Cancer therapy using 3,5-disubstituted benzene alkynyl compound and MEK inhibitor

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

Cancer treatment using 3,5-disubstituted benzenealkynyl compounds and MEK inhibitors [Technology Field]

[0001] [Cross-reference of related applications] This application claims priority to Japanese Patent Application No. 2020-071355, filed on 10 April 2020 (the entire disclosure thereof is incorporated herein by reference). This disclosure relates to antitumor agents, antitumor effect enhancers, and kit formulations. [Background technology]

[0002] Fibroblast growth factor (FGF) is expressed in a wide range of tissues and is one of the growth factors that govern cell proliferation and differentiation. The physiological activity of FGF is mediated by a specific cell surface receptor, the fibroblast growth factor receptor (FGFR). FGFR belongs to the receptor-type protein tyrosine kinase family and is composed of an extracellular ligand-binding domain, a one-pass transmembrane domain, and an intracellular tyrosine kinase domain. Four types of FGFR have been identified to date (FGFR1, FGFR2, FGFR3, and FGFR4). FGFR forms a dimer upon binding to FGF and is activated by phosphorylation. Receptor activation induces the recruitment and activation of specific downstream signaling molecules, thereby expressing physiological functions. Abnormalities in FGF / FGFR signaling have been reported to be associated with various human tumors. Abnormal activation of the FGF / FFFR signaling pathway in human tumors is thought to be due to autocrine or paracrine mechanisms resulting from FGF overexpression and / or gene amplification, gene mutation, chromosomal translocation, insertion, inversion, gene fusion, or overproduction of the ligand FGF (Non-Patent Documents 1, 2, 3, and 4). (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one (hereinafter sometimes referred to as "compound 1" in this specification), which is a 3,5-disubstituted benzenealkynyl compound, or a salt thereof, is known as an FGFR inhibitor, and combinations of FGF inhibitors with various antitumor agents have been reported to date (Patent Documents 1 and 2).

[0003] RAS is a central factor in the RAS / MAPK kinase pathway that promotes cell proliferation. When RAS binds to GDP, it becomes inactive, and when GDP is exchanged for GTP by guanine nucleotide exchange factor (GEF), it becomes active. This induces the recruitment and activation of specific downstream signaling molecules, thereby expressing physiological functions. Furthermore, activated RAS becomes inactive again when it binds to GTPase-activating protein (GAP), by hydrolyzing GTP and converting it to GDP.

[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 cancer, lung cancer, and pancreatic cancer. When these activating mutations in the RAS gene are forcibly expressed in normal cells, the cells transform. Cancers with RAS gene activating 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, in cancers with RAS gene activating mutations is known to be limited. For example, the efficacy of EGFR inhibitors in colorectal cancer with KRAS mutations, or MEK inhibitors in lung cancer patients with KRAS mutations, is limited.

[0005] Recently, it has been revealed that treating lung cancer cell lines with KRAS mutations with MEK inhibitors activates the proliferation signaling pathway via FGF receptors. Based on these results, it was expected that co-administration of FGFR inhibitors and MEK inhibitors would yield antitumor effects. Regarding the co-administration of FGFR inhibitors and MEK inhibitors, there are descriptions of combining MEK inhibitors with RTK inhibitors (Patent Document 3), and, limited to mesenchymal cells, combining MEK inhibitors with KRAS-mutated cancer treatment agents (Patent Document 4). Under these circumstances, there is still a strong desire for cancer treatment methods different from those using these combinations.

[0006] International Publication No. 2013 / 108809, International Publication No. 2017 / 150725, International Publication No. 2016 / 130917, International Publication No. 2017 / 086332, International Publication No. 2015 / 008839

[0007] Nat. Rev. Cancer 10:116-129 (2010) J. Clin. Oncol. 24, 3664-3671 (2006) Mol. Cancer Res. 3, 655-667 (2005) Cancer Res. 70, 2085-2094 (2010) [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] This disclosure aims to provide a novel combination therapy involving a compound that inhibits FGFR and a MEK inhibitor, exhibiting excellent antitumor effects. [Means for solving the problem]

[0009] In view of the current situation, the present inventors investigated the combined use of various compounds having FGFR inhibitory activity with MEK inhibitors and found that the above problems can be solved by using (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof, which is an FGFR inhibitor, in combination with a MEK inhibitor. Accordingly, this disclosure provides the following items [1] to

[44] . [1] An antitumor agent containing (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof as an active ingredient, administered in combination with a MEK inhibitor. [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)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered once daily in 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 in 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)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered once daily in 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 in 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)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered once daily in 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 in 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)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered intermittently in doses 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 daily in doses selected from the group consisting of 1 mg, 1.5 mg, and 2 mg per dose. [9] The antitumor agent according to [3], wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered intermittently in doses 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 daily in doses 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)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered intermittently in doses 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 daily in doses selected from the group consisting of 40 mg and 60 mg per dose.

[11] An antitumor agent according to any one of the following paragraphs [1] to

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

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

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

[13] An antitumor agent according to any one of the items [1] to

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

[14] An antitumor agent according to any one of paragraphs [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 MEK inhibitors, comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof as an active ingredient.

[16] An antitumor agent for treating cancer patients administered with a MEK inhibitor, comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof as an active ingredient.

[17] A pharmaceutical composition for treating tumors by co-administration with a MEK inhibitor, comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof and a pharmaceutical carrier as active ingredients.

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

[19] Combination of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof with a MEK inhibitor for use in the treatment of tumors.

[20] A method for treating a tumor, comprising administering a therapeutically effective amount of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-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)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof to a patient who has been administered 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)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-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)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof for the treatment of tumors in combination with MEK inhibitors.

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

[25] Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof for the treatment of cancer patients administered with MEK inhibitors.

[26] Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-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]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof for the manufacture of an enhancer of the antitumor effect of MEK inhibitors.

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

[29] Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof and a MEK inhibitor in combination 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]pyrimidine-1-yl)pyrrolidine-1-yl)propa-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 according to

[18] or a salt thereof; 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 according to

[18] or a salt thereof; 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 according to

[18] or a salt thereof; 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] (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof administered once daily in 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 administered once daily in a dose selected from the group consisting of 1 mg, 1.5 mg, and 2 mg per dose, as described in

[32] , an antitumor effect enhancer, antitumor agent, pharmaceutical composition, compound 1 or a salt thereof, combination, method, or use.

[36] (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof administered once daily in doses selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg per dose, and binimetinib or a salt thereof administered twice daily in doses selected from the group consisting of 30 mg and 45 mg per dose, as described in

[33] , an antitumor effect enhancer, antitumor agent, pharmaceutical composition, compound 1 or a salt thereof, combination, method, or use.

[37] (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof administered once daily in doses selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg per dose, and cobimetinib or a salt thereof administered once daily in doses selected from the group consisting of 40 mg and 60 mg per dose, as described in

[34] , an antitumor effect enhancer, antitumor agent, pharmaceutical composition, compound 1 or a salt thereof, combination, method, or use.

[38] (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered intermittently in doses 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 daily in doses selected from the group consisting of 1 mg, 1.5 mg, and 2 mg per dose, as described in

[32] , an antitumor effect enhancer, antitumor agent, pharmaceutical composition, compound 1 or a salt thereof, combination, method, or use.

[39] (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered intermittently in doses 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 daily in doses selected from the group consisting of 30 mg and 45 mg per dose, as described in

[33] , an antitumor effect enhancer, antitumor agent, pharmaceutical composition, compound 1 or a salt thereof, combination, method, or use.

[40] (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered intermittently in doses 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 daily in doses selected from the group consisting of 40 mg and 60 mg per dose, as described in

[34] , an antitumor effect enhancer, antitumor agent, pharmaceutical composition, compound 1 or a salt thereof, combination, method, or use.

[41] (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered before, simultaneously with, or after the MEK inhibitor as an antitumor effect enhancer according to

[15] , as an antitumor agent according to

[16] , as a pharmaceutical composition according to any one of

[17] ,

[30] , and

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

[18] , as a combination according to

[19] , as a method according to any one of

[20] to

[22] , or as a use according to any one of

[23] to

[29] , as an 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 tumor has an abnormality in the RAS / MAPK signaling pathway. 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 the items in

[15] to

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

[44] 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] , or 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 this disclosure, it is possible to provide a novel combination therapy of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof, which exhibits excellent antitumor effects, with a MEK inhibitor. [Brief explanation of the drawing]

[0011] This study demonstrates the combined efficacy of compound 1 (referred to as TAS-120) and selumetinib in A549 cells. KRAS-mutant lung cancer cell line A549 was treated with dimethyl sulfoxide (DMSO), 10 nM or 100 nM of compound 1, and DMSO, 0.1 μM, 1 μM, or 10 μM of selumetinib, either alone or in combination, and cultured for 10 days, changing the culture medium every 72 or 96 hours. The cell culture plates were then stained with crystal violet. KRAS-mutant lung cancer cell line A549 cells were treated with compound 1 (DMSO, 10 nM, 30 nM, or 100 nM) in combination with trametinib (DMSO, 0.3 nM, 1.0 nM, 3.0 nM, 10 nM, or 30 nM), vinimetinib (DMSO, 3 nM, 10 nM, 30 nM, 100 nM, or 300 nM), or cobimetinib (DMSO, 3 nM, 10 nM, 30 nM, 100 nM, or 300 nM). The cells were cultured for 10 days, changing the culture medium every 72 or 96 hours. The cell culture plates were then stained with crystal violet. KRAS-mutant lung cancer cell line LU99 cells were treated with compound 1 (DMSO, 10 nM, 30 nM, or 100 nM) and trametinib (DMSO, 0.3 nM, 1.0 nM, 3.0 nM, 10 nM, or 30 nM), vinimetinib (DMSO, 3 nM, 10 nM, 30 nM, 100 nM, or 300 nM), or cobimetinib (DMSO, 3 nM, 10 nM, 30 nM, 100 nM, or 300 nM). The cells were cultured for 10 days, changing the culture medium every 72 or 96 hours. The cell culture plates were then stained with crystal violet. AACR2018, R. Bahleda et al. The pharmacokinetic data (hereinafter referred to as PK data) for compound 1, as described in al, poster CT121, in the QD dose (daily administration) and QOD (once every two days) regimens are shown.

[0012] The present disclosure relates to the combined use of a compound having FGFR inhibitory activity and a MEK inhibitor, that is, an antitumor agent administered in combination with a MEK inhibitor containing a compound having FGFR inhibitory activity, an enhancer of the antitumor effect of a MEK inhibitor containing a compound having FGFR inhibitory activity, an antitumor agent having FGFR inhibitory activity to be administered to a patient treated with a MEK inhibitor, and these tumor treatment methods, the use of these agents, the use of a compound for the manufacture of these medicaments, combinations, and the like.

[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 benzene alkynyl compound having the structure of Chemical Formula 1 below. The free form of Compound 1 is sometimes referred to as TAS-120 or Futibatinib. Compound 1 is described as Example Compound 2 in Patent Document 3 above and can be synthesized, for example, based on the production method described in Patent Document 3. Compound 1 or a salt thereof has an excellent FGFR inhibitory effect and has been reported to inhibit the phosphorylation ability of tyrosine in the substrate peptide sequence of each of the receptor protein tyrosine kinases of FGFR1, FGFR3, and FGFR4 (Patent Document 3). In addition, a dosing method in which Compound 1 or a salt thereof is “administered according to a dosing schedule of twice or more per week with a dosing interval of one day or more” has been reported (Patent Document 5).

[0014] The daily dose 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 all indicates the dose in terms of the free form.

[0016] In the present disclosure, although the scope of the "MEK inhibitor" is already common technical knowledge, it is not particularly limited as long as it inhibits MEK1 and / or MEK2 in the MAPK / ERK signaling pathway that contributes to cell proliferation and exhibits an antitumor effect. Specifically, 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, or pharmaceutically acceptable salts thereof. Among these, preferably, trametinib, binimetinib, cobimetinib, selumetinib, or pharmaceutically acceptable salts thereof; more preferably, trametinib, binimetinib, cobimetinib, or pharmaceutically acceptable salts thereof; most preferably, trametinib or a pharmaceutically acceptable salt. In another aspect, as the "MEK inhibitor", preferably, it is a dimethyl sulfoxide adduct of trametinib, binimetinib, or a fumarate salt of cobimetinib; more preferably, it is a dimethyl sulfoxide adduct of trametinib.

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

[0018] In still another embodiment, as the "MEK inhibitor", most preferably, it is cobimetinib or a pharmaceutically acceptable salt. In another aspect, as the "MEK inhibitor", more preferably, it is a fumarate salt of cobimetinib. In these MEK inhibitors, pharmaceutically acceptable salts are not particularly limited, but include, for example, addition salts with inorganic acids such as hydrochloric acid and sulfuric acid, 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. A pharmaceutically acceptable salt of the above-mentioned MEK inhibitor compound may also be simply referred to as a salt of the above-mentioned compound (for example, a salt 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]pyrimidine-1(2H)-yl}phenyl)acetamide is a known compound and has the structure shown in Chemical Formula 2 below.

[0021] Trametinib can be synthesized according to the method described in International Publication 2005 / 121142. Alternatively, a commercially available drug (Mekinist Tablets® (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]pyrimidine-1(2H)-yl}phenyl)acetamido-(methylsulfinyl)methane (1:1)) may be used.

[0022] All daily doses of trametinib or its salts described in this specification are expressed in terms of 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 in Chemical Formula 3 below.

[0025] Binimetinib can be synthesized according to the method described in International Publication 2005 / 051906. Alternatively, a commercially available drug (Mectovi Tablets®) may be used.

[0026] All daily doses of binimetinib or its salts described in this specification are expressed in terms of 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 in Chemical Formula 4 below.

[0029] Cobimetinib can be synthesized according to the method described in International Publication No. 2007 / 044515. Alternatively, commercially available drugs (US trade name: Cotellic), or cobimetinib fumarate (chemical name: [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-piperidine-2-yl]azetidine-1-yl}methanone hemifmarate) and other pharmaceutically acceptable salts may be used.

[0030] All daily doses of cobimetinib or its salts described in this specification are expressed in terms of 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 structure shown in Chemical Formula 5 below.

[0033] Selmetinib can be synthesized according to the method described in International Publication 2003 / 077914. Alternatively, commercially available selmetinib 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 shown in Chemical Formula 6 below.

[0036] Pimasertib can be synthesized according to the method described in International Publication 2006 / 045514. Alternatively, commercially available products may be used.

[0037] Mildametinib (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 shown in Chemical Formula 7 below.

[0039] Mildametinib can be synthesized according to the method described in International Publication 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 in Chemical Formula 8 below.

[0042] Refametinib can be synthesized according to the method described in International Publication 2007 / 014011. Alternatively, commercially available refametinib may be used.

[0043] In this disclosure, "recommended dose" refers to the dosage that provides the greatest therapeutic effect while being safe to use without causing serious side effects, as determined by clinical trials or other means. Specifically, this includes dosages approved, recommended, or suggested by public institutions or organizations such as the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan, the Food and Drug Administration (FDA) of the United States, and the European Medicines Agency (EMA), and which are described in package inserts, interview forms, treatment guidelines, etc., with dosages approved by any of the public institutions of PMDA, FDA, or EMA being preferred.

[0044] In this disclosure, compound 1 can be used as is or in the form of a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts of compound 1 include, but are not limited to, addition salts with inorganic acids such as hydrochloric acid and sulfuric acid, 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 this disclosure, a pharmaceutically acceptable salt of compound 1 may also be simply referred to as a salt of compound 1.

[0045] In this disclosure, Compound 1 or a pharmaceutically acceptable salt thereof may be administered to humans or other mammals (e.g., rats, mice, rabbits, sheep, pigs, cattle, cats, dogs, monkeys, etc.). In this disclosure, MEK inhibitors may be administered to humans or other mammals (e.g., rats, mice, rabbits, sheep, pigs, cattle, cats, dogs, monkeys, etc.).

[0046] In this disclosure, when compound 1 or its salt is administered daily, the preferred daily dose on the day of administration is preferably 40% to 120% of the recommended dose when compound 1 or its salt is administered daily alone, more preferably 40% to 100%, even more preferably 60% to 100%, even more preferably 80% to 100%, and most preferably 100%, from the viewpoint of enhancing the antitumor effect of compound 1 or its salt on MEK inhibitors. In another embodiment, when compound 1 or its salt is administered daily, the preferred daily dose on the day of administration is 80% of the recommended dose when compound 1 or its salt is administered daily alone. In yet another embodiment, when compound 1 or its salt is administered daily, the preferred daily dose on the day of administration is 60% of the recommended dose when compound 1 or its salt is administered daily alone.

[0047] Specifically, preferred doses when compound 1 or its salt is administered once daily include 8 mg to 24 mg, 8 mg to 20 mg, 12 to 20 mg, and 20 mg. More specifically, preferred doses per day on administration days include once daily doses of 8 mg, 12 mg, 16 mg, 20 mg, and 24 mg. In another embodiment, preferred doses per day on administration days include once daily doses of 8 mg, 12 mg, 16 mg, and 20 mg. In another embodiment, preferred doses per day on administration days include once daily doses of 12 mg, 16 mg, and 20 mg. In another embodiment, preferred doses per day on administration days include once daily doses of 20 mg. In another embodiment, preferred doses per day on administration days include once daily doses of 16 mg. In yet another embodiment, preferred daily doses and administration frequencies on the day of administration include 12 mg once daily. All of these doses of compound 1 or its salts are in free form equivalents.

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

[0049] Specifically, when compound 1 or its salt is administered intermittently, a preferred daily dose on the day of administration is 24 mg to 200 mg. In another embodiment, a preferred daily dose on the day of administration is 56 mg to 160 mg. In another embodiment, a preferred daily dose on the day of administration is 120 to 160 mg. In another embodiment, a preferred daily dose on the day of administration is 160 mg. More specifically, the number of administrations and doses 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 embodiment, a preferred number of administrations and doses per day on the day of administration are 56 mg, 80 mg, 120 mg, 160 mg, etc. In another embodiment, a preferred number of administrations and doses per day on the day of administration are 80 mg, 120 mg, 160 mg, etc. In another embodiment, preferred daily doses and administration rates on administration days include 160 mg, etc. All of these dosages of compound 1 or its salts are in free form equivalents.

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

[0051] In this disclosure, the daily dose of trametinib or its salt on the day of administration is preferably 25% to 200% of the recommended dose when trametinib or its salt is administered alone, more preferably 50% to 100%, and most preferably 100%, from the viewpoint of enhancing the antitumor effect of compound 1 or its salt on MEK inhibitors. Specifically, the recommended dose when trametinib or its salt is 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 administration frequencies on the day of administration include once daily doses of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, etc. In another embodiment, preferred daily doses and administration frequencies on the day of administration include once daily doses of 1 mg, 1.5 mg, 2 mg, etc. In another embodiment, preferred daily doses and administration frequencies on the day of administration include once daily doses of 2 mg, etc. All of these doses of trametinib or its salts are in free form equivalent.

[0052] In this disclosure, the daily dose of binimetinib or its salt on the day of administration is preferably 66% to 133% of the recommended dose when binimetinib or its salt is administered alone, more preferably 66% to 100%, and most preferably 100%, from the viewpoint of enhancing the antitumor effect of compound 1 or its salt on MEK inhibitors. Specifically, the recommended dose when binimetinib or its salt is administered alone in humans is 15 to 60 mg per dose, more preferably 30 to 60 mg, more preferably 30 to 45 mg, and even more preferably 45 mg, when administered twice daily, according to the approval information in the package insert and interview form. In one embodiment, preferred daily doses on the day of administration include twice daily doses of 15 mg, 30 mg, 45 mg, 60 mg, etc. In another embodiment, preferred daily doses on the day of administration include twice daily doses of 15 mg, 30 mg, 45 mg, etc. In another embodiment, preferred daily doses and frequencies on the day of administration include twice a day, with 45 mg each time. In yet another embodiment, preferred daily doses and frequencies on the day of administration include twice a day, with 30 mg each time. In yet another embodiment, preferred daily doses and frequencies on the day of administration include twice a day, with 15 mg each time. All of these doses of binimetinib or its salts are in free form equivalent.

[0053] In this disclosure, the daily dose of cobimetinib or its salt on the day of administration is preferably 66% to 133% of the recommended dose when cobimetinib or its salt is administered alone, more preferably 66% to 100%, and most preferably 100%, from the viewpoint of enhancing the antitumor effect of compound 1 or its salt on MEK inhibitors. Specifically, the recommended dose when cobimetinib or its salt is administered alone in humans is 40 to 80 mg, more preferably 40 to 60 mg, and most preferably 60 mg, per dose when administered once daily, according to the approval information in the package insert and interview form. In one embodiment, preferred daily doses and administration frequencies on the day of administration include 40 mg, 60 mg, 80 mg, etc., once daily. In another embodiment, preferred daily doses and administration frequencies on the day of administration include 40 mg, 60 mg, etc., once daily. In another embodiment, preferred daily doses and administration frequencies on the day of administration include once daily, once daily, 60 mg, etc. All of these doses of cobimetinib or its salts are in free form equivalent.

[0054] In this disclosure, the daily dose of selumetinib or its salt on the day of administration is preferably 66% to 133% of the recommended dose when selumetinib or its salt is administered alone, more preferably 66% to 100%, and most preferably 100%, from the viewpoint of enhancing the antitumor effect of compound 1 or its salt on MEK inhibitors. Specifically, the recommended dose when selumetinib or its salt is administered alone in humans is 5 to 25 mg / m² per dose when administered twice daily, according to the approval information in the package insert and interview form. ２ More preferably 20 to 25 mg / m² ２ More preferably 25 mg / m² ２ In one embodiment, preferred daily doses and administration frequencies 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, and 10 mg twice daily. All of these doses of selumetinib or its salts are in free form equivalents.

[0055] In this disclosure, the daily dose of pimacertib or its salt on the day of administration is preferably 66% to 133% of the recommended dose when pimacertib or its salt is administered alone, more preferably 66% to 100%, and most preferably 100%, from the viewpoint of enhancing the antitumor effect of compound 1 or its salt on the MEK inhibitor. In one embodiment, preferred daily doses and frequencies on the day of administration include 10 to 60 mg twice a day. In another embodiment, preferred daily doses and frequencies on the day of administration include 10 to 60 mg once a day. In yet another embodiment, preferred daily doses and frequencies on the day of administration include 90 mg, 75 mg, 60 mg, 42 mg, 30 mg, 23 mg, 15 mg, and 8 mg twice a day. All doses of pimacertib or its salt are in free form equivalent.

[0056] In this disclosure, the daily dose of mildametinib or its salt on the day of administration is preferably 66% to 133% of the recommended dose when mildametinib or its salt is administered alone, more preferably 66% to 100%, and most preferably 100%, from the viewpoint of enhancing the antitumor effect of compound 1 or its salt on MEK inhibitors. Specifically, the recommended dose when mildametinib or its salt is administered alone in humans is 1 to 5 mg / m² per dose when administered twice daily. ２ More preferably 2 to 4 mg / m² ２ Therefore, all dosages of mildametinib or its salts are in free-form equivalent amounts.

[0057] In this disclosure, the daily dose of refametinib or its salt on the day of administration is preferably 66% to 133% of the recommended dose when refametinib or its salt is administered alone, more preferably 66% to 100%, and most preferably 100%, from the viewpoint of enhancing the antitumor effect of compound 1 or its salt on MEK inhibitors. Specifically, the recommended doses for refametinib or its salt administered alone in humans are 60 mg, 50 mg, 40 mg, 30 mg, 20 mg, and 10 mg per dose, for once-daily or twice-daily administration. All of these doses of refametinib or its salt are in free form equivalent.

[0058] The following are examples of preferred daily doses of Compound 1 or its salt on administration days, and of trametinib or its salt, or preferred combinations of dosage and administration: Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 to 20 mg, and trametinib or a salt thereof is administered once daily at a dose of 1 to 2 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 to 20 mg, and trametinib or a salt thereof is administered once daily at a dose of 1.5 to 2 mg. Compound 1 or a salt thereof, once daily, at a dose of 8 to 20 mg, and trametinib or a salt thereof, once daily, at a dose of 1 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 to 20 mg, and trametinib or a salt thereof is administered once daily at a dose of 1.5 mg. Compound 1 or a salt thereof, once daily, at a dose of 8 to 20 mg, and trametinib or a salt thereof, once daily, at a dose of 2 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 to 20 mg, and trametinib or a salt thereof is administered once daily at a dose of 1 to 2 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 to 20 mg, and trametinib or a salt thereof is administered once daily at a dose of 1.5 to 2 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 to 20 mg, and trametinib or a salt thereof is administered once daily at a dose of 1 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 to 20 mg, and trametinib or a salt thereof is administered once daily at a dose of 1.5 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 to 20 mg, and trametinib or a salt thereof is administered once daily at a dose of 2 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and trametinib or a salt thereof is administered once daily at a dose of 1 to 2 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and trametinib or a salt thereof is administered once daily at a dose of 1.5 to 2 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and trametinib or a salt thereof is administered once daily at a dose of 1 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and trametinib or a salt thereof is administered once daily at a dose of 1.5 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and trametinib or a salt thereof is administered once daily at a dose of 2 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1 to 2 mg per dose. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg, and trametinib or a salt thereof is administered once daily at a dose of 1.5 to 2 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg each day, and trametinib or a salt thereof is administered once daily at a dose of 1 mg each day. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg each day, and trametinib or a salt thereof is administered once daily at a dose of 1.5 mg each day. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg, and trametinib or a salt thereof is administered once daily at a dose of 2 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1 to 2 mg per dose. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg, and trametinib or a salt thereof is administered once daily at a dose of 1.5 to 2 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg, and trametinib or a salt thereof is administered once daily at a dose of 1 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg, and trametinib or a salt thereof is administered once daily at a dose of 1.5 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg, and trametinib or a salt thereof is administered once daily at a dose of 2 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg each, and trametinib or a salt thereof is administered once daily at a dose of 1 to 2 mg each. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg each, and trametinib or a salt thereof is administered once daily at a dose of 1.5 to 2 mg each. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg each day, and trametinib or a salt thereof is administered once daily at a dose of 1 mg each day. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg each, and trametinib or a salt thereof is administered once daily at a dose of 1.5 mg each. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg each, and trametinib or a salt thereof is administered once daily at a dose of 2 mg each.

[0059] Preferred daily doses of Compound 1 or its salt on administration days, and preferred daily doses of binimetinib or its salt, or preferred combinations of administration and dose, are as follows: Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 to 20 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 60 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 to 20 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 45 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 to 20 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 to 20 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 45 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 to 20 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 60 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 to 20 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 45 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 to 20 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 to 20 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 45 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 60 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 45 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 45 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 60 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 45 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 45 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 60 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 45 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg each, and binimetinib or a salt thereof is administered twice daily at a dose of 30 mg each. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 45 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg each, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 60 mg each. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg each, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 45 mg each. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg each, and binimetinib or a salt thereof is administered twice daily at a dose of 30 mg each. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 45 mg.

[0060] Preferred daily doses of Compound 1 or its salt on administration days, and preferred daily doses of cobimetinib or its salt, or combinations of dosage and administration, are as follows: Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 to 20 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 80 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 to 20 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 60 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 to 20 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 mg. Compound 1 or a salt thereof, once daily, at a dose of 8 to 20 mg, and cobimetinib or a salt thereof, once daily, at a dose of 60 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 to 20 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 80 mg. Compound 1 or a salt thereof, once daily, at a dose of 12 to 20 mg, and cobimetinib or a salt thereof, once daily, at a dose of 40 to 60 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 to 20 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 to 20 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 60 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 80 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 60 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 60 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 80 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 60 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 60 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 80 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 60 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 60 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg per dose, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 80 mg per dose. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg per dose, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 60 mg per dose. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg each, and cobimetinib or a salt thereof is administered once daily at a dose of 40 mg each. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg each, and cobimetinib or a salt thereof is administered once daily at a dose of 60 mg each.

[0061] In another embodiment, preferred daily doses of Compound 1 or its salt on administration days, and preferred daily doses of trametinib or its salt, or preferred combinations of dosage and administration, include: Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1 to 2 mg per dose. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1.5 to 2 mg per dose. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1 mg per dose. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 24 to 200 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 in this disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 2 mg per dose. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 56 to 160 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1 to 2 mg per dose. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 56 to 160 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1.5 to 2 mg per dose. Compound 1 or a salt thereof is administered intermittently at a dose of 56 to 160 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1 mg per dose. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 56 to 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 is administered intermittently at a dose of 56 to 160 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 2 mg per dose. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 80 to 160 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1 to 2 mg per dose. Compound 1 or a salt thereof is administered intermittently at a dose of 80 to 160 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1.5 to 2 mg per dose. Compound 1 or a salt thereof is administered intermittently at a dose of 80 to 160 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1 mg per dose. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 80 to 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 is administered intermittently at a dose of 80 to 160 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 2 mg per dose. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 56 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1 to 2 mg per dose. Compound 1 or a salt thereof as described herein is administered intermittently at a dose of 56 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1.5 to 2 mg per dose. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 56 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1 mg per dose. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 56 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 as disclosed herein is administered intermittently at a dose of 56 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 2 mg per dose. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 80 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1 to 2 mg per dose. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 80 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 1.5 to 2 mg per dose. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 80 mg each, and trametinib or a salt thereof is administered once daily at a dose of 1 mg each. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 80 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 as disclosed herein is administered intermittently at a dose of 80 mg per dose, and trametinib or a salt thereof is administered once daily at a dose of 2 mg per dose. Compound 1 or a salt thereof in this 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 to 2 mg per dose. Compound 1 or a salt thereof as disclosed herein 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 to 2 mg per dose. Compound 1 or a salt thereof in this 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 mg per dose. Compound 1 or a salt thereof as disclosed herein 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 as disclosed herein 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 2 mg per dose. Compound 1 or a salt thereof in this 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 to 2 mg per dose. Compound 1 or a salt thereof as disclosed herein 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 to 2 mg per dose. Compound 1 or a salt thereof as disclosed herein 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 mg per dose. Compound 1 or a salt thereof as disclosed herein 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 in this 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 2 mg per dose.

[0062] In another embodiment, preferred daily doses of compound 1 or a salt thereof in this disclosure, and daily doses of binimetinib or a salt thereof, or preferred combinations of dosage and administration, include the following: Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 60 mg per dose. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 45 mg per dose. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and binimetinib or a salt thereof is administered twice daily at a dose of 30 mg per dose. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 24 to 200 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 is administered intermittently at a dose of 56 to 160 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 60 mg. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 56 to 160 mg per dose, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 45 mg per dose. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 56 to 160 mg per dose, and binimetinib or a salt thereof is administered twice daily at a dose of 30 mg per dose. Compound 1 or a salt thereof is administered intermittently at a dose of 56 to 160 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 is administered intermittently at a dose of 80 to 160 mg per dose, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 60 mg per dose. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 80 to 160 mg per dose, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 45 mg per dose. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 80 to 160 mg per dose, and binimetinib or a salt thereof is administered twice daily at a dose of 30 mg per dose. Compound 1 or a salt thereof is administered intermittently at a dose of 80 to 160 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 as disclosed herein is administered intermittently at a dose of 56 mg per dose, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 60 mg per dose. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 56 mg per dose, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 45 mg per dose. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 56 mg per dose, and binimetinib or a salt thereof is administered twice daily at a dose of 30 mg per dose. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 56 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 as disclosed herein is administered intermittently at a dose of 80 mg per dose, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 60 mg per dose. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 80 mg each, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 45 mg each. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 80 mg each, and binimetinib or a salt thereof is administered twice daily at a dose of 30 mg each. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 80 mg each, and binimetinib or a salt thereof is administered twice daily at a dose of 45 mg each. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 120 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 60 mg. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 120 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 45 mg. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 120 mg each, and binimetinib or a salt thereof is administered twice daily at a dose of 30 mg each. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 120 mg each, and binimetinib or a salt thereof is administered twice daily at a dose of 45 mg each. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 160 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 60 mg. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 160 mg each, and binimetinib or a salt thereof is administered twice daily at a dose of 30 to 45 mg each. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 160 mg per dose, and binimetinib or a salt thereof is administered twice daily at a dose of 30 mg per dose. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 160 mg, and binimetinib or a salt thereof is administered twice daily at a dose of 45 mg.

[0063] In another embodiment, preferred daily doses of Compound 1 or its salt on administration days, and preferred daily doses of cobimetinib or its salt, or combinations of dosage and administration, include: Compound 1 or a salt thereof is administered intermittently at a dose of 24 to 200 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 80 mg. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 24 to 200 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 in this disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and cobimetinib or a salt thereof is administered once daily at a dose of 60 mg per dose. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 24 to 200 mg per dose, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 60 mg per dose. Compound 1 or a salt thereof is administered intermittently at a dose of 56 to 160 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 80 mg. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 56 to 160 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 mg. Compound 1 or a salt thereof is administered intermittently at a dose of 56 to 160 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 60 mg. Compound 1 or a salt thereof is administered intermittently at a dose of 56 to 160 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 60 mg. Compound 1 or a salt thereof is administered intermittently at a dose of 80 to 160 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 80 mg. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 80 to 160 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 mg. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 80 to 160 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 60 mg. Compound 1 or a salt thereof is administered intermittently at a dose of 80 to 160 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 60 mg. Compound 1 or a salt thereof as described herein is administered intermittently at a dose of 56 mg per dose, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 80 mg per dose. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 56 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 as disclosed herein is administered intermittently at a dose of 56 mg per dose, and cobimetinib or a salt thereof is administered once daily at a dose of 60 mg per dose. Compound 1 or a salt thereof as described herein is administered intermittently at a dose of 56 mg per dose, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 60 mg per dose. Compound 1 or a salt thereof as described herein is administered intermittently at a dose of 80 mg per dose, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 80 mg per dose. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 80 mg each, and cobimetinib or a salt thereof is administered once daily at a dose of 40 mg each. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 80 mg each, and cobimetinib or a salt thereof is administered once daily at a dose of 60 mg each. Compound 1 or a salt thereof as described herein is administered intermittently at a dose of 80 mg per dose, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 60 mg per dose. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 120 mg per dose, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 80 mg per dose. Compound 1 or a salt thereof as disclosed herein is administered intermittently at a dose of 120 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 in this disclosure is administered intermittently at a dose of 120 mg per dose, and cobimetinib or a salt thereof is administered once daily at a dose of 60 mg per dose. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 120 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 60 mg. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 160 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 80 mg. Compound 1 or a salt thereof as disclosed herein 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 in this disclosure is administered intermittently at a dose of 160 mg each, and cobimetinib or a salt thereof is administered once daily at a dose of 60 mg each. Compound 1 or a salt thereof in this disclosure is administered intermittently at a dose of 160 mg, and cobimetinib or a salt thereof is administered once daily at a dose of 40 to 60 mg.

[0064] In some aspects, this disclosure includes the fact that in cases of cancer types where a stronger effect is desired (e.g., brain tumors), the dose of compound 1 or a salt thereof may be greater than 20 mg once daily. Trametinib or a salt thereof may be greater than 2 mg once daily. Binimetinib or a salt thereof may be greater than 45 mg twice daily. Cobimetinib or a salt thereof may be greater than 60 mg once daily.

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

[0066] The administration schedule for the antitumor agents disclosed herein can be appropriately selected depending on the type of cancer, disease, etc. For compound 1 or a pharmaceutically acceptable salt thereof, daily administration or intermittent administration is preferred. For trametinib or its salt, a daily administration schedule of once daily is preferred. For binimetinib or its salt, a daily administration schedule of twice daily is preferred. For cobimetinib or its salt, a daily administration schedule of once daily is preferred. For selumetinib or its salt, a daily administration schedule of twice daily is preferred. Furthermore, the administration schedule may be repeated, and drug-free periods may be provided as appropriate depending on side effects, etc.

[0067] In this specification, "combined administration" is synonymous with administration in the same treatment regimen.

[0068] In this specification, "daily administration" refers to an administration schedule in which the drug is administered continuously for 21 days, for example, if the treatment regimen is 21 days long, it means administering the drug daily for 21 days. A drug-free period may be provided after each cycle.

[0069] In this specification, "intermittent administration" is not particularly limited, as long as it satisfies the conditions of being administered at least twice a week with an interval of at least one day between administrations (the number of days between one administration day and the next administration day). Preferably, it is administered three or more times a week, and more preferably three times a week.

[0070] For example, a dosing schedule consisting of one cycle per week, in which compound 1 or a pharmaceutically acceptable salt thereof is administered two or more times at intervals of 1 to 3 days per cycle (with an interval of 1 to 3 days between administration days), and the cycle is repeated one or more times; A 14-day administration cycle in which compound 1 or a pharmaceutically acceptable salt thereof is administered 4 to 7 times per cycle, with intervals of 1 to 3 days between administrations (1 to 3 days between administrations), and the cycle is repeated once or more times; A 14-day administration cycle, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered on the 1st, 4th, 8th, and 11th days of the 14-day cycle; A 14-day administration cycle, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered on the 1st, 3rd, 5th, 7th, 9th, 11th, and 13th days of the 14-day cycle; An example of an administration schedule is one cycle of 14 days, in which compound 1 or a pharmaceutically acceptable salt thereof is administered on the 1st, 3rd, 5th, 8th, 10th, and 12th days of the 14-day cycle.

[0071] In this specification, administration of drug A at X-day intervals means that if the day drug A is administered is designated as day 1, the following day as day 2, the day after that as day 3, and so on, then the next administration of drug A will be on day X+2.

[0072] The therapeutically effective dose of compound 1 or its salt and MEK inhibitor depends on several factors, including, but not limited to, the stage and severity of the cancer, as well as other factors related to the patient's health. Those skilled in the art will know how to determine the therapeutically effective dose.

[0073] The combination therapy methods described herein are useful for the treatment of proliferative disorders. These methods require the administration of compound 1 or a salt thereof and an effective dose of the MEK agent. In some embodiments, the effective dose is sufficient to slow tumor growth. In some embodiments, the effective dose is sufficient to prevent or delay recurrence. The effective dose can be administered in one or more doses.

[0074] In the case of cancer, the effective amount of drug or composition is the amount that can produce one of the following:

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

[0076] (ii) Reduce the size of the tumor.

[0077] (iii) Reduce the burden caused by the tumor.

[0078] (iv) Suppress, delay, slow to some extent, and ideally stop the invasion of cancer cells into peripheral organs.

[0079] (v) Inhibit tumor metastasis (i.e., slow it down to some extent, preferably stopping it).

[0080] (vi) Inhibits tumor growth.

[0081] (vii) Reduce the growth rate of tumors.

[0082] (viiii) Prevention or delay of the development and / or recurrence of tumors.

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

[0084] (x) to prolong life; and / or (xi) to extend progression-free survival.

[0085] The number of daily doses of the antitumor agents disclosed herein may be appropriately selected depending on the type of cancer, stage of the disease, etc. When compound 1 or a salt thereof is administered in combination with a MEK inhibitor, it is preferable that compound 1 or a salt thereof is administered once daily, trametinib or a salt thereof once daily, binimetinib or a salt thereof twice daily, cobimetinib or a salt thereof once daily, and selumetinib or a salt thereof twice daily.

[0086] In this disclosure, "treatment" includes procedures performed with the aim of curing or relieving a disease, or of preventing disease progression or relapse, or alleviating symptoms. Treatment includes the administration of drugs before or after surgical procedures, or the administration of drugs during or before or after radiation therapy.

[0087] As used herein, the term “combination (therapy)” is intended to define a therapy that involves the use of a combination of two or more compounds / agents (as defined above). Accordingly, the use of compounds / agents in combination, combination, and in combination in this application may mean compounds / agents administered as part of the same overall treatment regimen.

[0088] A "regmen" or "treatment regimen" refers to a plan in drug therapy that outlines the types, amounts, duration, and procedures of medications in chronological order. Treatment under the same treatment regimen means administering one drug and another drug within a set period, at the prescribed intervals and dosages for each drug. For example, this could involve starting the administration of drugs to be used in combination on the first day of a cycle, either simultaneously or substantially at the same time. Another example is a three-week cycle in which drug A is administered first, followed by drug B one week later, but this is still considered part of a treatment regimen as it is administered substantially simultaneously within a single cycle. A set period could be, for example, 28 days, but can be appropriately selected depending on the type of cancer or disease.

[0089] Before and / or after the start of a treatment regimen, a washout period may be established, during which no medication is administered, in order to eliminate the effects of previously given drugs.

[0090] The therapeutic regimen of compound 1 or a salt thereof and a MEK inhibitor of this disclosure may also include other agents in addition to compound 1 or a salt thereof and a MEK inhibitor.

[0091] "Use before," "use simultaneously," and "use after" refer to the administration order of compound 1 or its pharmaceutically acceptable salt and the MEK inhibitor on the same scheduled administration day. "Use before" is synonymous with compound 1 or its salt being administered before the MEK inhibitor on the same scheduled administration day; "use simultaneously" is synonymous with compound 1 or its salt being administered at the same time as the MEK inhibitor on the same scheduled administration day; and "use after" is synonymous with compound 1 or its salt being administered after the MEK inhibitor on the same scheduled administration day.

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

[0093] In one embodiment, the combination therapy of this disclosure is administered to patients who have not previously received treatment with hormone therapy, immunotherapy (such as cancer peptide vaccine therapy), surgery, radiotherapy, or chemotherapeutic agents, i.e., treatment-naïve patients. In another embodiment, the combination therapy is administered to patients who have failed to achieve a sustained response after prior treatment with chemotherapeutic agents.

[0094] In this disclosure, “cancer” or “tumor” refers to a physiological condition in mammals characterized by uncontrolled cell proliferation. “Cancer” and “tumor” are synonymous and used interchangeably herein. Cancer includes solid tumors and hematological malignancies. Examples include, but are not limited to, carcinomas, lymphomas, leukemias, blastomas, sarcomas, and borderline malignancies (carcinoids).

[0095] In some embodiments, this disclosure may prevent and / or treat diseases (particularly tumors) that involve the RAS / MAPK signaling pathway.

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

[0097] The RAS / MAPK signaling pathway is not particularly limited, but typical examples include signals from RAS and its downstream signaling cascades such as RAF, MEK, ERK, PI3K, AKT, mTOR, and RAL-GEF. Diseases in which the incidence of disease (especially tumors) is reduced, symptoms are relieved or alleviated, disease progression is suppressed, disease relapse is suppressed, and / or complete cure is achieved by deleting, suppressing, and / or inhibiting these functions. Diseases involving the RAS / MAPK signaling pathway are preferably tumors having abnormalities in the RAS / MAPK signaling pathway, and more preferably tumors having RAS overexpression, RAS gene abnormalities, or abnormal RAS / MAPK signaling activity.

[0098] Tumors exhibiting RAS overexpression are preferably tumors exhibiting high gene expression and high expression of gene product proteins.

[0099] Tumors having abnormalities in the RAS gene preferably include gene amplification, gene mutation, chromosomal translocation / insertion / inversion, gene fusion, gene rearrangement, etc. Tumors having gene mutations preferably use this method for tumors having abnormalities in the RAS gene, and more preferably use this method for tumors having mutations in the NRAS, KRAS, or HRAS isoforms. Even more preferably use this method for tumors having mutations in the KRAS isoform.

[0100] Tumors exhibiting abnormal RAS / MAPK signaling activity preferably include tumors in which RAS or MEK activity is elevated.

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

[0102] In another embodiment of this disclosure, the disease involving the RAS / MAPK signaling pathway is preferably a tumor having abnormalities in the RAS / MAPK signaling pathway, and more preferably a tumor having abnormalities in FGFR.

[0103] Tumors having abnormalities in the FGFR gene preferably include gene amplification, gene mutation, chromosomal translocation / insertion / inversion, gene fusion, gene rearrangement, etc., and it is preferably used for tumors having mutations in FGFR. More preferably, it is used for tumors having mutations selected from the group consisting of FGFR1, FGFR2, FGFR3, and FGFR4 as FGFR mutations.

[0104] In some embodiments, this 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 (immunohistochemical staining, enzyme immunoassay (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 (Genechip, microarray, etc.).

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

[0106] Furthermore, in some embodiments, this disclosure is used for tumors in which the RAS signaling and / or FGFR signaling are activated. Activation of the RAS signaling can be detected by methods known to those skilled in the art. Detection of signal activation can be performed, for example, by detecting the direct binding state of RAS to GTP or GDP, the phosphorylation state of intracellular substrates and proteins downstream of the RAS signaling cascade, biological activity including enzyme activity, or by detecting gene products or gene transcripts. Activation of the FGFR signaling can be detected by methods known to those skilled in the art. Detection of signal activation can be performed, for example, by detecting FGF, a ligand for FGFR, the direct phosphorylation state or biological activity including enzyme activity of FGFR, a phosphorylation enzyme, the phosphorylation state of intracellular substrates and proteins downstream of the FGFR signaling cascade, biological activity including enzyme activity, or by detecting gene products or gene transcripts.

[0107] The tumors covered by this disclosure are not particularly limited, but examples include head and neck cancer, gastrointestinal cancer (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 cancer (ovarian cancer, uterine cancer (cervical cancer, endometrial cancer, etc.), urinary tract cancer (kidney cancer, bladder cancer, prostate cancer, testicular tumor, etc.), hematopoietic tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors, skin cancer, brain tumors, neurofibromas, thyroid cancer, etc. Preferably, lung cancer, pancreatic cancer, and colorectal cancer.

[0108] Here, cancer includes not only the primary tumor but also cancer that has metastasized to other organs (such as the liver). Furthermore, the antitumor agents disclosed herein may be used in adjuvant chemotherapy administered after surgical removal of a tumor to prevent recurrence, or in neoadjuvant chemotherapy administered prior to surgical removal of a tumor.

[0109] Methods for detecting the mechanisms of action of FGFR inhibitors and MEK inhibitors include investigating the regulation of the tumor immune microenvironment (Cellular Physiology and Biochemistry, 33, pp. 633-645 (2014)), but the methods are not limited to these.

[0110] There are no particular restrictions on the administration form of the antitumor agent disclosed herein, whether it be compound 1 or a pharmaceutically acceptable salt thereof, or a MEK inhibitor. The appropriate form can be selected as appropriate depending on the therapeutic purpose. Examples include oral preparations (tablets, coated tablets, powders, granules, capsules, liquids, etc.), injections, suppositories, patches, ointments, etc. In the case of compound 1 or a salt thereof, the above-mentioned administration forms are listed, with oral preparations being preferred. Similarly, in the case of a MEK inhibitor, the above-mentioned administration forms are listed, with oral preparations being preferred.

[0111] The antitumor agent of this disclosure may be compound 1 or a salt thereof, or the MEK inhibitor itself, which is the active ingredient, or it may be a pharmaceutical composition prepared by a commonly known method using a pharmaceutically acceptable carrier, depending on the form of administration. Examples of such carriers include various types commonly used in conventional drugs, such as excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, isotonic agents, pH adjusters, buffers, stabilizers, colorants, flavoring agents, and odorants.

[0112] The antitumor agents of this disclosure may be formulated by dividing each active ingredient into multiple dosage forms, or by combining them into a single dosage form, based on the administration form and / or administration schedule of each active ingredient. Furthermore, each formulation may be manufactured and sold together in a single package suitable for concomitant administration, or each formulation may be manufactured and sold in separate packages. The same applies to embodiments of pharmaceutical compositions. Accordingly, "a pharmaceutical composition containing compound 1 or its salt and a MEK inhibitor as active ingredients" includes formulations in which each active ingredient is divided into multiple dosage forms, as well as formulations in which each active ingredient is combined into a single dosage form. The pharmaceutical composition in which each active ingredient is divided into multiple dosage forms includes formulations in which each formulation is combined into a single package suitable for concomitant administration, as well as formulations in which each formulation is separated into separate packages.

[0113] In one embodiment, this disclosure relates to a kit formulation that includes an antitumor agent comprising compound 1 or a salt thereof, and instructions for use that describe the co-administration of compound 1 or a salt thereof with a MEK inhibitor to cancer patients. Here, "instructions for use" refers to any document that describes the above dosage, and does not need to be legally binding, but preferably one that recommends the above dosage. Specifically, examples include package inserts, brochures, etc. Furthermore, a kit formulation that includes instructions for use may be one in which the instructions for use are printed and attached to the package of the kit formulation, or in which the instructions for use are enclosed together with the antitumor agent in the package of the kit formulation.

[0114] This disclosure also relates to a method for treating tumors, characterized by co-administering compound 1 or a salt thereof with a MEK inhibitor.

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

[0116] This disclosure also relates to a method of treating cancer patients who have been administered a MEK inhibitor, comprising administering an antitumor agent comprising compound 1 or a salt thereof to the cancer patient.

[0117] This disclosure also relates to the antitumor agents of this disclosure used to treat tumors.

[0118] This disclosure also relates to an antitumor enhancer containing compound 1 or a salt thereof, used to enhance antitumor effects.

[0119] This disclosure also relates to an antitumor agent comprising compound 1 or a salt thereof, for use in treating cancer patients who have been administered a MEK inhibitor.

[0120] This disclosure also relates to the use of the antitumor agents of this disclosure in combination therapy with MEK inhibitors for the treatment of tumors.

[0121] This disclosure also relates to the use of the antitumor agents of this disclosure for enhancing the antitumor effect of MEK inhibitors.

[0122] This disclosure also relates to the use of an agent containing compound 1 or a salt thereof for treating cancer patients who have been administered a MEK inhibitor.

[0123] This disclosure also relates to the use of the antitumor agents of this disclosure in combination therapy with MEK inhibitors for the manufacture of pharmaceuticals for the treatment of tumors.

[0124] This disclosure also relates to the use of the antitumor agents of this disclosure for the manufacture of pharmaceuticals for enhancing the antitumor effects of MEK inhibitors.

[0125] This disclosure also relates to the use of an antitumor agent comprising compound 1 or a salt thereof for the manufacture of a pharmaceutical product for the treatment of cancer patients administered a MEK inhibitor.

[0126] In one embodiment of this disclosure, the drug is administered to patients with RAS mutations or abnormalities in the RAS / MAPK signaling pathway. Preferably, it is used for tumors with abnormalities in the RAS gene. More preferably, it is used for tumors with mutations in the NRAS, KRAS, or HRAS isoforms. Even more preferably, it is used for tumors with mutations in the KRAS isoform.

[0127] The antitumor agents of this disclosure can be used in the treatment of cancer. When referring to cancer patients receiving treatment regimens such as combination therapies described herein, “antitumor effect” means at least one evaluation such as PFS (progression-free survival), DCR (disease control rate), DOR (duration of response), OS (overall survival), ORR (objective response rate), DCR (disease control rate), PROs (patient-reported outcomes). In one embodiment, when targeting solid tumors, the tumor evaluation for the combination therapy described herein is evaluated using the RECIST 1.1 criteria (solid tumor response evaluation criteria), and the antitumor effect is indicated as SD (stable), PR (partial response), CR (complete response), or PD (progression). In the case of brain tumors, tumor evaluation can also be performed using Gd-MRI (standard brain tumor MRI including pre- and post-enhancement with gadolium (Gd) chelate contrast agent).

[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 in any way by these examples, and many modifications are possible within the technical concept of the present disclosure by those who are ordinary skill in the art. [Example 1: Evaluation of the in vitro combination effect of Compound 1 and selumetinib] <A. Materials and Methods> Human lung cancer cell line A549 (obtained from Dainippon Pharmaceutical Co., Ltd.) was cultured in DMEM medium containing 10% fetal bovine serum at 37°C and 5% CO2. ２ The cells were maintained and subculturised once or twice a week at a ratio of 1:5 to 1:20. A549 cells have been reported to carry the KRAS G12S mutation. <Cell viability assay> Cell viability was measured using Crystal Violet. Cells were harvested by conventional methods, suspended in the above medium containing 10% fetal bovine serum, and then seeded in 12-well plates. The seeding rate was 1000 cells / 800 μL per well. Cells were incubated at 37°C in 5% CO2. ２ After incubation for 24 hours, 100 μL of medium containing compound 1 and selumetinib or Vehicle was added.

[0129] Considering the sensitivity of cells to each drug, compound 1 was tested using two 10-fold dilution series at 10 and 100 nM, as well as zero concentration (DMSO), and selumetinib was tested using three 10-fold dilution series at 0.1, 1, and 10 μM, as well as zero concentration (DMSO). Each combination was investigated.

[0130] After drug addition, the cells were subjected to 37°C and 5% CO2. ２The cells were incubated for a further 10 days. During incubation, the culture medium was changed and the drug was re-added 3 and 7 days after drug addition. Cell viability was measured by adding 500 μL of glutaraldehyde solution per well, incubating at room temperature for 20 minutes, and then washing with tap water. After washing, 500 μL of crystal violet solution was added per well, incubating at room temperature for 20 minutes, and then washing with tap water. After washing, the plates were measured using a plate reader, Gelcount. For quantification, the dye was extracted using an extractant (0.1N sodium dihydrogen phosphate / ethanol), and the results are shown in Figure 1. The absorbance at a wavelength of 550 nm was measured using a plate reader, SpectraMAX Plus 384 Microplate Reader. Cell viability at the time of drug addition was calculated as a ratio with the control group set to 100% according to the following formula: Cell viability (%) = (Absorbance when drug is added) / (Absorbance of the control group) × 100 Furthermore, the Fa (Fraction of Affect) value was calculated by subtracting 1 / 100th of the cell viability value from 1.

[0131] Next, based on the drug effects of compound 1 and selumetinib monotherapy, the bliss addictiveness value, which is the calculated additive effect at each combination concentration, was determined according to the following formula.

[0132] Bliss Adhesion Value = (Fa value obtained from one compound alone) + (Fa value obtained from selumetinib monotherapy) - (Fa value obtained from one compound alone) × (Fa value obtained from selumetinib alone) The presence or absence of a combined effect of the two drugs was determined according to the following formula: a synergistic effect was determined if the judgment value was 10 or more, an additive effect if it was between -10 and less than 10, or an antagonistic effect if it was less than -10. Judgment value = 100 × (Fa value obtained from actual combined effect) - (Blissful Adhesion value) For strain A549, the judgment values ​​were calculated when compound 1 and selumetinib were used in combination, and the judgment values ​​for each condition are listed in Table 1.

[0134] Compound 1 showed a synergistic effect when combined with selumetinib in the Bliss additivity assay, with a positive value in the concentration range of 10 to 100 nM of Compound 1 itself confirmed. [Example 2: Evaluation of in vitro combined effects of Compound 1 and trametinib, binimetinib or cobimetinib] Human lung cancer cell lines A549 (obtained from American Type Culture Collection) and LU99 (obtained from JCRB Cell Bank) were cultured using DMEM medium and RPMI medium containing 10% fetal bovine serum, respectively. Maintained at 37°C, 5% CO ２ and subcultured and maintained at a ratio of 1:5 to 1:20 once or twice a week. A549 cells are reported to have a G12S mutation in KRAS, and LU99 cells are reported to have a G12C mutation in KRAS. <Cell Viability Assay> The measurement of cell viability was performed using crystal violet. Cells were collected by a conventional method, suspended in the above medium containing 10% fetal bovine serum, and then seeded in a 24-well plate. The seeding numbers were 1500 cells / 500 μL (A549) and 3000 cells / 500 μL (LU99) per well. The cells were incubated at 37°C, 5% CO ２ for 24 hours and then replaced with 500 μL of medium containing Compound 1 and trametinib, binimetinib, cobimetinib or Vehicle.

[0135] Compound 1 was prepared as a three-point dilution series at 10, 30 and 100 nM and zero concentration (DMSO), trametinib at 0.3, 1, 3, 10 and 30 μM, binimetinib and cobimetinib as a five-point dilution series at 3, 10, 30, 100 and 300 μM and zero concentration (DMSO), and each combination was examined.

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

[0137] Cell viability (%) = (Absorbance when drug is added) / (Absorbance of the control group) × 100 Furthermore, the Fa (Fraction of Affect) value was calculated by subtracting 1 / 100th of the cell viability value from 1.

[0138] Next, based on the effects of compound 1, trametinib, binimetinib, and cobimetinib as single agents, the bliss addictiveness value, which is the calculated additive effect at each combination concentration, was determined according to the following formula.

[0139] Bliss Adhesion Value = (Fa value obtained from one compound alone) + (Fa value obtained from trametinib, binimetinib, or cobimetinib monotherapy) - (Fa value obtained from one compound alone) × (Fa value obtained from trametinib, binimetinib, or cobimetinib alone) The presence or absence of a combined effect between the two drugs was determined according to the following formula: a synergistic effect was determined if the judgment value was 10 or higher, an additive effect if it was between -10 and less than 10, or an antagonistic effect if it was less than -10. Judgment value = 100 × (Fa value obtained from actual combined effect) - (Blissful Adhesion value) For strain A549, the judgment values ​​were calculated when compound 1 was used in combination with trametinib, binimetinib, or cobimetinib, and the judgment values ​​for each condition are listed in Table 2. For strain LU99, the judgment values ​​were calculated when compound 1 was used in combination with trametinib, binimetinib, or cobimetinib, and the judgment values ​​for each condition are listed in Table 3.

[0142] In strains A549 and LU99, compound 1, when used in combination with trametinib, showed a judgment value of -10 or higher in the region where the concentration of compound 1 itself was 10 nM or higher and the concentration of trametinib was 10 nM or higher, as analyzed by bliss additivity. This indicated an additive effect in strain A549 and an additive or synergistic effect in strain LU99.

[0143] In strains A549 and LU99, compound 1, when used in combination with binimetinib, showed a judgment value of -10 or higher in the region where the concentration of compound 1 itself was 10 nM or higher and the concentration of binimetinib was 100 nM or higher, as analyzed by bliss additivity. This indicated an additive effect in strain A549 and an additive or synergistic effect in strain LU99.

[0144] In strains A549 and LU99, compound 1, when used in combination with cobimetinib, showed a positive result of -10 or higher in bliss-adhesion analysis, both at concentrations of 10 nM or higher and at concentrations of 100 nM or higher for cobimetinib, demonstrating an additive or synergistic combination effect in both strains A549 and LU99.

[0145] A concentration of 10 nM of compound 1 corresponds to a blood concentration of 4.2 ng / mL in human pharmacokinetics, and is maintained at this concentration 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 described in AACR2018, R. Bahleda et al., poster CT121, at daily QD doses of 4 mg, 8 mg, 16 mg, 20 mg, and 24 mg, it became clear that blood concentrations could be maintained for approximately 16 hours or more at doses of 8 mg or higher, and that the total AUC over 24 hours was also higher. From this, it is considered that, in the case of daily administration, additive or synergistic effects with MEK inhibitors can be observed in the range of at least 8 mg to 24 mg.

[0147] Similarly, when comparing the PK data (Figure 4) for compound 1 administered as a QOD (once every two days) at doses of 8 mg, 16 mg, 24 mg, 36 mg, 56 mg, 80 mg, 120 mg, 160 mg, and 200 mg, it was found that blood concentrations could be maintained for approximately 36 hours or more at doses of 24 mg or higher, and at the same time, the total AUC over 48 hours was also higher at doses of 24 mg or higher. Therefore, it is considered that when compound 1 is administered intermittently, additive or synergistic effects with MEK inhibitors can be observed at least in the range of 24 mg to 200 mg.

[0148] A trametinib concentration of 10 nM corresponds to a blood concentration of 1.3 ng / mL in human pharmacokinetics, which is equivalent to maintaining that concentration for 24 hours. Comparing the PK data for once-daily administration of trametinib at doses of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, and 4 mg, which are publicly known from Lancet Oncol, 13, 773-81 (2012), it became clear that doses of 0.5 mg or more generally resulted in blood concentrations exceeding 1.3 ng / mL for more than 24 hours, and also exceeded the total AUC over 24 hours. From this, it is considered that when trametinib is administered once daily, an additive or synergistic effect with compound 1 is observed at least in the range of 0.5 mg to 4 mg.

[0149] Clinically, the dosage of trametinib (Mekinist tablets) used is 2 mg once daily, followed by a one-step reduction to 1.5 mg once daily, and then a two-step reduction to 1 mg once daily (Mekinist Tablets Interview Form). From this, it is thought that when trametinib is administered once daily for several days, an additive or synergistic effect 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 human pharmacokinetics. Comparing the PK data for 30 mg, 45 mg, and 60 mg of binimetinib administered twice daily, as published in BJC, 116, 575-583, (2017), it was found that blood concentrations of 18.45 ng / mL were maintained for more than 8 hours at doses of 30 mg or more, and the total AUC over 8 hours was also more than twice that of 18.45 ng / mL. From this, it is considered that when binimetinib is administered twice daily, an additive or synergistic effect with compound 1 is observed at least in the range of 30 mg to 60 mg.

[0151] Clinically, the dosage of binimetinib (Mectovi tablets) used is 45 mg twice daily, followed by a one-step reduction to 30 mg twice daily, and then a two-step reduction to 15 mg twice daily (Mectovi tablet interview form). From this, it is thought that when binimetinib is administered twice daily, an additive or synergistic effect with compound 1 is 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 human pharmacokinetics. We compared the PK data for once-daily administration of 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg cobimetinib, as publicly known in Inv New Drug, 34, 604-13, (2016) Supply Figure 2. In steady-state PK, it was found that at approximately Stage 1 (21 / 7), the 40 mg dose exceeded this concentration for 14 hours, and also exceeded the total AUC over 24 hours. From this, it is considered that when cobimetinib is administered once daily, an additive or synergistic effect with compound 1 is observed at least in the range of 40 mg to 60 mg.

[0153] Clinically, the dosage of cobimetinib (Cotelic tablets) is 60 mg once daily for 21 days, followed by a 28-day cycle, then a one-step reduction to 40 mg once daily for 21 days, followed by a 28-day cycle, followed by a two-step reduction to 20 mg once daily for 21 days, followed by a 28-day cycle (Cotelic Tablets Data Sheet). From this, it is thought that, when cobimetinib is administered once daily, an additive or synergistic effect with compound 1 is observed clinically in the range of 40-60 mg.

Claims

1. An antitumor agent administered in combination with a MEK inhibitor, which 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 active ingredient.

2. The antitumor agent according to claim 1, wherein the MEK inhibitor is trametinib or a salt thereof.

3. The antitumor agent according to claim 1, wherein the MEK inhibitor is binimetinib or a salt thereof.

4. The antitumor agent according to claim 1, wherein the MEK inhibitor is cobimetinib or a salt thereof.

5. The antitumor agent according to claim 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 claim 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 claim 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 claim 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 single dose selected from the group consisting of 24 mg, 36 mg, 56 mg, 80 mg, 120 mg, and 160 mg, and trametinib or a salt thereof is administered once a day at a single dose selected from the group consisting of 1 mg, 1.5 mg, and 2 mg.

9. The antitumor agent according to claim 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 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.

10. The antitumor agent according to claim 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 single dose selected from the group consisting of 24 mg, 36 mg, 56 mg, 80 mg, 120 mg, and 160 mg, and cobimetinib or a salt thereof is administered once a day at a single dose selected from the group consisting of 40 mg and 60 mg.

11. The antitumor agent according to any one of claims 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 an MEK inhibitor.

12. The antitumor agent according to any one of claims 1 to 11, wherein the tumor has an abnormality in the RAS / MAPK signaling pathway.

13. The antitumor agent according to any one of claims 1 to 12, 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.

14. The antitumor agent according to any one of claims 1 to 13, wherein the tumor is lung cancer, pancreatic cancer, colorectal cancer, or brain cancer.

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 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.

17. A pharmaceutical composition for treating tumors 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 active ingredients.

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 a tumor.

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 a tumor.

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 anti-tumor 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 who has been administered 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 a tumor 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 a tumor.

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.