Cancer therapy using 3,5-disubstituted benzenealkynyl compounds and MEK inhibitors

Abstract

Provided is a novel combination therapy that exhibits an excellent antitumor effect and combines an FGFR-inhibiting compound with an MEK inhibitor.　An antitumor agent contains (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an effective ingredient and is administered in combination with an MEK inhibitor.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims priority to Japanese Patent Application No. 2020-071355, filed on April 10, 2020, the entire disclosure of which is incorporated herein by reference. The present disclosure relates to an antitumor agent, an antitumor effect enhancing agent, and a kit formulation. [Background technology]

[0002] Fibroblast growth factors (FGFs) are expressed in a wide range of tissues and are one of the growth factors that regulate cell proliferation and differentiation. The physiological activity of FGFs is mediated by specific cell surface receptors, called fibroblast growth factor receptors (FGFRs). FGFRs belong to the receptor protein tyrosine kinase family and consist of an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain. Four FGFRs have been identified to date: FGFR1, FGFR2, FGFR3, and FGFR4. Upon FGF binding, FGFRs form dimers and are activated by phosphorylation. Receptor activation induces the recruitment and activation of specific downstream signaling molecules, resulting in physiological functions. Abnormalities in FGF / FGFR signaling have been reported to be associated with various human tumors. Abnormal activation of FGF / FGFR signaling in human tumors is believed to be due to autocrine or paracrine mechanisms caused by overexpression of FGFR and / or gene amplification, gene mutation, chromosomal translocation, insertion, or inversion, gene fusion, or overproduction of its ligand, FGF (Non-Patent Documents 1, 2, 3, and 4). The 3,5-disubstituted benzenealkynyl compound (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (hereinafter sometimes referred to as "Compound 1" in this specification) or a salt thereof is known as an FGFR inhibitor, and combinations of FGFR inhibitors with various antitumor agents have been reported (Patent Documents 1 and 2).

[0003] RAS plays a central role in the RAS / MAPK kinase pathway, which promotes cell proliferation. When RAS binds GDP, it becomes inactive. When GDP is exchanged for GTP by guanine nucleotide exchange factors (GEFs), it becomes active. This induces the recruitment and activation of specific downstream signaling molecules, resulting in physiological functions. Furthermore, when activated RAS binds to GTPase-activating proteins (GAPs), it hydrolyzes GTP to convert it to GDP, thereby becoming inactive.

[0004] The RAS gene is known to be an oncogene, and activating mutations in the RAS gene have been reported in various cancers, including colorectal, lung, and pancreatic cancers. Forced expression of these activating RAS genes in normal cells transforms the cells. Cancers with activating RAS gene mutations are resistant to molecular targeted therapy, and the clinical efficacy of receptor kinase or RAS / MAPK kinase pathway component inhibitors, such as EGFR inhibitors, MEK inhibitors, and ERK inhibitors, is known to be limited in cancers with activating RAS gene mutations. For example, the efficacy of EGFR inhibitors in KRAS-mutated colorectal cancer and MEK inhibitors in KRAS-mutated lung cancer patients is limited.

[0005] Recently, it has been shown that treatment of lung cancer cell lines with KRAS mutations with MEK inhibitors activates growth signaling pathways mediated by FGF receptors. Based on these results, it was anticipated that combined administration of an FGFR inhibitor and a MEK inhibitor would have an antitumor effect. Regarding combined administration of an FGFR inhibitor and a MEK inhibitor, there are descriptions of a method in which an MEK inhibitor is used in combination with an RTK inhibitor (Patent Document 3), and a method in which a MEK inhibitor is combined with a KRAS mutant cancer therapeutic agent, limited to the mesenchymal lineage (Patent Document 4). Under these circumstances, there remains a strong demand for cancer treatment methods that differ from these combinations. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2013 / 108809 [Patent Document 2] International Publication No. 2017 / 150725 [Patent Document 3] International Publication No. 2016 / 130917 [Patent Document 4] International Publication No. 2017 / 086332 [Patent Document 5] International Publication No. 2015 / 008839 [Non-patent literature]

[0007] [Non-Patent Document 1] Nat.Rev.Cancer 10:116-129(2010) [Non-patent document 2] J. Clin. Oncol. 24, 3664-3671 (2006) [Non-patent document 3] Mol. Cancer Res. 3, 655-667 (2005) [Non-patent document 4] Cancer Res.70, 2085-2094 (2010) Summary of the Invention [Problem to be solved by the invention]

[0008] An objective of the present disclosure is to provide a novel combination therapy of an FGFR-inhibiting compound and a MEK inhibitor, which exhibits excellent antitumor effects. [Means for solving the problem]

[0009] In view of the current situation, the present inventors have investigated the combined use of a wide variety of compounds having FGFR inhibitory activity with MEK inhibitors, and have found that the above-mentioned problems can be solved by combining the FGFR inhibitor (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof with a MEK inhibitor. Therefore, the present disclosure provides the following items [1] to

[44] . [1] An antitumor agent administered in combination with an MEK inhibitor, comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient. [2] The antitumor agent according to [1], wherein the MEK inhibitor is trametinib or a salt thereof. [3] The antitumor agent according to [1], wherein the MEK inhibitor is binimetinib or a salt thereof. [4] The antitumor agent according to [1], wherein the MEK inhibitor is cobimetinib or a salt thereof. [5] The antitumor agent according to [2], wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg per dose, and trametinib or a salt thereof is administered once daily at a dose selected from the group consisting of 1 mg, 1.5 mg, and 2 mg per dose. [6] The antitumor agent according to [3], wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg per dose, and binimetinib or a salt thereof is administered twice daily at a dose selected from the group consisting of 30 mg and 45 mg per dose. [7] The antitumor agent according to [4], wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg per dose, and cobimetinib or a salt thereof is administered once daily at a dose selected from the group consisting of 40 mg and 60 mg per dose. [8] The antitumor agent according to [2], wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered intermittently at a dose selected from the group consisting of 24 mg, 36 mg, 56 mg, 80 mg, 120 mg, and 160 mg per administration, and trametinib or a salt thereof is administered once a day at a dose selected from the group consisting of 1 mg, 1.5 mg, and 2 mg per administration. [9] The antitumor agent according to [3], wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered intermittently at a dose selected from the group consisting of 24 mg, 36 mg, 56 mg, 80 mg, 120 mg, and 160 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose selected from the group consisting of 30 mg and 45 mg per dose.

[10] The antitumor agent according to [4], wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered intermittently at a dose selected from the group consisting of 24 mg, 36 mg, 56 mg, 80 mg, 120 mg, and 160 mg per dose, and cobimetinib or a salt thereof is administered once a day at a dose selected from the group consisting of 40 mg and 60 mg per dose.

[11] The antitumor agent according to any one of [1] to

[10] , wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered before, simultaneously with, or after the MEK inhibitor.

[12] The antitumor agent according to any one of [1] to

[11] , wherein the tumor has an abnormality in the RAS / MAPK signaling pathway.

[13] The antitumor agent according to any one of [1] to

[12] , wherein the tumor is at least one selected from the group consisting of head and neck cancer, digestive tract cancer, lung cancer, breast cancer, reproductive tract cancer, hematopoietic tumor, bone and soft tissue tumor, skin cancer, and brain tumor.

[14] The antitumor agent according to any one of [1] to

[13] , wherein the tumor is lung cancer, pancreatic cancer, colorectal cancer, or brain tumor.

[15] An antitumor effect enhancer for enhancing the antitumor effect of a MEK inhibitor, comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient.

[16] An antitumor agent for treating a cancer patient administered an MEK inhibitor, comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient.

[17] A pharmaceutical composition for treating a tumor by administering in combination with a MEK inhibitor, comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and a pharmaceutical carrier as an active ingredient.

[18] (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for use in combination therapy with a MEK inhibitor in the treatment of tumors.

[19] A combination of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and a MEK inhibitor for use in treating tumors.

[20] A method for treating a tumor, comprising administering a therapeutically effective amount of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and a therapeutically effective amount of a MEK inhibitor to a patient in need thereof.

[21] A method for enhancing the antitumor effect of a MEK inhibitor, comprising administering a therapeutically effective amount of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof to a patient receiving a MEK inhibitor.

[22] A method for treating a tumor, comprising administering a therapeutically effective amount of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof to a patient who has been administered a MEK inhibitor.

[23] Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for the treatment of tumors in combination therapy with a MEK inhibitor.

[24] Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof to enhance the antitumor effect of a MEK inhibitor.

[25] Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for treating a cancer patient receiving a MEK inhibitor.

[26] Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for the manufacture of an antitumor agent for use in combination therapy with a MEK inhibitor.

[27] Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for the manufacture of an agent for enhancing the antitumor effect of a MEK inhibitor.

[28] Use of a combination of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and a MEK inhibitor for the treatment of tumors.

[29] Use of a combination of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and a MEK inhibitor for the manufacture of an antitumor agent.

[30] A pharmaceutical composition comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and a MEK inhibitor as active ingredients.

[31] The pharmaceutical composition according to

[30] for treating a tumor.

[32] The antitumor effect enhancer according to

[15] , wherein the MEK inhibitor is trametinib or a salt thereof, the antitumor agent according to

[16] , the pharmaceutical composition according to any one of

[17] ,

[30] and

[31] , compound 1 or a salt thereof according to

[18] , the combination according to

[19] , the method according to any one of

[20] to

[22] , or the use according to any one of

[23] to

[29] .

[33] The antitumor effect enhancer according to

[15] , wherein the MEK inhibitor is binimetinib or a salt thereof, the antitumor agent according to

[16] , the pharmaceutical composition according to any one of

[17] ,

[30] and

[31] , compound 1 or a salt thereof according to

[18] , the combination according to

[19] , the method according to any one of

[20] to

[22] , or the use according to any one of

[23] to

[29] .

[34] The antitumor effect enhancer according to

[15] , wherein the MEK inhibitor is cobimetinib or a salt thereof, the antitumor agent according to

[16] , the pharmaceutical composition according to any one of

[17] ,

[30] and

[31] , compound 1 or a salt thereof according to

[18] , the combination according to

[19] , the method according to any one of

[20] to

[22] , or the use according to any one of

[23] to

[29] .

[35] The antitumor effect enhancer, antitumor agent, pharmaceutical composition, compound 1 or a salt thereof, combination, method, or use according to

[32] , wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg per dose, and trametinib or a salt thereof is administered once daily at a dose selected from the group consisting of 1 mg, 1.5 mg, and 2 mg per dose.

[36] The antitumor effect enhancer, antitumor agent, pharmaceutical composition, compound 1 or a salt thereof, combination, method, or use according to

[33] , wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg per dose, and binimetinib or a salt thereof is administered twice daily at a dose selected from the group consisting of 30 mg and 45 mg per dose.

[37] The antitumor effect enhancer, antitumor agent, pharmaceutical composition, Compound 1 or a salt thereof, combination, method, or use according to

[34] , wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg per dose, and cobimetinib or a salt thereof is administered once daily at a dose selected from the group consisting of 40 mg and 60 mg per dose.

[38] The antitumor effect enhancer, antitumor agent, pharmaceutical composition, compound 1 or a salt thereof, combination, method, or use according to

[32] , wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered intermittently at a dose selected from the group consisting of 24 mg, 36 mg, 56 mg, 80 mg, 120 mg, and 160 mg per dose, and trametinib or a salt thereof is administered once a day at a dose selected from the group consisting of 1 mg, 1.5 mg, and 2 mg per dose.

[39] The antitumor effect enhancer, antitumor agent, pharmaceutical composition, compound 1 or a salt thereof, combination, method, or use according to

[33] , wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered intermittently at a dose selected from the group consisting of 24 mg, 36 mg, 56 mg, 80 mg, 120 mg, and 160 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose selected from the group consisting of 30 mg and 45 mg per dose.

[40] The antitumor effect enhancer, antitumor agent, pharmaceutical composition, Compound 1 or a salt thereof, combination, method, or use according to

[34] , wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered intermittently at a dose selected from the group consisting of 24 mg, 36 mg, 56 mg, 80 mg, 120 mg, and 160 mg per dose, and cobimetinib or a salt thereof is administered once a day at a dose selected from the group consisting of 40 mg and 60 mg per dose.

[41] The antitumor effect enhancer according to

[15] , wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered before, simultaneously with, or after an MEK inhibitor; the antitumor effect enhancer, antitumor agent, pharmaceutical composition, compound 1 or a salt thereof, combination, method, or use according to any one of

[32] to

[40] .

[42] The antitumor effect enhancer according to

[15] , the antitumor agent according to

[16] , the pharmaceutical composition according to any one of

[17] ,

[30] and

[31] , compound 1 or a salt thereof according to

[18] , the combination according to

[19] , the method according to any one of

[20] to

[22] or the use according to any one of

[23] to

[29] , the antitumor effect enhancer, antitumor agent, pharmaceutical composition, compound 1 or a salt thereof, combination, method or use according to any one of

[32] to

[41] .

[43] The antitumor effect enhancer, antitumor agent, pharmaceutical composition, compound 1 or a salt thereof, combination, method, or use according to any one of

[15] to

[42] , wherein the tumor is at least one selected from the group consisting of head and neck cancer, digestive cancer, lung cancer, breast cancer, reproductive cancer, hematopoietic tumor, bone and soft tissue tumor, skin cancer, and brain tumor.

[44] The tumor is lung cancer, pancreatic cancer, colorectal cancer, or brain tumor; the antitumor effect enhancer according to

[15] , the antitumor agent according to

[16] , the pharmaceutical composition according to any one of

[17] ,

[30] , and

[31] , compound 1 or a salt thereof according to

[18] , the combination according to

[19] , the method according to any one of

[20] to

[22] , or the use according to any one of

[23] to

[29] ; the antitumor effect enhancer, antitumor agent, pharmaceutical composition, compound 1 or a salt thereof, combination, method, or use according to any one of

[32] to

[43] . [Effects of the Invention]

[0010] According to the present disclosure, it is possible to provide a new combination therapy of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, which exhibits excellent antitumor effects, with a MEK inhibitor. [Brief explanation of the drawings]

[0011] [Figure 1]The combined effect of compound 1 (referred to as TAS-120) and selumetinib on A549 cells is shown. KRAS mutant lung cancer cell line A549 was treated with dimethyl sulfoxide (DMSO), 10 nM or 100 nM compound 1, and DMSO, 0.1 μM, 1 μM, or 10 μM selumetinib, either alone or in combination, and cultured for 10 days with medium changes every 72 or 96 hours. Cell culture plates were then stained with crystal violet. [Figure 2] KRAS mutant lung cancer cell line A549 cells were treated with DMSO, 10 nM, 30 nM, or 100 nM Compound 1 in combination with DMSO, 0.3 nM, 1.0 nM, 3.0 nM, 10 nM, or 30 nM trametinib, DMSO, 3 nM, 10 nM, 30 nM, 100 nM, or 300 nM binimetinib, or DMSO, 3 nM, 10 nM, 30 nM, 100 nM, or 300 nM cobimetinib, and cultured for 10 days with medium changes every 72 or 96 hours. Cell culture plates were then stained with crystal violet. [Figure 3] KRAS mutant lung cancer cell line LU99 cells were treated with DMSO, 10 nM, 30 nM, or 100 nM Compound 1 in combination with DMSO, 0.3 nM, 1.0 nM, 3.0 nM, 10 nM, or 30 nM trametinib, DMSO, 3 nM, 10 nM, 30 nM, 100 nM, or 300 nM binimetinib, or DMSO, 3 nM, 10 nM, 30 nM, 100 nM, or 300 nM cobimetinib, and cultured for 10 days with medium changes every 72 or 96 hours. Cell culture plates were then stained with crystal violet. [Figure 4] Pharmacokinetic data (hereinafter referred to as PK data) of Compound 1 at QD dose (daily administration) and QOD (administration once every two days) as described in AACR2018, R. Baleda et al., poster CT121 are shown. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present disclosure relates to the provision of a combination of a compound having FGFR inhibitory activity and a MEK inhibitor, i.e., an antitumor agent administered in combination with a MEK inhibitor comprising a compound having FGFR inhibitory activity, an agent that enhances the antitumor effect of a MEK inhibitor comprising a compound having FGFR inhibitory activity, an antitumor agent having FGFR inhibitory activity that is administered to patients treated with a MEK inhibitor, and methods for treating tumors using these agents, uses of these agents, uses of compounds for producing these medicines, combinations, etc.

[0013] In the present disclosure, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one is a known disubstituted benzenealkynyl compound having the structure of Chemical Formula 1 below. The free form of Compound 1 is sometimes called TAS-120 or Futibatinib. Compound 1 is described as Example Compound 2 in the above-mentioned Patent Document 3, and can be synthesized, for example, based on the production method described in Patent Document 3. It has been reported that Compound 1 or a salt thereof has excellent FGFR inhibitory activity and inhibits the ability of the receptor protein tyrosine kinases FGFR1, FGFR3, and FGFR4 to phosphorylate tyrosine in the substrate peptide sequence (Patent Document 3). In addition, it has been reported that Compound 1 or a salt thereof is administered "at least twice a week with an interval of at least one day between doses" (Patent Document 5).

[0014] The daily doses of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 1) or a salt thereof described in this specification are all expressed as the dose in free form.

[0015] [ka]

[0016] In the present disclosure, the scope of the term "MEK inhibitor" is already known by common general technical knowledge, but is not particularly limited as long as it exhibits an antitumor effect by inhibiting MEK1 and / or MEK2 in the MAPK / ERK signaling pathway, which contributes to cell proliferation. Specific examples include trametinib, binimetinib, cobimetinib, selumetinib, pimasertib, mirdametinib, refametinib, NFX-179, HL-085, CS-3006, BI-3011441, FCN-159, E6201, TQ-B3234, SHR-7390, VS-6766, and pharmaceutically acceptable salts thereof. Among these, preferred are trametinib, binimetinib, cobimetinib, selumetinib, or a pharmaceutically acceptable salt thereof, more preferred are trametinib, binimetinib, cobimetinib, or a pharmaceutically acceptable salt thereof, and most preferred is trametinib or a pharmaceutically acceptable salt thereof. In another embodiment, the "MEK inhibitor" is preferably the dimethyl sulfoxide adduct of trametinib, binimetinib, or the fumarate salt of cobimetinib, more preferably the dimethyl sulfoxide adduct of trametinib.

[0017] In yet another embodiment, the "MEK inhibitor" is most preferably binimetinib or a pharmaceutically acceptable salt thereof. In another aspect, the "MEK inhibitor" is more preferably binimetinib.

[0018] In yet another embodiment, the "MEK inhibitor" is most preferably cobimetinib or a pharmaceutically acceptable salt thereof. In yet another aspect, the "MEK inhibitor" is more preferably cobimetinib fumarate. Pharmaceutically acceptable salts of these MEK inhibitors include, but are not limited to, addition salts with inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid, citric acid, fumaric acid, tartaric acid, and maleic acid, salts with alkali metals such as potassium and sodium, salts with alkaline earth metals such as calcium and magnesium, and salts with organic bases such as ammonium salts, ethylamine salts, and arginine salts. Pharmaceutically acceptable salts of the above-mentioned compounds that are MEK inhibitors are sometimes simply referred to as salts of the above-mentioned compounds (e.g., salts of trametinib).

[0019] Trametinib (chemical name: N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide is a known compound and has the structure shown below.

[0020] [ka]

[0021] Trametinib can be synthesized according to the method described in International Publication WO 2005 / 121142. Alternatively, a commercially available drug (Mekinist Tablets (registered trademark) (chemical name: N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamido-(methylsulfinyl)methane (1:1)) may also be used.

[0022] The daily doses of trametinib or a salt thereof described in this specification are all expressed as doses converted into the free form.

[0023] Binimetinib (chemical name: 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide) is a known compound and has the structure shown below.

[0024] [ka]

[0025] Binimetinib can be synthesized according to the method described in International Publication No. 2005 / 051906. Alternatively, a commercially available drug (Mektovi Tablets (registered trademark)) may be used.

[0026] The daily doses of binimetinib or a salt thereof described in this specification are all expressed as doses converted into the free form.

[0027] Cobimetinib (chemical name: [3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl][3-hydroxy-3-[(2S)-2-piperidinyl]-1-azetidinyl]methanone) is a known compound and has the structure shown below.

[0028] [ka]

[0029] Cobimetinib can be synthesized according to the method described in WO 2007 / 044515. Alternatively, a commercially available drug (US brand name: Cotellic) or cobimetinib fumarate (chemical name: [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}methanone hemifumarate) or other pharmaceutically acceptable salts may be used.

[0030] The daily doses of cobimetinib or a salt thereof described in this specification are all expressed as doses converted into the free form.

[0031] Selumetinib (chemical name: 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide) is a known compound and has the following structure:

[0032] [ka]

[0033] Selumetinib can be synthesized according to the method described in International Publication No. 2003 / 077914. Alternatively, commercially available products may be used.

[0034] Pimasertib (chemical name: N-[(2S)-2,3-Dihydroxypropyl]-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide) is a known compound and has the structure of Chemical Formula 6 below.

[0035] [ka]

[0036] Pimasertib can be synthesized according to the method described in International Publication No. 2006 / 045514. Alternatively, commercially available products may be used.

[0037] Mirdametinib (chemical name: (R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide) is a known compound and has the structure of Chemical Formula 7 below.

[0038] [ka]

[0039] Mirdametinib can be synthesized according to the method described in International Publication No. 2002 / 006213. Alternatively, commercially available products may be used.

[0040] Refametinib (chemical name: (R)-3-(1-((3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-6-methoxybenzyl)sulfonyl)cyclopropyl)propane-1,2-diol) is a known compound and has the structure shown below.

[0041] [ka]

[0042] Lefametinib can be synthesized according to the method described in International Publication No. 2007 / 014011. Alternatively, a commercially available product may be used.

[0043] In the present disclosure, the term "recommended dose" refers to a dosage that provides the greatest therapeutic effect within the range that can be used safely without causing serious side effects, as determined by clinical trials or the like. Specifically, this refers to a dosage approved, recommended, or advised by a public institution or organization such as the Pharmaceuticals and Medical Devices Agency (PMDA), the U.S. Food and Drug Administration (FDA), or the European Medicines Agency (EMA), and is described in package inserts, interview forms, treatment guidelines, etc., with a dosage approved by any of the public institutions, PMDA, FDA, or EMA, being preferred.

[0044] In the present disclosure, Compound 1 can be used as is or in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of Compound 1 include, but are not limited to, addition salts with inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid, citric acid, fumaric acid, tartaric acid, and maleic acid; salts with alkali metals such as potassium and sodium; salts with alkaline earth metals such as calcium and magnesium; and salts with organic bases such as ammonium salts, ethylamine salts, and arginine salts. In the present disclosure, a pharmaceutically acceptable salt of Compound 1 may be simply referred to as a salt of Compound 1.

[0045] In the present disclosure, Compound 1 or a pharmaceutically acceptable salt thereof can be administered to humans or other mammals (e.g., rats, mice, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.). In the present disclosure, the MEK inhibitor can be administered to humans or other mammals (e.g., rats, mice, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.).

[0046] In the present disclosure, when Compound 1 or a salt thereof is administered daily, the preferred daily dose on the day of administration is, from the viewpoint of enhancing the antitumor effect of the MEK inhibitor by Compound 1 or a salt thereof, preferably 40% to 120%, more preferably 40% to 100%, even more preferably 60 to 100%, even more preferably 80 to 100%, and most preferably 100% of the recommended dose when Compound 1 or a salt thereof is administered alone daily. In another aspect, the preferred daily dose on the day of administration when Compound 1 or a salt thereof is administered daily is 80% of the recommended dose when Compound 1 or a salt thereof is administered alone daily. In yet another aspect, the preferred daily dose on the day of administration when Compound 1 or a salt thereof is administered daily is 60% of the recommended dose when Compound 1 or a salt thereof is administered alone daily.

[0047] Specifically, preferred dosages of Compound 1 or a salt thereof when administered once daily for consecutive days include 8 mg to 24 mg, 8 mg to 20 mg, 12 to 20 mg, 20 mg, etc. More specifically, the number of administrations and dosages per day on the day of administration include once a day, 8 mg, 12 mg, 16 mg, 20 mg, 24 mg, etc. In another aspect, preferred number of administrations and dosages per day on the day of administration include once a day, 8 mg, 12 mg, 16 mg, 20 mg, etc. In another aspect, preferred number of administrations and dosages per day on the day of administration include once a day, 12 mg, 16 mg, 20 mg, etc. In another aspect, preferred number of administrations and dosages per day on the day of administration include once a day, 20 mg, etc. In another aspect, preferred number of administrations and dosages per day on the day of administration include once a day, 16 mg, etc. In yet another aspect, preferred daily doses and dosages on the day of administration include once a day, 12 mg, etc. All of these dosages of Compound 1 or a salt thereof are calculated as the amount of the free form.

[0048] In the present disclosure, when compound 1 or a salt thereof is administered intermittently, the daily dose on the day of administration is preferably 15% to 125%, more preferably 35% to 100%, even more preferably 75 to 100%, still more preferably 80 to 100%, and most preferably 100%, of the recommended dose when compound 1 or a salt thereof is administered intermittently alone, from the viewpoint of the enhancing effect of compound 1 or a salt thereof on the antitumor effect of the MEK inhibitor.

[0049] Specifically, when Compound 1 or a salt thereof is administered intermittently, a preferred daily dose on the day of administration is 24 mg to 200 mg, etc. In another aspect, a preferred daily dose on the day of administration is 56 mg to 160 mg, etc. In another aspect, a preferred daily dose on the day of administration is 120 to 160 mg, etc. In another aspect, a preferred daily dose on the day of administration is 160 mg, etc. More specifically, the number of administrations and the dose per day on the day of administration are once a day, 24 mg, 36 mg, 56 mg, 80 mg, 120 mg, 160 mg, 200 mg, etc. In another aspect, the preferred number of administrations and the dose per day on the day of administration are 56 mg, 80 mg, 120 mg, 160 mg, etc. In another aspect, the preferred number of administrations and the dose per day on the day of administration are 80 mg, 120 mg, 160 mg, etc. In another aspect, preferred daily doses and administration amounts on the day of administration include 160 mg, etc. These administration amounts of Compound 1 or a salt thereof are all calculated as the free form.

[0050] In the present disclosure, the daily dose of the MEK inhibitor on the day of administration is preferably 25% to 200%, more preferably 66% to 100%, and most preferably 100% of the recommended dose when the MEK inhibitor is administered alone, from the viewpoint of the enhancing effect of compound 1 or a salt thereof on the antitumor effect of the MEK inhibitor.

[0051] In the present disclosure, the daily dose of trametinib or a salt thereof on the day of administration is preferably 25% to 200%, more preferably 50 to 100%, and most preferably 100% of the recommended dose when trametinib or a salt thereof is administered alone, from the viewpoint of enhancing the antitumor effect of the MEK inhibitor by Compound 1 or a salt thereof. Specifically, the recommended dose of trametinib or a salt thereof when administered alone in humans is 0.5 to 4 mg, more preferably 1 to 2 mg, and most preferably 2 mg, when administered once daily, according to the approval information in the package insert and interview form. In one embodiment, preferred daily doses and dosages on the day of administration include once daily, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, and 4 mg. In another embodiment, preferred daily doses and dosages on the day of administration include once daily, 1 mg, 1.5 mg, and 2 mg. In another aspect, preferred daily doses and dosages on the day of administration include once a day, 2 mg, etc. All of these dosages of trametinib or a salt thereof are calculated as the amount of the free form.

[0052] In the present disclosure, the daily dose of binimetinib or a salt thereof on the day of administration is preferably 66% to 133%, more preferably 66% to 100%, and most preferably 100% of the recommended dose when binimetinib or a salt thereof is administered alone, from the viewpoint of enhancing the antitumor effect of the MEK inhibitor by Compound 1 or a salt thereof. Specifically, the recommended dose of binimetinib or a salt thereof when administered alone in humans is 15 to 60 mg, more preferably 30 to 60 mg, more preferably 30 to 45 mg, and even more preferably 45 mg, per twice-daily administration, according to the approval information in the package insert and interview form. In one embodiment, preferred daily doses and dosages on the day of administration include 15 mg, 30 mg, 45 mg, and 60 mg twice-daily. In another embodiment, preferred daily doses and dosages on the day of administration include 15 mg, 30 mg, and 45 mg twice-daily. In another aspect, preferred administration frequency and dosage per day on the day of administration include twice a day, 45 mg per administration, etc. In another aspect, preferred administration frequency and dosage per day on the day of administration include twice a day, 30 mg per administration. In yet another aspect, preferred administration frequency and dosage per day on the day of administration include twice a day, 15 mg per administration. All of these dosages of binimetinib or a salt thereof are calculated as the amount of free form.

[0053] In the present disclosure, the daily dose of cobimetinib or a salt thereof on the day of administration is preferably 66% to 133%, more preferably 66% to 100%, and most preferably 100% of the recommended dose when cobimetinib or a salt thereof is administered alone, from the viewpoint of enhancing the antitumor effect of the MEK inhibitor by Compound 1 or a salt thereof. Specifically, the recommended dose of cobimetinib or a salt thereof when administered alone in humans is 40 to 80 mg, more preferably 40 to 60 mg, and most preferably 60 mg, per administration once daily, according to the approval information in the package insert and interview form. In one embodiment, preferred daily doses and dosages on the day of administration include 40 mg, 60 mg, and 80 mg once daily. In another embodiment, preferred daily doses and dosages on the day of administration include 40 mg, 60 mg, and the like once daily. In another aspect, preferred daily administration numbers and dosages on the day of administration include once a day, once a day, 60 mg, etc. All of these dosages of cobimetinib or a salt thereof are calculated as the amount of free form.

[0054] In the present disclosure, the daily dose of selumetinib or a salt thereof on the day of administration is preferably 66% to 133%, more preferably 66% to 100%, and most preferably 100% of the recommended dose when selumetinib or a salt thereof is administered alone, from the viewpoint of the potentiation of the antitumor effect of the MEK inhibitor by Compound 1 or a salt thereof. Specifically, the recommended dose when selumetinib or a salt thereof is administered alone in humans is 5 to 25 mg / m per dose when administered twice a day, according to the approval information in the package insert and interview form. 2 , more preferably 20 to 25 mg / m 2 , more preferably 25 mg / m 2 In one embodiment, preferred daily doses and dosages on the day of administration include 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 10 mg, etc., twice a day. All of the dosages of selumetinib or a salt thereof are calculated as the amount of free form.

[0055] In the present disclosure, the daily dose of pimasertib or a salt thereof on the day of administration is preferably 66% to 133%, more preferably 66% to 100%, and most preferably 100% of the recommended dose when pimasertib or a salt thereof is administered alone, from the viewpoint of the potentiation of the antitumor effect of the MEK inhibitor by Compound 1 or a salt thereof. In one embodiment, the preferred number of administrations and dosage per day on the day of administration include 10 to 60 mg twice a day. In another embodiment, the preferred number of administrations and dosage per day on the day of administration include 10 to 60 mg once a day. In yet another embodiment, the preferred number of administrations and dosage per day on the day of administration include 90 mg, 75 mg, 60 mg, 42 mg, 30 mg, 23 mg, 15 mg, 8 mg twice a day. All of the doses of pimasertib or a salt thereof are calculated as the free form.

[0056] In the present disclosure, the daily dose of mirdametinib or a salt thereof on the day of administration is preferably 66% to 133%, more preferably 66% to 100%, and most preferably 100% of the recommended dose when mirdametinib or a salt thereof is administered alone, from the viewpoint of enhancing the antitumor effect of the MEK inhibitor by Compound 1 or a salt thereof. Specifically, the recommended dose when mirdametinib or a salt thereof is administered alone in humans is 1 to 5 mg / m2 per administration when administered twice a day. 2 , more preferably 2 to 4 mg / m 2 All of the doses of mirdametinib or a salt thereof are calculated as free form.

[0057] In the present disclosure, the daily dose of refametinib or a salt thereof on the day of administration is preferably 66% to 133%, more preferably 66% to 100%, and most preferably 100% of the recommended dose when refametinib or a salt thereof is administered alone, from the viewpoint of enhancing the antitumor effect of the MEK inhibitor by Compound 1 or a salt thereof. Specifically, the recommended doses of refametinib or a salt thereof when administered alone in humans are 60 mg, 50 mg, 40 mg, 30 mg, 20 mg, or 10 mg per administration when administered once or twice daily. All of these doses of refametinib or a salt thereof are calculated as the free form.

[0058] Preferred combinations of the daily dose of Compound 1 or a salt thereof on the day of administration and the daily dose of trametinib or a salt thereof in the present disclosure, or the method of administration and dosage, include the following: Compound 1 or a salt thereof according to the present disclosure, once a day for consecutive days, 8 to 20 mg per dose, and trametinib or a salt thereof, once a day, 1 to 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure, once a day for consecutive days, 8 to 20 mg per dose, and trametinib or a salt thereof, once a day, 1.5 to 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure, once a day for consecutive days, 8 to 20 mg per dose, and trametinib or a salt thereof, 1 mg per dose, once a day. Compound 1 or a salt thereof according to the present disclosure, once a day for consecutive days, 8 to 20 mg per dose, and trametinib or a salt thereof, 1.5 mg per dose, once a day. Compound 1 or a salt thereof according to the present disclosure, once a day for consecutive days, 8 to 20 mg per dose, and trametinib or a salt thereof, once a day, 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure, once a day for consecutive days, 12 to 20 mg per dose, and trametinib or a salt thereof, once a day, 1 to 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure, once a day for consecutive days, 12 to 20 mg per dose, and trametinib or a salt thereof, once a day, 1.5 to 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 12 to 20 mg per dose, and trametinib or a salt thereof is administered once a day at a dose of 1 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 12 to 20 mg per dose, and trametinib or a salt thereof is administered once a day at a dose of 1.5 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 12 to 20 mg per dose, and trametinib or a salt thereof is administered once a day at a dose of 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure, once a day for consecutive days, 8 mg per dose, and trametinib or a salt thereof, 1 to 2 mg per dose, once a day. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 8 mg per dose, and trametinib or a salt thereof is administered once a day at a dose of 1.5 to 2 mg per dose. Compound 1 or a salt thereof in the present disclosure, once daily for consecutive days, 8 mg per dose, and trametinib or a salt thereof, 1 mg per dose, once daily. Compound 1 or a salt thereof in the present disclosure, once daily for consecutive days, 8 mg per dose, and trametinib or a salt thereof, once daily, 1.5 mg per dose. Compound 1 or a salt thereof of the present disclosure, once daily for consecutive days, 8 mg per dose, and trametinib or a salt thereof, once daily, 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure, once a day for consecutive days, 12 mg per dose, and trametinib or a salt thereof, 1 to 2 mg per dose, once a day. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 12 mg per dose, and trametinib or a salt thereof is administered once a day at a dose of 1.5 to 2 mg per dose. Compound 1 or a salt thereof in the present disclosure, once daily for consecutive days, 12 mg per dose, and trametinib or a salt thereof, 1 mg per dose, once daily. Compound 1 or a salt thereof in the present disclosure, once daily for consecutive days, 12 mg per dose, and trametinib or a salt thereof, 1.5 mg per dose, once daily. Compound 1 or a salt thereof of the present disclosure, once daily for consecutive days, 12 mg per dose, and trametinib or a salt thereof, 2 mg per dose, once daily. Compound 1 or a salt thereof according to the present disclosure, once a day for consecutive days, 16 mg per dose, and trametinib or a salt thereof, 1 to 2 mg per dose, once a day. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 16 mg per dose, and trametinib or a salt thereof is administered once a day at a dose of 1.5 to 2 mg per dose. Compound 1 or a salt thereof in the present disclosure, once daily for consecutive days, 16 mg per dose, and trametinib or a salt thereof, 1 mg per dose, once daily. Compound 1 or a salt thereof of the present disclosure, once daily for consecutive days, 16 mg per dose, and trametinib or a salt thereof, 1.5 mg per dose, once daily. Compound 1 or a salt thereof of the present disclosure, once daily for consecutive days, 16 mg per dose, and trametinib or a salt thereof, 2 mg per dose, once daily. Compound 1 or a salt thereof according to the present disclosure, once a day for consecutive days, 20 mg per dose, and trametinib or a salt thereof, 1 to 2 mg per dose, once a day. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 20 mg per dose, and trametinib or a salt thereof is administered once a day at a dose of 1.5 to 2 mg per dose. Compound 1 or a salt thereof in the present disclosure, once daily for consecutive days, 20 mg per dose, and trametinib or a salt thereof, 1 mg per dose, once daily. Compound 1 or a salt thereof in the present disclosure, once daily for consecutive days, 20 mg per dose, and trametinib or a salt thereof, 1.5 mg per dose, once daily. Compound 1 or a salt thereof in the present disclosure, once daily for consecutive days, 20 mg per dose, and trametinib or a salt thereof, 2 mg per dose, once daily.

[0059] Preferred combinations of the daily dose of Compound 1 or a salt thereof on the day of administration and the daily dose of binimetinib or a salt thereof, or the use method and dosage, according to the present disclosure, include the following: Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 8 to 20 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 to 60 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 8 to 20 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 to 45 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 8 to 20 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 8 to 20 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 45 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 12 to 20 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 to 60 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 12 to 20 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 to 45 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 12 to 20 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 12 to 20 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 45 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 8 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 to 60 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 8 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 to 45 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered once a day for consecutive days at 8 mg per dose, and binimetinib or a salt thereof is administered twice a day at 30 mg per dose. Compound 1 or a salt thereof of the present disclosure, once daily for consecutive days, 8 mg per dose, and binimetinib or a salt thereof, 45 mg per dose, twice daily. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 12 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 to 60 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 12 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 to 45 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered once a day for consecutive days at a dose of 12 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered once daily for consecutive days at a dose of 12 mg per dose, and binimetinib or a salt thereof is administered twice daily at a dose of 45 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 16 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 to 60 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 16 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 to 45 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered once a day for consecutive days at a dose of 16 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 mg per dose. Compound 1 or a salt thereof of the present disclosure, once daily for consecutive days, 16 mg per dose, and binimetinib or a salt thereof, 45 mg per dose, twice daily. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 20 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 to 60 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 20 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 to 45 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered once a day for consecutive days at a dose of 20 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered once a day for consecutive days at a dose of 20 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 45 mg per dose.

[0060] Preferred daily doses on the day of administration of Compound 1 or a salt thereof and daily doses of cobimetinib or a salt thereof in the present disclosure, or preferred combinations of dosage and administration, include the following: Compound 1 or a salt thereof according to the present disclosure, once a day for consecutive days, 8 to 20 mg per dose, and cobimetinib or a salt thereof, once a day, 40 to 80 mg per dose. Compound 1 or a salt thereof according to the present disclosure, once a day for consecutive days, 8 to 20 mg per dose, and cobimetinib or a salt thereof, 40 to 60 mg per dose, once a day. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 8 to 20 mg per dose, and cobimetinib or a salt thereof is administered once a day at a dose of 40 mg per dose. Compound 1 or a salt thereof according to the present disclosure, once a day for consecutive days, 8 to 20 mg per dose, and cobimetinib or a salt thereof, once a day, 60 mg per dose. Compound 1 or a salt thereof according to the present disclosure, once a day for consecutive days, 12 to 20 mg per dose, and cobimetinib or a salt thereof, once a day, 40 to 80 mg per dose. Compound 1 or a salt thereof according to the present disclosure, once a day for consecutive days, 12 to 20 mg per dose, and cobimetinib or a salt thereof, once a day, 40 to 60 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 12 to 20 mg per dose, and cobimetinib or a salt thereof is administered once a day at a dose of 40 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 12 to 20 mg per dose, and cobimetinib or a salt thereof is administered once a day at a dose of 60 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 8 mg per dose, and cobimetinib or a salt thereof is administered once a day at a dose of 40 to 80 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 8 mg per dose, and cobimetinib or a salt thereof is administered once a day at a dose of 40 to 60 mg per dose. Compound 1 or a salt thereof of the present disclosure, once daily for consecutive days, 8 mg per dose, and cobimetinib or a salt thereof, 40 mg per dose, once daily. Compound 1 or a salt thereof of the present disclosure, once daily for consecutive days, 8 mg per dose, and cobimetinib or a salt thereof, once daily, 60 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 12 mg per dose, and cobimetinib or a salt thereof is administered once a day at a dose of 40 to 80 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 12 mg per dose, and cobimetinib or a salt thereof is administered once a day at a dose of 40 to 60 mg per dose. Compound 1 or a salt thereof of the present disclosure, once daily for consecutive days, 12 mg per dose, and cobimetinib or a salt thereof, 40 mg per dose, once daily. Compound 1 or a salt thereof of the present disclosure, once daily for consecutive days, 12 mg per dose, and cobimetinib or a salt thereof, once daily, 60 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 16 mg per dose, and cobimetinib or a salt thereof is administered once a day at a dose of 40 to 80 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 16 mg per dose, and cobimetinib or a salt thereof is administered once a day at a dose of 40 to 60 mg per dose. Compound 1 or a salt thereof of the present disclosure, once daily for consecutive days, 16 mg per dose, and cobimetinib or a salt thereof, 40 mg per dose, once daily. Compound 1 or a salt thereof of the present disclosure, once daily for consecutive days, 16 mg per dose, and cobimetinib or a salt thereof, once daily, 60 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 20 mg per dose, and cobimetinib or a salt thereof is administered once a day at a dose of 40 to 80 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered once a day for consecutive days at a dose of 20 mg per dose, and cobimetinib or a salt thereof is administered once a day at a dose of 40 to 60 mg per dose. Compound 1 or a salt thereof of the present disclosure, once daily for consecutive days, 20 mg per dose, and cobimetinib or a salt thereof, 40 mg per dose, once daily. Compound 1 or a salt thereof of the present disclosure, once daily for consecutive days, 20 mg per dose, and cobimetinib or a salt thereof, once daily, 60 mg per dose.

[0061] In another embodiment, preferred combinations of the daily dose on the day of administration of Compound 1 or a salt thereof and the daily dose of trametinib or a salt thereof in the present disclosure, or the use method and dosage, include the following: Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1 to 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1.5 to 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 24 to 200 mg per administration, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1 mg per administration. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1.5 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 56 to 160 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1 to 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 56 to 160 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1.5 to 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 56 to 160 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 56 to 160 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1.5 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 56 to 160 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 80 to 160 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1 to 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 80 to 160 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1.5 to 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 80 to 160 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 80 to 160 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1.5 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 80 to 160 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 56 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1 to 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 56 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1.5 to 2 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 56 mg per dose, and trametinib or a salt thereof is administered once daily for consecutive days at a dose of 1 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 56 mg per dose, and trametinib or a salt thereof is administered once daily for consecutive days at a dose of 1.5 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 56 mg per dose, and trametinib or a salt thereof is administered once daily for consecutive days at a dose of 2 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at 80 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at 1 to 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 80 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1.5 to 2 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 80 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 80 mg per dose, and trametinib or a salt thereof is administered once daily for consecutive days at a dose of 1.5 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 80 mg per dose, and trametinib or a salt thereof is administered once daily for consecutive days at a dose of 2 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 120 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1 to 2 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 120 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1.5 to 2 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 120 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 120 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1.5 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 120 mg per dose, and trametinib or a salt thereof is administered once daily for consecutive days at a dose of 2 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 160 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1 to 2 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 160 mg per dose, and trametinib or a salt thereof is administered once a day for consecutive days at a dose of 1.5 to 2 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 160 mg per dose, and trametinib or a salt thereof is administered once daily for consecutive days at a dose of 1 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 160 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1.5 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 160 mg per dose, and trametinib or a salt thereof is administered once daily for consecutive days at a dose of 2 mg per dose.

[0062] In another aspect, preferred combinations of the daily dose on the day of administration of Compound 1 or a salt thereof and the daily dose of binimetinib or a salt thereof in the present disclosure, or the usage and dosage, include the following: Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 to 60 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 24 to 200 mg per administration, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 to 45 mg per administration. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 24 to 200 mg per administration, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 mg per administration. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 24 to 200 mg per administration, and binimetinib or a salt thereof is administered twice a day at a dose of 45 mg per administration. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 56 to 160 mg per administration, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 to 60 mg per administration. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 56 to 160 mg per dose, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 to 45 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 56 to 160 mg per dose, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 56 to 160 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 45 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 80 to 160 mg per dose, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 to 60 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 80 to 160 mg per dose, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 to 45 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 80 to 160 mg per dose, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 80 to 160 mg per administration, and binimetinib or a salt thereof is administered twice a day at a dose of 45 mg per administration. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 56 mg per administration, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 to 60 mg per administration. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 56 mg per dose, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 to 45 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 56 mg per dose, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 56 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 45 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 80 mg per dose, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 to 60 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 80 mg per dose, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 to 45 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 80 mg per dose, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 80 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 45 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 120 mg per dose, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 to 60 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 120 mg per administration, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 to 45 mg per administration. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 120 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 120 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 45 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 160 mg per dose, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 to 60 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 160 mg per dose, and binimetinib or a salt thereof is administered twice a day for consecutive days at a dose of 30 to 45 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 160 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 30 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 160 mg per dose, and binimetinib or a salt thereof is administered twice a day at a dose of 45 mg per dose.

[0063] In another aspect, preferred combinations of the daily dose on the day of administration of Compound 1 or a salt thereof and the daily dose of cobimetinib or a salt thereof in the present disclosure, or the use method and dosage, include the following: Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 40 to 80 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 40 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 60 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 40 to 60 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 56 to 160 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 40 to 80 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 56 to 160 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 40 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 56 to 160 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 60 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 56 to 160 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 40 to 60 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered intermittently at a dose of 80 to 160 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 40 to 80 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 80 to 160 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 40 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 80 to 160 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 60 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 80 to 160 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 40 to 60 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 56 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 40 to 80 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 56 mg per dose, and cobimetinib or a salt thereof is administered once daily for consecutive days at a dose of 40 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 56 mg per dose, and cobimetinib or a salt thereof is administered once daily for consecutive days at a dose of 60 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 56 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 40 to 60 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 80 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 40 to 80 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 80 mg per dose, and cobimetinib or a salt thereof is administered once daily for consecutive days at a dose of 40 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 80 mg per dose, and cobimetinib or a salt thereof is administered once daily for consecutive days at a dose of 60 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 80 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 40 to 60 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 120 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 40 to 80 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 120 mg per dose, and cobimetinib or a salt thereof is administered once daily for consecutive days at a dose of 40 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 120 mg per dose, and cobimetinib or a salt thereof is administered once daily for consecutive days at a dose of 60 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 120 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 40 to 60 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 160 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 40 to 80 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 160 mg per dose, and cobimetinib or a salt thereof is administered once daily at a dose of 40 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 160 mg per dose, and cobimetinib or a salt thereof is administered once daily for consecutive days at a dose of 60 mg per dose. Compound 1 or a salt thereof of the present disclosure is administered intermittently at a dose of 160 mg per dose, and cobimetinib or a salt thereof is administered once a day for consecutive days at a dose of 40 to 60 mg per dose.

[0064] In some embodiments, the present disclosure includes administration of Compound 1 or a salt thereof at a dose of more than 20 mg once daily for cancer types where stronger efficacy is desired (e.g., brain tumors), administration of trametinib or a salt thereof at a dose of more than 2 mg once daily, administration of binimetinib or a salt thereof at a dose of more than 45 mg twice daily, and administration of cobimetinib or a salt thereof at a dose of more than 60 mg once daily.

[0065] The order of administration of Compound 1 or a salt thereof and the MEK inhibitor can be appropriately selected depending on the type of cancer, stage of disease, etc., but in one treatment regimen, they may be administered either first or simultaneously.

[0066] The administration schedule of the antitumor agent of the present disclosure may be selected appropriately depending on the carcinoma, disease, etc. The administration schedule of Compound 1 or a pharmaceutically acceptable salt thereof is preferably daily administration or intermittent administration. A preferred administration schedule for trametinib or a salt thereof is once daily administration. A preferred administration schedule for binimetinib or a salt thereof is twice daily administration. A preferred administration schedule for cobimetinib or a salt thereof is once daily administration. A preferred administration schedule for selumetinib or a salt thereof is twice daily administration. The administration schedule may be repeated, and a drug holiday period may be appropriately set depending on side effects, etc.

[0067] As used herein, the term "co-administration" is synonymous with administration in the same therapeutic regimen.

[0068] As used herein, "daily administration" refers to an administration schedule in which consecutive administrations are performed during the same treatment regimen, with one cycle consisting of the administration of the drug. For example, if the treatment regimen is 21 days long, the drug is administered every 21 days. A drug holiday may be provided after each cycle.

[0069] As used herein, "intermittent administration" is not particularly limited as long as it satisfies the conditions of two or more times per week and the administration interval (the number of days between one administration day and the next administration day) being one day or more. Preferably, it is administered three or more times per week, and more preferably, it is administered three times per week.

[0070] For example, an administration schedule in which one cycle is one week, in which Compound 1 or a pharmaceutically acceptable salt thereof is administered two or more times every one to three days per cycle (the interval between one administration day and the next administration day is one to three days), and the cycle is repeated one or more times; an administration schedule in which one cycle is 14 days, in which Compound 1 or a pharmaceutically acceptable salt thereof is administered 4 to 7 times every 1 to 3 days (the interval between one administration day and the next administration day is 1 to 3 days) per cycle, and the cycle is repeated once or twice or more times; an administration schedule in which one cycle is 14 days, in which Compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1, 4, 8, and 11 of the 14 days in one cycle; an administration schedule in which one cycle is 14 days, in which Compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1, 3, 5, 7, 9, 11, and 13 of the 14 days in one cycle; An example of such a schedule is an administration schedule in which one cycle is 14 days, and compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1, 3, 5, 8, 10, and 12 of the 14 days included in one cycle.

[0071] As used herein, administration of drug A at X-day intervals means that if the day on which drug A is administered is designated day 1, the following day is designated day 2, the day after that is designated day 3, etc., then the next administration of drug A will be on day X+2.

[0072] The therapeutically effective amount of Compound 1 or a salt thereof and MEK inhibitor will depend on several factors, including, but not limited to, the stage and severity of the cancer, as well as other factors related to the health of the patient. Those skilled in the art will know how to determine a therapeutically effective amount.

[0073] The combination therapy methods described herein are useful for treating proliferative diseases. The methods involve the administration of effective amounts of Compound 1 or a salt thereof and a MEK agent. In some embodiments, the effective amount is sufficient to slow tumor growth. In some embodiments, the effective amount is sufficient to prevent or delay recurrence. The effective amount can be administered in one or more doses.

[0074] In the case of cancer, an effective amount of a drug or composition is one that can result in either:

[0075] (i) Reducing the number of cancer cells.

[0076] (ii) reducing tumor size;

[0077] (iii) Reduce the tumor burden.

[0078] (iv) inhibiting, delaying, slowing to some degree, and possibly stopping the invasion of cancer cells into peripheral organs;

[0079] (v) inhibiting (i.e., slowing to some extent and preferably halting) tumor metastasis;

[0080] (vi) inhibiting tumor growth;

[0081] (vii) reducing the rate of tumor growth;

[0082] (viii) preventing or delaying the onset and / or recurrence of tumors;

[0083] (ix) alleviating to some extent one or more symptoms associated with cancer.

[0084] (x) prolonging survival; and / or (xi) extending progression-free survival.

[0085] The number of times per day the antitumor agent of the present disclosure is administered may be selected as appropriate depending on the type of cancer, the stage of the disease, etc. When compound 1 or a salt thereof is administered in combination with a MEK inhibitor, it is preferred that compound 1 or a salt thereof is administered once a day, trametinib or a salt thereof once a day, binimetinib or a salt thereof twice a day, cobimetinib or a salt thereof once a day, and selumetinib or a salt thereof twice a day.

[0086] Treatment, as used herein, includes procedures performed with the intent to cure or ameliorate a disease, or to inhibit the progression or recurrence of a disease, or to alleviate symptoms. Treatment also includes the administration of medications before or after a surgical procedure, or before or after radiation therapy.

[0087] As used herein, the term "combination therapy" is intended to define a therapy that includes the use of a combination of two or more compounds / agents (as defined above). Thus, the use of "combination therapy," "combination," and compounds / agents "in combination" in this application can refer to compounds / agents that are administered as part of the same overall treatment regimen.

[0088] A "regimen" or "treatment regimen" refers to a plan that chronologically indicates the type, amount, duration, and procedure of drug therapy. Treatment with the same treatment regimen refers to the administration of one drug and another drug within a specified period of time at a prescribed interval and dosage for each drug. For example, administration of concomitant drugs is initiated simultaneously or substantially simultaneously on the first day of a cycle. Another example is a three-week cycle in which drug A is administered first, followed by drug B one week later. This essentially simultaneous administration is also included in treatment with a single treatment regimen. A specified period of time can be, for example, 28 days, but can be selected appropriately depending on the cancer, disease, etc.

[0089] Before and / or after a treatment regimen begins, there may be a washout period during which no medication is administered to eliminate the effects of previous medications.

[0090] The treatment regimen of the present disclosure comprising Compound 1 or a salt thereof and a MEK inhibitor may further comprise other drugs in addition to Compound 1 or a salt thereof and a MEK inhibitor.

[0091] "Use before," "use simultaneously," and "use after" refer to the order of administration of Compound 1 or a pharmaceutically acceptable salt thereof and a MEK inhibitor on the same scheduled administration day. "Use before" is synonymous with "administration of Compound 1 or a salt thereof before the MEK inhibitor on the same scheduled administration day," "use simultaneously" is synonymous with "administration of Compound 1 or a salt thereof simultaneously with the MEK inhibitor on the same scheduled administration day," and "use after" is synonymous with "administration of Compound 1 or a salt thereof after the MEK inhibitor on the same scheduled administration day.

[0092] The order of administration of Compound 1 or a salt thereof and the MEK inhibitor can be appropriately selected depending on the type of cancer, stage of disease, etc., but in one treatment regimen, either may be administered first, or they may be administered simultaneously.

[0093] In one embodiment, the combination therapy of the present disclosure is administered to a patient who has not previously been treated with hormone therapy, immunotherapy (such as cancer peptide vaccine therapy), surgery, radiation therapy, or chemotherapy, i.e., a treatment-naive patient. In another embodiment, the combination therapy is administered to a patient who has failed to achieve a durable response after previous treatment with a chemotherapy agent.

[0094] In this disclosure, "cancer" or "tumor" refers to a physiological condition in mammals characterized by unregulated cell growth. "Cancer" and "tumor" have the same meaning and are used interchangeably herein. Cancer includes solid tumors and hematological cancers. Examples include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma, sarcoma, and borderline malignant tumors (carcinoid).

[0095] In one aspect, the present disclosure can prevent and / or treat diseases (particularly tumors) in which the RAS / MAPK signaling pathway is involved.

[0096] Examples of "diseases involving the RAS / MAPK signaling pathway" include, but are not limited to, cancer, autoimmune diseases, macroglobulinemia, and the like.

[0097] The RAS / MAPK signaling pathway is not particularly limited, but representative examples include signals from RAS and downstream RAS signaling cascades such as RAF, MEK, ERK, PI3K, AKT, mTOR, and RAL-GEF. Examples of diseases that can be cured by deleting, suppressing, and / or inhibiting these functions include a reduction in the incidence of disease (particularly tumors), remission or alleviation of symptoms, suppression of disease progression, suppression of recurrence of disease, and / or complete cure. Diseases involving the RAS / MAPK signaling pathway are preferably tumors with abnormalities in the RAS / MAPK signaling pathway, and more preferably tumors with overexpression of RAS, abnormalities in the RAS gene, or abnormal activity of the RAS / MAPK signaling pathway.

[0098] A tumor overexpressing RAS is preferably a tumor with high expression of the gene and the gene product protein.

[0099] Tumors having an abnormality in the RAS gene preferably include those having gene amplification, gene mutation, chromosomal translocation / insertion / inversion, gene fusion, gene rearrangement, etc. Tumors having a gene mutation are preferably used for tumors having an abnormality in the RAS gene, more preferably for tumors having a mutation in an isoform of NRAS, KRAS, or HRAS, and even more preferably for tumors having a mutation in an isoform of KRAS.

[0100] Tumors with abnormal RAS / MAPK signaling activity preferably include tumors with increased RAS or MEK activity.

[0101] Tumors with abnormalities in the RAS / MAPK signaling pathway are more preferably tumors with overexpression of RAS, abnormalities in the RAS gene, or abnormal activity of the RAS / MAPK signaling pathway, even more preferably tumors with abnormalities in the RAS gene, and most preferably tumors with mutations in KRAS isoforms.

[0102] In another embodiment of the present disclosure, the disease involving the RAS / MAPK signaling pathway is preferably a tumor having an abnormality in the RAS / MAPK signaling pathway, and more preferably is used for a tumor having an abnormality in FGFR.

[0103] Tumors having an abnormality in the FGFR gene preferably include gene amplification, gene mutation, chromosomal translocation / insertion / inversion, gene fusion, gene rearrangement, etc., and are preferably used for tumors having an FGFR mutation, more preferably for tumors having an FGFR mutation selected from the group consisting of FGFR1, FGFR2, FGFR3, and FGFR4.

[0104] In one aspect, the present disclosure is used for tumors that overexpress RAS and / or FGFR. The presence or absence of RAS and / or FGFR expression can be detected by methods known to those skilled in the art. Detection of gene expression and high expression of gene product proteins can be performed by known methods, such as antibody-based methods (immunohistological staining, enzyme-linked immunosorbent assay (ELISA), flow cytometry, immunoblotting, etc.), nucleic acid-based methods (in situ hybridization, PCR, Northern blotting, etc.), and methods based on principles common to these. Detection devices can be known devices (gene chips, microarrays, etc.).

[0105] In one aspect, the present disclosure is used for tumors having abnormalities in the RAS and / or FGFR genes. Some abnormalities in the RAS and / or FGFR genes in tumors have already been reported in literature available to those skilled in the art (Non-Patent Documents). Abnormalities in the RAS and / or FGFR genes can be detected by methods known to those skilled in the art, such as DNA sequencing including pyrosequencing and NGS (next-generation sequencing), PCR-based methods including allele-specific PCR chain reaction, microarray-based comparative genomic hybridization (aCGH), fluorescent in situ hybridization (FISH), chromogenic in situ hybridization (CISH), etc.

[0106] In certain embodiments, the present disclosure is used for tumors in which RAS signaling and / or FGFR signaling is activated. RAS signaling activation can be detected by methods known to those skilled in the art. Detection of signaling activation can be performed, for example, by detecting the direct binding state of RAS with GTP or GDP, the phosphorylation state of intracellular substrates and intracellular proteins downstream of the RAS signaling cascade, biological activities including enzymatic activity, or detection of gene products or gene transcripts. FGFR signaling activation can be detected by methods known to those skilled in the art. Detection of signaling activation can be performed, for example, by detecting FGF, which is an FGFR ligand, the direct phosphorylation state or biological activities including enzymatic activity of FGFR, which is a phosphorylating enzyme, the phosphorylation state of intracellular substrates and intracellular proteins downstream of the FGFR signaling cascade, biological activities including enzymatic activity, or detection of gene products or gene transcripts.

[0107] Tumors that are the subject of the present disclosure are not particularly limited, and examples thereof include head and neck cancer, digestive cancers (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder and bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.)), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, reproductive cancers (ovarian cancer, uterine cancer (cervical cancer, endometrial cancer, etc.)), urinary tract cancers (kidney cancer, bladder cancer, prostate cancer, testicular tumors, etc.), hematopoietic tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors, skin cancer, brain tumors, neurofibromas, thyroid cancer, etc. Preferred are lung cancer, pancreatic cancer, and colorectal cancer.

[0108] Here, cancer includes not only primary lesions but also cancer that has metastasized to other organs (such as the liver). The antitumor agent of the present disclosure may be used in postoperative adjuvant chemotherapy performed to prevent recurrence after surgical removal of a tumor, or in preoperative adjuvant chemotherapy performed before surgical removal of a tumor.

[0109] Methods for detecting the mechanism of action of FGFR inhibitors and the mechanism of action of MEK inhibitors include, but are not limited to, a method of examining the regulation of the tumor immune microenvironment (Cellular Physiology and Biochemistry, 33, p. 633-645 (2014)).

[0110] The dosage form of the antitumor agent of the present disclosure is not particularly limited for Compound 1 or a pharmaceutically acceptable salt thereof, and can be appropriately selected depending on the purpose of treatment. Specific examples include oral preparations (tablets, coated tablets, powders, granules, capsules, liquid preparations, etc.), injections, suppositories, patches, ointments, etc. In the case of Compound 1 or a salt thereof, the above-mentioned dosage forms are exemplified, with oral preparations being preferred. In the case of MEK inhibitors, the above-mentioned dosage forms are exemplified, with oral preparations being preferred.

[0111] The antitumor agent of the present disclosure may be used as the active ingredients, Compound 1 or a salt thereof and a MEK inhibitor, themselves as an antitumor agent, or may be prepared as a pharmaceutical composition prepared by a commonly known method using a pharmaceutically acceptable carrier depending on the administration form. Examples of such carriers include various carriers commonly used in conventional pharmaceuticals, such as excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, isotonicity agents, pH adjusters, buffers, stabilizers, colorants, flavoring agents, and odorants.

[0112] The antitumor agent of the present disclosure may be formulated by dividing each active ingredient into multiple dosage forms or by combining them into a single dosage form, depending on the dosage form and / or administration schedule of each active ingredient. Furthermore, each formulation may be manufactured and sold in a single package suitable for combined administration, or each formulation may be manufactured and sold in separate packages. The same applies to pharmaceutical composition embodiments. Therefore, a "pharmaceutical composition comprising Compound 1 or a salt thereof and a MEK inhibitor as active ingredients" includes both formulations in which each active ingredient is divided into multiple dosage forms and formulations in which each active ingredient is divided into a single dosage form. The pharmaceutical composition in which each active ingredient is divided into multiple dosage forms includes both formulations in which each formulation is divided into a single package suitable for combined administration and formulations in which each formulation is divided into separate packages.

[0113] In one aspect, the present disclosure relates to a kit formulation comprising an antitumor agent comprising Compound 1 or a salt thereof and instructions for use describing the co-administration of Compound 1 or a salt thereof with a MEK inhibitor to a cancer patient. Here, the "instructions" may be any instructions that describe the dosage, and may be legally binding or not, but preferably recommend the dosage. Specific examples include package inserts, pamphlets, etc. Furthermore, the kit formulation including instructions for use may be one in which the instructions for use are printed or attached to the package of the kit formulation, or one in which the instructions for use are enclosed in the package of the kit formulation together with the antitumor agent.

[0114] The present disclosure also relates to a method for treating tumors, comprising administering Compound 1 or a salt thereof in combination with a MEK inhibitor.

[0115] The present disclosure also relates to a method for enhancing the antitumor effect of a MEK inhibitor, which comprises administering an antitumor agent comprising compound 1 or a salt thereof.

[0116] The present disclosure also relates to a method for treating a cancer patient who has been administered a MEK inhibitor, by administering to the cancer patient an antitumor agent comprising Compound 1 or a salt thereof.

[0117] The present disclosure also relates to the antitumor agents of the present disclosure for use in treating tumors.

[0118] The present disclosure also relates to an antitumor effect enhancing agent containing Compound 1 or a salt thereof, which is used to enhance an antitumor effect.

[0119] The present disclosure also relates to an antitumor agent comprising Compound 1 or a salt thereof, which is used to treat a cancer patient who has been administered a MEK inhibitor.

[0120] The present disclosure also relates to the use of the anti-tumor agents of the present disclosure in combination therapy with a MEK inhibitor for the treatment of tumors.

[0121] The present disclosure also relates to the use of the antitumor agent of the present disclosure for enhancing the antitumor effect of a MEK inhibitor.

[0122] The present disclosure also relates to the use of an agent containing Compound 1 or a salt thereof for treating a cancer patient who has been administered a MEK inhibitor.

[0123] The present disclosure also relates to the use of an anti-tumor agent of the present disclosure in combination therapy with a MEK inhibitor for the manufacture of a medicament for the treatment of a tumor.

[0124] The present disclosure also relates to the use of an antitumor agent of the present disclosure for the manufacture of a medicament for enhancing the antitumor effect of a MEK inhibitor.

[0125] The present disclosure also relates to the use of an antitumor agent comprising Compound 1 or a salt thereof for the manufacture of a medicament for treating cancer patients administered a MEK inhibitor.

[0126] In one embodiment of the present disclosure, the composition is administered to a patient having a RAS mutation or an abnormality in the RAS / MAPK signaling pathway. Preferably, the composition is used for tumors having an abnormality in the RAS gene. More preferably, the composition is used for tumors having a mutation in an isoform of NRAS, KRAS, or HRAS. Even more preferably, the composition is used for tumors having a mutation in an isoform of KRAS.

[0127] The antitumor agents of the present disclosure can be used to treat cancer. When referring to a cancer patient receiving treatment with a therapeutic regimen, such as the combination therapy described herein, "antitumor effect" refers to at least one evaluation, such as progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), overall survival (OS), objective response rate (ORR), disease control rate (DCR), or patient-reported outcomes (PROs). In one embodiment, when targeting solid tumors, tumor evaluation for the combination therapy described herein is evaluated using RECIST 1.1 (Response Evaluation Criteria in Solid Tumors), and antitumor effect is indicated by stable disease (SD), partial response (PR), complete response (CR), or progressive disease (PD). Tumor evaluation for brain tumors can also be performed using standard brain tumor MRI, including pre- and post-enhancement with a gadolinium (Gd) chelate contrast agent. [Example]

[0128] The present disclosure will now be described in more detail with reference to examples and reference examples, but the present disclosure is not limited to these examples in any way, and many variations are possible within the technical spirit of the present disclosure by those skilled in the art. Example 1: Evaluation of in vitro combined effects of Compound 1 and selumetinib <a 材料及び方法> The human lung cancer cell line A549 (obtained from Dainippon Pharmaceutical Co., Ltd.) was cultured in DMEM medium containing 10% fetal bovine serum. The cells were maintained at 37°C, 5% CO2, and passaged once or twice a week at a ratio of 1:5 to 1:20. A549 cells have been reported to harbor a KRAS G12S mutation. Cell viability assay Cell viability was measured using crystal violet. Cells were harvested using standard methods, suspended in the above medium containing 10% fetal bovine serum, and then seeded into a 12-well plate. 1,000 cells were seeded per well in 800 μL of solution. The cells were incubated at 37°C and 5% CO2 for 24 hours, after which 100 μL of medium containing compound 1 and selumetinib or vehicle was added.

[0129] Taking into consideration the sensitivity of the cells to each drug, Compound 1 was diluted at two 10-fold dilutions of 10 and 100 nM and at zero concentration (DMSO), and selumetinib was diluted at three 10-fold dilutions of 0.1, 1, and 10 μM and at zero concentration (DMSO), and each combination was examined.

[0130] After drug addition, the cells were incubated at 37°C and 5% CO2 for an additional 10 days. During the incubation period, the medium was replaced and drugs were added again 3 and 7 days after drug addition. Cell viability was assessed by adding 500 μL of glutaraldehyde solution per well, incubating at room temperature for 20 minutes, and then rinsing with tap water. After rinsing, 500 μL of crystal violet solution per well was added, incubating at room temperature for 20 minutes, and then rinsing with tap water. After rinsing, the plate was measured using a Gelcount plate reader. For quantification, the dye was extracted using an extraction solution (0.1 N sodium dihydrogen phosphate / ethanol). The results are shown in Figure 1. Absorbance at a wavelength of 550 nm was measured using a SpectraMAX Plus 384 Microplate Reader. Cell viability after drug addition was calculated as a percentage of the control group, using the following formula: Cell viability (%) = (absorbance at the time of drug addition) / (absorbance of control group) x 100 The Fa (Fraction of Affect) value was calculated by subtracting 1 / 100 of the cell survival rate from 1.

[0131] Next, from the effects of Compound 1 and selumetinib alone, a Bliss additivity value, which is the additive effect calculated at each combined concentration, was determined according to the following formula.

[0132] Bliss aditivity value = (Fa value obtained from compound 1 alone) + (Fa value calculated from selumetinib monotherapy) - (Fa value obtained from Compound 1 alone) × (Fa value obtained from selumetinib alone) The presence or absence of an effect of the combined use of the two drugs was determined according to the following formula, with a value of 10 or more indicating a synergistic effect, a value of -10 or more but less than 10 indicating an additive effect, and a value less than -10 indicating an antagonistic effect. Judgment value = 100 × (Fa value calculated from the actual combined effect) - (Bliss aditivity value) The evaluation values ​​were calculated when Compound 1 and selumetinib were used in combination in the A549 strain, and the evaluation values ​​under each condition are shown in Table 1.

[0133] [Table 1]

[0134] <b 結果> When compound 1 was used in combination with selumetinib, analysis by the Bliss additivity method confirmed an additive effect of compound 1 itself, showing a positive value in the concentration range of 10 to 100 nM. Example 2: Evaluation of in vitro combination effects of Compound 1 with trametinib, binimetinib, or cobimetinib <b 結果> <a 材料及び方法> Human lung cancer cell lines A549 (obtained from the American Type Culture Collection) and LU99 (obtained from the JCRB Cell Bank) were cultured in DMEM medium and RPMI medium containing 10% fetal bovine serum, respectively. They were maintained at 37°C, 5% CO2, and passaged and maintained at a ratio of 1:5 to 1:20 once or twice a week. A549 cells have been reported to harbor a KRAS G12S mutation, and LU99 cells have been reported to harbor a KRAS G12C mutation. Cell viability assay Cell viability was measured using crystal violet. Cells were harvested using standard methods, suspended in the above medium containing 10% fetal bovine serum, and then seeded into 24-well plates. The seeding density was 1,500 cells / 500 μL (A549) or 3,000 cells / 500 μL (LU99) per well. The cells were incubated at 37°C and 5% CO2 for 24 hours, after which the medium was replaced with 500 μL of medium containing compound 1 and trametinib, binimetinib, cobimetinib, or vehicle.

[0135] Compound 1 was diluted at three points (10, 30, and 100 nM) and at zero concentration (DMSO), trametinib at 0.3, 1, 3, 10, and 30 μM, and binimetinib and cobimetinib at five points (3, 10, 30, 100, and 300 μM) and at zero concentration (DMSO), and each combination was examined.

[0136] After drug addition, the cells were incubated at 37°C and 5% CO2 for an additional 10 days. During the incubation period, the medium was replaced with drug-containing medium 3 and 7 days after drug addition. Cell viability was assessed by adding 300 μL of glutaraldehyde solution per well, incubating at room temperature for 20 minutes, and then rinsing with tap water. After rinsing, 500 μL of crystal violet solution per well was added, incubating at room temperature for 20 minutes, and then rinsing with tap water. After rinsing, the plates were photographed. The photographed results for the A549 strain and the LU99 strain are shown in Figure 2 and Figure 3, respectively. For quantification, the dye was extracted using an extraction solution (0.1 N sodium dihydrogen phosphate / ethanol), and the absorbance at a wavelength of 490 nm was measured using a FlexStation 3 plate reader. The cell survival rate upon addition of the drug was calculated as a percentage of the control group, which was set at 100%, according to the following formula.

[0137] Cell viability (%) = (absorbance at the time of drug addition) / (absorbance of control group) x 100 The Fa (Fraction of Affect) value was calculated by subtracting 1 / 100 of the cell survival rate from 1.

[0138] Next, from the effects of Compound 1, trametinib, binimetinib, and cobimetinib as single agents, a Bliss additivity value, which is the additive effect calculated at each combined concentration, was determined according to the following formula.

[0139] Bliss aditivity value = (Fa value obtained from compound 1 alone) + (Fa value calculated from trametinib, binimetinib, or cobimetinib alone) - (Fa value obtained from compound 1 alone) × (Fa value obtained from trametinib, binimetinib, or cobimetinib alone) The combined effect of two drugs was judged according to the following formula: a judged value of 10 or more was deemed to indicate a synergistic effect, a judged value of -10 or more but less than 10 was deemed to indicate an additive effect, and a judged value of less than -10 was deemed to indicate an antagonistic effect. Judgment value = 100 × (Fa value calculated from the actual combined effect) - (Bliss aditivity value) The judgment values ​​when compound 1 was used in combination with trametinib, binimetinib, or cobimetinib in the A549 strain were calculated, and the judgment values ​​under each condition are shown in Table 2. The judgment values ​​when compound 1 was used in combination with trametinib, binimetinib, or cobimetinib in the LU99 strain were calculated, and the judgment values ​​under each condition are shown in Table 3.

[0140] [Table 2]

[0141] [Table 3]

[0142] <b 結果> In the A549 or LU99 strain, when compound 1 was used in combination with trametinib, analysis by the Bliss additivity method showed a judgment value of -10 or higher when the concentration of compound 1 itself was 10 nM or higher and the concentration of trametinib was 10 nM or higher, indicating an additive combination effect in the A549 strain and an additive or synergistic combination effect in the LU99 strain.

[0143] In the A549 or LU99 strain, when compound 1 was used in combination with binimetinib, analysis by the Bliss additivity method showed a judgment value of -10 or higher when the concentration of compound 1 itself was 10 nM or higher and the concentration of binimetinib was 100 nM or higher, indicating an additive combination effect in the A549 strain and an additive or synergistic combination effect in the LU99 strain.

[0144] In the A549 or LU99 strains, compound 1, when used in combination with cobimetinib, showed additive or synergistic combined effects in analysis by the Bliss additivity method. The judgement value was -10 or higher when the compound 1 concentration itself was 10 nM or higher and the cobimetinib concentration was 100 nM or higher.

[0145] A concentration of 10 nM of Compound 1 corresponds to a blood concentration of 4.2 ng / mL in human pharmacokinetics, which is maintained for 24 hours in the case of daily administration and for 48 hours in the case of intermittent administration.

[0146] Comparing this with the PK data (Figure 4) for compound 1 at QD doses (daily) of 4 mg, 8 mg, 16 mg, 20 mg, and 24 mg described in AACR2018, R. Baleda et al., poster CT121, it was revealed that at doses of 8 mg or higher, blood concentrations could be maintained for approximately 16 hours or more, and the total AUC over 24 hours was also exceeded. From this, it is believed that when administered daily, additive or synergistic pharmacological effects with MEK inhibitors can be observed at least in the range of 8 mg to 24 mg.

[0147] Similarly, in the case of QOD (once every other day) administration of Compound 1, a comparison of the PK data (Figure 4) for 8 mg, 16 mg, 24 mg, 36 mg, 56 mg, 80 mg, 120 mg, 160 mg, and 200 mg revealed that blood concentrations could be maintained for approximately 36 hours or more at doses of 24 mg or more, and at the same time, the total AUC over 48 hours was also exceeded at doses of 24 mg or more. Therefore, when Compound 1 is administered intermittently, it is thought that additive or synergistic efficacy with MEK inhibitors can be observed at least in the range of 24 mg to 200 mg.

[0148] A 10 nM trametinib concentration corresponds to a blood concentration of 1.3 ng / mL in humans, maintained for 24 hours. A comparison of the PK data for once-daily trametinib doses of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, and 4 mg published in Lancet Oncol, 13, 773-81 (2012) revealed that doses of 0.5 mg or more generally exceeded blood concentrations of 1.3 ng / mL for 24 hours or more, and also exceeded the 24-hour total AUC. This suggests that once-daily trametinib exerts additive or synergistic effects with Compound 1 at doses ranging from 0.5 mg to 4 mg.

[0149] The clinical dose of trametinib (Mekinist tablets) is 2 mg once daily, with a one-step dose reduction to 1.5 mg once daily, and a two-step dose reduction to 1 mg once daily (Mekinist tablets interview form). From this, it is believed that when trametinib is administered once daily for consecutive days, additive or synergistic efficacy with Compound 1 is observed at least in the range of 0.5 to 2 mg.

[0150] A binimetinib concentration of 100 nM corresponds to a blood concentration of 18.45 ng / mL maintained for at least 24 hours in humans. Comparing the PK data for twice-daily doses of binimetinib (BJC, 116, 575-583, (2017)) of 30 mg, 45 mg, and 60 mg, it was found that at doses of 30 mg and above, blood concentrations exceeded 18.45 ng / mL for 8 hours, and the total AUC over 8 hours was more than twice that of 18.45 ng / mL. This suggests that binimetinib, when administered twice daily, exhibits additive or synergistic efficacy with Compound 1 at doses ranging from 30 mg to 60 mg.

[0151] The clinical dose of binimetinib (Mectovi tablets) is 45 mg twice daily, with a one-step dose reduction to 30 mg twice daily, and a two-step dose reduction to 15 mg twice daily (Mectovi tablets interview form). From this, it is thought that when binimetinib is administered twice daily, additive or synergistic efficacy with Compound 1 can be observed clinically in the range of 30 to 45 mg.

[0152] A cobimetinib concentration of 100 nM corresponds to a blood concentration of 53 ng / mL, maintained for at least 24 hours in humans. PK data for once-daily cobimetinib at 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg were compared in Supplementary Figure 2 of Inv New Drug, 34, 604-13, (2016). Steady-state PK data revealed that at 40 mg in Stage 1 (21 / 7), the concentration exceeded this value for 14 hours and the total AUC over 24 hours was also exceeded. This suggests that once-daily cobimetinib exerts additive or synergistic effects with Compound 1 at doses ranging from 40 mg to 60 mg.

[0153] The clinical dose of cobimetinib (Cotellic tablets) is 60 mg once daily for 21 days in a 28-day cycle, with a one-step dose reduction to 40 mg once daily for 21 days in a 28-day cycle, and a two-step dose reduction to 20 mg once daily for 21 days in a 28-day cycle (Cotellic tablets data sheet). Based on this, it is believed that when cobimetinib is administered once daily, additive or synergistic efficacy with Compound 1 is clinically observed in the range of 40-60 mg.

Claims

1. An antitumor agent containing (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient, which is administered in combination with at least one MEK inhibitor selected from the group consisting of trametinib, binimetinib, cobimetinib, and salts thereof, wherein the tumor has an abnormality in the RAS / MAPK signaling pathway.

2. An antitumor effect enhancer for enhancing the antitumor effect of at least one MEK inhibitor selected from the group consisting of trametinib, binimetinib, cobimetinib, and salts thereof, comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient, wherein the tumor has an abnormality in the RAS / MAPK signaling pathway.

3. An antitumor agent for treating a cancer patient who has been administered at least one MEK inhibitor selected from the group consisting of trametinib, binimetinib, cobimetinib, and salts thereof, comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient, wherein the tumor has an abnormality in the RAS / MAPK signaling pathway.

4. A pharmaceutical composition for treating a tumor having an abnormality in the RAS / MAPK signaling pathway by administering in combination with at least one MEK inhibitor selected from the group consisting of trametinib, binimetinib, cobimetinib, and salts thereof, comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and a pharmaceutical carrier as active ingredients.

5. The antitumor agent according to claim 1 or 3, the antitumor effect enhancer according to claim 2, or the pharmaceutical composition according to claim 4, wherein the MEK inhibitor is trametinib or a salt thereof.

6. The antitumor agent according to claim 1 or 3, the antitumor effect enhancer according to claim 2, or the pharmaceutical composition according to claim 4, wherein the MEK inhibitor is binimetinib or a salt thereof.

7. The antitumor agent according to claim 1 or 3, the antitumor effect enhancer according to claim 2, or the pharmaceutical composition according to claim 4, wherein the MEK inhibitor is cobimetinib or a salt thereof.

8. The antitumor agent, antitumor effect enhancer, or pharmaceutical composition according to claim 5, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg per dose, and trametinib or a salt thereof is administered once daily at a dose selected from the group consisting of 1 mg, 1.5 mg, and 2 mg per dose.

9. The antitumor agent, antitumor effect enhancer, or pharmaceutical composition according to claim 6, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg per dose, and binimetinib or a salt thereof is administered twice daily at a dose selected from the group consisting of 30 mg and 45 mg per dose.

10. The antitumor agent, antitumor effect enhancer, or pharmaceutical composition according to claim 7, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg per dose, and cobimetinib or a salt thereof is administered once daily at a dose selected from the group consisting of 40 mg and 60 mg per dose.

11. The antitumor agent, antitumor effect enhancer, or pharmaceutical composition according to claim 5, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolin-1-yl)prop-2-en-1-one or a salt thereof is administered intermittently at a dose selected from the group consisting of 24 mg, 36 mg, 56 mg, 80 mg, 120 mg, and 160 mg per dose, and trametinib or a salt thereof is administered once a day at a dose selected from the group consisting of 1 mg, 1.5 mg, and 2 mg per dose.

12. The antitumor agent, antitumor effect enhancer, or pharmaceutical composition according to claim 6, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered intermittently at a single dose selected from the group consisting of 24 mg, 36 mg, 56 mg, 80 mg, 120 mg, and 160 mg, and binimetinib or a salt thereof is administered twice a day at a single dose selected from the group consisting of 30 mg and 45 mg.

13. The antitumor agent, antitumor effect enhancer, or pharmaceutical composition according to claim 7, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered intermittently at a dose selected from the group consisting of 24 mg, 36 mg, 56 mg, 80 mg, 120 mg, and 160 mg per dose, and cobimetinib or a salt thereof is administered once a day at a dose selected from the group consisting of 40 mg and 60 mg per dose.

14. The antitumor agent according to claim 1 or 3, the antitumor effect enhancer according to claim 2, the pharmaceutical composition according to claim 4, or the antitumor agent, antitumor effect enhancer, or pharmaceutical composition according to any one of claims 5 to 13, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered before, simultaneously with, or after an MEK inhibitor.

15. The antitumor agent according to claim 1 or 3, the antitumor effect enhancer according to claim 2, the pharmaceutical composition according to claim 4, or the antitumor agent, antitumor effect enhancer, or pharmaceutical composition according to any one of claims 5 to 14, wherein the tumor is at least one selected from the group consisting of head and neck cancer, digestive cancer, lung cancer, breast cancer, reproductive cancer, hematopoietic tumor, bone and soft tissue tumor, skin cancer, and brain tumor.

16. The antitumor agent according to claim 1 or 3, the antitumor effect enhancer according to claim 2, the pharmaceutical composition according to claim 4, or the antitumor agent, antitumor effect enhancer, or pharmaceutical composition according to any one of claims 5 to 15, wherein the tumor is lung cancer, pancreatic cancer, colorectal cancer, or brain tumor.

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