan-cancer.

11. The use according to claim 1, wherein the cancer comprises one or more EGFR mutations selected from the group consisting of EGFR gene copy number increase, EGFR gene amplification, polysomy of chromosome 7, EGFR L858R, EGFR exon 19 deletion, EGFR exon 19 insertion, EGFR L861Q, EGFR G719C, EGFR G719S, EGFR G719A, EGFR V765A, EGFR T783A, EGFR exon 20 insertion, EGFR splice variants, EGFR A289D, EGFR A289T, EGFR A289V, EGFR G598A, EGFR G598V, EGFR T790M, and EGFR C797S.

12. The use according to claim 1, wherein the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, salivary gland tumor, thyroid cancer, colorectal cancer (CRC), or esophageal cancer.

13. The use according to claim 1, wherein the cancer is non-small cell lung cancer (NSCLC).

14. The use according to claim 13, wherein the NSCLC is EGFR mutant NSCLC, KRAS G12C, G12D, G12S, G12V, G13D, Q61H, or Q61K mutant NSCLC, NRAS Q61R mutant NSCLC, MAPKm / MAPKi-naïve NSCLC, V600 NSCLC treated with BRAFi, G12C, G12D, G12S, G12V, G13D, Q61H, or Q61K NSCLC treated with KRAS, or Q61R NSCLC treated with NRAS.

15. The use according to claim 1, wherein the cancer is pancreatic cancer.

16. The use according to claim 15, wherein the cancer is MAPKm / MAPKi-naïve pancreatic cancer.

17. The use according to claim 1, wherein the cancer is melanoma.

18. The use according to claim 17, wherein the melanoma is BRAF V600E or V600K mutant tumor or V600 melanoma treated with BRAFi.

19. The use according to claim 1, wherein the cancer is salivary gland tumor.

20. The use according to claim 1, wherein the cancer is thyroid cancer.

21. The use according to claim 1, wherein the cancer is colorectal cancer (CRC).

22. The use according to claim 21, wherein the CRC is BRAF V600E CRC, KRAS mutant CRC, KRAS G12C, G12D, G12S, G12V, G13D, Q61H, or Q61K mutant CRC, or NRAS Q61R mutant CRC.

23. The use according to claim 1, wherein the cancer is esophageal cancer.

24. The use according to claim 1, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg / day to about 300 mg / day.

25. The use according to claim 1, wherein compound 1, or a pharmaceutically acceptable salt, is administered once daily (QD), twice daily (BID), three times daily (TID), or once a week.

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