Combination of RAF and MEK inhibitors

Abstract

The present specification describes methods and compositions for treating subjects suffering from cancer.In some aspects, the present specification describes a method for treating patients suffering from cancer, comprising administering to the subject (i) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamide) ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (compound A) or its pharmaceutically acceptable salt; and (ii) the MEK inhibitor provided herein.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 151,425, filed February 19, 2021, and U.S. Provisional Patent Application No. 63 / 173,158, filed April 9, 2021, the contents of each of which are incorporated by reference in their entirety herein. [Background technology]

[0002] 2. Background of the Invention In 2018, there were 18.1 million new cases of cancer and 9.5 million cancer-related deaths worldwide. By 2040, the number of new cancer cases and cancer-related deaths per year is expected to increase to 29.5 million and 16.4 million, respectively. In 2020, there were an estimated 1.8 million new cancer cases diagnosed and 606,520 cancer deaths in the United States. Cancer remains the second leading cause of death in the United States, accounting for nearly 1 in 24 deaths. Medical advances have improved cancer survival rates, but new effective treatments remain needed. Summary of the Invention [Means for solving the problem]

[0003] Summary of the Invention In certain aspects, the present disclosure provides a method of treating a subject suffering from cancer, comprising administering to the subject: (i) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharma- ceutically acceptable salt thereof; and (ii) a MEK inhibitor that is pimasertib or a pharma- ceutically acceptable salt thereof; administering The method provides a method in which Compound A or a pharma- ceutically acceptable salt thereof and pimasertib or a pharma- ceutically acceptable salt thereof are administered in a therapeutically effective amount to treat cancer. In some embodiments, Compound A or a pharma- ceutically acceptable salt thereof is administered to a subject in an amount of about 50 mg to about 800 mg per week, or about 100 mg / m per week. 2 ~about 600mg / m 2 and pimasertib or a pharma- ceutical acceptable salt thereof is administered to the subject in an amount of about 5 mg to about 150 mg per day. In some embodiments, Compound A or a pharma- ceutical acceptable salt thereof is administered to the subject in an amount of about 200 mg to about 600 mg per week, or about 140 mg / m per week. 2 ~about 420mg / m 2and pimasertib or a pharma- ceutically acceptable salt thereof is administered to the subject in an amount of about 10 mg to about 60 mg per day. In some embodiments, the method includes administering Compound A. In some embodiments, the method includes administering pimasertib HCl. In some embodiments, the subject has been identified as having one or more of the following fusions: AGK:BRAF, BRAF-AGAP3, AGAP3:BRAF, TNS3:BRAF, or KIAA1549:BRAF. In some embodiments, the method includes identifying a subject having one or more of the following fusions: AGK:BRAF, BRAF-AGAP3, AGAP3:BRAF, TNS3:BRAF, or KIAA1549:BRAF. In some embodiments, the subject has been identified as having a mutation selected from PIK3CA H1047R, KRAS G12C, KRAS G12D, and KRAS G12S. In some embodiments, the method comprises identifying a subject having a mutation selected from KRAS G12C, KRAS G12D, and KRAS G12S. In some embodiments, the method comprises identifying a subject having a mutation selected from KRAS G12C, KRAS G12D, and KRAS G12S. In some embodiments, the subject is identified as having a BRAF mutation selected from BRAF G464V, BRAF indel, BRAF L597R, BRAF G466V, BRAF G469A, BRAF K601E, and BRAF G469R. In some embodiments, the method comprises identifying a subject having a BRAF mutation selected from BRAF G464V, BRAF indel, BRAF L597R, BRAF G466V, BRAF G469A, BRAF K601E, and BRAF G469R. In some embodiments, the cancer is a recurrent, progressive, or refractory solid tumor associated with a mitogen-activated protein kinase (MAPK) pathway abnormality.

[0004] In another aspect, the disclosure provides a method of treating a subject suffering from cancer, comprising administering to the subject: (i) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharma- ceutically acceptable salt thereof; and (ii) a MEK inhibitor or a pharma- ceutically acceptable salt thereof administering the total amount of compound A, or a pharma- ceutically acceptable salt thereof, and the MEK inhibitor, or a pharma- ceutically acceptable salt thereof, is therapeutically effective in treating cancer; Compound A or a pharma- ceutically acceptable salt thereof is administered to a subject in an amount of about 50 mg to about 800 mg per week, or about 100 mg / m per week. 2 ~about 600mg / m 2 In some embodiments, the MAPK pathway abnormality is selected from one or more of BRAF mutation or fusion and KRAS mutation or fusion. In some embodiments, the BRAF mutation or fusion and KRAS mutation or fusion are selected from the following gene mutations or gene fusions: BRAF V600E, BRAF G464V, BRAF G466V, BRAF G464V, BRAF K601E, KRAS Q61, KRAS G12S, BRAF G464V, BRAF indel, BRAF L597R, BRAF G466V, BRAF G469A, BRAF K601E, BRAF G469R, KRAS G12C, KRAS G12D, KRAS G12S, AGK:BRAF, BRAF-AGAP3, AGAP3:BRAF, TNS3:BRAF, or KIAA1549:BRAF. In some embodiments, the MEK inhibitor is cobimetinib, selumetinib, pimasertib, PD0325901, refametinib, binimetinib, BI-847325, trametinib, GDC-0623, G-573, CH5126766, CIP-137401, and [ka] In some embodiments, the MEK inhibitor is selected from compounds having the structure: In some embodiments, the MEK inhibitor is selumetinib, binimetinib, or pimasertib. In some embodiments, the MEK inhibitor is pimasertib. In some embodiments, the cancer has one or more of the following mutations: RAS positive mutation, RAF positive mutation, MEK positive mutation, and ERK positive mutation. In some embodiments, the cancer has a RAS or RAF alteration. In some embodiments, the cancer has an NRAS mutation, a KRAS mutation, or an HRAS mutation. In some embodiments, the cancer has a BRAF mutation, a BRAF fusion, or a CRAF fusion. In some embodiments, the BRAF mutation is a non-V600 BRAF mutation. In some embodiments, the BRAF mutation is a V600 BRAF mutation. In some embodiments, the cancer has a genomic alteration that results in a dependency on signaling through the MAPK pathway. In some embodiments, the method further comprises identifying a subject suffering from cancer, the cancer having one or more of RAF alterations, RAS mutations, NF-1 mutations, or genomic alterations that result in dependency on signaling through the MAPK pathway. In some embodiments, before administering compound A or a pharmaceutically acceptable salt thereof or a MEK inhibitor, the subject's cancer sample is subjected to BRAF, KRAS, CRAF, HRAS, NF-1 and / or NRAS mutation testing. In some embodiments, before administering compound A or a pharmaceutically acceptable salt thereof or a MEK inhibitor, the subject's cancer sample is subjected to genomic testing, and the genomic testing demonstrates that the genomic alterations create dependency on MPAK signaling. In some embodiments, the patient is diagnosed with a histologically confirmed non-hematologic tumor. In some embodiments, the cancer has a mutation in NF-1 that results in NF-1 loss of function.In some embodiments, the subject has one or more of the following fusions: KIAA1549:BRAF, STARD3NL:BRAF, BCAS1:BRAF, KHDRBS2:BRAF, CCDC6:BRAF, FAM131B:BRAF, SRGAP:BRAF, CLCN6:BRAF, GNAI1:BRAF, MRKN1:BRAF, GIT2:BRAF, GTF21:BRAF, FXR1:BRAF, RNF130:BRAF, BRAF:MACF1, TMEM106B:BRAF, PPC1CC:BRAF, CUX1:B The subject is identified as having one or more of the following fusions: RAF, AGK:BRAF, AGAP3:BRAF, TNS3:BRAF, TARDBP:BRAF, ARMC10:BRAF, CUL1:BRAF, TRIM24:BRAF, AKAP9:BRAF, FKBP15:BRAF, SKAP2:BRAF, ZKSCAN1:BRAF, KLHL7:BRAF, SEPT3:BRAF, SRGAP3:RAF1, QK1:RAF1, FYCO:RAF1, ATG7:RAF1, or NFIA:RAF1. In some embodiments, the subject is identified as having one or more of the following fusions: AGK:BRAF, AGAP3:BRAF, TNS3:BRAF, or KIAA1549:BRAF. In some embodiments, the subject is identified as having AGAP3:BRAF fusion. In some embodiments, the subject is identified as having KIAA1549:BRAF fusion. In some embodiments, the non-V600 BRAF mutation is selected from V600E, G469A, G464V, G466V, K601E, G469R, and L597R. In some embodiments, the non-V600 BRAF mutation is selected from V600E, G464A, G464V, K601E, and G469R. In some embodiments, the non-V600 BRAF mutation is selected from G464V, K601E, G469A, and G466V. In some embodiments, the cancer has a KRAS mutation. In some embodiments, the KRAS mutation is selected from KRAS G12C, KRAS G12V, KRAS G12D, KRAS Q61K, KRAS Q61H, KRAS G13D, and KRAS G12S.In some embodiments, the KRAS mutation is selected from KRAS G12C, KRAS G12D, KRAS G13D, and KRAS G12S. In some embodiments, Compound A is administered in an amount of about 100 mg to about 700 mg per week. In some embodiments, Compound A is administered at about 200 mg, about 400 mg, or about 600 mg per week. In some embodiments, the subject is at least 18 years old. In some embodiments, Compound A is administered at about 100 mg / m per week. 2 to about 500 mg / m 2 In some embodiments, Compound A is administered in an amount between about 140 mg / m per week. 2 , about 280mg / m 2 , or about 420 mg / m 2In some embodiments, the subject is 12, 13, 14, 15, 16, or 17 years old. In some embodiments, compound A is administered once a week. In some embodiments, the MEK inhibitor or a pharma- ceutically acceptable salt thereof is administered in an amount of about 10 mg to about 150 mg per day. In some embodiments, the MEK inhibitor or a pharma- ceutically acceptable salt thereof is administered in an amount between about 5 mg and about 75 mg twice a day. In some embodiments, the MEK inhibitor or a pharma- ceutically acceptable salt thereof is administered at about 15 mg, about 30 mg, about 45 mg, or about 60 mg twice a day. In some embodiments, the subject has not previously been administered a pan-RAF treatment. In some embodiments, the subject has not previously been administered a cytochrome P450 CYP3A4 inhibitor, a cytochrome P450 CYP2C19 inhibitor, a P450 CYP3A4 inducer, or a substrate of CYP2C9. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is an advanced solid tumor. In some embodiments, the cancer is selected from lung cancer, colorectal cancer, pancreatic cancer, skin cancer, glioma, non-glioma brain cancer, osteosarcoma, gastrointestinal cancer, breast cancer, thyroid cancer, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and multiple myeloma (MM). In some embodiments, the cancer is lung cancer, melanoma, cervix cancer, breast cancer, colorectal cancer, or pancreatic cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is a recurrent or advanced solid tumor. In some embodiments, the subject has undergone at least one prior treatment considered standard of care prior to administration of Compound A or a pharmacologic salt thereof or a MEK inhibitor. In some embodiments, the prior treatment is a systemic treatment. In some embodiments, the prior treatment is chemotherapy, hormonal therapy, immunotherapy, or radiation therapy. In some embodiments, the subject has not undergone any previous cancer treatment.In some embodiments, the weekly dose of Compound A or a pharma- ceutically acceptable salt thereof required to achieve an IC80 of pERK inhibition as measured by PMA-induced peripheral blood mononuclear cells (PBMCs) is at least about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, or about 50% less than the weekly dose of Compound A or a pharma- ceutically acceptable salt thereof required to achieve the same IC80 of pERK inhibition as measured by monotherapy. In some embodiments, the weekly dose of the MEK inhibitor or a pharma- ceutically acceptable salt thereof required to achieve an IC80 of pERK inhibition as measured by PMA-induced peripheral blood mononuclear cells (PBMCs) is at least about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, or about 50% less than the weekly dose of the MEK inhibitor or a pharma- ceutically acceptable salt thereof required to achieve the same IC80 of pERK inhibition as measured by monotherapy.

[0005] In another aspect, the disclosure provides a method of treating a subject suffering from cancer, comprising administering to the subject: (i) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharma- ceutically acceptable salt thereof; and (ii) a MEK inhibitor or a pharma- ceutically acceptable salt thereof administering the total amount of compound A, or a pharma- ceutically acceptable salt thereof, and the MEK inhibitor, or a pharma- ceutically acceptable salt thereof, is therapeutically effective in treating cancer; The method is provided, wherein the subject has one or more mitogen-activated protein kinase (MAPK) pathway abnormalities.In some embodiments, the MAPK pathway abnormalities are selected from one or more BRAF mutations or fusions and KRAS mutations or fusions.In some embodiments, the BRAF mutations or fusions and KRAS mutations or fusions are selected from the following gene mutations or gene fusions: BRAF V600E, BRAF G464V, BRAF G466V, BRAF G464V, BRAF K601E, KRAS Q61, KRAS G12S, BRAF G464V, BRAF indel, BRAF L597R, BRAF G466V, BRAF G469A, BRAF K601E, BRAF G469R, KRAS G12C, KRAS G12D, KRAS G12S, AGK:BRAF, BRAF-AGAP3, AGAP3:BRAF, TNS3:BRAF, or KIAA1549:BRAF. In some embodiments, the MEK inhibitor is cobimetinib, selumetinib, pimasertib, PD0325901, refametinib, binimetinib, BI-847325, trametinib, GDC-0623, G-573, CH5126766, CIP-137401, and [ka] In some embodiments, the MEK inhibitor is selected from compounds having the structure: In some embodiments, the MEK inhibitor is selumetinib, binimetinib, or pimasertib. In some embodiments, the MEK inhibitor is pimasertib. In some embodiments, the cancer has one or more of the following mutations: RAS positive mutation, RAF positive mutation, MEK positive mutation, and ERK positive mutation. In some embodiments, the cancer has a RAS or RAF alteration. In some embodiments, the cancer has an NRAS mutation, a KRAS mutation, or an HRAS mutation. In some embodiments, the cancer has a BRAF mutation, a BRAF fusion, or a CRAF fusion. In some embodiments, the BRAF mutation is a non-V600 BRAF mutation. In some embodiments, the BRAF mutation is a V600 BRAF mutation. In some embodiments, the cancer has a genomic alteration that results in a dependency on signaling through the MAPK pathway. In some embodiments, the method further comprises identifying a subject suffering from cancer, the cancer having one or more of RAF alterations, RAS mutations, NF-1 mutations, or genomic alterations that result in dependency on signaling through the MAPK pathway. In some embodiments, before administering compound A or a pharmaceutically acceptable salt thereof or a MEK inhibitor, the subject's cancer sample is subjected to BRAF, KRAS, CRAF, HRAS, NF-1 and / or NRAS mutation testing. In some embodiments, before administering compound A or a pharmaceutically acceptable salt thereof or a MEK inhibitor, the subject's cancer sample is subjected to genomic testing, which demonstrates that the genomic alterations create dependency on MPAK signaling. In some embodiments, the patient is diagnosed with a histologically confirmed non-hematologic tumor. In some embodiments, the cancer has a mutation in NF-1 that results in NF-1 loss of function.In some embodiments, the subject has one or more of the following fusions: KIAA1549:BRAF, STARD3NL:BRAF, BCAS1:BRAF, KHDRBS2:BRAF, CCDC6:BRAF, FAM131B:BRAF, SRGAP:BRAF, CLCN6:BRAF, GNAI1:BRAF, MRKN1:BRAF, GIT2:BRAF, GTF21:BRAF, FXR1:BRAF, RNF130:BRAF, BRAF:MACF1, TMEM106B:BRAF, PPC1CC:BRAF, CUX1:B The subject is identified as having one or more of the following fusions: RAF, AGK:BRAF, AGAP3:BRAF, TNS3:BRAF, TARDBP:BRAF, ARMC10:BRAF, CUL1:BRAF, TRIM24:BRAF, AKAP9:BRAF, FKBP15:BRAF, SKAP2:BRAF, ZKSCAN1:BRAF, KLHL7:BRAF, SEPT3:BRAF, SRGAP3:RAF1, QK1:RAF1, FYCO:RAF1, ATG7:RAF1, or NFIA:RAF1. In some embodiments, the subject is identified as having one or more of the following fusions: AGK:BRAF, AGAP3:BRAF, TNS3:BRAF, or KIAA1549:BRAF. In some embodiments, the subject is identified as having AGAP3:BRAF fusion. In some embodiments, the subject is identified as having KIAA1549:BRAF fusion. In some embodiments, the non-V600 BRAF mutation is selected from V600E, G469A, G464V, G466V, K601E, G469R, and L597R. In some embodiments, the non-V600 BRAF mutation is selected from V600E, G464A, G464V, K601E, and G469R. In some embodiments, the non-V600 BRAF mutation is selected from G464V, K601E, G469A, and G466V. In some embodiments, the cancer has a KRAS mutation. In some embodiments, the KRAS mutation is selected from KRAS G12C, KRAS G12V, KRAS G12D, KRAS Q61K, KRAS Q61H, KRAS G13D, and KRAS G12S.In some embodiments, the KRAS mutation is selected from KRAS G12C, KRAS G12D, KRAS G13D, and KRAS G12S. In some embodiments, Compound A is administered in an amount of about 100 mg to about 700 mg per week. In some embodiments, Compound A is administered at about 200 mg, about 400 mg, or about 600 mg per week. In some embodiments, the subject is at least 18 years old. In some embodiments, Compound A is administered at about 100 mg / m per week. 2 to about 500 mg / m 2 In some embodiments, Compound A is administered in an amount between about 140 mg / m per week. 2 , about 280mg / m 2 , or about 420 mg / m 2In some embodiments, the subject is 12, 13, 14, 15, 16, or 17 years old. In some embodiments, compound A is administered once a week. In some embodiments, the MEK inhibitor or a pharma- ceutically acceptable salt thereof is administered in an amount of about 10 mg to about 150 mg per day. In some embodiments, the MEK inhibitor or a pharma- ceutically acceptable salt thereof is administered in an amount between about 5 mg and about 75 mg twice per day. In some embodiments, the MEK inhibitor or a pharma- ceutically acceptable salt thereof is administered at about 15 mg, about 30 mg, about 45 mg, or about 60 mg twice per day. In some embodiments, the subject has not previously been administered a pan-RAF treatment. In some embodiments, the subject has not previously been administered a cytochrome P450 CYP3A4 inhibitor, a cytochrome P450 CYP2C19 inhibitor, a P450 CYP3A4 inducer, or a substrate of CYP2C9. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is an advanced solid tumor. In some embodiments, the cancer is selected from lung cancer, colorectal cancer, pancreatic cancer, skin cancer, glioma, non-glioma brain cancer, osteosarcoma, gastrointestinal cancer, breast cancer, thyroid cancer, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and multiple myeloma (MM). In some embodiments, the cancer is lung cancer, melanoma, cervical cancer, breast cancer, colorectal cancer, or pancreatic cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is a recurrent or advanced solid tumor. In some embodiments, the subject has undergone at least one prior treatment considered standard of care prior to administration of Compound A or a pharmacologic salt thereof or a MEK inhibitor. In some embodiments, the prior treatment is a systemic treatment. In some embodiments, the prior treatment is chemotherapy, hormone therapy, immunotherapy, or radiation therapy. In some embodiments, the subject has not undergone any previous cancer treatment.In some embodiments, the weekly dose of Compound A or a pharma- ceutically acceptable salt thereof required to achieve an IC80 of pERK inhibition as measured by PMA-induced peripheral blood mononuclear cells (PBMCs) is at least about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, or about 50% less than the weekly dose of Compound A or a pharma- ceutically acceptable salt thereof required to achieve the same IC80 of pERK inhibition as measured by monotherapy. In some embodiments, the weekly dose of the MEK inhibitor or a pharma- ceutically acceptable salt thereof required to achieve an IC80 of pERK inhibition as measured by PMA-induced peripheral blood mononuclear cells (PBMCs) is at least about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, or about 50% less than the weekly dose of the MEK inhibitor or a pharma- ceutically acceptable salt thereof required to achieve the same IC80 of pERK inhibition as measured by monotherapy.

[0006] Incorporation 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.

[0007] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description and accompanying drawings that set forth illustrative embodiments, in which the principles of the invention are utilized. [Brief description of the drawings]

[0008] [Figure 1]FIG. 1 illustrates a Phase 1b / 2 study design using the combination of Compound A and pimasertib. The multicenter, open-label substudy consists of patients aged 12 years or older with recurrent or progressive solid tumors with abnormalities of key proteins in the MAPK pathway, such as tumors with RAS or RAF alterations. Compound A is administered weekly (days 1, 8, 15, and 22) and pimasertib is administered once daily (QD) or twice daily (BID), with cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity. Abbreviations: BRAF (v-raf murine sarcoma viral oncogene homolog B); F / U (follow-up); KRAS (Kirsten rat sarcoma viral oncogene); MAPK (mitogen-activated protein kinase); and NRAS (neuroblastoma sarcoma viral oncogene). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Detailed Description of the Invention While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will readily occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein can be used in practicing the invention. It is intended that the following claims define the scope of the invention, and that methods and structures that fall within the scope of these claims, and their equivalents, are covered thereby.

[0010] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference.

[0011] As used in this specification and the claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0012] "Aryl" refers to an aromatic monocyclic or polycyclic moiety preferably having 6 to 20 carbon atoms and preferably selected from phenyl, biphenyl, naphthyl, tetrahydronaphthyl, fluorenyl, indenyl or phenanthrenyl, more preferably phenyl or naphthyl.

[0013] "Heteroaryl" refers to an aromatic moiety having 6 to 20 carbon atoms and at least one ring containing a heteroatom selected from O, N and / or S; or, a heteroaryl is an aromatic ring containing at least one heteroatom selected from O, N and / or S and 1 to 6 carbon atoms. Heteroaryl preferably contains 1 to 4, more preferably 1, 2 or 3 heteroatoms selected from O and / or N, and is preferably selected from pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Spiro moieties also fall within the scope of this definition. Preferred heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, isoxazolyl, oxazolyl, isothiazolyl, oxadiazolyl, triazolyl. Heteroaryl groups may be optionally mono-, di- or trisubstituted with, for example, halogen, lower alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl, and hydroxy.

[0014] "Heterocyclyl" refers to a saturated or unsaturated ring containing at least one heteroatom selected from O, N and / or S, and 1 to 6 carbon atoms. Heterocyclyl preferably contains 1 to 4, more preferably 1, 2 or 3, heteroatoms selected from O and / or N, and is preferably pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3- It is preferably selected from pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl imidazolinyl, imidazolidinyl, azetidin-2-one-1-yl, pyrrolidin-2-one-1-yl, piperid-2-one-1-yl, azepan-2-one-1-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl and quinolizinyl. Spiro moieties also fall within the scope of this definition.

[0015] "Carbocyclyl" refers to a monocyclic or polycyclic ring system of 3 to 20 carbon atoms, which may be saturated, unsaturated or aromatic.

[0016] "Alkyl" refers to a saturated hydrocarbon moiety, i.e., a straight chain or branched alkyl, having 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, or heptyl.

[0017] "Cycloalkyl" refers to an alkyl ring having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0018] "Alkenyl" refers to an unsaturated hydrocarbon moiety having 1 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 4 carbon atoms, and one or more double bonds, preferably one double bond, i.e., a straight-chain or branched alkenyl, such as vinyl, allyl, methallyl, buten-2-yl, buten-3-yl, penten-2-yl, penten-3-yl, penten-4-yl, 3-methyl-but-3-enyl, 2-methyl-but-3-enyl, 1-methyl-but-3-enyl, hexenyl, or heptenyl.

[0019] "Alkynyl" refers to an unsaturated hydrocarbon moiety having 1 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 2 to 4 carbon atoms, and one or more triple bonds, preferably one triple bond, i.e., a straight-chain or branched alkynyl, such as ethynyl, propynyl, butyn-2-yl, butyn-3-yl, pentyn-2-yl, pentyn-3-yl, pentyn-4-yl, 2-methyl-but-3-ynyl, 1-methyl-but-3-ynyl, hexynyl, or heptynyl.

[0020] "Halo" or "halogen" refers to a halogen atom, preferably selected from F, Cl, Br and I, preferably selected from F, Cl and Br.

[0021] The definitions of cycloalkylalkyl, arylalkyl, heteroarylalkyl and heterocyclylalkyl contemplate that cycloalkyl, aryl, heteroaryl and heterocyclyl are linked via an alkylene moiety, which may be a straight or branched chain group. The alkylene moiety preferably has 1 to 6 carbon atoms. Examples include methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, iso-propylene, sec.-butylene, tert.-butylene, 1,1-dimethylpropylene, 1,2-dimethylpropylene, 2,2-dimethylpropylene, 1,1-dimethylbutylene, 1,2-dimethylbutylene, 1,3-dimethylbutylene, 2,2-dimethylbutylene, 2,3-dimethylbutylene, 3,3-dimethylbutylene, 1-ethylbutylene, 2-ethylbutylene, 3-ethylbutylene, 1-n-propylpropylene, 2-n-propylpropylene, 1-iso-propylpropylene, 2-iso-propylpropylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene and 4-methylpentylene. More preferably, the alkylene moiety has 1 to 3 carbon atoms, such as, for example, methylene, ethylene, n-propylene, and iso-propylene. Methylene is most preferred.

[0022] "Acyl" refers to the group -C(O)R, where R includes "C1-C6-alkyl", "aryl", "heteroaryl", "C3-C8-cycloalkyl", "C3-C8-heterocycloalkyl", "C1-C6-alkylaryl" or "C1-C6-alkylheteroaryl". "Acyloxy" refers to the group -OC(O)R, where R includes "C1-C6-alkyl", "aryl", "hetero-aryl", "C1-C6-alkylaryl" or "C1-C6-alkylheteroaryl".

[0023] "Arylacyl" refers to aryl groups having an acyl substituent, including 2-acetylphenyl and the like.

[0024] "Heteroaryl acyl" refers to heteroaryl groups having an acyl substituent, including 2-acetylpyridyl and the like.

[0025] "Alkoxy" refers to the -OR group, where R includes "C1-C6-alkyl", "C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C2-C6-alkylaryl" or "C1-C6-alkylheteroaryl", "C2-C6-alkenylaryl", "C2-C6-alkenylheteroaryl", "C2-C6-alkynylaryl", "C2-C6-alkynylheteroaryl", "C1-C6-alkylcycloalkyl", "C1-C6-alkylheterocycloalkyl". Examples of preferred alkoxy groups include methoxy, ethoxy, phenoxy, and the like.

[0026] "Alkoxycarbonyl" refers to the group C(O)OR, where R includes "C1-C6-alkyl" or "aryl" or "heteroaryl" or "C1-C6-alkylaryl" or "C1-C6-alkylheteroaryl".

[0027] "Alkoxycarbonylamino" refers to the group -NR'C(O)OR, where R includes "C1-C6-alkyl" or "aryl" or "heteroaryl" or "C1-C6-alkylaryl" or "C1-C6-alkylheteroaryl" and R' includes hydrogen or "C1-C6-alkyl".

[0028] "Aminocarbonyl" refers to the group C(O)NRR', where each R, R' is independently hydrogen or C1-C6-alkyl or aryl or heteroaryl or "C1-C6-alkylaryl" or "C1-C6-alkylhetero-aryl".

[0029] "Acylamino" refers to the group -NR(CO)R', where R, R' are each independently hydrogen or "C1-C6-alkyl" or "aryl" or "heteroaryl" or "C1-C6-alkylaryl" or "C1-C6-alkylheteroaryl".

[0030] "Sulfonyloxy" refers to the -OSO2-R group, where R is selected from H, "C1-C6-alkyl", "C1-C6-alkyl" substituted with halogen, e.g., -OSO2-CF3 group, "C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C1-C6-alkylaryl" or "C1-C6-alkylheteroaryl", "C2-C6-alkenylaryl", "C2-C6-alkenylheteroaryl", "C2-C6-alkynylaryl", "C2-C6-alkynylheteroaryl", "C1-C6-alkylcycloalkyl", "C1-C6-alkylheterocycloalkyl".

[0031] "Sulfonyl" refers to the group "-SO2-R", where R is selected from H, "aryl", "heteroaryl", "C1-C6-alkyl", "C1-C6-alkyl" substituted with halogen, e.g., -SO2-CF3 group, "C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C1-C6-alkylaryl" or "C1-C6-alkylheteroaryl", "C2-C6-alkenylaryl", "C2-C6-alkenylheteroaryl", "C2-C6-alkynylaryl", "C2-C6-alkynylheteroaryl", "C1-C6-alkylcycloalkyl", "C1-C6-alkylheterocycloalkyl".

[0032] "Sulfinyl" refers to the group "-(O)-R" where R is H, "C1-C6-alkyl", "C1-C6-alkyl" substituted with halogen, e.g., -SO-CF3 group, "C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "heterocycloalkyl" 3 or "aryl", "heteroaryl", "C1-C6-alkylaryl" or "C1-C6-alkylheteroaryl", "C2-C6-alkenylaryl", "C2-C6-alkenylheteroaryl", "C2-C6-alkynylaryl", "C2-C6-alkynylheteroaryl", "C1-C6-alkylcycloalkyl", or "C1-C6-alkylheterocycloalkyl".

[0033] "Sulfanyl" refers to the -SR group, where R is H, "C1-C6-alkyl", "C1-C6-alkyl" optionally substituted with halogen, such as the -S-CF3 group, "C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C1-C6-alkylaryl" or "C1-C6-alkylheteroaryl", "C2-C6-alkenylaryl", "C2-C6-alkenylheteroaryl", "C2-C6-alkynylaryl", "C2-C6-alkynylheteroaryl", "C1-C6-alkylcycloalkyl", "C1-C6-alkylheterocycloalkyl". Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl, and the like.

[0034] "Sulfonylamino" refers to the group -NRSO2-R', where R, R' each independently include hydrogen, "C1-C6-alkyl", "C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C1-C6-alkylaryl" or "C1-C6-alkylheteroaryl", "C2-C6-alkenylaryl", "C2-C6-alkenylheteroaryl", "C2-C6-alkynylaryl", "C2-C6-alkynylheteroaryl", "C1-C6-alkylcycloalkyl", "C1-C6-alkylheterocycloalkyl".

[0035] "Aminosulfonyl" refers to the group -SO2-NRR', where R, R' each independently include hydrogen, "C1-C6-alkyl", "C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C1-C6-alkylaryl" or "C1-C6-alkylheteroaryl", "C2-C6-alkenylaryl", "C2-C6-alkenylheteroaryl", "C2-C6-alkynylaryl", "C2-C6-alkynylheteroaryl", "C1-C6-alkylcycloalkyl", "C1-C6-alkylheterocycloalkyl".

[0036] "Amino" refers to the group -NRR', where R, R' are each independently hydrogen, "C1-C6-alkyl", "C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C1-C6-alkylaryl" or "C1-C6-alkylheteroaryl", "C2-C6-alkenylaryl", "C2-C6-alkenylheteroaryl", "C2-C8-alkynylaryl", "C2-C6-alkynylheteroaryl", "C1-C6-alkylcycloalkyl", "C1-C6-alkylheterocycloalkyl", and R and R', together with the nitrogen atom to which they are attached, may optionally form a 3-8 membered hetero-cycloalkyl ring.

[0037] "Substituted or unsubstituted": Unless otherwise limited by the definition of the individual substituents, the above groups, such as "alkyl", "alkenyl", "alkynyl", "alkoxy", "aryl" and "heteroaryl" groups, may be optionally substituted with from 1 to 5 substituents independently selected from the group consisting of "C1-C6-alkyl", "C1-C6-alkylaryl", "C1-C6-alkylheteroaryl", "C2-C6-alkenyl", "C2-C6-alkynyl", primary, secondary or tertiary amino groups or quaternary ammonium moieties, "acyl", "acyloxy", "acylamino", "aminocarbonyl", "alkoxycarbonylamino", "alkoxycarbonyl", "aryl", "aryloxy", "heteroaryl", "heteroaryloxy", carboxyl, cyano, halogen, hydroxy, nitro, sulfanyl, sulfoxy, sulfonyl, sulfonamide, alkoxy, thioalkoxy, trihalomethyl, and the like. Within the framework of the present invention, said "substitution" also includes situations in which adjacent substituents are ring-closed, particularly when vicinal functional substituents are involved, thus forming, for example, lactams, lactones, cyclic anhydrides, and further includes acetals, thioacetals, animals formed by ring closure, for example to obtain a protecting group.

[0038] Tautomers (e.g., keto-enol tautomers) of the compounds of the present invention or their prodrugs may exist in individual forms (e.g., keto, enol forms, and together as mixtures in any ratio). The same applies to stereoisomers (e.g., enantiomers, cis / trans isomers, conformers, etc.).

[0039] Isomers can be separated by methods well known in the art, for example, by liquid chromatography. Enantiomers can be separated, for example, by using chiral stationary phases. Furthermore, enantiomers can be converted to diastereomers, i.e., coupled with an enantiomerically pure auxiliary compound, followed by separation of the resulting diastereomers and isolation by cleavage of the auxiliary residue. Alternatively, any enantiomer of the compound of the present invention can be obtained by stereoselective synthesis using optically pure starting materials.

[0040] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0041] As used herein, "mutation" encompasses an amino acid residue deletion, an amino acid residue insertion, and / or an amino acid residue substitution of at least one amino acid residue in a defined primary amino acid sequence, e.g., a primary amino acid sequence of a target protein. An amino acid "substitution" means that at least one amino acid component of a defined primary amino acid sequence is replaced with another amino acid (e.g., a cysteine ​​residue or a lysine residue). It is desirable that the mutation or substitution (e.g., a conservative mutation or substitution, etc.) of one or more amino acid residues in a primary amino acid sequence does not substantially change the susceptibility of the target protein encoded by the amino acid sequence to conformational changes when bound to a ligand of the target protein or to an unknown candidate drug that can bind allosterically to the target protein. Methods for making mutations or substitutions in a primary amino acid sequence of a protein, such as a target protein, by standard techniques are well known in the art.

[0042] As used herein, the term "Raf kinase" refers to any one of a family of serine / threonine-protein kinases. This family consists of three isoform members: B-Raf, C-Raf (Raf-1), and A-Raf. Raf protein kinases participate in the MAPK signaling pathway, which consists of a kinase cascade that sends extracellular signals to the nucleus to control gene expression and important cellular functions. Unless the context indicates otherwise, the term "Raf kinase" refers to any Raf kinase protein from any species. In one embodiment, the Raf kinase is a human Raf kinase.

[0043] The term "Raf inhibitor" or "inhibitor of Raf" is used to refer to a compound capable of interacting with one or more isoform members of serine / threonine-protein kinase Raf, including B-Raf, C-Raf (Raf-1) and / or A-Raf, mutant forms. Some examples of Raf mutant forms include, but are not limited to, B-Raf V600E, B-Raf V600D, B-Raf V600K, B-Raf V600E+T5291 and / or B-Raf V600E+G468A.

[0044] The term "in vivo" is used to describe events that take place inside a subject's body.

[0045] The term "ex vivo" is used to describe events that occur outside of a subject's body. Ex vivo assays are not performed on a subject. Instead, ex vivo assays are performed on a sample that is separated from a subject. An example of an ex vivo assay performed on a sample is an "in vitro" assay.

[0046] The term "in vitro" is used to describe events that occur in a container to hold an experimental reagent separate from the biological source from which the material was obtained. In vitro assays can include cell-based assays that use live or dead cells. In vitro assays can also include cell-free assays that do not use intact cells.

[0047] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, etc.). In various embodiments, a subject may be a human (e.g., an adult male, adult female, adolescent male, adolescent female, boy, girl) under the care of a physician or other medical practitioner in a hospital, as an outpatient, or in other clinical settings. In certain embodiments, a subject may be a subject not under the care or prescription of a physician or other medical practitioner.

[0048] As used herein, the phrase "subject in need thereof" refers to a subject suffering from or at risk of a pathology to be treated prophylactically or therapeutically with a compound or salt described herein, as described below.

[0049] The terms "determining," "measuring," "assessing," "assessing," "assaying," and "analyzing" are often used interchangeably herein to refer to forms of measurement. These terms include determining whether an element is present (e.g., detecting). These terms can include quantitative, qualitative, or both quantitative and qualitative determinations. Assessing can be relative or absolute. "Detecting the presence of" can include determining the amount of something present in addition to determining the presence or absence of something, depending on the context.

[0050] The terms "administer", "administered", "administers" and "administering" are defined as providing a composition to an individual by a route known in the art, including, but not limited to, intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, the oral route of administering the composition can be used. The terms "administer", "administered", "administers" and "administering" a compound should be understood to mean providing a compound of the disclosure or a prodrug of a compound of the disclosure to an individual in need thereof.

[0051] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or salt described herein that is sufficient to bring about the intended application, including but not limited to disease treatment as defined below. Therapeutically effective amounts may vary depending on the intended application (in vitro or in vivo) or the subject and disease state being treated, such as the subject's weight and age, the severity of the disease state, the mode of administration, etc., and can be easily determined by those skilled in the art. These terms also apply to a dose that can induce a particular response in target cells, such as reduced proliferation or downregulation of the activity of a target protein. The specific dose may vary depending on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system in which it is delivered.

[0052] As used herein, "treatment" or "treating" refers to an approach to obtain a beneficial or desired result for a disease, disorder, or medical condition, including, but not limited to, a therapeutic benefit. In certain embodiments, treating or treating involves administering a compound or composition disclosed herein to a subject. Therapeutic benefit can include eradication or reversal of the underlying disorder being treated. Therapeutic benefit can also be achieved by eradicating or reversing one or more of the physiological symptoms associated with the underlying disorder, for example, an improvement in the subject even though the subject still suffers from the underlying disorder. Treating can include, for example, reducing, delaying, or reducing the severity of one or more symptoms of a disease or condition, or treating can include reducing the frequency with which a symptom, such as a disease, defect, disorder, or adverse condition, occurs in a patient.

[0053] As used herein, "synergy," "synergetic," "synergism," or "synergistic effect" refers to two or more compounds or compositions that individually produce an effect, but together produce a combined effect that is greater than their individual effects.

[0054] In certain embodiments, the term "prevent" or "preventing", when referring to a disease or disorder, may refer to a compound reducing the occurrence of the disorder or condition in a treated sample compared to an untreated control sample, or delaying the onset or reducing the severity of one or more symptoms of the disorder or condition in a statistical sample compared to an untreated control sample.

[0055] The term "about" or "approximately" can mean within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more standard deviations, as is customary in the art. Alternatively, "about" can mean within a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% for a given value.

[0056] Every maximum numerical limitation given throughout this specification will include every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

[0057] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0058] Any aspect or embodiment described herein may be combined with any other aspect or embodiment disclosed herein.

[0059] Methods of Treating a Subject Suffering from Cancer In one aspect, the disclosure provides a method of treating a subject suffering from cancer, comprising administering to the subject a RAF inhibitor or a pharma- ceutically acceptable salt thereof and a MEK inhibitor or a pharma- ceutically acceptable salt thereof. In one aspect, the disclosure provides a method of treating a subject suffering from cancer, comprising administering to the subject a RAF inhibitor and a MEK inhibitor, wherein the total amount of the RAF inhibitor and the MEK inhibitor is therapeutically effective in treating the cancer. In one aspect, the disclosure provides a method of treating a subject suffering from cancer, comprising administering to the subject a RAF inhibitor or a pharma- ceutically acceptable salt thereof. (i) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharma- ceutically acceptable salt thereof; and (ii) a MEK inhibitor as provided herein; wherein the total amount of Compound A or a pharma- ceutical acceptable salt thereof and the MEK inhibitor is therapeutically effective in treating cancer. In some embodiments, the cancer is a recurrent, progressive, or refractory solid tumor with mitogen-activated protein kinase (MAPK) pathway abnormality. In some embodiments, the subject has a gene mutation or gene fusion as described in Tables 1-7. In some embodiments, the cancer may be previously untreated. In some embodiments, administration of compound A or a pharma- ceutically acceptable salt thereof disclosed herein and a MEK inhibitor or a pharma- ceutically acceptable salt may result in a synergistic effect. In some embodiments, the synergy is measured using a method disclosed herein. In some embodiments, the synergy may be determined using a mutant cell line. In some embodiments, the mutant cell line is a non-V600 BRAF mutant cell line. In some embodiments, the mutant cell line is a KRAS mutant cell line. In some embodiments, the mutant cell line is an NRAS mutant cell line. In some embodiments, the synergy is measured using a model with a BRAF fusion. In some embodiments, the BRAF fusion is a BRAF fusion as disclosed herein. In some embodiments, the mutant cell line has a mutation as presented in Table 1 or Table 2. In some embodiments, the mutant cell is a cell line provided in Table 1 or Table 2.

[0060] A. Raf inhibitors In one aspect, the RAF inhibitors described herein are B-Raf and / or C-Raf kinase inhibitors. In some embodiments, the Raf inhibitors are selective for B-Raf and C-Raf kinases. In some embodiments, the Raf inhibitors are selective for B-Raf (wild type), B-Raf V600E and C-Raf. In some embodiments, the Raf inhibitors are selective for B-Raf (wild type), B-Raf V600D and C-Raf. In some embodiments, the Raf inhibitors are selective for B-Raf (wild type), B-Raf V600K and C-Raf. In some embodiments, the Raf inhibitors are selective for mutant B-Raf. In some embodiments, the Raf inhibitors are selective for mutant B-Raf V600E. In some embodiments, the Raf inhibitors are selective for mutant B-Raf V600D. In some embodiments, the Raf inhibitors are selective for mutant B-Raf V600K.

[0061] Compounds capable of inhibiting the activity of Raf kinase can be used in the methods of the present disclosure. In some embodiments, the Raf inhibitor inhibits more isoforms of Raf kinase protein than just B-Raf V600. In some embodiments, the Raf inhibitor inhibits more isoforms of Raf kinase protein than just B-Raf V600E. In some embodiments, the Raf inhibitor inhibits B-Raf (wild type), mutant B-Raf, A-Raf, and C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild type), B-Raf V600E, A-Raf, and / or C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild type), B-Raf V600K, A-Raf, and / or C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild type), B-Raf V600D, A-Raf, and / or C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild type), B-Raf V600K, and C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild type), B-Raf V600E, and C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild type), B-Raf V600D, and C-Raf. In some embodiments, the Raf inhibitor is selective for B-Raf (wild type), B-Raf V600K, and C-Raf. In some embodiments, the Raf inhibitor is selective for mutant B-Raf. In some embodiments, the Raf inhibitor is selective for mutant B-Raf V600E. In some embodiments, the Raf inhibitor is selective for mutant B-Raf V600D. In some embodiments, the Raf inhibitor is selective for mutant B-Raf V600K.

[0062] The present disclosure provides RAF inhibitors useful in the methods disclosed herein. In some embodiments, the RAF inhibitor is (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamide)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharma- ceutically acceptable salt thereof. In some embodiments, the RAF inhibitor is [ka] In some embodiments, the RAF inhibitor is one described in U.S. Patent No. 8,293,752, which is incorporated herein by reference in its entirety.

[0063] In some embodiments, compound A inhibits RAF monomer and dimer without activating MAPK pathway.In some embodiments, compound A does not induce the activation of MAPK signaling in wild-type BRAF.In some embodiments, compound A does not induce the activation of MAPK activation in BRAF fusion.In some embodiments, BRAF fusion is KIAA1549-BRAF.In some embodiments, compound A inhibits RAF monomer and dimer without inducing MAPK signaling.

[0064] In some embodiments, the RAF inhibitor is administered to the subject at about 50 mg to about 800 mg. In some embodiments, the RAF inhibitor is administered to the subject at about 100 mg to about 600 mg. In some embodiments, the RAF inhibitor is administered to the subject at about 100 mg to about 500 mg. In some embodiments, the RAF inhibitor is administered to the subject at about 200 mg to about 600 mg. In some embodiments, the RAF inhibitor is administered to the subject at about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, or about 700 mg. In some embodiments, the RAF inhibitor is administered to the subject at about 200 mg, about 400 mg, or about 600 mg. In some embodiments, the RAF inhibitor is administered to the subject at about 200 mg. In some embodiments, the RAF inhibitor is administered to the subject at about 400 mg. In some embodiments, the RAF inhibitor is administered to the subject at about 600 mg. In some embodiments, the RAF inhibitor is administered to the subject at 100 mg to 800 mg. In some embodiments, the RAF inhibitor is administered to the subject at 100 mg to 700 mg. In some embodiments, the RAF inhibitor is administered to the subject at 100 mg to 600 mg. In some embodiments, the RAF inhibitor is administered to the subject at 100 mg to 500 mg. In some embodiments, the RAF inhibitor is administered to the subject at 200 mg to 600 mg. In some embodiments, the RAF inhibitor is administered to the subject at about 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg. In some embodiments, the RAF inhibitor is administered to the subject at about 200 mg, 400 mg, or 600 mg. In some embodiments, the RAF inhibitor is administered to the subject at 200 mg. In some embodiments, the RAF inhibitor is administered to the subject at 400 mg. In some embodiments, the RAF inhibitor is administered to the subject at 600 mg. In some embodiments, the subject is an adult. In some embodiments, the subject is over 18 years old or is 18 years old.

[0065] In some embodiments, the RAF inhibitor (e.g., Compound A, etc.) is administered to the subject at about 50 mg to about 800 mg per week. In some embodiments, the RAF inhibitor is administered to the subject at about 100 mg to about 700 mg per week. In some embodiments, the RAF inhibitor is administered to the subject at about 100 mg to about 600 mg per week. In some embodiments, the RAF inhibitor is administered to the subject at about 100 mg to about 500 mg per week. In some embodiments, the RAF inhibitor is administered to the subject at about 200 mg to about 600 mg per week. In some embodiments, the RAF inhibitor is administered to the subject at about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, 700 mg, or about 800 mg per week. In some embodiments, the RAF inhibitor is administered to the subject at about 200 mg, about 400 mg, or about 600 mg per week. In some embodiments, the RAF inhibitor is administered to the subject at about 200 mg per week. In some embodiments, the RAF inhibitor is administered to the subject at about 400 mg per week. In some embodiments, the RAF inhibitor is administered to the subject at about 600 mg per week. In some embodiments, the RAF inhibitor is administered to the subject at 100 mg to 800 mg per week. In some embodiments, the RAF inhibitor is administered to the subject at 100 mg to 700 mg per week. In some embodiments, the RAF inhibitor is administered to the subject at 100 mg to 600 mg per week. In some embodiments, the RAF inhibitor is administered to the subject at 100 mg to 500 mg per week. In some embodiments, the RAF inhibitor is administered to the subject at 200 mg to 600 mg per week. In some embodiments, the RAF inhibitor is administered to the subject at 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg or 800mg per week.In some embodiments, the RAF inhibitor is administered to the subject at 200mg, 400mg or 600mg per week.In some embodiments, the RAF inhibitor is administered to the subject at 200mg per week.In some embodiments, the RAF inhibitor is administered to the subject at 400mg per week.In some embodiments, the RAF inhibitor is administered to the subject at 600mg per week. In some embodiments, the weekly dosage is a once-weekly dosage. In some embodiments, the subject is an adult. In some embodiments, the subject is over 18 years old or is 18 years old.

[0066] In some embodiments, the RAF inhibitor (such as, for example, Compound A) is administered to a subject at about 100 mg / m 2 ~about 600mg / m 2 In some embodiments, the RAF inhibitor is administered to the subject at about 100 mg / m 2 , about 120mg / m 2 , about 140mg / m 2 , about 160mg / m 2 , about 180mg / m 2 , about 200mg / m 2 , about 220mg / m 2 , about 240mg / m 2 , about 260mg / m 2 , about 280mg / m 2 , about 300mg / m 2 , about 320mg / m 2 , about 340mg / m 2 , about 360mg / m 2 , about 380mg / m 2 , about 400mg / m 2 , about 420mg / m 2 , about 440mg / m 2 , about 460mg / m 2 , about 480mg / m 2 , about 500mg / m 2 , about 520mg / m 2 , about 540mg / m 2 , about 560mg / m 2 , about 580mg / m 2 , about 600mg / m 2 In some embodiments, the RAF inhibitor is administered to the subject at about 140 mg / m 2 , about 280mg / m 2 , or about 420 mg / m 2 In some embodiments, the RAF inhibitor is administered to the subject at about 140 mg / m 2In some embodiments, the RAF inhibitor is administered to the subject at about 280 mg / m 2 In some embodiments, the RAF inhibitor is administered to the subject at about 480 mg / m 2 In some embodiments, the RAF inhibitor is administered to the subject at a dose of at least about 25 mg / m 2 In some embodiments, the RAF inhibitor is administered to the subject at a dose of 50 mg / m 2 ~600mg / m 2 In some embodiments, the RAF inhibitor is administered to the subject at a dose of 100 mg / m 2 ~600mg / m 2 In some embodiments, the RAF inhibitor is administered to the subject at a dose of 100 mg / m 2 , 120 mg / m 2 , 140 mg / m 2 , 160 mg / m 2 , 180 mg / m 2 , 200 mg / m 2 , 220 mg / m 2 , 240 mg / m 2 , 260 mg / m 2 , 280 mg / m 2 , 300 mg / m 2 , 320 mg / m 2 , 340 mg / m 2 , 360 mg / m 2 , 380 mg / m 2 , 400 mg / m 2 , 420 mg / m 2 , 440 mg / m 2 , 460 mg / m 2 , 480 mg / m 2 , 500 mg / m 2 , 520 mg / m 2 , 540 mg / m 2 , 560 mg / m 2 , 580 mg / m 2 , or 600 mg / m 2 In some embodiments, the RAF inhibitor is administered to the subject at a dose of 140 mg / m 2 , 280 mg / m 2 , or 420 mg / m 2 In some embodiments, the RAF inhibitor is administered to the subject at a dose of 140 mg / m2 In some embodiments, the RAF inhibitor is administered to the subject at a dose of 280 mg / m 2 In some embodiments, the RAF inhibitor is administered to the subject at a dose of 480 mg / m 2 In some embodiments, the subject is between 12 and 18 years of age. In some embodiments, the subject is between about 12 and about 18 years of age. In some embodiments, the subject is greater than or equal to 12 years of age to less than or equal to 18 years of age. In some embodiments, the subject is less than 12 years of age. In some embodiments, the subject is at least 6 months of age.

[0067] In some embodiments, the RAF inhibitor is administered to the subject at about 50 mg / m per week. 2 ~about 800mg / m 2 In some embodiments, the RAF inhibitor is administered to the subject at about 100 mg / m per week. 2 ~about 500mg / m 2 In some embodiments, the RAF inhibitor is administered to the subject at about 100 mg / m per week. 2 , about 120mg / m 2 , about 140mg / m 2 , about 160mg / m 2 , about 180mg / m 2 , about 200mg / m 2 , about 220mg / m 2 , about 240mg / m 2 , about 260mg / m 2 , about 280mg / m 2 , about 300mg / m 2 , about 320mg / m 2 , about 340mg / m 2 , about 360mg / m 2 , about 380mg / m 2 , about 400mg / m 2 , about 420mg / m 2 , about 440mg / m 2 , about 460mg / m 2 , about 480mg / m 2 , or about 500 mg / m 2 , about 520mg / m 2 , about 540mg / m 2, about 560mg / m 2 , about 580mg / m 2 , or about 600 mg / m 2 In some embodiments, the RAF inhibitor is administered to the subject at about 140 mg / m per week. 2 , about 280mg / m 2 , or about 420 mg / m 2 In some embodiments, the RAF inhibitor is administered to the subject at about 140 mg / m per week. 2 In some embodiments, the RAF inhibitor is administered to the subject at about 280 mg / m per week. 2 In some embodiments, the RAF inhibitor is administered to the subject at about 480 mg / m per week. 2 In some embodiments, the RAF inhibitor is administered to the subject at a dose of 100 mg / m per week. 2 ~600mg / m 2 In some embodiments, the RAF inhibitor is administered to the subject at about 100 mg / m per week. 2 , about 120mg / m 2 , about 140mg / m 2 , about 160mg / m 2 , about 180mg / m 2 , about 200mg / m 2 , about 220mg / m 2 , about 240mg / m 2 , about 260mg / m 2 , 280 mg / m 2 , 300 mg / m 2 , 320 mg / m 2 , 340 mg / m 2 , 360 mg / m 2 , 380 mg / m 2 , 400 mg / m 2 , 420 mg / m 2 , 440 mg / m 2 , 460 mg / m 2 , 480 mg / m 2 , or 500 mg / m 2 , 520 mg / m 2 , 540 mg / m 2 , 560 mg / m 2 , 580 mg / m 2 , or 600 mg / m2 In some embodiments, the RAF inhibitor is administered to the subject at about 140 mg / m per week. 2 , 280 mg / m 2 , or 420 mg / m 2 In some embodiments, the RAF inhibitor is administered to the subject at a dose of 140 mg / m per week. 2 In some embodiments, the RAF inhibitor is administered to the subject at a dose of 280 mg / m per week. 2 In some embodiments, the RAF inhibitor is administered to the subject at a dose of 480 mg / m per week. 2 In some embodiments, the weekly dose is a one-time dose per week. In some embodiments, the subject is between 12 and 18 years old. In some embodiments, the subject is about 12 to about 18 years old. In some embodiments, the subject is greater than or equal to 12 years old to less than or equal to 18 years old. In some embodiments, the subject is less than 12 years old. In some embodiments, the subject is at least 6 months old.

[0068] In some embodiments, compound A is administered to the subject at about 50 mg to about 800 mg. In some embodiments, compound A is administered to the subject at about 100 mg to about 600 mg. In some embodiments, compound A is administered to the subject at about 100 mg to about 500 mg. In some embodiments, compound A is administered to the subject at about 200 mg to about 600 mg. In some embodiments, compound A is administered to the subject at about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, 700 mg, or about 800 mg. In some embodiments, compound A is administered to the subject at about 200 mg, about 400 mg, or about 600 mg. In some embodiments, compound A is administered to the subject at about 200 mg. In some embodiments, compound A is administered to the subject at about 400 mg. In some embodiments, compound A is administered to the subject at about 600 mg. In some embodiments, compound A is administered to the subject at 100 mg to 800 mg. In some embodiments, compound A is administered to the subject at 100 mg to 600 mg. In some embodiments, compound A is administered to the subject at 100 mg to 500 mg. In some embodiments, compound A is administered to the subject at 200 mg to 600 mg. In some embodiments, compound A is administered to the subject at 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg. In some embodiments, compound A is administered to the subject at 200 mg, 400 mg, or 600 mg. In some embodiments, compound A is administered to the subject at 200 mg. In some embodiments, compound A is administered to the subject at 400 mg. In some embodiments, compound A is administered to the subject at 600 mg. In some embodiments, the subject is an adult. In some embodiments, the subject is over 18 years of age or is 18 years of age.

[0069] In some embodiments, compound A is administered to the subject at about 100 mg to about 800 mg per week. In some embodiments, compound A is administered to the subject at about 100 mg to about 600 mg per week. In some embodiments, compound A is administered to the subject at about 100 mg to about 500 mg per week. In some embodiments, compound A is administered to the subject at about 200 mg to about 600 mg per week. In some embodiments, compound A is administered to the subject at about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, or about 700 mg, about 800 mg per week. In some embodiments, compound A is administered to the subject at about 200 mg, about 400 mg, or about 600 mg per week. In some embodiments, compound A is administered to the subject at about 200 mg. In some embodiments, compound A is administered to the subject at about 400 mg per week. In some embodiments, compound A is administered to the subject at about 600 mg per week. In some embodiments, compound A is administered to the subject at 100 mg to 700 mg per week. In some embodiments, compound A is administered to the subject at 100 mg to 600 mg per week. In some embodiments, compound A is administered to the subject at 100 mg to 500 mg per week. In some embodiments, compound A is administered to the subject at 200 mg to 600 mg per week. In some embodiments, compound A is administered to the subject at 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 700 mg per week. In some embodiments, compound A is administered to the subject at 200 mg, 400 mg, or 600 mg per week. In some embodiments, Compound A is administered to the subject at 200 mg per week. In some embodiments, Compound A is administered to the subject at 400 mg per week. In some embodiments, Compound A is administered to the subject at 600 mg per week. In some embodiments, the weekly dosage is a once-weekly dosage. In some embodiments, the subject is an adult. In some embodiments, the subject is over 18 years old or is 18 years old.

[0070] In some embodiments, Compound A is administered to a subject at about 500 mg / m 2 ~about 800mg / m 2 In some embodiments, Compound A is administered to a subject at about 100 mg / m 2 ~about 500mg / m 2 In some embodiments, Compound A is administered to a subject at about 100 mg / m 2 , about 120mg / m 2 , about 140mg / m 2 , about 160mg / m 2 , about 180mg / m 2 , about 200mg / m 2 , about 220mg / m 2 , about 240mg / m 2 , about 260mg / m 2 , about 280mg / m 2 , about 300mg / m 2 , about 320mg / m 2 , about 340mg / m 2 , about 360mg / m 2 , about 380mg / m 2 , about 400mg / m 2 , about 420mg / m 2 , about 440mg / m 2 , about 460mg / m 2 , about 480mg / m 2 , or about 500 mg / m 2 , about 520mg / m 2 , about 540mg / m 2 , about 560mg / m 2 , about 580mg / m 2 , or about 600 mg / m 2 In some embodiments, Compound A is administered to a subject at about 140 mg / m 2 , about 280mg / m 2 , or about 420 mg / m 2 In some embodiments, Compound A is administered to a subject at about 140 mg / m 2 In some embodiments, Compound A is administered to a subject at about 280 mg / m 2 In some embodiments, Compound A is administered to a subject at about 480 mg / m 2In some embodiments, Compound A is administered to a subject at a dose of 100 mg / m 2 ~500mg / m 2 In some embodiments, Compound A is administered to a subject at a dose of 100 mg / m 2 , 120 mg / m 2 , 140 mg / m 2 , 160 mg / m 2 , 180 mg / m 2 , 200 mg / m 2 , 220 mg / m 2 , 240 mg / m 2 , 260 mg / m 2 , 280 mg / m 2 , 300 mg / m 2 , 320 mg / m 2 , 340 mg / m 2 , 360 mg / m 2 , 380 mg / m 2 , 400 mg / m 2 , 420 mg / m 2 , 440 mg / m 2 , 460 mg / m 2 , 480 mg / m 2 , or 500 mg / m 2 , 520 mg / m 2 , 540 mg / m 2 , 560 mg / m 2 , 580 mg / m 2 , or 600 mg / m 2 In some embodiments, Compound A is administered to a subject at a dose of 140 mg / m 2 , 280 mg / m 2 , or 420 mg / m 2 In some embodiments, Compound A is administered to a subject at a dose of 140 mg / m 2 In some embodiments, Compound A is administered to a subject at a dose of 280 mg / m 2 In some embodiments, Compound A is administered to a subject at 480 mg / m 2In some embodiments, the subject is between 12 and 18 years of age. In some embodiments, the subject is about 12 to 18 years of age. In some embodiments, the subject is greater than or equal to 12 years of age and less than or equal to 18 years of age. In some embodiments, the subject is less than 12 years of age. In some embodiments, the subject is at least 6 months of age.

[0071] In some embodiments, Compound A is administered to a subject at about 100 mg / m per week. 2 ~about 500mg / m 2 In some embodiments, Compound A is administered to a subject at about 100 mg / m per week. 2 , about 120mg / m 2 , about 140mg / m 2 , about 160mg / m 2 , about 180mg / m 2 , about 200mg / m 2 , about 220mg / m 2 , about 240mg / m 2 , about 260mg / m 2 , about 280mg / m 2 , about 300mg / m 2 , about 320mg / m 2 , about 340mg / m 2 , about 360mg / m 2 , about 380mg / m 2 , about 400mg / m 2 , about 420mg / m 2 , about 440mg / m 2 , about 460mg / m 2 , about 480mg / m 2 , or about 500 mg / m 2 , about 520mg / m 2 , about 540mg / m 2 , about 560mg / m 2 , about 580mg / m 2 , or about 600 mg / m 2 In some embodiments, Compound A is administered to a subject at about 140 mg / m per week. 2 , about 280mg / m 2 , or about 420 mg / m 2In some embodiments, Compound A is administered to a subject at about 140 mg / m per week. 2 In some embodiments, Compound A is administered to a subject at about 280 mg / m per week. 2 In some embodiments, Compound A is administered to a subject at about 480 mg / m per week. 2 In some embodiments, Compound A is administered to a subject at a dose of 100 mg / m per week. 2 ~500mg / m 2 In some embodiments, Compound A is administered to a subject at a dose of 100 mg / m per week. 2 , 120 mg / m 2 , 140 mg / m 2 , 160 mg / m 2 , 180 mg / m 2 , 200 mg / m 2 , 220 mg / m 2 , 240 mg / m 2 , 260 mg / m 2 , 280 mg / m 2 , 300 mg / m 2 , 320 mg / m 2 , 340 mg / m 2 , 360 mg / m 2 , 380 mg / m 2 , 400 mg / m 2 , 420 mg / m 2 , 440 mg / m 2 , 460 mg / m 2 , 480 mg / m 2 , or 500 mg / m 2 , 520 mg / m 2 , 540 mg / m 2 , 560 mg / m 2 , 580 mg / m 2 , or 600 mg / m 2 In some embodiments, Compound A is administered to a subject at a dose of 140 mg / m per week. 2 , 280 mg / m 2 , or 420 mg / m 2 In some embodiments, Compound A is administered to a subject at a dose of 140 mg / m per week. 2In some embodiments, Compound A is administered to a subject at a dose of 280 mg / m per week. 2 In some embodiments, Compound A is administered to a subject at a dose of 480 mg / m per week. 2 In some embodiments, the weekly dose is a dose once a week. In some embodiments, the subject is between 12 and 18 years old. In some embodiments, the subject is between 12 years old or older and 18 years old or younger. In some embodiments, the subject is younger than 12 years old. In some embodiments, the subject is at least 6 months old.

[0072] In some embodiments, compound A is administered in a weekly (QW) dose. In some embodiments, the weekly (QW) dose of compound A administered is greater than 600 mg. In some embodiments, the weekly (QW) dose of compound A administered is up to 600 mg. In some embodiments, the weekly (QW) dose of compound A administered is up to 530 mg. In some embodiments, the weekly (QW) dose of compound A administered is up to 420 mg. In some embodiments, the weekly (QW) dose of compound A administered is up to 350 mg. In some embodiments, the weekly (QW) dose of compound A administered is up to 280 mg. In some embodiments, the weekly (QW) dose of compound A administered is 600 mg. In some embodiments, the weekly (QW) dose of compound A administered is 530 mg. In some embodiments, the weekly (QW) dose of compound A administered is 420 mg. In some embodiments, the once weekly (QW) dose administered is 350 mg. In some embodiments, the once weekly (QW) dose of Compound A administered is 280 mg.

[0073] In some embodiments, compound A is administered orally (PO) at a maximum dose of up to once a week (QW). In some embodiments, the maximum oral dose (PO) of compound A administered once a week (QW) is greater than 600 mg. In some embodiments, the maximum oral dose (PO) of compound A administered once a week (QW) is up to 600 mg. In some embodiments, the maximum oral dose (PO) of compound A administered once a week (QW) is up to 530 mg. In some embodiments, the maximum oral dose (PO) of compound A administered once a week (QW) is up to 420 mg. In some embodiments, the maximum oral dose (PO) of compound A administered once a week (QW) is up to 350 mg. In some embodiments, the maximum oral dose (PO) of compound A administered once a week (QW) is up to 280 mg. In some embodiments, the maximum oral dose (PO) of compound A administered once a week (QW) is 600 mg. In some embodiments, the maximum oral dose (PO) of Compound A administered once weekly (QW) is 530 mg. In some embodiments, the maximum oral dose (PO) of Compound A administered once weekly (QW) is 420 mg. In some embodiments, the maximum oral dose (PO) of Compound A administered once weekly (QW) is 350 mg. In some embodiments, the maximum oral dose (PO) of Compound A administered once weekly (QW) is 280 mg. In some embodiments, Compound A or a pharma- ceutically acceptable salt or solvate thereof is Compound A.

[0074] In some embodiments, about 140 mg / m 2 Compound A is administered chronically to a subject once a week. In some embodiments, about 280 mg / m 2 Compound A is administered chronically to a subject once a week. In some embodiments, about 350 mg / m 2 Compound A is administered chronically to a subject once a week. In some embodiments, about 420 mg / m 2 Compound A is administered chronically to a subject once a week. In some embodiments, about 530 mg / m 2 Compound A is administered chronically to a subject once a week. In some embodiments, about 140 mg / m 2of Compound A is administered chronically once a week for 360 days. In some embodiments, about 280 mg / m 2 Compound A is administered chronically once a week for 360 days. In some embodiments, about 350 mg / m 2 Compound A is administered chronically once a week for 360 days. In some embodiments, about 420 mg / m 2 of Compound A is administered chronically once a week for 360 days. In some embodiments, about 530 mg / m 2 of Compound A is administered chronically once a week for 360 days. In some embodiments, about 140 mg / m 2 Compound A is administered chronically once a week for at least one year. In some embodiments, Compound A is administered at a dose of about 280 mg / m 2 Compound A is administered chronically once a week for at least one year. In some embodiments, Compound A is administered at a dose of about 350 mg / m 2 Compound A is administered chronically once a week for at least one year. In some embodiments, Compound A is administered at a dose of about 420 mg / m 2 Compound A is administered chronically once a week for at least one year. In some embodiments, about 530 mg / m 2 Compound A is administered chronically once a week for at least one year.

[0075] In some embodiments, about 200 mg of Compound A is administered chronically to a subject once per week. In some embodiments, about 400 mg of Compound A is administered chronically to a subject once per week. In some embodiments, about 600 mg of Compound A is administered chronically to a subject once per week. In some embodiments, about 200 mg of Compound A is administered chronically once per week for 360 days. In some embodiments, about 400 mg of Compound A is administered chronically once per week for 360 days. In some embodiments, about 420 mg / m 2of Compound A is administered chronically once a week for 360 days. In some embodiments, about 600 mg of Compound A is administered chronically once a week for 360 days. In some embodiments, about 200 mg of Compound A is administered chronically once a week for at least one year. In some embodiments, about 400 mg of Compound A is administered chronically once a week for at least one year. In some embodiments, about 600 mg of Compound A is administered chronically once a week for at least one year.

[0076] In some embodiments, the dosages described herein for compound A or a salt thereof are based on the weight of compound A. In some embodiments, the dosages described herein for compound A or a salt thereof correspond to the weight of the free base form of compound A. For example, in some embodiments, the dosages of compound A or a salt thereof are described by the weight of compound A in such dosages. In some embodiments, the dosages described herein for compound A or a salt thereof correspond to the weight of the salt of compound A.

[0077] B. MEK Inhibitors The present disclosure provides a MEK inhibitor for the methods disclosed herein. In some embodiments, the MEK inhibitor is a compound having the structure of formula (I) or a pharma- ceutically acceptable salt thereof; [ka] (In the formula, R1, R2, R9, R 10 , R 11 , R 12 , R 13 and R 14 are independently hydrogen, halogen, cyano, nitro, azido, -OR3, -NR4C(O)OR6, -OC(O)R3, -NR4S(O) j R6, -S(O) j NR3R4, -S(O) j NR4C(O)R3, -C(O)NR4S(O) j R6, -S(O) jR6, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, - NR5C(NCN)NR3R4, -NR3R4, C1~C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, -S(O) j (C1-C6 alkyl), -S(O) j (CR4R5) m -aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5) m -Aryl, -NR4(CR4R5) m -aryl, -O(CR4R5) m -heteroaryl, -NR4(CR4R5) m , heteroaryl, -O(CR4R5) m -Heterocyclyl, -NR4(CR4R5) m -heterocyclyl and -S(C1-C2 alkyl) substituted with 1-5 fluorines, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is independently substituted or unsubstituted; R3 is hydrogen, trifluoromethyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10and aryl is selected from cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, and aryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocyclyl is independently substituted or unsubstituted; and aryl is selected from oxo, halogen, nitro, CF, CHF, CHF, OCF, OCHF, OCHF, azido, NR'SOR'', S. optionally substituted with 1 to 5 groups independently selected from O2N'', C(O)R', C(O)OR', OC(0)R', NR'C(O)OR'''', NR'C(O)R'', C(O)NR'R'', SR'''', S(0)R'''', S02R', NR'R'', NR'C(O)NR''R''', NR'C(NCN)N''R''', OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R4 is hydrogen or C 1~6 alkyl, which may be substituted or unsubstituted; or R3 and R4, together with the atoms to which they are attached, may each form a substituted or unsubstituted 4-10 membered heteroaryl or heterocyclic ring; R5 is hydrogen or C1-C6 alkyl, which may be substituted or unsubstituted; or R4 and R5, together with the atoms to which they are attached, may each form a substituted or unsubstituted 4-10 membered carbocyclic, heteroaryl, or heterocyclic ring; R6 is trifluoromethyl, C1-C 10 Alkyl, C3-C 10 selected from cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is independently substituted or unsubstituted; R', R'', and R''' are independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, aryl, and arylalkyl; R'''' is selected from C1-C4 alkyl, C2-C4 alkenyl, aryl and arylalkyl; W is 1) unsubstituted or 1 to 5 substituents ZR 15 and 2) a heteroaryl containing 1 to 4 heteroatoms or a heterocyclyl containing 1 to 4 heteroatoms, each substituted by -C(O)OR 15 , -C(O)NR4R 15 , -C(O)NR4OR 15 , -C(O)NR4S(O) j R6, -C(O)NR4NR4NR 15 , -NR'R'', -NR'C(O)R', -NR'S(O) j R', -NRC(O)NR'R'', NR'S(O) j NR'R'', or -C(O)NR4NR4C(O)R 15 with the proviso that W is not -C(O)OH; Z is a bond, NR 16 , O, N.R. 16 SO2 or S; R 15 is hydrogen, trifluoromethyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 selected from cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is independently substituted or unsubstituted; R 16 is hydrogen or C1-C 10 alkyl; or R 15 and R 16together with the atom to which they are attached form a 4-10 membered ring having 1 or 2 nitrogen atoms and optionally an oxygen atom, said ring being substituted or unsubstituted; X is N or N + O - and; m is 0, 1, 2, 3, 4 or 5; j is 1 or 2); Wherein the total amount of compound A or a pharma- ceutically acceptable salt thereof and the MEK inhibitor is one that is therapeutically effective in treating cancer. In some embodiments, the MEK inhibitor is not 3-(4-methoxy-phenylamino)-isonicotinic acid, 3-phenylamino-isonicotinic acid methyl ester, 2,3,6-trifluoro-5-phenylamino-isonicotinic acid, or 3-oxo-3-(3-phenylamino-pyridin-4-yl)-propionic acid ethyl ester.

[0078] In some embodiments of the compound having the structure of Formula (I) or a pharma- ceutically acceptable salt thereof, R1 is selected from H and F. In some embodiments, R1 is H.

[0079] In some embodiments of a compound having the structure of Formula (I) or a pharma- ceutically acceptable salt thereof, R2 is selected from hydrogen, F, Cl, and Me, where the methyl group is optionally substituted with 1 to 3 fluorines. In some embodiments, R2 is F.

[0080] In some embodiments of the compound having the structure of Formula (I) or a pharma- ceutically acceptable salt thereof, R9 is selected from H, F, and Cl. In some embodiments, R9 is H.

[0081] In some embodiments of a compound having the structure of Formula (I) or a pharma- ceutically acceptable salt thereof, R 10is selected from H, F, Cl, Br, nitro, -SONR3R4 or -C(O)NR3R4, -Me, and -OMe, where the methyl group is optionally substituted with 1 to 3 fluorines. 10 is H.

[0082] In some embodiments of a compound having the structure of Formula (I) or a pharma- ceutically acceptable salt thereof, R 11 is selected from H, F, Cl, Br, Me, and -OMe, where the methyl group is optionally substituted with 1 to 3 fluorines. 11 is H.

[0083] In some embodiments of a compound having the structure of Formula (I) or a pharma- ceutically acceptable salt thereof, R 12 is selected from H, F, Cl, Br, nitro, Me, -SCF3, -SCHF2, -SCH2F, -SO2NR3R4, -C(O)NR3R4, and -OMe, where the methyl group is optionally substituted with 1 to 3 fluorines. 12 is I.

[0084] In some embodiments of a compound having the structure of Formula (I) or a pharma- ceutically acceptable salt thereof, R 13 is H or F. In some embodiments, R 13 is H. In some embodiments of a compound having the structure of Formula (I) or a pharma- ceutically acceptable salt thereof, R 14 is H or F. In some embodiments, R 14 is H.

[0085] In some embodiments of a compound having the structure of Formula (I) or a pharma- ceutically acceptable salt thereof, W is —C(O)OR 15 , -C(O)NR4R 15 , -C(O)NR4OR 15 , -C(O)(C2-C 10 alkyl), or -C(O)NR4S(O) jIn some embodiments, W is -C(O)NHR 15 In some embodiments, R 15 is C1-C4 alkyl or C1-C4 alkenyl, each independently and optionally substituted with 1-3 -OH, -OMe, -NH2, -N(methyl)2, or -N(ethyl)2. 15 is C1-C4 alkyl substituted with 1-3 -OH. In some embodiments, W is [ka] In some embodiments, W is [ka] It is.

[0086] In some embodiments of the compounds having the structure of Formula (I) or a pharma- ceutically acceptable salt thereof, X is N.

[0087] In some embodiments, the MEK inhibitor is a compound having the structure of Formula (Ia) or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, R2, R 12 , R 10 , and R 11 are independently hydrogen, halogen, cyano, nitro, azido, -OR3, -NR4C(O)OR6, -OC(O)R3, -NR4S(O) j R6, -S(O) j NR3R4, -S(O) j NR4C(O)R3, -C(O)NR4S(O) j R6, -S(O) j R6, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, - NR5C(NCN)NR3R4, -NR3R4, C1~C 10 Alkyl, C2-C 10 Alkenyl, C2-C10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, -S(O) j (C1-C6 alkyl), -S(O) j (CR4R5) m -aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5) m -Aryl, -NR4(CR4R5) m -aryl, -O(CR4R5) m -heteroaryl, -NR4(CR4R5) m , heteroaryl, -O(CR4R5) m -Heterocyclyl, -NR4(CR4R5) m -heterocyclyl and -S(C1-C2 alkyl) substituted with 1-5 fluorines, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is independently substituted or unsubstituted; R3 is hydrogen, trifluoromethyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10and aryl is selected from cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, and aryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocyclyl is independently substituted or unsubstituted; and aryl is selected from oxo, halogen, nitro, CF, CHF, CHF, OCF, OCHF, OCHF, azido, NR'SOR'', S. optionally substituted with 1 to 5 groups independently selected from O2N'', C(O)R', C(O)OR', OC(0)R', NR'C(O)OR'''', NR'C(O)R'', C(O)NR'R'', SR'''', S(0)R'''', S02R', NR'R'', NR'C(O)NR''R''', NR'C(NCN)N''R''', OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R4 is hydrogen or C 1~6 alkyl, which may be substituted or unsubstituted; or R3 and R4, together with the atoms to which they are attached, may each form a substituted or unsubstituted 4-10 membered heteroaryl or heterocyclic ring; R5 is hydrogen or C1-C6 alkyl, which may be substituted or unsubstituted; or R4 and R5, together with the atoms to which they are attached, may each form a substituted or unsubstituted 4-10 membered carbocyclic, heteroaryl, or heterocyclic ring; R6 is trifluoromethyl, C1-C 10 Alkyl, C3-C 10 selected from cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is independently substituted or unsubstituted; R', R'', and R''' are independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, aryl, and arylalkyl; R'''' is selected from C1-C4 alkyl, C2-C4 alkenyl, aryl and arylalkyl; m is 0, 1, 2, 3, 4 or 5; j is 1 or 2).

[0088] In some embodiments, the MEK inhibitor is a compound having the structure of Formula (Ia) or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, R2, R 12 , R 10 , and R 11 are independently hydrogen, halogen, cyano, nitro, azido, -OR3, -NR4C(O)OR6, -OC(O)R3, -NR4S(O) j R6, -S(O) j NR3R4, -S(O) j NR4C(O)R3, -C(O)NR4S(O) j R6, -S(O) j R6, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, - NR5C(NCN)NR3R4, -NR3R4, C1~C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, -S(O) j (C1-C6 alkyl), -S(O) j (CR4R5) m -aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5) m -Aryl, -NR4(CR4R5) m -aryl, -O(CR4R5) m-heteroaryl, -NR4(CR4R5) m , heteroaryl, -O(CR4R5) m -Heterocyclyl, -NR4(CR4R5) m -heterocyclyl and -S(C1-C2 alkyl) substituted with 1-5 fluorines, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is independently substituted or unsubstituted; R3 is hydrogen, trifluoromethyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 and aryl is selected from cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, and aryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocyclyl is independently substituted or unsubstituted; and aryl is selected from oxo, halogen, nitro, CF, CHF, CHF, OCF, OCHF, OCHF, azido, NR'SOR'', S. optionally substituted with 1 to 5 groups independently selected from O2N'', C(O)R', C(O)OR', OC(0)R', NR'C(O)OR'''', NR'C(O)R'', C(O)NR'R'', SR'''', S(0)R'''', S02R', NR'R'', NR'C(O)NR''R''', NR'C(NCN)N''R''', OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R4 is hydrogen or C 1~6 alkyl, which may be substituted or unsubstituted; or R3 and R4, together with the atoms to which they are attached, may each form a substituted or unsubstituted 4-10 membered heteroaryl or heterocyclic ring; R5 is hydrogen or C1-C6 alkyl, which may be substituted or unsubstituted; or R4 and R5, together with the atoms to which they are attached, may each form a substituted or unsubstituted 4-10 membered carbocyclic, heteroaryl, or heterocyclic ring; R6 is trifluoromethyl, C1-C 10 Alkyl, C3-C 10 selected from cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is independently substituted or unsubstituted; R', R'', and R''' are independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, aryl, and arylalkyl; R'''' is selected from C1-C4 alkyl, C2-C4 alkenyl, aryl and arylalkyl; m is 0, 1, 2, 3, 4 or 5; j is 1 or 2).

[0089] In some embodiments of the compound having the structure of Formula (Ia), Formula (Ia'), or a pharma- ceutically acceptable salt thereof, R2 is selected from hydrogen, F, Cl, and Me, where the methyl group is optionally substituted with 1 to 3 fluorines. In some embodiments, R2 is F.

[0090] In some embodiments of a compound having the structure of Formula (Ia), Formula (Ia'), or a pharma- ceutically acceptable salt thereof, R 12 is selected from H, F, Cl, Br, nitro, Me, -SCF3, -SCHF2, -SCH2F, -SO2NR3R4, -C(O)NR3R4, and -OMe, where the methyl group is optionally substituted with 1 to 3 fluorines. 12 is I.

[0091] In some embodiments of a compound having the structure of Formula (Ia), Formula (Ia'), or a pharma- ceutically acceptable salt thereof, R 10 is selected from H, F, Cl, Br, nitro, -SO2NR3R4 or -C(O)NR3R4, -Me, and -OMe, where the methyl group is optionally substituted with 1 to 3 fluorines. 10 is H.

[0092] In some embodiments of a compound having the structure of Formula (Ia), Formula (Ia'), or a pharma- ceutically acceptable salt thereof, R 11 is selected from H, F, Cl, Br, Me, and -OMe, where the methyl group is optionally substituted with 1 to 3 fluorines. 11 is H.

[0093] In some embodiments, the MEK inhibitor is a compound having the structure of Formula (Ib) or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, R2 and R 12 , independently represent hydrogen, halogen, cyano, nitro, azide, -OR3, -C1 to -C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 selected from cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is independently substituted or unsubstituted; W is -C(O)NR4R 15 , -C(O)NR4OR 15 , -C(O)NR4NR4NR 15, -NR'R'', -NR'C(O)R', -NRC(O)NR'R'', or -C(O)NR4NR4C(O)R 15 Selected from; R3 is hydrogen, trifluoromethyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 and aryl is selected from cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, and aryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocyclyl is independently substituted or unsubstituted; and aryl is selected from oxo, halogen, nitro, CF, CHF, CHF, OCF, OCHF, OCHF, azido, NR'SOR'', S. optionally substituted with 1 to 5 groups independently selected from O2N'', C(O)R', C(O)OR', OC(0)R', NR'C(O)OR'''', NR'C(O)R'', C(O)NR'R'', SR'''', S(0)R'''', S02R', NR'R'', NR'C(O)NR''R''', NR'C(NCN)N''R''', OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R4 is hydrogen or C 1~6 alkyl, which may be substituted or unsubstituted; R 15 is hydrogen, trifluoromethyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10selected from cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is independently substituted or unsubstituted; R', R'', and R''' are independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, aryl, and arylalkyl; R'''' is selected from C1-C4 alkyl, C2-C4 alkenyl, aryl and arylalkyl.

[0094] In some embodiments of a compound having the structure of Formula (Ib) or a pharma- ceutically acceptable salt thereof, R2 is selected from hydrogen, F, Cl, and Me, where the methyl group is optionally substituted with 1 to 3 fluorines. In some embodiments, R2 is F.

[0095] In some embodiments of a compound having the structure of Formula (Ib) or a pharma- ceutically acceptable salt thereof, R 12 is selected from H, F, Cl, Br, nitro, Me, -SCF3, -SCHF2, -SCH2F, -SO2NR3R4, -C(O)NR3R4, and -OMe, where the methyl group is optionally substituted with 1 to 3 fluorines. 12 is I.

[0096] In some embodiments of a compound having the structure of Formula (Ib) or a pharma- ceutically acceptable salt thereof, W is —C(O)OR 15 , -C(O)NR4R 15 , -C(O)NR4OR 15 , -C(O)(C2-C 10 alkyl), or -C(O)NR4S(O) j In some embodiments, W is -C(O)NHR 15 In some embodiments, R 15is C1-C4 alkyl or C1-C4 alkenyl, each independently and optionally substituted with 1-3 -OH, -OMe, -NH2, -N(methyl)2, or -N(ethyl)2. 15 is C1-C4 alkyl substituted with 1-3 -OH. In some embodiments, W is [ka] It is.

[0097] In some embodiments, the MEK inhibitor is: [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the MEK inhibitor is [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the MEK inhibitor or salt thereof is N-[(2S)-2,3-dihydroxypropyl]-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide hydrochloride (i.e., N-[(2S)-2,3-dihydroxypropyl]-3-[(2-fluoro-4-iodophenyl)amino]pyridine-4-carboxamide hydrochloride). In some embodiments, the MEK inhibitor or salt thereof is [ka] In some embodiments, the MEK inhibitor is N-((1R,2S,3R)-2,3-dihydroxycyclohexyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide or a pharma- ceutically acceptable salt thereof.

[0098] In some embodiments, the MEK inhibitor is: [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the MEK inhibitor is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the MEK inhibitor is N-((S)-2,3-dihydroxy-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide (pimasertib) or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the MEK inhibitor, or a pharma- ceutically acceptable salt thereof, is selected from cobimetinib, selumetinib, pimasertib, PD0325901, refametinib, binimetinib, BI-847325, trametinib, GDC-0623, G-573, CH5126766, CI-1040, PD035901, and TAK-933. In some embodiments, the MEK inhibitor or a pharma- ceutically acceptable salt thereof is selected from cobimetinib, selumetinib, pimasertib, PD0325901, refametinib, binimetinib, BI-847325, trametinib, GDC-0623, G-573, CH5126766, CI-1040, PD035901, TAK-933, and CIP-137401. [ka] In some embodiments, the MEK inhibitor is selected from: In some embodiments, the MEK inhibitor is a MEK inhibitor described in U.S. Patent No. 7,777,050, U.S. Patent No. 8,178,693, U.S. Patent No. 9,562,016, U.S. Patent No. 7,425,637, U.S. Patent No. 8,178,693, U.S. Patent No. 9,156,795, U.S. Patent No. 9,562,017, U.S. Patent No. 7,378,423, U.S. Patent No. 8,703,781, U.S. Patent No. 9,290,468, each of which is hereby individually incorporated by reference in its entirety. In some embodiments, the MEK inhibitor is selected from: [ka] [ka] [ka] [ka] [ka] and pharmaceutically acceptable salts thereof. In some embodiments, the MEK inhibitor is CIP-137401. In some embodiments, the MEK inhibitor has CAS No. 1404099-63-3. In some embodiments, the MEK inhibitor is selumetinib.

[0100] In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 5 mg to about 500 mg. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 10 mg to about 150 mg. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 10 mg to about 125 mg. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 10 mg to about 100 mg. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 25 mg to about 100 mg. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 50 mg to about 100 mg. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 5 mg to about 75 mg. In some embodiments, the MEK inhibitor or its salt is administered to the subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg. In some embodiments, the MEK inhibitor or its salt is administered to the subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg. In some embodiments, the MEK inhibitor or its salt is administered to the subject at about 15 mg. In some embodiments, the MEK inhibitor or its salt is administered to the subject at about 30 mg. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 45 mg. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 60 mg. In some embodiments, the subject is between 12 and 18 years of age. In some embodiments, the subject is between the ages of more than or equal to 12 years of age and less than or equal to 18 years of age. In some embodiments, the subject is an adult. In some embodiments, the subject is more than or equal to 18 years of age.

[0101] In some embodiments, the MEK inhibitor or salt thereof described herein is administered once a day. In some embodiments, the MEK inhibitor or salt thereof is administered twice a day. In some embodiments, the MEK inhibitor or salt thereof is administered three times a day. In some embodiments, the MEK inhibitor or salt thereof is administered once a week. In some embodiments, the MEK inhibitor or salt thereof is administered every other day. In some embodiments, the MEK inhibitor or salt thereof is administered every third day.

[0102] In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at 10 mg to 150 mg. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at 10 mg to 125 mg. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at 10 mg to 100 mg. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at 25 mg to 100 mg. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at 50 mg to 100 mg. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at 5 mg to 75 mg. In some embodiments, the MEK inhibitor or its salt is administered to the subject at 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg. In some embodiments, the MEK inhibitor or its salt is administered to the subject at 15 mg, 30 mg, 45 mg, or 60 mg. In some embodiments, the MEK inhibitor or its salt is administered to the subject at 15 mg. In some embodiments, the MEK inhibitor or its salt is administered to the subject at 30 mg. In some embodiments, the MEK inhibitor or its salt is administered to the subject at 45 mg. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at 60 mg. In some embodiments, the subject is between 12 and 18 years old. In some embodiments, the subject is between 12 years old or older and 18 years old or younger. In some embodiments, the subject is an adult. In some embodiments, the subject is over 18 years old or older.

[0103] In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 10 mg to about 150 mg daily. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 10 mg to about 125 mg daily. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 10 mg to about 100 mg daily. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 25 mg to about 100 mg daily. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 50 mg to about 100 mg daily. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 5 mg to about 75 mg daily. In some embodiments, the MEK inhibitor or its salt is administered to the subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg daily. In some embodiments, the MEK inhibitor or its salt is administered to the subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg daily. In some embodiments, the MEK inhibitor or its salt is administered to the subject at about 15 mg daily. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 30 mg daily. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 45 mg daily. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 60 mg daily. In some embodiments, the MEK inhibitor or salt thereof is administered once a day. In some embodiments, the subject is between 12 and 18 years old. In some embodiments, the subject is between the ages of more than or equal to 12 years old and less than or equal to 18 years old. In some embodiments, the subject is an adult. In some embodiments, the subject is more than or equal to 18 years old.

[0104] In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 10 mg to about 150 mg twice daily. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 10 mg to about 125 mg twice daily. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 10 mg to about 100 mg twice daily. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 25 mg to about 100 mg twice daily. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 50 mg to about 100 mg twice daily. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 5 mg to about 75 mg twice daily. In some embodiments, the MEK inhibitor or its salt is administered to the subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg twice a day. In some embodiments, the MEK inhibitor or its salt is administered to the subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg twice a day. In some embodiments, the MEK inhibitor or its salt is administered to the subject at about 15 mg twice a day. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 30 mg twice a day. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 45 mg twice a day. In some embodiments, the MEK inhibitor or salt thereof is administered to the subject at about 60 mg twice a day. In some embodiments, the subject is between 12 and 18 years of age. In some embodiments, the subject is between the ages of more than or equal to 12 years of age and less than or equal to 18 years of age. In some embodiments, the subject is an adult. In some embodiments, the subject is more than or equal to 18 years of age.

[0105] In some embodiments, the MEK inhibitor or its salt is pimasertib or its salt. In some embodiments, the MEK inhibitor or its salt is pimasertib hydrochloride. In some embodiments, the MEK inhibitor is pimasertib. In some embodiments, the dosage described herein for the MEK inhibitor or its salt is based on the weight of the MEK inhibitor. In some embodiments, the dosage described herein for the MEK inhibitor or its salt corresponds to the weight of the free base form of the MEK inhibitor. For example, in some embodiments, the dosage of pimasertib or its salt is described as the weight of pimasertib in such dosage. In some embodiments, the dosage described herein for the MEK inhibitor or its salt corresponds to the weight of the salt of the MEK inhibitor.

[0106] In some embodiments, pimasertib (e.g., as a pimasertib salt or pimasertib free base) is administered to the subject at about 10 mg to about 150 mg. In some embodiments, pimasertib is administered to the subject at about 10 mg to about 125 mg. In some embodiments, pimasertib is administered to the subject at about 10 mg to about 100 mg. In some embodiments, pimasertib is administered to the subject at about 25 mg to about 100 mg. In some embodiments, pimasertib is administered to the subject at about 50 mg to about 100 mg. In some embodiments, pimasertib is administered to the subject at about 5 mg to about 75 mg. In some embodiments, pimasertib is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg. In some embodiments, pimasertib is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg. In some embodiments, pimasertib is administered to a subject at about 15 mg. In some embodiments, pimasertib is administered to a subject at about 30 mg. In some embodiments, pimasertib is administered to the subject at about 45 mg. In some embodiments, pimasertib is administered to the subject at about 60 mg. In some embodiments, the subject is between 12 and 18 years of age. In some embodiments, the subject is between 12 and 18 years of age and less than 18 years of age. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than 18 years of age. In some embodiments, pimasertib is administered in the form of a salt of pimasertib, such as pimasertib HCl.

[0107] In some embodiments, pimasertib (e.g., as a pimasertib salt or pimasertib free base) is administered to the subject at 10 mg to 150 mg. In some embodiments, pimasertib is administered to the subject at 10 mg to 125 mg. In some embodiments, pimasertib is administered to the subject at 10 mg to 100 mg. In some embodiments, pimasertib is administered to the subject at 25 mg to 100 mg. In some embodiments, pimasertib is administered to the subject at 50 mg to 100 mg. In some embodiments, pimasertib is administered to the subject at 5 mg to 75 mg. In some embodiments, pimasertib is administered to a subject at 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg. In some embodiments, pimasertib is administered to a subject at 15 mg, 30 mg, 45 mg, or 60 mg. In some embodiments, pimasertib is administered to a subject at 15 mg. In some embodiments, pimasertib is administered to a subject at 30 mg. In some embodiments, pimasertib is administered to a subject at 45 mg. In some embodiments, pimasertib is administered to the subject at 60 mg. In some embodiments, the subject is between 12 and 18 years of age. In some embodiments, the subject is between 12 years or older and 18 years or younger. In some embodiments, the subject is an adult. In some embodiments, the subject is over 18 years or older. In some embodiments, pimasertib is administered in the form of a salt of pimasertib, such as pimasertib HCl.

[0108] In some embodiments, pimasertib (e.g., as a pimasertib salt or pimasertib free base) is administered to a subject at about 10 mg to about 150 mg daily. In some embodiments, pimasertib is administered to a subject at about 10 mg to about 125 mg daily. In some embodiments, pimasertib is administered to a subject at about 10 mg to about 100 mg daily. In some embodiments, pimasertib is administered to a subject at about 25 mg to about 100 mg daily. In some embodiments, pimasertib is administered to a subject at about 50 mg to about 100 mg daily. In some embodiments, pimasertib is administered to a subject at about 5 mg to about 75 mg daily. In some embodiments, pimasertib is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg daily. In some embodiments, pimasertib is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg daily. In some embodiments, pimasertib is administered to a subject at about 15 mg daily. In some embodiments, pimasertib is administered to the subject at about 30 mg daily. In some embodiments, pimasertib is administered to the subject at about 45 mg daily. In some embodiments, pimasertib is administered to the subject at about 60 mg daily. In some embodiments, pimasertib is administered once a day. In some embodiments, the subject is between 12 and 18 years of age. In some embodiments, the subject is between the ages of greater than or equal to 12 years and less than or equal to 18 years. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years. In some embodiments, pimasertib is administered in the form of a salt of pimasertib, such as pimasertib HCl.

[0109] In some embodiments, pimasertib (e.g., as a pimasertib salt or pimasertib free base) is administered to a subject at about 10 mg to about 150 mg twice daily. In some embodiments, pimasertib is administered to a subject at about 10 mg to about 125 mg twice daily. In some embodiments, pimasertib is administered to a subject at about 10 mg to about 100 mg twice daily. In some embodiments, pimasertib is administered to a subject at about 25 mg to about 100 mg twice daily. In some embodiments, pimasertib is administered to a subject at about 50 mg to about 100 mg twice daily. In some embodiments, pimasertib is administered to a subject at about 5 mg to about 75 mg twice daily. In some embodiments, pimasertib is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg twice a day. In some embodiments, pimasertib is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg twice a day. In some embodiments, pimasertib is administered to a subject at about 15 mg twice a day. In some embodiments, pimasertib is administered to the subject at about 30 mg twice daily. In some embodiments, pimasertib is administered to the subject at about 45 mg twice daily. In some embodiments, pimasertib is administered to the subject at about 60 mg twice daily. In some embodiments, the subject is between 12 and 18 years of age. In some embodiments, the subject is between 12 and 18 years of age and less than 18 years of age. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than 18 years of age. In some embodiments, pimasertib is administered in the form of a salt of pimasertib, such as pimasertib HCl.

[0110] In some embodiments, pimasertib (e.g., as a pimasertib salt or pimasertib free base) is administered to a subject at about 10 mg to about 150 mg every other day. In some embodiments, pimasertib is administered to a subject at about 10 mg to about 125 mg every other day. In some embodiments, pimasertib is administered to a subject at about 10 mg to about 100 mg every other day. In some embodiments, pimasertib is administered to a subject at about 25 mg to about 100 mg every other day. In some embodiments, pimasertib is administered to a subject at about 50 mg to about 100 mg every other day. In some embodiments, pimasertib is administered to a subject at about 5 mg to about 75 mg every other day. In some embodiments, pimasertib is administered to a subject at about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg every other day. In some embodiments, pimasertib is administered to a subject at about 15 mg, about 30 mg, about 45 mg, or about 60 mg every other day. In some embodiments, pimasertib is administered to a subject at about 15 mg every other day. In some embodiments, pimasertib is administered to the subject at about 30 mg every other day. In some embodiments, pimasertib is administered to the subject at about 45 mg every other day. In some embodiments, pimasertib is administered to the subject at about 60 mg every other day. In some embodiments, the subject is between 12 and 18 years of age. In some embodiments, the subject is between the ages of greater than or equal to 12 years and less than or equal to 18 years of age. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than or equal to 18 years of age. In some embodiments, pimasertib is administered in the form of a salt of pimasertib, such as pimasertib HCl.

[0111] In some embodiments, selumetinib (e.g., as a selumetinib salt or selumetinib free base) is administered to the subject at about 2 mg to about 15 mg. In some embodiments, selumetinib is administered to the subject at about 5 mg to about 15 mg. In some embodiments, selumetinib is administered to the subject at about 10 mg to about 15 mg. In some embodiments, selumetinib is administered to the subject at about 2 mg to about 8 mg. In some embodiments, selumetinib is administered to the subject at about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg. In some embodiments, selumetinib is administered to the subject at about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 6 mg. In some embodiments, selumetinib is administered to a subject at about 7 mg, about 8 mg, about 9 mg, about 10 mg, or about 11 mg. In some embodiments, selumetinib is administered to a subject at about 12 mg, about 13 mg, about 14 mg, or about 15 mg. In some embodiments, the subject is between 12 and 18 years old. In some embodiments, the subject is between 12 years old or older and 18 years old or younger. In some embodiments, the subject is an adult. In some embodiments, the subject is over 18 years old or older.

[0112] In some embodiments, selumetinib (e.g., as a selumetinib salt or selumetinib free base) is administered to a subject at about 2 mg to about 15 mg daily. In some embodiments, selumetinib is administered to a subject at about 5 mg to about 15 mg daily. In some embodiments, selumetinib is administered to a subject at about 10 mg to about 15 mg daily. In some embodiments, selumetinib is administered to a subject at about 2 mg to about 8 mg daily. In some embodiments, selumetinib is administered to a subject at about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg daily. In some embodiments, selumetinib is administered to a subject at about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 6 mg daily. In some embodiments, selumetinib is administered to a subject at about 7 mg, about 8 mg, about 9 mg, about 10 mg, or about 11 mg daily. In some embodiments, selumetinib is administered to a subject at about 12 mg, about 13 mg, about 14 mg, or about 15 mg daily. In some embodiments, the subject is between 12 and 18 years old. In some embodiments, the subject is between 12 and 18 years old. In some embodiments, the subject is an adult. In some embodiments, the subject is over 18 years old or is 18 years old.

[0113] In some embodiments, selumetinib (e.g., as a selumetinib salt or selumetinib free base) is administered to a subject at about 2 mg to about 15 mg twice daily. In some embodiments, selumetinib is administered to a subject at about 5 mg to about 15 mg twice daily. In some embodiments, selumetinib is administered to a subject at about 10 mg to about 15 mg twice daily. In some embodiments, selumetinib is administered to a subject at about 2 mg to about 8 mg twice daily. In some embodiments, selumetinib is administered to a subject at about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg twice daily. In some embodiments, selumetinib is administered to a subject at about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 6 mg twice a day. In some embodiments, selumetinib is administered to a subject at about 7 mg, about 8 mg, about 9 mg, about 10 mg, or about 11 mg twice a day. In some embodiments, selumetinib is administered to a subject at about 12 mg, about 13 mg, about 14 mg, or about 15 mg twice a day. In some embodiments, the subject is between 12 and 18 years old. In some embodiments, the subject is between 12 and 18 years old. In some embodiments, the subject is an adult. In some embodiments, the subject is over 18 years old or is 18 years old.

[0114] C. Mutations and Indications The methods presented herein can be used to treat cancers with high unmet medical need. In some embodiments, the methods are used to treat a genetically defined subset of cancers. In some embodiments, the cancer has one or more of the following mutations: RAS positive mutation, RAF positive mutation, MEK positive mutation, and ERK positive mutation. In some embodiments, the cancer has an NRAS mutation, a KRAS mutation, or an HRAS mutation. In some embodiments, the cancer has a BRAF mutation, a BRAF fusion, or a CRAF fusion. In some embodiments, the BRAF mutation is a non-V600 BRAF mutation. In some embodiments, the BRAF mutation is a V600 BRAF mutation. In some embodiments, the cancer has a class I BRAF mutation, a class II BRAF mutation, or a class III BRAF mutation. In some embodiments, the subject has a class I BRAF mutation, a class II BRAF mutation, or a class III BRAF mutation. In some embodiments, the cancer has a class I BRAF mutation. In some embodiments, the cancer has a class II BRAF mutation. In some embodiments, the cancer has a class III BRAF mutation. In some embodiments, the subject has a class I BRAF mutation or a class II BRAF mutation. In some embodiments, the subject lacks a V600E mutation, a V600K mutation, or both. In some embodiments, the subject has a non-V600 BRAF mutation. In some embodiments, the methods disclosed herein have anti-proliferative activity in the subject. In some embodiments, the cancer has genomic alterations that result in dependency on signaling through the MAPK pathway.

[0115] In some embodiments, the cancer is a recurrent, progressive, or refractory solid tumor with mitogen-activated protein kinase (MAPK) pathway abnormalities. In some embodiments, the cancer is recurrent and has mitogen-activated protein kinase (MAPK) pathway abnormalities. In some embodiments, the cancer is progressive and has mitogen-activated protein kinase (MAPK) pathway abnormalities. In some embodiments, the cancer is refractory and has mitogen-activated protein kinase (MAPK) pathway abnormalities. In some embodiments, the cancer is a recurrent or progressive solid tumor with abnormalities of key proteins in the mitogen-activated protein kinase (MAPK) pathway, such as tumors with RAS or RAF alterations. In some embodiments, the cancer is a recurrent or progressive solid tumor with abnormalities of key proteins in the mitogen-activated protein kinase (MAPK) pathway, such as tumors with BRAF fusions or CRAF fusions.

[0116] In some embodiments, the cancer has a mitogen-activated protein kinase (MAPK) abnormality. In some embodiments, the cancer has a mitogen-activated protein kinase (MAPK) abnormality selected from mutation or gene fusion. In some embodiments, the MAPK abnormality is selected from RAS positive mutation, RAF positive mutation, MEK positive mutation, ERK positive mutation and gene fusion. In some embodiments, the cancer has a MAPK abnormality selected from NRAS mutation, KRAS mutation, or HRAS mutation. In some embodiments, the cancer has a MAPK abnormality selected from BRAF mutation, BRAF fusion, and CRAF fusion.

[0117] In some embodiments, the subject has been identified as having one or more BRAF fusions. In some embodiments, the subject has been identified as having one or more of the following fusions: KIAA1549:BRAF, STARD3NL:BRAF, BCAS1:BRAF, KHDRBS2:BRAF, CCDC6:BRAF, FAM131B:BRAF, SRGAP:BRAF, CLCN6:BRAF, GNAI1:BRAF, MRKN1:BRAF, GIT2:BRAF, GTF21:BRAF, FXR1:BRAF, RNF130:BRAF, BRAF:MACF1, TMEM106B:BRAF, PPC1CC:BRAF, CUX1:B:BRAF, ... The subject is identified as having one or more of RAF, AGK:BRAF, AGAP3:BRAF, TNS3:BRAF, TARDBP:BRAF, ARMC10:BRAF, CUL1:BRAF, TRIM24:BRAF, AKAP9:BRAF, FKBP15:BRAF, SKAP2:BRAF, ZKSCAN1:BRAF, KLHL7:BRAF, SEPT3:BRAF, SRGAP3:RAF1, QK1:RAF1, FYCO:RAF1, ATG7:RAF1 and NFIA:RAF1.In some embodiments, the subject is identified as having KIAA1549:BRAF fusion.In some embodiments, the method disclosed herein is BRAF fusion.

[0118] In some embodiments, the methods disclosed herein can be used to regulate RAF monomer or dimer. In some embodiments, regulate RAF monomer. In some embodiments, regulate RAF dimer. In some embodiments, the regulation disclosed herein is inhibition.

[0119] In some embodiments, the cancer is a B-Raf mutation-positive cancer (i.e., the cancer has one or more B-Raf mutations). In some embodiments, the B-Raf mutation is in exon 11 or 15. In some embodiments, the B-Raf mutation is in codon 466, 469, 594, 600, or 601. In some embodiments, the B-Raf mutation is in codon 600. In some embodiments, the B-Raf mutation includes, but is not limited to, a V600E, V600D, or V600K mutation. In some embodiments, the B-Raf mutation is V600E. In some embodiments, the B-Raf mutation is V600D. In some embodiments, the B-Raf mutation is V600K. In some embodiments, the B-Raf mutation is V600E+T5291. In some embodiments, the B-Raf mutation is V600E+G468A. "V600E mutation" refers to a substitution of valine with glutamic acid at amino acid position 600. T529I is a threonine to isoleucine B-Raf gatekeeper mutation and G468A is a G1403C B-Raf secondary mutation in exon 11. "V600K mutation" refers to a substitution of valine with lysine at amino acid position 600. "V600D mutation" refers to a substitution of valine with aspartic acid at amino acid position 600. The V600K mutation results in an amino acid substitution of valine (V) with lysine (K) at position 600 of B-Raf. The V600K mutation results in an amino acid substitution of valine (V) with lysine (K) at position 600 of B-Raf.

[0120] In some embodiments, the cancer is a non-V600 B-Raf mutation positive cancer (i.e., the cancer has one or more B-Raf mutations, and the one or more mutations are not B-Raf V600). In some embodiments, the B-Raf mutation is in exon 11 or 15. In some embodiments, the B-Raf mutation is in codon 466, 469, 594, or 601. In one aspect, the one or more non-V600E mutations are G466A, G466V, N581S, D594H, R146W, L613F, D565_splice, S394 *, P367R, G469A, G469V, G469 * , G466V, G464V, G397S, SI131, A762E, G469L, D594N, G596S, G596R, D594N, D594H, K601E, K601N, L597Q, L597V, G469R, D594G, or G327_splice. In one embodiment, the one or more non-V600E mutations are G469R, R95T, A621_splice, V639I, Q609H, G464V, or G466V. An asterisk " * " means a stop codon.

[0121] In some embodiments, the cancers described herein have a V600 BRAF mutation. In some embodiments, the cancers described herein have a genetic mutation or fusion as described in Tables 1-7.

[0122] In some embodiments, the cancer is identified as having a non-V600 BRAF mutation selected from V600E, G469A, G464V, G466V, K601E, G469R, and L597R. In some embodiments, the non-V600 BRAF mutation is selected from V600E, G464A, G464V, K601E, and G469R. In some embodiments, the non-V600 BRAF mutation is selected from G464V, K601E, G469A, and G466V.

[0123] In some embodiments, the cancer is a K-Ras mutation-positive cancer (i.e., the cancer has one or more K-Ras mutations). In some embodiments, the K-Ras mutation is in exon 2. In some embodiments, the K-Ras mutation is in codon 12 or 13. In some embodiments, the cancer has been identified as having a RAS mutation. In some embodiments, the RAS mutation is a KRAS mutation. In some embodiments, the KRAS mutation is selected from KRAS G12C, KRAS G12V, KRAS G12D, KRAS Q61K, KRAS Q61H, KRAS G13D, and KRAS G12S. In some embodiments, the KRAS mutation is selected from KRAS G12C, KRAS G12D, KRAS G13D, and KRAS G12S.

[0124] In some embodiments, the cancer is an N-Ras mutation-positive cancer (i.e., the cancer has one or more N-Ras mutations). In some embodiments, the N-Ras mutation is present in exon 2, 3, or 4. In some embodiments, the N-Ras mutation is present in exon 2. In some embodiments, the N-Ras mutation is present in exon 3. In some embodiments, the N-Ras mutation is present in exon 4. In some embodiments, the N-Ras mutation is Q61R, Q61K, Q61L, Q61H, or Q61P. In some embodiments, the N-Ras mutation is a Q61R mutation.

[0125] The present disclosure provides a method of treating a subject suffering from cancer. In some embodiments, the cancer is selected from lung cancer, colorectal cancer, pancreatic cancer, skin cancer, glioma, non-glioma brain cancer, osteosarcoma, gastrointestinal cancer, breast cancer, thyroid cancer, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and multiple myeloma (MM). In some embodiments, the lung cancer comprises non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). In some embodiments, the cancer is not NSCLC. In some embodiments, the cancer is a urothelial tumor. In some embodiments, the cancer is a low-grade glioma (LGG). In some embodiments, the cancer is a pediatric low-grade glioma (PLGG). In some embodiments, the LGG is newly diagnosed. In some embodiments, the cancer is a pediatric brain tumor. In some embodiments, the cancer is a neuroblastoma. In some embodiments, the cancer is a urothelial tumor with focal amplification of the RAF1 kinase gene. In some embodiments, the cancer is a RAF1-amplified tumor. In some embodiments, the cancer is a RAF1-amplified tumor that exhibits activation of the MAPK signaling pathway and exhibits a luminal gene expression pattern. In some embodiments, the cancer is an advanced solid tumor.

[0126] In some embodiments, the cancer is recurrent, progressive, or refractory. In some embodiments, the cancer is recurrent. In some embodiments, the cancer is progressive. In some embodiments, the cancer is refractory.

[0127] In some embodiments, the cancers described herein are newly diagnosed. In some embodiments, the cancers described herein have not undergone any previous cancer treatment. Thus, in some embodiments, the treatment methods described herein can be used as front-line therapy.

[0128] In some embodiments, the cancer is a hematological malignancy. In some embodiments, the hematological malignancy is selected from acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphoblastic leukemia (CLL), and myelodysplasia syndrome. In some embodiments, the hematological malignancy is selected from acute myelogenous leukemia (AML) and chronic lymphocytic leukemia (CLL).

[0129] In some embodiments, the cancer is selected from thyroid cancer, ovarian cancer, melanoma, acute myelogenous leukemia (AML), and colon cancer. In some embodiments, the cancer is melanoma or colon cancer.

[0130] In some embodiments, the cancer is selected from skin cancer and gastrointestinal cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the skin cancer is melanoma. In some embodiments, the melanoma is B-Raf mutated melanoma. In some embodiments, the melanoma is N-Ras mutated melanoma. In some embodiments, the cancer is gastrointestinal cancer. As used herein, "gastrointestinal cancer" includes cancer of the esophagus, cancer of the stomach (also known as gastric cancer), cancer of the biliary system, cancer of the pancreas, cancer of the small intestine, cancer of the colon, cancer of the rectum, and cancer of the anus. In some embodiments, the gastrointestinal cancer is esophageal adenocarcinoma, adenocarcinoma of the gastroesophageal junction, or gastric adenocarcinoma. In some embodiments, the gastrointestinal cancer is stomach cancer.

[0131] In some embodiments, the cancer is lung cancer, colorectal cancer or pancreatic cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is squamous NSCLC. In some embodiments, the cancer is non-squamous NSCLC.

[0132] In some embodiments, the cancer is colon cancer, which is also known as colorectal cancer (CRC), intestinal cancer, or rectal cancer.

[0133] In some embodiments, the cancer is a central nervous system cancer. In some embodiments, the central nervous system cancer is brain cancer. In some embodiments, the thyroid cancer is thyroid cancer. In some embodiments, the genitourinary cancer is bladder cancer.

[0134] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is an advanced solid tumor. In some embodiments, the cancer is non-small cell lung cancer.

[0135] In some embodiments, the cancer is a recurrent cancer. In some embodiments, the subject described herein has undergone at least one prior treatment that is considered standard of care before administration of compound A or its pharma- ceutically acceptable salt or MEK inhibitor. In some embodiments, the prior treatment is a systemic treatment. In some embodiments, the prior treatment is chemotherapy, hormonal therapy, immunotherapy, or radiation therapy. In some embodiments, the method disclosed herein may target MAPK signaling. In some embodiments, the method disclosed herein may have antitumor activity against solid tumors.

[0136] Identification method Provided herein is a method of treating cancer, comprising administering an amount of Compound A or a pharma- ceutically acceptable salt thereof, and a MEK inhibitor (e.g., pimasertib). In some embodiments, provided herein is a method of treating cancer, comprising administering an amount of Compound A or a pharma- ceutically acceptable salt thereof, and a MEK inhibitor (e.g., pimasertib), wherein the total amount of Compound A or a pharma- ceutically acceptable salt thereof and the MEK inhibitor is therapeutically effective in treating cancer. The present disclosure further provides a step of identifying a subject suffering from cancer. In some embodiments, the method provided herein provides a step of identifying a subject suffering from cancer, the cancer having one or more of RAF alterations, RAS mutations, NF-1 mutations, or genomic alterations that result in a dependency on signaling through the MAPK pathway. In some embodiments, the step of identifying the subject is performed prior to the step of administering a RAF inhibitor and a MEK inhibitor to the subject. In some embodiments, the method of treating a subject suffering from cancer includes: (a) identifying a subject suffering from cancer, the cancer having one or more of a RAF alteration, a RAS mutation, an NF-1 mutation, or a genomic alteration that results in a dependency on signaling through the MAPK pathway; and (b) To the subject, (i) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharma- ceutically acceptable salt thereof; and (ii) a MEK inhibitor as provided herein; and administering to the subject a total amount of compound A or a pharma- ceutically acceptable salt thereof and a MEK inhibitor that is therapeutically effective in treating cancer. In some embodiments, the MEK inhibitor is a MEK inhibitor described herein. In some embodiments, the method provides a synergistic effect when administered. The identification method described herein can be combined with any other aspect or embodiment disclosed herein. In some embodiments, the identification includes genomic testing (e.g., mutation testing). In some embodiments, genetic testing is performed on the subject's cancer sample. In some embodiments, prior to administering compound A or a pharma- ceutically acceptable salt thereof or a MEK inhibitor, the subject's cancer sample has been subjected to BRAF, KRAS, CRAF, HRAS, NF-1 and / or NRAS mutation testing. In some embodiments, prior to administering compound A or a pharma- ceutically acceptable salt thereof or a MEK inhibitor, the subject's cancer sample has been subjected to genomic testing, where the genomic testing demonstrates that the genomic alteration creates a dependency on MPAK signaling. In some embodiments, the subject has been diagnosed with a histologically confirmed non-hematological tumor. In some embodiments, the subject has been diagnosed with a histologically confirmed hematological neoplasm.

[0137] In some embodiments, the identifying step comprises identifying a subject having one or more cancer mutations or gene fusions as described herein. In some embodiments, the cancer has one or more of the following mutations: RAS positive mutation, RAF positive mutation, MEK positive mutation, ERK positive mutation, or any combination thereof. In some embodiments, the identifying step comprises identifying a cancer mutation disclosed herein. In some embodiments, the cancer has a RAS mutation. In some embodiments, the RAS mutation is an HRAS mutation, a KRAS, or an NRAS mutation. In some embodiments, the cancer has a mutation in NF-1 that results in NF-1 loss of function.

[0138] In some embodiments, the identifying step comprises identifying a subject having a RAF alteration. In some embodiments, the RAF alteration is a BRAF mutation, a BRAF fusion, or a CRAF fusion. In some embodiments, the cancer has a non-V600 BRAF mutation. In some embodiments, the subject has a class I BRAF mutation or a class II BRAF mutation. In some embodiments, the subject lacks a V600E mutation, a V600K mutation, or both.

[0139] In some embodiments, the identifying step comprises identifying a subject having a fusion. In some embodiments, the subject has one or more of the following fusions: KIAA1549:BRAF, STARD3NL:BRAF, BCAS1:BRAF, KHDRBS2:BRAF, CCDC6:BRAF, FAM131B:BRAF, SRGAP:BRAF, CLCN6:BRAF, GNAI1:BRAF, MRKN1:BRAF, GIT2:BRAF, GTF21:BRAF, FXR1:BRAF, RNF130:BRAF, BRAF:MACF1, TMEM106B:BRAF, PPC1CC:BRAF, CUX1:BRAF, ... The subject is identified as having one or more of the following fusions: RAF, AGK:BRAF, AGAP3:BRAF, TNS3:BRAF, TARDBP:BRAF, ARMC10:BRAF, CUL1:BRAF, TRIM24:BRAF, AKAP9:BRAF, FKBP15:BRAF, SKAP2:BRAF, ZKSCAN1:BRAF, KLHL7:BRAF, SEPT3:BRAF, SRGAP3:RAF1, QK1:RAF1, FYCO:RAF1, ATG7:RAF1, and NFIA:RAF1. In some embodiments, the subject is identified as having one or more of the following fusions: AGK:BRAF, AGAP3:BRAF, TNS3:BRAF, or KIAA1549:BRAF. In some embodiments, the subject is identified as having AGAP3:BRAF fusion. In some embodiments, the subject is identified as having SRGAP3:RAF1 fusion. In some embodiments, the subject is identified as having KIAA1549:BRAF fusion.In some embodiments, the MEK inhibitor is N-((S)-2,3-dihydroxy-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide (pimasertib) or a pharmaceutically acceptable salt thereof.In some embodiments, the MEK inhibitor is a compound disclosed herein.

[0140] In some embodiments, the identifying step includes identifying a subject having a non-V600 BRAF mutation. In some embodiments, the non-V600 BRAF mutation is selected from V600E, G469A, G464V, G466V, K601E, G469R, and L597R. In some embodiments, the non-V600 BRAF mutation is selected from V600E, G464A, G464V, K601E, and G469R. In some embodiments, the non-V600 BRAF mutation is selected from G464V, K601E, G469A, and G466V.

[0141] In some embodiments, the identifying step comprises identifying the subject having a RAS mutation. In some embodiments, the RAS mutation is a KRAS mutation. In some embodiments, the KRAS mutation is selected from KRAS G12C, KRAS G12V, KRAS G12D, KRAS Q61K, KRAS Q61H, KRAS G13D and KRAS G12S. In some embodiments, the KRAS mutation is selected from KRAS G12C, KRAS G12D, KRAS G13D and KRAS G12S.

[0142] In some embodiments, the identifying step comprises identifying a subject having low-grade glioma (LGG). In some embodiments, the identifying step comprises identifying a subject having newly diagnosed LGG.

[0143] In some embodiments, the subject does not currently or previously have central serous retinopathy, retinal vein occlusion, or eye disease, unstable neurological condition, uncontrolled cardiovascular condition, and has not been administered any pan-RAF inhibitor.In some embodiments, the subject has not previously been administered pan-RAF treatment.In some embodiments, the subject has not been simultaneously administered other chemotherapeutic agents (such as conventional chemotherapy, targeted agents, monoclonal antibodies, etc.), or drugs with immunosuppressive properties (other than steroids).

[0144] In some embodiments, the subject has not received any prior therapy for treating cancer. In some embodiments, the methods described herein are used as a frontline therapy for treating cancer.

[0145] In some embodiments, the subject in need thereof is between about 6 months and 25 years old. In some embodiments, the subject in need thereof is between about 1 and 25 years old. In some embodiments, the subject in need thereof is 25 years old or younger. In some embodiments, the subject in need thereof is 20 years old or younger. In some embodiments, the subject in need thereof is 15 years old or younger. In some embodiments, the subject in need thereof is 10 years old or younger. In some embodiments, the subject in need thereof is 20 years old, 19 years old, 18 years old, 17 years old, 16 years old, 15 years old, 14 years old, 13 years old, 12 years old, 11 years old, 10 years old or younger. In some embodiments, the subject in need thereof is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 years old. In some embodiments, the subject in need thereof is under 18 years old. In some embodiments, the subject in need thereof is at least 18 years old. In some embodiments, the subject in need thereof is older than 18 years old.

[0146] In some embodiments, the dose of Compound A or a pharma- ceutically acceptable salt thereof required to achieve IC80 of pERK inhibition as measured by PMA-induced peripheral blood mononuclear cells (PBMCs) is at least about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% less than the dose of Compound A or a pharma- ceutically acceptable salt thereof required to achieve the same IC80 of pERK inhibition as monotherapy as measured by PMA-induced peripheral blood mononuclear cells (PBMCs). In some embodiments, the dose of Compound A or a pharma- ceutically acceptable salt thereof required to achieve IC80 of pERK inhibition as monotherapy is at least about 20% less than the dose of Compound A or a pharma- ceutically acceptable salt thereof required to achieve the same IC80 of pERK inhibition as monotherapy as measured by PMA-induced peripheral blood mononuclear cells (PBMCs). In some embodiments, the dose of Compound A or a pharma- ceutically acceptable salt thereof is a daily dose. In some embodiments, the dose of compound A or a pharma- ceutically acceptable salt thereof is a weekly dose. In some embodiments, the weekly dose of compound A or a pharma- ceutically acceptable salt thereof required to achieve IC80 of pERK inhibition measured by PMA-induced peripheral blood mononuclear cells (PBMC) is at least about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, or about 50% less than the weekly dose of compound A or a pharma- ceutically acceptable salt thereof required to achieve the same IC80 of pERK inhibition in monotherapy. In some embodiments, the dose of the MEK inhibitor or a pharma- ceutically acceptable salt thereof required to achieve an IC80 of pERK inhibition as measured by PMA-induced peripheral blood mononuclear cells (PBMCs) is at least about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% less than the dose of the MEK inhibitor or a pharma- ceutically acceptable salt thereof required to achieve the same IC80 of pERK inhibition as monotherapy. In some embodiments, the dose of the MEK inhibitor or a pharma- ceutically acceptable salt thereof required to achieve an IC80 of pERK inhibition as measured by PMA-induced peripheral blood mononuclear cells (PBMCs) is at least about 20% less than the dose of the MEK inhibitor or a pharma- ceutically acceptable salt thereof required to achieve the same IC80 of pERK inhibition as monotherapy.In some embodiments, the dose of the MEK inhibitor or pharma- ceutically acceptable salt thereof required to achieve IC80 of pERK inhibition as measured by PMA-induced peripheral blood mononuclear cells (PBMCs) is at least about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, or about 50% less than the dose of the MEK inhibitor or pharma- ceutically acceptable salt thereof required to achieve the same IC80 of pERK inhibition as monotherapy. In some embodiments, the dose of the MEK inhibitor or pharma- ceutically acceptable salt thereof is a daily dose. In some embodiments, the dose of the MEK inhibitor or pharma- ceutically acceptable salt thereof is a weekly dose. The IC80 of the pERK inhibitor can be measured by any suitable method known in the art, for example, as described in Adelmann et al., Oncotarget. 2016 May 24; 7 (21): 30453-30460. EXAMPLES

[0147] The invention outlined herein will be readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention in any way.

[0148] Example 1 Marker identification Markers with alterations or mutations can be identified by routine molecular assays performed in a Clinical Laboratory Improvement Amendments of 1988 (CLIA) certified laboratory or other similarly certified laboratories locally. Specifically, markers can be identified for any one of the following alterations or mutations: RAF alterations, RAS mutations, NF-1 mutations, or genomic alterations that result in dependency on signaling through the MAPK pathway.

[0149] Example 2 Treatment with RAF and MEK inhibitors Compound A in combination with MEK inhibitors described herein can be evaluated using mutant cell models or mutant cancer cell models. Animal models can be inoculated with tumor cells for tumor development. Weight and tumor growth can be monitored during tumor development. Inoculated subjects can be treated with Compound A, MEK inhibitors described herein, or a combination of Compound A and MEK inhibitors described herein. To investigate differences between control and treated groups, statistical tests can be used to determine tumor inhibition scores. Bliss Independence Analysis can be used for both 2D and 3D combination assays, with a score above 0 indicating synergy and a score below 0 indicating antagonism. A score of 0 indicates additive.

[0150] Example 3 Synergistic effects using RAF and MEK inhibitors in non-V600 BRAF mutant tumor cell lines Synergy was assessed for human tumor cell lines in a 5x5 matrix combination format in a CellTiter-Glo based 2D monolayer assay. All compounds were added once at the beginning of the experiment 24 hours after cell seeding. Cultures were incubated at 37°C and 5% CO2 in a humidified incubator. Duration of compound treatment was 72 hours. Cell viability was analyzed by using CellTiter-Glo reagent, where luminescence was measured using an EnVision Xcite multilabel plater reader. Synergy was measured by using Bliss independence Analysis.

[0151] In the 3D clonogenic assay, tumor cell suspensions were prepared directly from human non-V600 BRAF mutant tumor xenografts growing in nude mice. These ex vivo PDX models were assessed in the 3D clonogenic assay using ultra-low attachment plates where cells were mixed with cell culture medium and soft agar in a 5 × 5 matrix combination format. Compounds were added 24 hours after cell seeding. Cultures were incubated at 37 °C and 7.5% CO2 in a humidified incubator for 8–13 days and closely monitored for colony growth using an inverted microscope. Compound A was added every 2–3 days. After 8–13 days, live colonies were stained with a sterile aqueous solution of 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-phenyltetrazolium chloride (INT, 1 mg / ml, 25 μl / well) for 48 hours, and colony counting was performed using an automated image analysis system (Bioreader 5000 Vα, BIO-SYS). Synergy was determined using Bliss Independent Analysis.

[0152] Bliss Independence Analysis was used for both 2D and 3D combination assays. A score above 0 indicates synergy, while a score below 0 indicates antagonism.

[0153] Table 1 shows the responses observed between Compound A and MEK inhibitors in non-V600 BRAF mutant tumor cell lines. [Table 1]

[0154] Example 4 Synergistic effects using RAF and MEK inhibitors in KRAS mutant tumor cell lines Synergy was assessed using a CellTiter-Glo based 2D monolayer assay in a 6x6 matrix combination format. All compounds were added 24 hours after cell seeding. Compound A was added on days 2 and 3. Duration of compound treatment was 72 hours. Viability was measured using CellTiter-Glo measuring luminescence using an EnVision Multi Label Reader. Synergy was measured by Combination Index. Synergy scores were calculated using both Bliss independence and Loewe additivity models. A score higher than 5 indicates synergy and a score lower than -5 indicates antagonism.

[0155] Table 2 shows the responses observed between Compound A and MEK inhibitors in KRAS mutant tumor cell lines. [Table 2]

[0156] Example 5 Synergistic effects using Compound A and pimasertib ex vivo in 3D PDX models In the 3D PDX ex vivo assay, tumor cell suspensions were prepared directly from human BRAF fusion tumor xenografts growing in nude mice. These ex vivo PDX models were assessed in a 3D growth assay using ultra-low attachment plates where cells were mixed with cell culture medium and 1% methylcellulose in a 5x5 matrix combination format. 24 hours after seeding, day 0 luminescence readings were taken after Cell-Titer Glo addition. Control and test compounds were added 24 hours after cell seeding. Cultures were incubated at 37°C and 7.5% CO2 in a humidified incubator for 7 days and closely monitored for growth and viability using an inverted microscope. Compound A and pimasertib were added once on day 0. After 7 days, Cell Titer Glo reagent (Promega) was added to each well, incubated, and luminescence was read. Synergy is calculated based on Crownsyn, an effect-based method developed by CrownBio, under the assumption that both drugs act independently.

[0157] Table 3 shows the synergistic responses observed between Compound A and pimasertib in ex vivo BRAF fusion PDX models. [Table 3]

[0158] Example 6 Synergistic Effects Using Compound A and Pimasertib in 3D Organoid Models In the 3D organoid assay, the required number of organoids were treated 1:1 with 50% Matrigel to define the appropriate size of organoids to be used for screening. On day 0, organoids were harvested from all wells, filtered, and seeded. Matrigel was added to a final concentration of 5%. Compounds were added at the time of seeding, after the organoids had settled. Cultures were incubated at 37°C and 7.5% CO2 in a humidified incubator for 5 days and closely monitored for growth and viability using an inverted microscope. Compound A and pimasertib were added once on day 0. After 5 days, Cell Titer Glo reagent (Promega) was added to each well, incubated, and luminescence was read. Synergy is calculated based on the effect-based method, Crownsyn, under the assumption that both drugs act independently.

[0159] Table 4 shows the responses observed between Compound A and pimasertib in PDX organoid models. The synergy scores in Table 4 were calculated using the Loewe algorithm, with a score greater than 5 indicating synergy and a score less than 5 indicating antagonism. [Table 4]

[0160] Example 7 Synergistic effects using Compound A and pimasertib in non-V600 BRAF mutant cell lines in vitro (2D) or ex vivo in PDX models (3D) In the 2D cell proliferation monolayer assay, cells were seeded and treated for 72 hours. All compounds were added once at the beginning of the experiment. Compound A was applied repeatedly every 24 hours. Cultures were incubated at 37°C and 7.5% CO2 in a humidified incubator for 72 hours and closely monitored for growth and viability using an inverted microscope. After 72 hours, Cell Titer Glo reagent (Promega) was added to each well, incubated, and luminescence was read.

[0161] In the 3D clonogenic assay, compound A was applied repeatedly every 2-3 days, whereas pimasertib was added once at the beginning of the experiment. Colony counts were performed at the time of maximum colony formation, between days 8 and 13.

[0162] Table 5 shows the synergistic responses observed between Compound A and pimasertib in non-V600 BRAF mutant tumor cell lines in vitro (2D) or ex vivo in PDX models (3D). A positive number indicated synergy as the number of combination pairs that achieved a Bliss Index ≥ 0.15. A score of 0 indicated an additive effect with a Bliss Index between -0.15 and +0.15 for all combination pairs. A negative number indicated antagonism as the number of combination pairs that achieved a Bliss Index ≤ -0.15.

[0163] Table 6 shows the synergistic responses observed between Compound A and pimasertib in non-V600 BRAF mutant tumor cell lines in vitro (2D). Synergy was assessed in a 6x6 matrix combination format to determine Combination Index synergy scoring and present the Loewe score. A score greater than 5 indicated synergy and a score less than 5 indicated antagonism.

[0164] Table 7 shows the synergistic responses observed between Compound A and pimasertib in KRAS mutant cell lines in vitro (2D). Synergy was assessed in a 5x5 matrix combination format followed by Bliss independence Analysis. A positive number indicated synergy as the number of combination pairs that achieved a Bliss Index ≥ 0.15. A score of 0 indicated an additive effect with a Bliss Index between -0.15 and +0.15 for all combination pairs. A negative number indicated antagonism as the number of combination pairs that achieved a Bliss Index ≤ -0.15. [Table 5] [Table 6] [Table 7]

[0165] Example 8 Treatment Schedule, Inclusion and Exclusion Criteria for the Combination of Compound A and Pimasertib Part 1

[0166] This study is a multicenter, open-label substudy of patients aged 12 years or older with recurrent or progressive solid tumors, including tumors with abnormalities in key proteins of the MAPK pathway, e.g., RAS or RAF alterations. Patients with these alterations will be identified by molecular assays routinely performed in a Clinical Laboratory Improvement Amendments of 1988 (CLIA)-certified laboratory or other similarly certified laboratories locally.

[0167] The study consists of a screening period, a treatment period, a safety follow-up period, and a long-term follow-up period collecting survival and subsequent anti-cancer treatment.

[0168] Compound A is administered weekly (days 1, 8, 15, and 22), and pimasertib is initially administered twice daily (BID). Patients undergo radiographic evaluation for disease at the end of every 2 cycles for 1 year, then every 3 cycles thereafter. Patients continue to receive compound A + pimasertib until radiographic evidence of disease progression by criteria appropriate for the disease setting, unacceptable toxicity, patient withdrawal of consent, or death. In general, response assessments are performed according to RECIST version 1.1 for solid tumors. Alternative criteria may be used in certain disease settings, for example, for gliomas, response assessments are assessed by RANO criteria. Patients with radiographic evidence of disease progression may be allowed to continue with compound A + pimasertib if, in the opinion of a medical professional, continued study treatment with the combination of compound A + pimasertib provides clinical benefit to the patient.

[0169] Figure 1 presents the study design for the treatment of patients aged 12 years or older with recurrent or progressive solid tumors with abnormalities of key proteins of the MAPK pathway, such as tumors with RAS and RAF alterations. The study consists of a screening period, a treatment period, a safety follow-up period, and a long-term follow-up period that collects survival and subsequent anticancer treatment. Compound A is administered once a week (days 1, 8, 15, and 22), and pimasertib is administered once a day (QD) or twice a day (BID). The doses of compound A and pimasertib are determined for each dose cohort to which patients are assigned in the Phase 1b part of the study. The doses and schedules of compound A and pimasertib administered in the Phase 2 part of the study are determined during the Phase 1b part. In the absence of disease progression or unacceptable toxicity, cycles are repeated every 28 days. Patients undergo radiographic evaluation for disease at the end of every 2 cycles for 1 year, and then every 3 cycles thereafter. Patients will continue to receive Compound A plus pimasertib until radiographic evidence of disease progression by criteria appropriate to their disease status, unacceptable toxicity, patient withdrawal of consent, or death.

[0170] A Bayesian Optimal Interval with 3+3 Design Lead (BOIN) design will be utilized for dose escalation of Compound A and pimasertib in the dose escalation portion of the study.

[0171] Inclusion criteria may include one or more of the following: confirmed MAPK pathway abnormalities, ECOG performance status 0–1, and adequate organ function.

[0172] Exclusion criteria may include one or more of the following: current or previous central serous retinopathy, retinal vein occlusion, or ocular disease; unstable neurological condition despite adequate treatment; uncontrolled cardiovascular condition; and previous receipt of any pan-RAF inhibitor.

[0173] Exclusion criteria may also include: (a) prior receipt of any pan-RAF inhibitor treatment (e.g., LXH254 / napolafenib, BGB-283, BGB-3245, belbalafenib) and / or (b) concomitant medications with a narrow therapeutic index (strong inhibitors of cytochrome P450 CYP3A4 or CYP2C19, strong inducers of CYP3A4, or substrates of CYP2C9).

[0174] Part 2:

[0175] Following review of safety, efficacy and pharmacodynamic evaluations from Part 1, the recommended dose of the combination of Compound A and pimasertib will be determined.

[0176] In this Part 2 dose expansion portion, patients will be enrolled in biomarker-defined expansion cohorts to receive the combination. The number of cohorts will be determined after analysis of Part 1 data. Patients will be enrolled in biomarker-defined (e.g., NRAS, KRAS, HRAS, BRAF-mutated, BRAF / CRAF fusion-positive, CRAF-amplified solid tumors, etc.) expansion cohorts to receive the combination of Compound A and pimasertib. The primary endpoint is the estimated response rate for each cohort, as assessed by medical experts. Secondary endpoints include safety and tolerability, duration of response, progression-free survival, overall survival, and pharmacokinetics.

[0177] Table 8 provides treatment regimens for the combination of Compound A and pimasertib. [Table 8-1]

[0178] BID=twice daily; QD=once daily; QW=once weekly.

[0179] Adult: 18 years of age or older.

[0180] Youth: 12 to 18 years old, BSA ≥ 1.3m 2 .

[0181] Example 9 Dose modification of Compound A and pimasertib The dose of Compound A in the methods described herein can be modified, for example, as illustrated in the table below. For individual patients, dose levels can be modified to manage toxicity.

[0182] Table 8 provides dose modifications for Compound A for adults (age 18 and older). Up to two dose reductions from the starting dose may be permitted.

[0183] Table 9 provides dose modifications of Compound A for adolescents (ages 12 to 17). BSA should be calculated and updated doses should be provided on day 1 of each cycle. BSA can be determined by any suitable calculation method. In some embodiments, BSA is determined by the Mosteller Formula (√((height x weight) / 3600)). In some embodiments, BSA is determined at the beginning of each cycle of administration.

[0184] Dose modifications for pimasertib are presented in Table 10. Up to two dose reductions from the starting dose are permitted. [Table 8-2]

[0185] QW=every week. [Table 9]

[0186] BSA = Body Surface Area. BSA can be determined by any suitable calculation method. In some embodiments, BSA is determined by the Mosteller Formula (√((height x weight) / 3600)). In some embodiments, BSA is determined at the start of each cycle of administration.

[0187] QOW = biweekly. [Table 10] In some cases, when administered in the form of a pimasertib salt, such as pimasertib HCl, the doses listed in Table 10 represent the weight of pimasertib free base present in the salt.

[0188] Example 10 Evaluating the preclinical efficacy of Compound A and pimasertib as single agents in a BRAF fusion model of melanoma (AGK-BRAF fusion) Preclinical evaluation is performed using in vivo therapeutic efficacy as single agents of compound A and pimasertib in treating melanoma cancer xenograft model ME11971 (AGK-BRAF fusion) in female NOD / SCID mice. Tumor fragments are harvested from stock mice and used for inoculation into mice. For tumor development, ME11971 model tumor fragments (2-3 mm in diameter) are inoculated subcutaneously into the right flank of each mouse.

[0189] Table 11 presents the study parameters for the study mice: A total of 100 mice were enrolled in the study and randomly assigned to 10 study groups with 10 mice per group. The mean tumor size was approximately 150 (100-200) mm 3 Randomization will begin when the randomization period is reached. Randomization will be performed based on a "Matched distribution" / "Stratified" (StudyDirector™ software, version 3.1.399.19) randomized block design. The day of randomization will be designated as day 0.

[0190] After tumor inoculation, animals are checked daily for morbidity and mortality. During routine monitoring, animals are checked for any effects of tumor growth and treatment on behavior, such as mobility, food and water consumption, weight gain / loss (body weight is measured twice a week after randomization), eye / coat mattness, and any other abnormalities. Mortality and observed clinical signs are recorded in detail for each animal. Tumor volume is measured twice a week after randomization. Dosing and tumor and body weight measurements are performed in a Laminar Flow Cabinet. Body weights of all animals are monitored throughout the study. Animals are euthanized if their body weight decreases by more than 15% for three consecutive days compared to the body weight on the first day of treatment or if their body weight decreases by more than 20% compared to the body weight on the first day of treatment.

[0191] Body weights and tumor volumes are measured by using StudyDirector™ software (version 3.1.399.19). Treatment begins one day after group allocation (day 1) or the same day as randomization (day 0).

[0192] Ten groups of mice are dosed over a 14-day period according to Table 11 above. The three doses selected for Compound A are 12.5 mg / kg, 25 mg / kg, and 50 mg / kg, and the three doses selected for pimasertib are 10 mg / kg, 30 mg / kg, and 60 mg / kg. The vehicle control group had a mean tumor volume of 2000 mm 3 The study will be terminated when the tumor and plasma samples are collected after the last dose, whichever comes first. Treatment will be administered for 14 days. If treatment is not escalated, the study will be terminated 4 hours (Groups 1, 2, 3, 4) / 0.5 hours (Groups 5, 6, 7, 8) after the last dose. [Table 11]

[0193] Example 11 Evaluating the preclinical efficacy of the combination of Compound A and pimasertib in a BRAF fusion model of melanoma (AGK-BRAF fusion) A preclinical evaluation is performed using in vivo therapeutic efficacy of the combination of compound A and pimasertib in treating melanoma cancer xenograft model ME11971 (AGK-BRAF fusion) in female NOD / SCID mice. Tumor fragments are harvested from stock mice and used for inoculation into mice. ME11971 model tumor fragments (2-3 mm in diameter) are inoculated subcutaneously into the right flank of each mouse for tumor development.

[0194] Table 11 presents the mouse study parameters: A total of 70 mice were enrolled in the study and randomly assigned to 10 study groups with 10 mice per group. The mean tumor size was approximately 150 (100-200) mm 3Randomization will begin when the randomization period is reached. Randomization will be performed based on a "Matched distribution" / "Stratified" (StudyDirector™ software, version 3.1.399.19) randomized block design. The day of randomization will be designated as day 0.

[0195] After tumor inoculation, animals are checked daily for morbidity and mortality. During routine monitoring, animals are checked for any effects of tumor growth and treatment on behavior, such as mobility, food and water consumption, weight gain / loss (weight is measured twice a week after randomization), eye / coat mattness, and any other abnormalities. Mortality and observed clinical signs are recorded in detail for each individual animal.

[0196] Tumor volumes are measured twice weekly after randomization. Dosing and tumor and body weight measurements are performed in a Laminar Flow Cabinet. The weight of all animals is monitored throughout the study. Animals are euthanized if their body weight is reduced by more than 15% for three consecutive days compared to the weight on the first day of treatment or if their body weight is reduced by more than 20% compared to the weight on the first day of treatment.

[0197] Body weights and tumor volumes are measured by using StudyDirector™ software (version 3.1.399.19). Treatment begins one day after group allocation (day 1) or the same day as randomization (day 0).

[0198] Mice are dosed in groups of 10 according to the above table over a period of 14 days. The two doses selected for Compound A are 12.5 mg / kg and 25 mg / kg, and the dose selected for pimasertib is 10 mg / kg. The vehicle control group had a mean tumor volume of 2000 mm 3 The study will be terminated when 0.01 is reached or when tumor and plasma samples are collected after the last dose, whichever occurs first. Treatment will be administered for 14 days. If treatment escalation is not performed, the study will be terminated at the endpoint gating for single agent efficacy studies. [Table 12]

[0199] The disclosure of the present application is further illustrated in the following list of embodiments, which are provided for illustrative purposes only and are not intended to limit the disclosure in any way.

[0200] Additional Embodiments Embodiment 1. A method of treating a subject suffering from cancer, comprising administering to the subject: (i) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharma- ceutically acceptable salt thereof; and (ii) a MEK inhibitor having the structure of formula (I) or a pharma- ceutically acceptable salt thereof; [ka] (In the formula, R1, R2, R9, R 10 , R 11 , R 12 , R 13 and R 14 are independently hydrogen, halogen, cyano, nitro, azido, -OR3, -NR4C(O)OR6, -OC(O)R3, -NR4S(O) j R6, -S(O) j NR3R4, -S(O) j NR4C(O)R3, -C(O)NR4S(O) j R6, -S(O) j R6, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, - NR5C(NCN)NR3R4, -NR3R4, C1~C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10Cycloalkylalkyl, -S(O) j (C1-C6 alkyl), -S(O) j (CR4R5) m -aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5) m -Aryl, -NR4(CR4R5) m -aryl, -O(CR4R5) m -heteroaryl, -NR4(CR4R5) m , heteroaryl, -O(CR4R5) m -Heterocyclyl, -NR4(CR4R5) m -heterocyclyl and -S(C1-C2 alkyl) substituted with 1-5 fluorines, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is independently substituted or unsubstituted; R3 is hydrogen, trifluoromethyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10each alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, and aryl is independently substituted or unsubstituted; and aryl is selected from oxo, halogen, nitro, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, azido, NR'SO2R'''', SO2 optionally substituted with 1 to 5 groups independently selected from N'', C(O)R', C(O)OR', OC(0)R', NR'C(O)OR'''', NR'C(O)R'', C(O)NR'R'', SR'''', S(0)R'''', SOR', NR'R'', NR'C(O)NR''R''', NR'C(NCN)N''R''', OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R4 is hydrogen or C 1~6 alkyl, which may be substituted or unsubstituted; or R3 and R4, together with the atoms to which they are attached, may each form a substituted or unsubstituted 4-10 membered heteroaryl or heterocyclic ring; R5 is hydrogen or C1-C6 alkyl, which may be substituted or unsubstituted; or R4 and R5, together with the atoms to which they are attached, may each form a substituted or unsubstituted 4-10 membered carbocyclic, heteroaryl, or heterocyclic ring; R6 is trifluoromethyl, C1-C 10 Alkyl, C3-C 10 selected from cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is independently substituted or unsubstituted; R', R'', and R''' are independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, aryl, and arylalkyl; R'''' is selected from C1-C4 alkyl, C2-C4 alkenyl, aryl and arylalkyl; W is 1) unsubstituted or 1 to 5 substituents ZR 15 and 2) a heteroaryl containing 1 to 4 heteroatoms or a heterocyclyl containing 1 to 4 heteroatoms, each substituted by -C(O)OR 15 , -C(O)NR4R 15 , -C(O)NR4OR 15 , -C(O)NR4S(O) j R6, -C(O)NR4NR4NR 15 , -NR'R'', -NR'C(O)R', -NR'S(O) j R', -NRC(O)NR'R'', NR'S(O) j NR'R'', or -C(O)NR4NR4C(O)R 15 with the proviso that W is not -C(O)OH; Z is a bond, NR 16 , O, N.R. 16 SO2 or S; R 15 is hydrogen, trifluoromethyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 selected from cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is independently substituted or unsubstituted; R 16 is hydrogen or C1-C 10 alkyl; or R 15 and R 16together with the atom to which they are attached form a 4-10 membered ring having 1 or 2 nitrogen atoms and optionally an oxygen atom, said ring being substituted or unsubstituted; X is N or N + O - and; m is 0, 1, 2, 3, 4 or 5; j is 1 or 2) administering The method, wherein the total amount of compound A, or a pharma- ceutically acceptable salt thereof, and the MEK inhibitor is therapeutically effective in treating cancer.

[0201] Embodiment 2. A method of treating a subject suffering from cancer, comprising: (a) identifying a subject suffering from cancer, the cancer having one or more of a RAF alteration, a RAS mutation, an NF-1 mutation, or a genomic alteration that results in a dependency on signaling through the MAPK pathway; and (b) To the subject, (i) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharma- ceutically acceptable salt thereof; and (ii) a MEK inhibitor having the structure of formula (I) or a pharma- ceutically acceptable salt thereof; [ka] (In the formula, R1, R2, R9, R 10 , R 11 , R 12 , R 13 and R 14 are independently hydrogen, halogen, cyano, nitro, azido, -OR3, -NR4C(O)OR6, -OC(O)R3, -NR4S(O) j R6, -S(O) j NR3R4, -S(O) j NR4C(O)R3, -C(O)NR4S(O)j R6, -S(O) j R6, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, - NR5C(NCN)NR3R4, -NR3R4, C1~C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, -S(O) j (C1-C6 alkyl), -S(O) j (CR4R5) m -aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5) m -Aryl, -NR4(CR4R5) m -aryl, -O(CR4R5) m -heteroaryl, -NR4(CR4R5) m , heteroaryl, -O(CR4R5) m -Heterocyclyl, -NR4(CR4R5) m -heterocyclyl and -S(C1-C2 alkyl) substituted with 1-5 fluorines, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is independently substituted or unsubstituted; R3 is hydrogen, trifluoromethyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10and aryl is selected from cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, and aryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocyclyl is independently substituted or unsubstituted, and aryl is selected from oxo, halogen, nitro, CF, CHF, CHF, OCF, OCHF, OCHF, azido, NR'SOR'', S. optionally substituted with 1 to 5 groups independently selected from O2N'', C(O)R', C(O)OR', OC(0)R', NR'C(O)OR'''', NR'C(O)R'', C(O)NR'R'', SR'''', S(0)R'''', S02R', NR'R'', NR'C(O)NR''R''', NR'C(NCN)N''R''', OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R4 is hydrogen or C 1~6 alkyl, which may be substituted or unsubstituted; or R3 and R4, together with the atoms to which they are attached, may each form a substituted or unsubstituted 4-10 membered heteroaryl or heterocyclic ring; R5 is hydrogen or C1-C6 alkyl, which may be substituted or unsubstituted; or R4 and R5, together with the atoms to which they are attached, may each form a substituted or unsubstituted 4-10 membered carbocyclic, heteroaryl, or heterocyclic ring; R6 is trifluoromethyl, C1-C 10 Alkyl, C3-C 10 selected from cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is independently substituted or unsubstituted; R', R'', and R''' are independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, aryl, and arylalkyl; R'''' is selected from C1-C4 alkyl, C2-C4 alkenyl, aryl and arylalkyl; W is 1) unsubstituted or 1 to 5 substituents ZR 15 and 2) a heteroaryl containing 1 to 4 heteroatoms or a heterocyclyl containing 1 to 4 heteroatoms, each substituted by -C(O)OR 15 , -C(O)NR4R 15 , -C(O)NR4OR 15 , -C(O)NR4S(O) j R6, -C(O)NR4NR4NR 15 , -NR'R'', -NR'C(O)R', -NR'S(O) j R', -NRC(O)NR'R'', NR'S(O) j NR'R'', or -C(O)NR4NR4C(O)R 15 with the proviso that W is not -C(O)OH; Z is a bond, NR 16 , O, N.R. 16 SO2 or S; R 15 is hydrogen, trifluoromethyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 selected from cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is independently substituted or unsubstituted; R 16 is hydrogen or C1-C 10 alkyl; or R 15 and R 16together with the atom to which they are attached form a 4-10 membered ring having 1 or 2 nitrogen atoms and optionally an oxygen atom, said ring being substituted or unsubstituted; X is N or N + O - and; m is 0, 1, 2, 3, 4 or 5; j is 1 or 2) administering The method, wherein the total amount of compound A, or a pharma- ceutically acceptable salt thereof, and the MEK inhibitor is therapeutically effective in treating cancer.

[0202] Embodiment 3. A method of treating a subject suffering from cancer, comprising administering to the subject: (i) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharma- ceutically acceptable salt thereof; and (ii) a MEK inhibitor selected from cobimetinib, selumetinib, pimasertib, PD0325901, refametinib, binimetinib, BI-847325, trametinib, GDC-0623, G-573, and CH5126766, or a pharma- ceutically acceptable salt thereof. administering The method, wherein the total amount of compound A, or a pharma- ceutically acceptable salt thereof, and the MEK inhibitor, or a pharma- ceutically acceptable salt thereof, is therapeutically effective in the treatment of cancer.

[0203] Embodiment 4. The method of any of the preceding embodiments, wherein the cancer has one or more of the following mutations: a RAS positive mutation, a RAF positive mutation, a MEK positive mutation, and an ERK positive mutation.

[0204] Embodiment 5. The method of any of the preceding embodiments 1 to 4, wherein the cancer has an NRAS mutation, a KRAS mutation, or an HRAS mutation.

[0205] Embodiment 6 The method of any of the preceding embodiments 1 to 4, wherein the cancer has a BRAF mutation, a BRAF fusion, or a CRAF fusion.

[0206] Embodiment 7 The method of embodiment 6, wherein the BRAF mutation is a non-V600 BRAF mutation.

[0207] Embodiment 8. The method of embodiment 7, wherein the non-V600 BRAF mutation is selected from V600E, G469A, G464V, G466V, K601E, G469R, and L597R.

[0208] Embodiment 9. The method of embodiment 8, wherein the non-V600 BRAF mutation is selected from V600E, G464A, G464V, K601E, and G469R.

[0209] Embodiment 10. The method of embodiment 9, wherein the non-V600 BRAF mutation is selected from G464V, K601E, G469A, and G466V.

[0210] Embodiment 11 The method of embodiment 5, wherein the RAS mutation is a KRAS mutation.

[0211] Embodiment 12. The method of embodiment 11, wherein the KRAS mutation is selected from KRAS G12C, KRAS G12V, KRAS G12D, KRAS Q61K, KRAS Q61H, KRAS G13D, and KRAS G12S.

[0212] Embodiment 13 The method of any of the preceding embodiments 11 or 12, wherein the KRAS mutation is selected from KRAS G12C, KRAS G12D, KRAS G13D, and KRAS G12S.

[0213] Embodiment 14 The method of embodiment 6, wherein the BRAF mutation is a V600 BRAF mutation.

[0214] Embodiment 15 The method of any of the preceding embodiments 1 to 8, wherein the cancer has a genomic alteration that results in a dependency on signaling through the MAPK pathway.

[0215] Embodiment 16 The method of any of the preceding embodiments 1 to 3, wherein the cancer has a mutation in NF-1 that results in loss of NF-1 function.

[0216] Embodiment 17 The method of any of the preceding embodiments 1 to 3, wherein the cancer sample is obtained from a subject.

[0217] Embodiment 18. The method of embodiment 17, wherein prior to the step of administering compound A or a pharma- ceutically acceptable salt thereof or a MEK inhibitor, the subject's cancer sample has been subjected to BRAF, KRAS, CRAF, HRAS, NF-1 and / or NRAS mutation testing.

[0218] Embodiment 19. The method of embodiment 18, wherein prior to the step of administering compound A or a pharma- ceutically acceptable salt thereof or a MEK inhibitor, the subject's cancer sample has been subjected to genomic testing, and the genomic testing demonstrates that the genomic alteration creates a dependency on MPAK signaling.

[0219] Embodiment 20 The method of any of the preceding embodiments 17 to 19, wherein the subject has been diagnosed with a histologically confirmed non-hematological tumor.

[0220] Embodiment 21 The method of any of the preceding embodiments 17 to 19, wherein the subject has been diagnosed with a histologically confirmed hematological neoplasm.

[0221] Embodiment 22 The method of any of the preceding embodiments 18 to 21, wherein the cancer has a RAS mutation.

[0222] Embodiment 23 The method of any of the preceding embodiments 18 to 22, wherein the RAS mutation is an HRAS mutation, a KRAS, or an NRAS mutation.

[0223] Embodiment 24 The method of any of the preceding embodiments 18 to 21, wherein the cancer has a mutation in NF-1 that results in loss of NF-1 function.

[0224] Embodiment 25 The method of any of the preceding embodiments 18 to 21, wherein the cancer has a RAF alteration.

[0225] Embodiment 26 The method of embodiment 25, wherein the RAF alteration is a BRAF mutation, a BRAF fusion, or a CRAF fusion.

[0226] Embodiment 27 The method of embodiment 26, wherein the cancer has a non-V600 BRAF mutation.

[0227] Embodiment 28. The method of embodiment 27, wherein the subject has been identified as having a non-V600 BRAF mutation selected from V600E, G469A, G464V, G466V, K601E, G469R, and L597R.

[0228] Embodiment 29. The method of embodiment 28, wherein the subject has been identified as having a non-V600 BRAF mutation selected from V600E, G464A, G464V, K601E, and G469R.

[0229] Embodiment 30. The method of embodiment 29, wherein the subject has been identified as having a non-V600 BRAF mutation selected from G464V, K601E, G469A, and G466V.

[0230] Embodiment 31 The method of embodiment 23, wherein the subject has been identified as having a KRAS mutation.

[0231] Embodiment 32. The method of embodiment 31, wherein the subject has been identified as having a KRAS mutation selected from KRAS G12C, KRAS G12V, KRAS G12D, KRAS Q61K, KRAS Q61H, KRAS G13D, and KRAS G12S.

[0232] Embodiment 33 The method of any of the preceding embodiments 31 or 32, wherein the subject has been identified as having a KRAS mutation selected from KRAS G12C, KRAS G12D, KRAS G13D, and KRAS G12S.

[0233] Embodiment 34 The method of any of the preceding embodiments 1 to 21, wherein the subject has a class I BRAF mutation or a class II BRAF mutation.

[0234] Embodiment 35 The method of any of the preceding embodiments 1 to 21, wherein the subject lacks a V600E mutation, a V600K mutation, or both.

[0235] Embodiment 36. The subject has one or more of the following fusions: KIAA1549:BRAF, STARD3NL:BRAF, BCAS1:BRAF, KHDRBS2:BRAF, CCDC6:BRAF, FAM131B:BRAF, SRGAP:BRAF, CLCN6:BRAF, GNAI1:BRAF, MRKN1:BRAF, GIT2:BRAF, GTF21:BRAF, FXR1:BRAF, RNF130:BRAF, BRAF:MACF1, TMEM106B:BRAF, PPC1CC:BRAF, CUX1:BRAF, AGK:BRAF 27. The method of any of the preceding embodiments 6 or 26, wherein the patient is identified as having one or more of the following: AGAP3:BRAF, TNS3:BRAF, TARDBP:BRAF, ARMC10:BRAF, CUL1:BRAF, TRIM24:BRAF, AKAP9:BRAF, FKBP15:BRAF, SKAP2:BRAF, ZKSCAN1:BRAF, KLHL7:BRAF, SEPT3:BRAF, SRGAP3:RAF1, QK1:RAF1, FYCO:RAF1, ATG7:RAF1, or NFIA:RAF1.

[0236] Embodiment 37. The method of embodiment 36, wherein the subject has been identified as having one or more of the following fusions: AGK:BRAF, AGAP3:BRAF, TNS3:BRAF, or KIAA1549:BRAF.

[0237] Embodiment 38 The method of any of the preceding embodiments 36 or 37, wherein the subject has been identified as having a KIAA1549:BRAF fusion.

[0238] Embodiment 39 The method of any of the preceding embodiments 36 or 37, wherein the subject has been identified as having an AGAP3:BRAF fusion.

[0239]

[0240] Embodiment 40 The method of any of the preceding embodiments 1 to 39, wherein the cancer is a solid tumor.

[0241] Embodiment 41 The method of embodiment 40, wherein the cancer is an advanced solid tumor.

[0242] Embodiment 42. The method of any of the preceding embodiments 1 to 41, wherein the cancer is selected from lung cancer, colorectal cancer, pancreatic cancer, skin cancer, glioma, non-glioma brain cancer, osteosarcoma, gastrointestinal cancer, breast cancer, thyroid cancer, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and multiple myeloma (MM).

[0243] Embodiment 43 The method of any of the preceding embodiments 1 to 41, wherein the cancer is lung cancer, colorectal cancer, or pancreatic cancer.

[0244] Embodiment 44 The method of any one of the preceding embodiments 1 to 41, wherein the cancer is non-small cell lung cancer.

[0245] Embodiment 45 The method of any one of the preceding embodiments 1 to 44, wherein the cancer is a recurrent cancer.

[0246] Embodiment 46. The method of any of the preceding embodiments 1 to 45, wherein the subject has undergone at least one prior treatment considered to be standard of care prior to administration of Compound A or a pharma- ceutically acceptable salt thereof, or a MEK inhibitor.

[0247] Embodiment 47 The method of embodiment 46, wherein the previous treatment is a systemic treatment.

[0248] Embodiment 48 The method of embodiment 46, wherein the previous treatment is chemotherapy, hormonal therapy, immunotherapy, or radiation therapy.

[0249] Embodiment 49. The method of any of the preceding embodiments 1 to 48, wherein the MEK inhibitor is N-((S)-2,3-dihydroxy-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide (pimasertib) or a pharma- ceutically acceptable salt thereof.

[0250] Embodiment 50. The MEK inhibitor is of formula (Ia): [ka] (In the formula, R2, R 12 , R 10 , and R 11 are independently hydrogen, halogen, cyano, nitro, azido, -OR3, -NR4C(O)OR6, -OC(O)R3, -NR4S(O) j R6, -S(O) j NR3R4, -S(O) j NR4C(O)R3, -C(O)NR4S(O) j R6, -S(O) j R6, -NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, - NR5C(NCN)NR3R4, -NR3R4, C1~C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, -S(O) j (C1-C6 alkyl), -S(O) j (CR4R5) m -aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5) m -Aryl, -NR4(CR4R5) m -aryl, -O(CR4R5) m-heteroaryl, -NR4(CR4R5) m , heteroaryl, -O(CR4R5) m -Heterocyclyl, -NR4(CR4R5) m -heterocyclyl and -S(C1-C2 alkyl) substituted with 1-5 fluorines, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is independently substituted or unsubstituted; R3 is hydrogen, trifluoromethyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 and aryl is selected from cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, and aryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocyclyl is independently substituted or unsubstituted; and aryl is selected from oxo, halogen, nitro, CF, CHF, CHF, OCF, OCHF, OCHF, azido, NR'SOR'', S. optionally substituted with 1 to 5 groups independently selected from O2N'', C(O)R', C(O)OR', OC(0)R', NR'C(O)OR'''', NR'C(O)R'', C(O)NR'R'', SR'''', S(0)R'''', S02R', NR'R'', NR'C(O)NR''R''', NR'C(NCN)N''R''', OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R4 is hydrogen or C 1~6 alkyl, which may be substituted or unsubstituted; or R3 and R4, together with the atoms to which they are attached, may each form a substituted or unsubstituted 4-10 membered heteroaryl or heterocyclic ring; R5 is hydrogen or C1-C6 alkyl, which may be substituted or unsubstituted; or R4 and R5, together with the atoms to which they are attached, may each form a substituted or unsubstituted 4-10 membered carbocyclic, heteroaryl, or heterocyclic ring; R6 is trifluoromethyl, C1-C 10 Alkyl, C3-C 10 selected from cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is independently substituted or unsubstituted; R", R" and R"' are independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, aryl and arylalkyl; R'''' is selected from C1-C4 alkyl, C2-C4 alkenyl, aryl and arylalkyl; m is 0, 1, 2, 3, 4 or 5; j is 1 or 2) 49. The method of any of the preceding embodiments 1 to 48, wherein the compound has the structure:

[0251] Embodiment 51. The MEK inhibitor is [ka] or a pharma- ceutically acceptable salt thereof.

[0252] Embodiment 52. The MEK inhibitor or a pharma- ceutically acceptable salt thereof is [ka] 49. The method of any of the preceding embodiments 1 to 48, selected from:

[0253] Embodiment 53. The MEK inhibitor or a pharma- ceutically acceptable salt thereof is [ka] 53. The method of any of the preceding embodiments 1 to 48, or 52, selected from the group consisting of

[0254] Embodiment 54 The method of any of the preceding embodiments 1 to 53, wherein compound A is administered in an amount of between about 100 mg and about 700 mg per week.

[0255] Embodiment 55 The method of embodiment 54, wherein Compound A is administered at about 200 mg, about 400 mg, or about 600 mg per week.

[0256] Embodiment 56. Compound A is administered at about 100 mg / m per week. 2 to about 500 mg / m 2 54. The method of any of the preceding embodiments 1 to 53, wherein the amount of

[0257] Embodiment 57. Compound A is administered at about 140 mg / m per week. 2 , about 280mg / m 2 , or about 420 mg / m 2 57. The method of embodiment 56, wherein the patient is administered

[0258] Embodiment 58 The method of any of the preceding embodiments 1 to 57, wherein compound A is administered once a week.

[0259] Embodiment 59. The method of any of the preceding embodiments 1 to 58, wherein the MEK inhibitor is administered in an amount of between about 10 mg and about 150 mg per day.

[0260] Embodiment 60. The method of any of the preceding embodiments 1 to 58, wherein the MEK inhibitor is administered in an amount of between about 5 mg and about 75 mg twice daily.

[0261] Embodiment 61 The method of embodiment 60, wherein the MEK inhibitor is administered at about 15 mg, about 30 mg, about 45 mg, or about 60 mg twice daily.

[0262] Embodiment 62. The method of any of the preceding embodiments 1 to 61, wherein the subject has not previously received pan-RAF therapy.

[0263] Embodiment 63. The method of any of the preceding embodiments 1 to 62, wherein the subject has not previously received a cytochrome P450 CYP3A4 inhibitor, a cytochrome P450 CYP2C19 inhibitor, a P450 CYP3A4 inducer, or a CYP2C9 substrate.

Claims

1. A combination for treating a subject suffering from cancer, comprising: (i) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharma- ceutically acceptable salt thereof; and (ii) A MEK inhibitor or a pharma- ceutically acceptable salt thereof, wherein the MEK inhibitor is selected from pimasertib, selumetinib, and PD0325901. Including, A combination, characterized in that compound A, or a pharma- ceutically acceptable salt thereof, and a MEK inhibitor, or a pharma- ceutically acceptable salt thereof, are administered in a therapeutically effective amount for treating said cancer.

2. Compound A or a pharma- ceutically acceptable salt thereof is administered to the subject in an amount of about 50 mg to about 800 mg per week, or in an amount of about 100 mg / m2 to about 600 mg / m2 per week; The combination of claim 1, wherein the MEK inhibitor or a pharma- ceutically acceptable salt thereof is administered to the subject in an amount of about 5 mg to about 150 mg per day.

3. The combination of claim 1 or claim 2, wherein the cancer has been identified as having one or more of the following fusions: AGK:BRAF, AGAP3:BRAF, TNS3:BRAF, or KIAA1549:BRAF.

4. The combination of any one of claims 1 to 3, wherein the cancer has been identified as having a mutation selected from KRAS G12C, KRAS G12D, and KRAS G12S, and the subject has been identified as having a BRAF mutation selected from BRAF G464V, BRAF indel, BRAF L597R, BRAF G466V, BRAF G469A, BRAF K601E, and BRAF G469R.

5. The combination described in any one of claims 1 to 4, wherein the cancer is a recurrent, progressive, or refractory solid tumor associated with a mitogen-activated protein kinase (MAPK) pathway abnormality.

6. A combination for treating a subject suffering from cancer, comprising: (i) (R)-2-(1-(6-amino-5-chloropyrimidine-4-carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide (Compound A) or a pharma- ceutically acceptable salt thereof; and (ii) a MEK inhibitor or a pharma- ceutically acceptable salt thereof. Including, Compound A or a pharma- ceutically acceptable salt thereof and the MEK inhibitor or a pharma- ceutically acceptable salt thereof are administered in a therapeutically effective amount for treating the cancer; The combination, wherein the subject has one or more mitogen-activated protein kinase (MAPK) pathway abnormalities.

7. The combination of claim 6, wherein the MAPK pathway abnormality is selected from one or more BRAF mutations or fusions and one or more KRAS mutations or fusions, and the BRAF mutations or fusions and KRAS mutations or fusions are selected from the following gene mutations or gene fusions: BRAF V600E, BRAF G464V, BRAF G466V, BRAF K601E, KRAS Q61, KRAS G12S, BRAF indels, BRAF L597R, BRAF G469A, BRAF G469R, KRAS G12C, KRAS G12D, AGK:BRAF, BRAF-AGAP3, AGAP3:BRAF, TNS3:BRAF, and KIAA1549:BRAF.

8. The combination described in claim 6 or claim 7, wherein the MEK inhibitor is pimasertib, selumetinib, PD0325901, or a pharma- ceutically acceptable salt of any one thereof.

9. A combination described in any one of claims 1 to 8, wherein the MEK inhibitor is pimasertib or a pharma- ceutically acceptable salt thereof.

10. The combination of any one of claims 1 to 8, wherein the MEK inhibitor is selumetinib or a pharma- ceutically acceptable salt thereof.

11. The combination of any one of claims 1 to 8, wherein the MEK inhibitor is PD0325901 or a pharma- ceutically acceptable salt thereof.

12. A combination described in any one of claims 1 to 11, wherein the cancer has a BRAF mutation, a BRAF fusion, or a CRAF fusion.

13. The cancer comprising the fusion of: KIAA1549:BRAF, STARD3NL:BRAF, BCAS1:BRAF, KHDRBS2:BRAF, CCDC6:BRAF, FAM131B:BRAF, SRGAP:BRAF, CLCN6:BRAF, GNAI1:BRAF, MRKN1:BRAF, GIT2:BRAF, GTF21:BRAF, FXR1:BRAF, RNF130:BRAF, BRAF:MACF1, TMEM106B:BRAF, PPC1CC:BRAF, CUX1:BRAF, AGK:BRAF, AGAP 13. The combination of any one of claims 1 to 12, wherein the combination has been identified as having one or more of the following: TNS3:BRAF, TARDBP:BRAF, ARMC10:BRAF, CUL1:BRAF, TRIM24:BRAF, AKAP9:BRAF, FKBP15:BRAF, SKAP2:BRAF, ZKSCAN1:BRAF, KLHL7:BRAF, SEPT3:BRAF, SRGAP3:RAF1, QK1:RAF1, FYCO:RAF1, ATG7:RAF1, or NFIA:RAF1.

14. The combination of any one of claims 1 to 13, wherein the cancer has a non-V600 BRAF mutation selected from G469A, G464V, G466V, K601E, G469R, and L597R.

15. The combination according to any one of claims 1 to 14, wherein compound A is administered in an amount of about 100 mg to about 700 mg per week, or compound A is administered in an amount between about 100 mg / m2 and about 500 mg / m2 per week.

16. The combination of any one of claims 1 to 15, wherein the MEK inhibitor or a pharma- ceutically acceptable salt thereof is administered in an amount of about 10 mg to about 150 mg per day.

17. The combination of any one of claims 1 to 15, wherein the MEK inhibitor or a pharma- ceutically acceptable salt thereof is administered in an amount of between about 5 mg and about 75 mg twice daily.

18. The combination of any one of claims 1 to 17, wherein the subject has not previously received pan-RAF therapy, a cytochrome P450 CYP3A4 inhibitor, a cytochrome P450 CYP2C19 inhibitor, a P450 CYP3A4 inducer, or a CYP2C9 substrate.

19. A combination described in any one of claims 1 to 18, wherein the cancer is a solid tumor.

20. The combination described in any one of claims 1 to 19, wherein the cancer is selected from lung cancer, colorectal cancer, pancreatic cancer, skin cancer, glioma, non-glioma brain cancer, osteosarcoma, gastrointestinal cancer, breast cancer, thyroid cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and multiple myeloma (MM).

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