Medicine for treating or preventing cancer

Abstract

The present invention provides a medicine for treating or preventing cancer, the medicine comprising a first active ingredient used together with a second active ingredient, the first active ingredient being a compound represented by formula (1) or a salt thereof, or a solvate thereof, the second active ingredient being an anticancer agent.

Description

Medicines for the treatment or prevention of cancer

[0001] The present invention relates to pharmaceuticals for the treatment or prevention of cancer, and more particularly to combination therapies including KRAS inhibitors.

[0002] Mutations in the KRAS gene are found in many types of cancer, and for example, G12C and G12D mutations are important therapeutic targets. Drugs targeting the KRAS-G12C mutation have been approved for non-small cell lung cancer, and inhibitors targeting mutations other than KRAS-G12C have also been reported to show initial antitumor activity in refractory cancers (see Patent Documents 2 and 4, and Non-Patent Document 1). Non-Patent Document 1 also describes ongoing research on the pathophysiology, therapeutic approaches, resistance mechanisms, and combination strategies of KRAS. Patent Document 1 describes the combination of specific compounds with specific molecular targeted agents. Furthermore, cancer treatment methods using KRAS inhibitors in combination with PD-1 or PD-L1 inhibitors, irinotecan, MEK inhibitors, etc. have been reported (see, for example, Patent Documents 3, 5, and 6). Patent Document 7 describes the combination of specific cyclic peptides with KRAS-G12C inhibitors, etc. Patent documents 12 and 13 describe cancer treatment using a combination of RAS(ON) inhibitors and RAS(OFF) inhibitors.

[0003] International Publication No. 2023 / 204259, International Publication No. 2024 / 020159, U.S. Patent Application Publication No. 2024 / 0156821, JP Publication No. 2024-146897, International Publication No. 2023 / 059600, International Publication No. 2024 / 173761, International Publication No. 2023 / 140329, International Publication No. 2023 / 214576, International Publication No. 2024 / 101402, International Publication No. 2024 / 219480, International Publication No. 2022 / 234853, International Publication No. 2024 / 206858, International Publication No. 2025 / 019318, International Publication No. 2022 / 060836, International Publication No. 2024 / 067857

[0004] Nature Medicine volume 30, pages969-983(2024)

[0005] The object of the present invention is to provide a pharmaceutical product that is effective in treating or preventing cancer.

[0006] The present invention provides the following [1] to

[69] : [1] A pharmaceutical for the treatment or prevention of cancer comprising a first active ingredient and used in combination with a second active ingredient, wherein the first active ingredient is a compound represented by the following formula (1) (hereinafter also referred to as "compound 1") or a salt thereof or a solvate thereof, and the second active ingredient is an anticancer agent. [2] A pharmaceutical for the treatment or prevention of cancer, comprising a first active ingredient and used in combination with a second active ingredient, wherein the first active ingredient is an anticancer agent and the second active ingredient is compound 1 or a salt thereof or a solvate thereof. [3] The pharmaceutical according to [1] or [2], wherein the first active ingredient and the second active ingredient are provided as a kit. [4] The pharmaceutical according to [1] or [2], used in combination as a combination agent. [5] A method for the treatment or prevention of cancer, comprising administering the first active ingredient and the second active ingredient to a subject, wherein the first active ingredient is compound 1 or a salt thereof or a solvate thereof and the second active ingredient is an anticancer agent. [6] The method according to [5], wherein the subject is a human. [7] A first active ingredient for use in the treatment or prevention of cancer, used in combination with a second active ingredient, wherein the first active ingredient is compound 1 or a salt thereof or a solvate thereof and the second active ingredient is an anticancer agent. [8] A first active ingredient for use in the treatment or prevention of cancer, used in combination with a second active ingredient, wherein the first active ingredient is an anticancer agent and the second active ingredient is compound 1 or a salt thereof or a solvate thereof. [9] A use of a first active ingredient for the manufacture of a pharmaceutical product for the treatment or prevention of cancer, used in combination with a second active ingredient, wherein the first active ingredient is compound 1 or a salt thereof or a solvate thereof and the second active ingredient is an anticancer agent.

[10] A use of a first active ingredient for the manufacture of a pharmaceutical product for the treatment or prevention of cancer, used in combination with a second active ingredient, wherein the first active ingredient is an anticancer agent and the second active ingredient is compound 1 or a salt thereof or a solvate thereof.

[11] A pharmaceutical product, method, first active ingredient for use, or use according to any one of [1] to

[10] , wherein compound 1 or a salt thereof or a solvate thereof is compound 1 or a salt thereof or a hydrate thereof.

[12] The pharmaceutical product, method, first active ingredient for use, or use according to any one of [1] to

[10] , wherein the compound 1 or a salt thereof or a solvate thereof is compound 1 or a hydrate thereof.

[13] The pharmaceutical, method, first active ingredient for use, or use according to any one of [1] to

[10] , wherein the compound 1 or a salt thereof or a solvate thereof is compound 1.

[14] The pharmaceutical, method, first active ingredient for use, or use according to any one of [1] to

[13] , wherein the first active ingredient and the second active ingredient are administered simultaneously or separately.

[15] The anticancer agent is a chemotherapeutic agent, a molecular targeted drug, or an immune checkpoint inhibitor, according to any one of [1] to

[13] .

[16] The anticancer agent is a molecular targeted drug, according to

[15] , the pharmaceutical, method, first active ingredient for use, or use.

[17] The molecular targeted drug is at least one selected from the group consisting of RAS(ON) inhibitors, RAS(OFF) inhibitors, and EGFR inhibitors, according to

[15] or

[16] . [17-1] The molecular targeted drug is a KRAS-G12C inhibitor, the first active ingredient for the pharmacopoeia, method, or use described in

[15] or

[16] . [17-2] The molecular targeted drug is a RAS(ON) inhibitor, the first active ingredient for the pharmacopoeia, method, or use described in

[17] .

[18] The molecular targeted drug is an EGFR inhibitor, the first active ingredient for the pharmacopoeia, method, or use described in

[17] .

[19] The above-mentioned RAS(ON) inhibitor is at least one selected from the group consisting of daraxone rasib, RMC-6291 (Elironrasib), RMC-7977, ERAS-0015, GFH547, ERAS-4001, PF-07934040, PF-07985045, BBO-8520, FMC-376, zoldon rasib (RMC-9805), GFH375 (also known as VS-7375), RMC-5127, ALTA3263, RAS-F, and AN-9025, which is the first active ingredient for the pharmacopoeia, method, use, or use described in

[17] or [17-2]. [19-1] The above-mentioned RAS(ON) inhibitor is daraxone rasib, the first active ingredient for the pharmacopoeia, method, or use described in

[17] or [17-2].

[20] The EGFR inhibitor is an EGFR tyrosine kinase inhibitor or an anti-EGFR antibody, which is the first active ingredient for the pharmaceutical, method, or use described in

[17] or

[18] .

[21] The anti-EGFR antibody is cetuximab or panitumumab, which is the first active ingredient for the pharmaceutical, method, or use described in

[20] .

[22] The EGFR tyrosine kinase inhibitor is gefitinib, erlotinib, afatinib, osimertinib, lapatinib, or a salt thereof or a solvate thereof, which is the first active ingredient for the pharmaceutical, method, or use described in

[20] .

[23] The EGFR inhibitor is cetuximab, panitumumab, gefitinib or a salt thereof or a solvate thereof, erlotinib or a salt thereof or a solvate thereof, afatinib or a salt thereof or a solvate thereof, osimertinib or a salt thereof or a solvate thereof, or lapatinib or a salt thereof or a solvate thereof, as described in any of

[17] to

[22] .

[24] The EGFR inhibitor is cetuximab, as described in any of

[17] to

[22] .

[25] The KRAS-G12C inhibitor is sotrasib or adaglasib or a salt thereof or a solvate thereof, as described in [17-1].

[26] The anticancer agent is a chemotherapeutic agent, the first active ingredient for the pharmacopoeia, method, or use described in

[15] .

[27] The chemotherapeutic agent is at least one selected from the group consisting of antimetabolites, platinum preparations, topoisomerase inhibitors, and taxane-based anticancer agents, the first active ingredient for the pharmacopoeia, method, or use described in

[15] or

[26] .

[28] The chemotherapeutic agent is an antimetabolite agent, the first active ingredient for the pharmacopoeia, method, or use described in

[27] .

[29] The antimetabolite agent is fluorouracil, tegafur, capecitabine, gemcitabine, methotrexate, pemetrexed or a salt thereof or a solvate thereof, the first active ingredient for the pharmacopoeia, method, or use described in

[27] .

[30] The antimetabolite is fluorouracil or a salt thereof or a solvate thereof, the first active ingredient for the pharmacopoeia, method, or use described in

[27] or

[28] .

[31] The chemotherapeutic agent is a platinum preparation, the first active ingredient for the pharmacopoeia, method, or use described in

[27] .

[32] The platinum preparation is oxaliplatin, cisplatin, carboplatin, or nedaplatin or a salt thereof or a solvate thereof, the first active ingredient for the pharmacopoeia, method, or use described in

[27] or

[31] .

[33] The platinum preparation is oxaliplatin or a salt thereof or a solvate thereof, the first active ingredient for the pharmacopoeia, method, or use described in

[32] .

[34] The chemotherapeutic agent is a topoisomerase inhibitor, the first active ingredient for the pharmacopoeia, method, or use described in

[27] .

[35] The topoisomerase inhibitor is irinotecan, topotecan, etoposide, or doxorubicin or a salt or solvate thereof, which is the first active ingredient or use for the pharmacopoeia, method, or use described in

[27] or

[34] .

[36] The topoisomerase inhibitor is irinotecan or a salt or solvate thereof, which is the first active ingredient or use for the pharmacopoeia, method, or use described in

[35] .

[37] The chemotherapeutic agent is a taxane-based anticancer agent, which is the first active ingredient or use for the pharmacopoeia, method, or use described in

[27] .

[38] The taxane-based anticancer agent is nab-paclitaxel, paclitaxel, docetaxel, or cabazitaxel or a salt or solvate thereof, which is the first active ingredient or use for the pharmacopoeia, method, or use described in

[27] or

[37] .

[39] The anticancer agent is an immune checkpoint inhibitor, the first active ingredient for the pharmacopoeia, method, or use described in

[15] .

[40] The immune checkpoint inhibitor is a PD-1 axis-binding antagonist or an anti-CTLA-4 antibody, the first active ingredient for the pharmacopoeia, method, or use described in

[15] or

[39] .

[41] The immune checkpoint inhibitor is a PD-1 axis-binding antagonist, which is the first active ingredient for the pharmacopoeia, method, or use described in

[15] or

[39] .

[42] The PD-1 axis-binding antagonist is an anti-PD-1 antibody or an anti-PD-L1 antibody, which is the first active ingredient for the pharmacopoeia, method, or use described in

[40] or

[41] .

[43] The immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody, which is the first active ingredient for the pharmacopoeia, method, or use described in

[15] or

[39] .

[44] The immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody, which is the first active ingredient for the pharmacopoeia, method, or use described in

[43] .

[45] The anti-PD-1 antibody is pembrolizumab, nivolumab, semiprimab, camrelizumab, or dostallimab, which is the first active ingredient for the pharmacopoeia, method, or use described in

[43] or

[44] .

[46] The anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, enfortumab, or vedotinsulfamab, which is the first active ingredient for the pharmacopoeia, method, or use described in

[43] or

[44] .

[47] The anti-CTLA-4 antibody is ipilimumab, tremelimumab, ciprizumab, kentreximab, or zarifenacin, which is the first active ingredient for the pharmacopoeia, method, or use described in

[43] .

[48] ​​The combination with the above anticancer agent is incorporated into a FOLFOX therapy or FOLFIRI therapy regimen, or the above anticancer agent is cetuximab, a KRAS-G12C inhibitor or a salt thereof or a solvate thereof, an anti-PD-1 antibody, or an anti-PD-L1 antibody, as described in any of [1] to

[14] , which is a pharmaceutical product, method, first active ingredient for use, or use.

[49] The above anticancer agent comprises fluorouracil and irinotecan, as described in any of [1] to

[14] , which is a pharmaceutical product, method, first active ingredient for use, or use.

[50] The above anticancer agent comprises fluorouracil and oxaliplatin, as described in any of [1] to

[14] , which is a pharmaceutical product, method, first active ingredient for use, or use.

[51] The combination of the above anticancer drug is incorporated into a FOLFOX therapy regimen, and is the first active ingredient for use or use described in any of [1] to

[14] .

[52] The combination of the above anticancer drug is incorporated into a FOLFIRI therapy regimen, and is the first active ingredient for use or use described in any of [1] to

[14] .

[53] The above anticancer drug is a KRAS-G12C inhibitor, and is the first active ingredient for use or use described in any of [1] to

[14] .

[54] The above anticancer drug is an anti-PD-1 antibody, and is the first active ingredient for use or use described in any of [1] to

[14] .

[55] The cancer is at least one selected from the group consisting of lung cancer, gastrointestinal cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, head and neck cancer, kidney cancer, prostate cancer, and malignant melanoma, as described in any of [1] to

[54] .

[56] The cancer is gastrointestinal cancer, as described in

[55] .

[57] The gastrointestinal cancer is at least one selected from the group consisting of esophageal cancer, stomach cancer, colorectal cancer, anal cancer, small intestine cancer, and biliary tract cancer, as described in

[55] or

[56] .

[58] The gastrointestinal cancer is colorectal cancer, as described in

[55] .

[59] The colorectal cancer is colon cancer or rectal cancer, the pharmaceutical product, method, first active ingredient for use, or use described in

[57] or

[58] .

[60] The cancer is lung cancer, the pharmaceutical product, method, first active ingredient for use, or use described in

[55] .

[61] The lung cancer is non-small cell lung cancer or small cell lung cancer, the pharmaceutical product, method, first active ingredient for use, or use described in

[55] or

[60] .

[62] The lung cancer is non-small cell lung cancer, the pharmaceutical product, method, first active ingredient for use, or use described in

[61] .

[63] The non-small cell lung cancer is adenocarcinoma, squamous cell carcinoma, or large cell carcinoma, according to

[61] or

[62] , the first active ingredient for use, or use.

[64] The cancer is a cancer associated with an abnormality of the KRAS gene, according to any one of [1] to

[63] , the first active ingredient for use, or use.

[65] The abnormality of the KRAS gene is a mutation in the coding region of the KRAS gene and / or an amplification of the copy number of the KRAS gene, according to

[64] , the first active ingredient for use, or use.

[66] The mutation of the KRAS gene includes a mutation at at least one amino acid position selected from the group consisting of G12, G13, Q61, and A146, according to

[65] , the first active ingredient for use, or use.

[67] The KRAS gene mutation is at least one mutation selected from the group consisting of G12A, G12C, G12D, G12S, G12V, G13D, Q61H, Q61K, and A146T, as described in

[65] .

[68] The cancer is non-small cell lung cancer, and the anticancer agent is one or more selected from the group consisting of pembrolizumab, cisplatin, carboplatin, and pemetrexed, as described in [1] to

[14] .

[69] The first active ingredient and the second active ingredient are different from each other, as described in any of [1] to

[68] .

[0007] According to the present invention, it is possible to provide a pharmaceutical product that exhibits excellent effects in the treatment or prevention of cancer. The present invention may be particularly effective in the treatment or prevention of cancers related to abnormalities in the KRAS gene.

[0008] Graph A shows the time course of tumor volume after transplantation of LoVo cell lines (colorectal cancer cell lines (ATCC) with the KRAS-G13D mutation) in the drug-free group, compound 1 monotherapy group, cetuximab monotherapy group, and combination therapy group. Graph B shows the time course of body weight in mice after transplantation of LoVo cell lines in the drug-free group, compound 1 monotherapy group, cetuximab monotherapy group, and combination therapy group. Graph B shows KRAS signaling inhibition in tumors of LoVo cell line-transplanted mice in the drug-free group, compound 1 monotherapy group, cetuximab monotherapy group, and combination therapy group. Graph B shows the cell viability of KRAS mutant cell lines after treatment with compound 1 and / or 5-FU (N=10, mean±SD). Graph C shows the cell viability of KRAS mutant cell lines after treatment with compound 1 and / or oxaliplatin (N=10, mean±SD). This graph shows the cell viability of KRAS mutant cell lines treated with compound 1 and / or SN-38 (N=10, mean±SD). The graph also shows the 50 percent cell proliferation inhibition rates (IC) for compound 1 and compound A99. ５０ This is an isobologram of compound 1. The horizontal axis represents the IC of compound 1. ５０ The values ​​are shown, with the vertical axis representing the IC of compound A99 or RMC-6236. ５０ The values ​​are shown. 50 percent cell proliferation inhibition rates (IC) of compound 1 and RMC-6236. ５０ This is an isobologram of compound 1. The horizontal axis represents the IC of compound 1. ５０ The values ​​are shown, with the vertical axis representing the IC of the RMC-6236. ５０ Show the value.

[0009] Embodiments of the present invention will now be described. However, the present invention is not limited to the following embodiments. The therapeutic or preventive medicine and therapeutic or preventive method of the present invention may be administered to or applied to humans. In this specification, the range “~” includes both ends of the range, for example, “A~B” means a range that is greater than or equal to A and less than or equal to B. In this specification, the term “about” when used in combination with a number means within ±10% of that number. In this invention, the meaning of the term “and / or” includes any combination in which “and” and “or” are appropriately combined. Specifically, for example, “A, B, and / or C” includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, (vii) A, B, and C.

[0010] In this specification, “combination use” means using a combination of active ingredients. The combination use of the first active ingredient and the second active ingredient includes modes in which the first and second active ingredients are used simultaneously and modes in which they are used separately. “Used simultaneously” means being administered at the same time without any time difference. Modes in which they are used simultaneously include “administering them as a single formulation containing the first and second active ingredients” (i.e., a medicine containing the first active ingredient further containing the second active ingredient, also called a “combination drug”) and “administering the first and second active ingredients simultaneously as separate medicines.” When administered simultaneously as separate medicines, they may be administered via the same route of administration or via different routes of administration (administration from different sites in the same patient). On the other hand, “used separately” means that the first and second active ingredients are formulated separately and administered at different times (with a time difference). For example, the second active ingredient may be administered after the first active ingredient is administered, or the first active ingredient may be administered after the second active ingredient is administered. When administered as separate pharmaceuticals with a time difference, they may be administered via the same route of administration or via different routes of administration (administration from different sites in the same patient). In the case of "formulating the first active ingredient and the second active ingredient separately and administering them simultaneously via the same route of administration," both active ingredients (the pharmaceutical containing the first active ingredient and the second active ingredient) may be mixed immediately before administration. "Used in combination" also includes the provision of a kit combining the pharmaceutical containing the first active ingredient and the pharmaceutical containing the second active ingredient.

[0011] "Combined use" may be any method of administering a first active ingredient and a second active ingredient for the purpose of treating or preventing cancer. Generally, the administered medicine gradually disappears from the body as it is metabolized or excreted outside the body. The second active ingredient may be administered to the patient while one active ingredient is present in the patient's body, or the second active ingredient may be administered after a certain period of time has elapsed since the administration of one active ingredient. "Combined use" also includes a method of alternately administering the first active ingredient and the second active ingredient. An embodiment in which the first active ingredient and the second active ingredient are simultaneously present in the body of the target patient, for example, in the blood, is preferred. The "target" may be a mammal, preferably a human.

[0012] The documents cited or referenced in this specification are incorporated herein by reference in their entirety. Such documents include International Publication No. 2022 / 234853 (Patent Document 11), International Publication No. 2023 / 214576 (Patent Document 8), International Publication No. 2024 / 101402 (Patent Document 9), and International Publication No. 2024 / 219480 (Patent Document 10).

[0013] [First Embodiment] One embodiment of the present invention is a medicament for treating or preventing cancer containing a first active ingredient, which is used in combination with a second active ingredient. In this embodiment, the first active ingredient is a compound represented by the following formula (1) or a salt or solvate thereof, and the second active ingredient is an anticancer agent.

[0014] In the description of this embodiment, for the sake of convenience, the "compound represented by formula (1)" may be referred to as "Compound 1", and the "compound represented by formula (1) or a salt or solvate thereof" may be referred to as the "first active ingredient". The first active ingredient includes the compound represented by formula (1), a salt of the compound represented by formula (1), a solvate of the compound represented by formula (1), and a solvate of a salt of the compound represented by formula (1).

[0015] In this embodiment, Compound 1 of the first active ingredient or a salt or solvate thereof is not included in the anticancer agent of the second active ingredient.

[0016] In this specification, specific examples of salts include hydrochloride; hydrobromide; hydroiodide; phosphate; phosphonate; sulfate; sulfonates such as methanesulfonate and p-toluenesulfonate; carboxylates such as acetate, citrate, malate, tartrate, succinate, salicylate, and adipate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, and tetraalkylammonium salt. These salts can be produced, for example, by contacting a compound with an acid or a base. Examples of salts of Compound 1 include pharmaceutically acceptable salts, specifically, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; salts with organic acids such as acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid; salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; salts with amino acids such as arginine. These salts can be produced, for example, by contacting a compound with an acid or a base, and reference may be made to the method described in Patent Document 10.

[0017] In this specification, a solvate is not particularly limited as long as it forms a single molecular group with the solvent, but it is a solvate formed with a solvent that can be ingested (taken) along with the administration of a drug. Examples of solvates of compound 1 or its salt include not only solvates with a single solvent such as hydrates, alcohol hydrates (ethanol hydrate, methanol hydrate, 1-propanol hydrate, 2-propanol hydrate, etc.), and dimethyl sulfoxide, but also solvates formed with multiple solvent molecules for one molecule of the compound, or solvates formed with multiple types of solvents for one molecule of the compound. When the solvent is water, it is called a hydrate. Solvates are produced, for example, by contact between the compound and the solvent, and solvates of salts are produced, for example, by contact between the compound salt and the solvent. Salts of compounds or solvates of compounds or salts of compounds may all be active, just like the compound (free form). Examples of solvates of compound 1 include solvates with water, alcohols (ethanol, methanol, 1-propanol, 2-propanol, etc.), dimethyl sulfoxide, etc., with hydrates being particularly preferred when the compound forms a solvate with water. Such hydrates are preferably 1 to 20 hydrates, more preferably 1 to 10 hydrates, and even more preferably 1 to 5 hydrates. Specifically, they may be hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, or pentahydrates, with 1 to 3 hydrates being preferred.

[0018] Compound 1, its salts, or their solvates may exist in polymorphic form, but may also be a single crystalline form or a mixture of any of the crystalline forms. Compound 1, its salts, or their solvates may also be amorphous. Solvates of compound 1 or its salts can be prepared by methods known to those skilled in the art, and the method described in Patent Document 10 may be referenced.

[0019] Compound 1 can be produced, for example, by the method described in Patent Document 8, the Fmoc method for peptide synthesis, or Solidphase peptide synthesis (published by Bachem, accessed December 24, 2021, Internet URL: https: / / www.bachem.com / wp-admin / admin-ajax.php?juwpfisadmin=false&action=wpfd&task=file.download&wpfd_category_id=180&wpfd_file_id=213455&token=&preview=1, or Peptide Guide, No: 2004505, published by Global Marketing BachemAG, 2020). Furthermore, the hydrate of Compound 1 can be produced by methods known to those skilled in the art, and the method described in Patent Document 10 may be referenced.

[0020] Anticancer drugs can be any component that is effective in treating or preventing cancer, such as chemotherapeutic agents, molecularly targeted drugs, and immune checkpoint inhibitors. Anticancer drugs can be obtained from commercial suppliers or manufactured according to known methods.

[0021] Furthermore, when used in combination with anticancer drugs, adjuvant agents may be added. Examples of adjuvant agents include those that enhance the antitumor effect of anticancer drugs, those that suppress the metabolism of anticancer drugs (inhibitors of metabolic enzymes), those that suppress or reduce side effects, and solubilizers. Examples of such adjuvant agents include leucovorin or its calcium salt, which enhances the action of fluorouracil; gimeracil, which inhibits the catabolic metabolic enzymes of fluorouracil; and oteracil or its potassium salt, which reduces side effects caused by the active metabolites of fluorouracil.

[0022] Chemotherapy agents are drugs that are mainly administered orally or by injection, circulate throughout the body via the bloodstream, and act on the proliferation process of cancer cells to inhibit their growth. Examples of chemotherapeutic agents include antimetabolites, platinum-based drugs, topoisomerase inhibitors, and taxane-based anticancer drugs.

[0023] Antimetabolites are drugs that inhibit the proliferation of cancer cells by inhibiting DNA synthesis or metabolism during cell division and proliferation. Antimetabolites have a chemical structure similar to nuclear bases (e.g., adenosine, thymine, guanosine, cytosine, uracil) or nucleosides. Examples of antimetabolites include fluorouracil, capecitabine, gemcitabine, methotrexate, pemetrexed, and their prodrugs. These antimetabolites may be in the form of their salts, solvates, or solvates of their salts, or combinations thereof.

[0024] Furthermore, the antimetabolite may be a combination drug with an adjuvant, such as the tegafur / gimeracil / oteracil potassium combination drug. The tegafur / gimeracil / oteracil potassium combination drug is a combination of 5-fluoro-1-[(2RS)-tetrahydrofuran-2-yl]uracil, 5-chloro-2,4-dihydroxypyridine, and 1,2,3,4-tetrahydro-2,4-dioxo-1,3,5-triazine-6-carboxylate monopotassium salt. Tegafur is a prodrug of fluorouracil. Gimeracil is an adjuvant that inhibits the catabolic metabolic enzymes of fluorouracil, and oteracil potassium is an adjuvant that reduces side effects caused by the active metabolites of fluorouracil in gastrointestinal tissue by inhibiting orotate phosphoribosyltransferase.

[0025] In certain embodiments, the antimetabolite is fluorouracil or a salt thereof or a solvate thereof.

[0026] Platinum preparations are drugs characterized by having a planar four-coordinate platinum ion at its center, with two donor ligands and two leaving groups coordinated to it, and two of the leaving groups in a cis configuration. After permeating a membrane, platinum preparations inhibit cell proliferation by replacing the leaving groups with water and forming chelate bonds with nuclear bases (especially guanidine). Examples of platinum preparations include oxaliplatin, cisplatin, carboplatin, and nedaplatin. These platinum preparations may be in the form of their salts, solvates, or solvates of their salts, or combinations thereof.

[0027] In a particular embodiment, the platinum preparation is oxaliplatin or a salt thereof or a solvate thereof.

[0028] Topoisomerase inhibitors are drugs that inhibit DNA replication by inhibiting the enzyme topoisomerase. Topoisomerase plays a role in altering the helical structure of DNA during replication. Examples of topoisomerase inhibitors include irinotecan, topotecan, etoposide, doxorubicin, and their prodrugs. These topoisomerase inhibitors may be in the form of their salts, solvates, or solvates of their salts, or combinations thereof.

[0029] Taxane-based anticancer drugs are a general term for compounds that have a taxane skeleton and possess anticancer activity. They are thought to inhibit the cell division of cancer cells by binding to microtubules, promoting microtubule polymerization, or stabilizing microtubules. Examples of taxane-based anticancer drugs include paclitaxel, docetaxel, cabazitaxel, their salts, or their solvates. Taxane-based anticancer drugs may also be in the form of nanoparticle formulations of paclitaxel bound to albumin (also called nab-paclitaxel).

[0030] In certain embodiments, the topoisomerase inhibitor is irinotecan or a salt thereof or a solvate thereof.

[0031] Molecularly targeted drugs are drugs that selectively act on specific molecules (e.g., the MAPK / ERK pathway, EGFR, VEGF, SHP2, and RAS proteins). EGFR (epidermal growth factor receptor) is a type of receptor on the cell surface and is involved in signal transduction for cell proliferation. Three types of RAS proteins are known: KRAS protein, NRAS protein, and HRAS protein. Mutations in the genes encoding these proteins (ras genes) produce mutant RAS proteins. RAS is a type of small GTPase that mediates signal transduction that promotes cell proliferation, and it is involved in regulating cell differentiation and proliferation by switching between GTP-bound (active) and GDP-bound (inactive) forms. For example, it is known that when a GEF (Guanine nucleotide exchange factor) such as SOS1 binds to a RAS protein, it releases GDP and promotes binding to GTP, thereby activating the RAS protein. Furthermore, a protein called RasGAP (Ras GTPase-activating proteins) is involved in the regulation of RAS activity. RasGAP promotes the GTP hydrolysis reaction of RAS, converting it to an inactive form. Activated RAS induces cell proliferation, survival, and differentiation by activating various downstream signals such as the MAPK pathway, PI3K / Akt pathway, and RAL pathway. Homeoactivation of RAS plays a crucial role in the development and progression of cancer. In cancer, the RAS-RAF-MEK-ERK pathway is known to be activated by the activation of upstream signals of RAS, homeoactivation of RAS, and / or mutations in the activating form of RAS. In addition, mutant KRAS proteins such as KRAS-G12C, KRAS-G12D, KRAS-G12V, and KRAS-G12A are known. KRAS-G12C is a mutant KRAS protein in which the 12th glycine (G) molecule is replaced with cysteine ​​(C). Mutations in the RAS gene have been identified in various types of cancer. For example, KRAS mutations are commonly seen in pancreatic cancer, colorectal cancer, lung cancer, multiple myeloma, and uterine cancer; NRAS mutations are commonly seen in malignant melanoma and multiple myeloma; and HRAS mutations are seen in bladder cancer and thyroid cancer.

[0032] Examples of molecularly targeted drugs include MAPK / ERK pathway inhibitors, EGFR inhibitors, VEGF inhibitors (e.g., anti-VEGF antibodies), SHP2 inhibitors, and RAS inhibitors. RAS inhibitors can be classified into RAS(ON) inhibitors (also called RAS-GTP inhibitors) and RAS(OFF) inhibitors (also called RAS-GDP inhibitors) depending on the mode of inhibition. RAS(ON) inhibitors include KRAS(ON) inhibitors, NRAS(ON) inhibitors, and HRAS(ON) inhibitors. In certain embodiments, the molecularly targeted drug is a RAS(ON) inhibitor. In certain embodiments, the molecularly targeted drug is a RAS(OFF) inhibitor.

[0033] Here, a RAS(ON) inhibitor refers to a drug that directly acts on the GTP-bound (active) RAS protein and has inhibitory activity. Furthermore, in one embodiment of the present invention, a RAS(ON) inhibitor has a higher binding affinity to the GTP-bound RAS protein than to the GDP-bound RAS protein. Furthermore, in one embodiment of the present invention, a KRAS(ON) inhibitor has a higher binding affinity to the GTP-bound KRAS protein than to the GDP-bound KRAS protein. In contrast, a RAS(OFF) inhibitor inhibits the interaction between the RAS protein and GEF, and inhibits the RAS signal by maintaining the inactive state in which the RAS protein is bound to GDP.

[0034] In this embodiment, the RAS(ON) inhibitor may be one or more selected from the group consisting of KRAS(ON) inhibitors, NRAS(ON) inhibitors, and HRAS(ON) inhibitors. Also in this embodiment, the RAS(ON) inhibitor may be a pan-RAS(ON) inhibitor or a pan-KRAS(ON) inhibitor, or a mutation-selective RAS(ON) inhibitor. Furthermore, in a particular embodiment, the RAS(ON) inhibitor is a pan-RAS(ON) inhibitor.

[0035] In this specification, KRAS(ON) inhibitors, NRAS(ON) inhibitors, and HRAS(ON) inhibitors refer to drugs that have inhibitory activity against GTP-bound (active) KRAS protein, GTP-bound (active) NRAS protein, and GTP-bound (active) HRAS protein, respectively. Furthermore, in this specification, pan-RAS(ON) inhibitors refer to drugs that have inhibitory activity against GTP-bound (active) RAS protein (including mutant RAS protein), and pan-RAS(ON) inhibitors bind to and inhibit the activity of GTP-bound KRAS protein, NRAS protein, HRAS protein, and their mutant proteins. Furthermore, a pan-KRAS(ON) inhibitor refers to a drug that has inhibitory activity against GTP-bound (active) KRAS protein (including mutant KRAS protein). Pan-KRAS(ON) inhibitors bind to and inhibit the activity of GTP-bound (active) KRAS protein and mutant KRAS protein.

[0036] RAS(ON) inhibitors may be selected from the group consisting of daraxone racib (RMC-6236), erylon racib (RMC-6291), RMC-7977, ERAS-0015 (compound 6A of International Publication No. 2024 / 067857 (any atrop isomer or mixture thereof)), GFH547, ERAS-4001, PF-07934040, PF-07985045, BBO-8520, FMC-376, zoldon racib (RMC-9805), GFH375 (also known as VS-7375), RMC-5127, ALTA3263, RAS-F, and AN-9025. The RAS(ON) inhibitor may be selected from the group consisting of daraxonrasib, RMC-6291, RMC-7977, GFH547, ERAS-0015, zoldonrasib (RMC-9805), RAS-F, and AN-9025. Furthermore, the RAS(ON) inhibitor is preferably daraxonrasib. These RAS(ON) inhibitors may also be in the form of their salts, solvates, or solvates of their salts. Daraxonrasib, elironrasib, and zoldonrasib are known as compounds having the following structures.

[0037] Furthermore, RAS inhibitors can be classified into pan-RAS inhibitors, isoform-selective inhibitors, and mutation-selective inhibitors depending on the type and / or mutation of the RAS protein. Examples of isoform-selective inhibitors include pan-KRAS inhibitors, pan-NRAS inhibitors, and pan-HRAS inhibitors. Examples of mutation-selective inhibitors include RAS-G12C inhibitors, RAS-G12D inhibitors, RAS-G12V inhibitors, RAS-G13C inhibitors, and RAS-Q61H inhibitors. Each of these inhibitors may be a RAS(ON) inhibitor or a RAS(OFF) inhibitor. Examples of mutation-selective inhibitors include KRAS-G12A inhibitors, KRAS-G12C inhibitors, KRAS-G12D inhibitors, KRAS-G12S inhibitors, KRAS-G12V inhibitors, KRAS-G13D inhibitors, KRAS-Q61H inhibitors, KRAS-Q61K inhibitors, NRAS-G12C inhibitors, NRAS-G12D inhibitors, NRAS-G13D inhibitors, NRAS-G13V inhibitors, NRAS-Q61K inhibitors, NRAS-Q61L inhibitors, and HRAS-G13R inhibitors. In a particular embodiment, the molecularly targeted drug is daraxone rasib (RMC-6236).

[0038] Examples of EGFR inhibitors include EGFR tyrosine kinase inhibitors (e.g., gefitinib, erlotinib, afatinib, osimertinib, lapatinib, and their prodrugs) and anti-EGFR antibodies (e.g., cetuximab, panitumumab). These EGFR inhibitors may also be in the form of their salts, solvates, or solvates of their salts.

[0039] The anti-EGFR antibody can be any antibody capable of recognizing EGFR as an antigen, and an antibody having a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 2 is preferred.

[0040] Gefitinib (CAS number: 184475-35-2, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholine-4-ylpropoxy)quinazoline-4-amine) is a compound represented by the following formula.

[0041] Erlotinib (CAS number: 183321-74-6, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine) is a compound represented by the following formula. Erlotinib hydrochloride is known as an active ingredient in pharmaceuticals.

[0042] Afatinib (CAS number: 439081-18-2, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide) is a compound represented by the following formula. Afatinib maleate is known as an active ingredient in pharmaceuticals.

[0043] Osimertinib (CAS number: 1421373-65-0, N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindole-3-yl)pyrimidine-2-yl]amino}phenyl)propa-2-enamide is a compound represented by the following formula. Osimertinib mesylate is known as an active ingredient in pharmaceuticals.

[0044] Lapatinib (CAS number: 231277-92-2, N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-2-furyl]quinazoline-4-amine) is a compound represented by the following formula. Lapatinib tosylate hydrate is known as an active ingredient in pharmaceuticals.

[0045] In certain embodiments, the EGFR tyrosine kinase inhibitor is gefitinib, erlotinib, afatinib, osimertinib, lapatinib, or a salt thereof or a solvate thereof.

[0046] In certain embodiments, the molecularly targeted drug is an EGFR inhibitor or a KRAS-G12C inhibitor.

[0047] In certain embodiments, the EGFR inhibitor is cetuximab, panitumumab, gefitinib, erlotinib, afatinib, osimertinib, lapatinib, or a salt thereof or a solvate thereof. In certain embodiments, the EGFR inhibitor is cetuximab.

[0048] Examples of KRAS-G12C inhibitors include sotrasib and adagrasib.

[0049] Sotrasib (CAS number: 2296729-00-3,4-((S)-4-acryloyl-2-methylpiperazine-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)pyrido[2,3-d]pyrimidine-2(1H)-one) is a compound represented by the following formula.

[0050] Adagracib (CAS number: 2326521-71-3, 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-yl)-1-(2-fluoroacryloyl)piperazine-2-yl)acetonitrile is a compound represented by the following formula.

[0051] In certain embodiments, the KRAS-G12C inhibitor is sotrasib, adaglasib, or a salt thereof or a solvate thereof.

[0052] Immune checkpoint inhibitors are drugs that exert therapeutic effects by inhibiting the mechanisms that cancer cells possess to evade attack by immune cells, thereby utilizing the body's natural immune function to attack cancer cells. It is known that when PD-1, which is present on the surface of immune cells, binds to PD-L1, which is present on the surface of cancer cells, the immune cells' attack on cancer cells is suppressed. Substances that suppress T cell dysfunction caused by such PD-1 signaling axis signaling, or that restore or enhance T cell function (e.g., proliferation, cytokine production, target cell death), are also called "PD-1 axis-binding antagonists." Furthermore, it is known that when CTLA-4, which is present on the surface of immune cells, binds to antigen-presenting cell B7 (CD80 / CD86), the attack on cancer cells is weakened. Such proteins are thought to be immune checkpoints that regulate the function of immune cells, and drugs that inhibit the binding of PD-1 to PD-L1 or the binding of CTLA-4 to B7 are called immune checkpoint inhibitors. Examples of immune checkpoint inhibitors include anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-CTLA-4 antibodies.

[0053] PD-1 (Programmed cell Death 1) is one of the receptors expressed on the surface of activated T cells. Normally, PD-1 is activated by binding to PD-L1 (Programmed cell Death 1-Ligand 1), which is expressed on the surface of antigen-presenting cells, and the T cell then ceases attacking the target cell (i.e., the cell possessing PD-L1).

[0054] The anti-PD-1 antibody can be any antibody capable of recognizing PD-1 as an antigen, and an antibody having a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 3 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 4 is preferred. Examples of anti-PD-1 antibodies include pembrolizumab, nivolumab, semiprimab, camrelizumab, and dostallimab.

[0055] Any anti-PD-L1 antibody that can recognize PD-L1 as an antigen is acceptable, and antibodies having such heavy chain variable regions and light chain variable regions are preferred. Examples of anti-PD-L1 antibodies include atezolizumab, avelumab, durvalumab, enfortumab, and vedotinsulfamab.

[0056] Any anti-CTLA-4 antibody that can recognize CTLA-4 (Cytotoxic T-lymphocyte Antigen-4) as an antigen is acceptable, and antibodies having such heavy chain variable regions and light chain variable regions are preferred. Examples of anti-CTLA-4 antibodies include ipilimumab, tremelimumab, cyprizumab, kentreximab, and zarifenacin.

[0057] In certain embodiments, the immune checkpoint inhibitor is a PD-1 axis-binding antagonist, preferably an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0058] In certain embodiments, the combination with an anticancer agent is incorporation into a FOLFOX therapy or FOLFIRI therapy regimen, or the anticancer agent is cetuximab, a KRAS-G12C inhibitor or a salt or solvate thereof, or an anti-PD-L1 antibody. FOLFOX therapy is known as a cancer treatment method that uses fluorouracil, leucovorin, oxaliplatin or a salt or solvate thereof in combination. FOLFIRI therapy is also known as a cancer treatment method that uses fluorouracil, leucovorin, irinotecan or a salt or solvate thereof in combination. In FOLFOX therapy or FOLFIRI therapy, leucovorin is not an anticancer agent, but it enhances the antitumor effect of fluorouracil by forming a complex with thymidylate synthase and its active metabolite (FdUMP). In this embodiment, the first active ingredient may be administered in combination with a FOLFOX therapy or FOLFIRI therapy regimen.

[0059] In this embodiment, the pharmaceutical product containing the first active ingredient may further contain a pharmaceutically acceptable carrier. Examples of pharmaceutically acceptable carriers include excipients, binders, lubricants, colorants, flavorings, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, and antioxidants commonly used in formulation. The pharmaceutical product containing the first active ingredient may contain the above carriers individually or in any combination, depending on the form of the formulation.

[0060] In this embodiment, the pharmaceutical and anticancer agents containing the first active ingredient can be administered independently by methods such as oral, rectal, parenteral (intravenous, intramuscular, subcutaneous, transdermal), intracisional, intravaginal, intraperitoneal, intravesical, topical administration, and inhalation. Forms of the formulation include, for example, tablets, capsules, granules, powders, pills, injections, infusions, patches, ointments, lotions, creams, gels, aqueous and non-aqueous oral solutions and suspensions, eye drops, dry syrups, lozenges, suppositories, and parenteral solutions filled in containers suitable for individual doses. The administration method can also be adapted to various administration methods, including controlled-release formulations such as subcutaneous implantation. Those skilled in the art can select a suitable formulation depending on the method of administration and / or purpose of administration of the pharmaceutical.

[0061] When administering a pharmaceutical product containing the first active ingredient by any of the above methods, the second active ingredient may be administered by the same method or by a different method. Specifically, the pharmaceutical product containing the first active ingredient may be administered orally, and the second active ingredient may be administered by injection or intravenous infusion. Alternatively, the pharmaceutical product containing the first active ingredient may be administered orally, and the second active ingredient may be administered orally. The interval between the administration of the pharmaceutical product containing the first active ingredient and the administration of the second active ingredient can be appropriately selected by a person skilled in the art, and can be, for example, 0 to 14 days, 0 to 10 days, or 0 to 7 days. When the administration interval is 0 days, it means that the pharmaceutical product containing the first active ingredient and the second active ingredient are administered on the same day. The administration interval is, for example, measured by the area under the curve of the blood concentration profile (AUC), the maximum blood concentration (Cmax), the time to reach the maximum blood concentration (Tmax), and the elimination half-life (t). １／２The decision can be made considering the health condition of the individual, etc.

[0062] The dosage of the drug containing the first active ingredient can be changed depending on the type of cancer and the type of anticancer drug. The dosage can be 0.0001 to 1000 mg per kg of body weight per dose. Alternatively, the dosage can be selected within the range of 0.001 to 100,000 mg / body per patient, but it is not necessarily limited to these values. The dosage and method of administration will vary depending on the patient's weight, age, symptoms, etc., but a person skilled in the art can select them appropriately.

[0063] The number of times a drug containing the first active ingredient is administered can be set to any number of times, for example, once every two weeks (14 days), once every week (7 days), once every six days, once every five days, once every four days, once every three days, once every two days, once every day (24 hours), twice a day, or three times a day.

[0064] In administering the second active ingredient (anticancer drug), known dosages and / or administration schedules depending on the type of anticancer drug can be applied. The dosage of the second active ingredient (anticancer drug) may be set to 0.005 to 100 mg per kg of body weight of the recipient. The dosage of the anticancer drug may be 0.005 to 100 mg / kg body weight / day, 0.01 to 75 mg / kg body weight / day, 0.02 to 50 mg / kg body weight / day, or 5 to 40 mg / kg body weight / day per kg of body weight of the recipient. When the dosage of the anticancer drug falls within these ranges, the therapeutic or preventive effect of cancer is enhanced. The number of times the medicine containing the second active ingredient (anticancer drug) is administered can be, for example, once or twice a week.

[0065] The number of times the second active ingredient (anticancer drug) is administered can be set to any number of times, for example, once every two weeks (14 days), once every week (7 days), once every six days, once every five days, once every four days, once every three days, once every two days, once every day (24 hours), twice a day, or three times a day. When determining the appropriate dosage and number of administrations (administration frequency), you may refer to the package insert for the anticancer drug.

[0066] The dosage of the second active ingredient (anticancer agent) can be changed depending on the cancer type and the type of anticancer agent.

[0067] For example, when the cancer is non-small cell lung cancer, it can be set as follows. When the anticancer agent is pemetrexed, pemetrexed in an amount of 500 mg / m ２ can be administered by intravenous drip injection over 10 minutes. To reduce the side effects of pemetrexed, folic acid and vitamin B １２ may be further administered. When the anticancer agent is a combination of cisplatin and pemetrexed, cisplatin in an amount of 75 mg / m ２ is administered by intravenous drip injection over 2 hours, and pemetrexed in an amount of 500 mg / m ２ can be administered by intravenous drip injection over 10 minutes. To reduce the side effects of pemetrexed, folic acid and vitamin B １２ may be further administered. When the anticancer agent is a combination of cisplatin, pemetrexed, and pembrolizumab, cisplatin in an amount of 75 mg / m ２ is administered by intravenous drip injection over 2 hours, pemetrexed in an amount of 500 mg / m ２ can be administered by intravenous drip injection over 10 minutes, and pembrolizumab in an amount of 200 mg / body can be administered by intravenous drip injection over 30 minutes. To reduce the side effects of pemetrexed, folic acid and vitamin B １２ may be further administered. When the anticancer agent is a combination of carboplatin and pemetrexed, carboplatin is administered by intravenous drip injection over 30 minutes or more, and pemetrexed in an amount of 500 mg / m ２ can be administered by intravenous drip injection over 10 minutes. To reduce the side effects of pemetrexed, folic acid and vitamin B １２ may be further administered. When the anticancer agent is a combination of carboplatin, pemetrexed, and pembrolizumab, carboplatin can be administered by intravenous drip injection over 30 minutes, pemetrexed can be administered by intravenous drip injection over 10 minutes, and pembrolizumab can be administered by intravenous drip injection over 30 minutes. To reduce the side effects of pemetrexed, folic acid and vitamin B １２Further administration is also possible. If the anticancer drug is pembrolizumab, 200 mg may be administered intravenously by infusion over 30 minutes at 3-week intervals, or 400 mg at 6-week intervals.

[0068] For example, if the cancer is colorectal cancer, the dosage can be set as follows: If the anticancer drugs are fluorouracil and oxaliplatin, and are administered in combination with FOLFOX therapy (combination administration of fluorouracil, leucovorin, and oxaliplatin), the adult dose is 85 mg / m². ２ The amount of oxaliplatin is administered by intravenous infusion over 120 minutes, and 200 mg / m² of levofolinate is administered at a time. ２ The (body surface area) is administered by intravenous infusion over 120 minutes. Immediately after the completion of the levofolinate intravenous infusion, 400 mg / m² of fluorouracil is administered. ２ In addition to intravenous injection of (body surface area), 2400-3000 mg / m² of fluorouracil is administered. ２ (Body surface area) can be administered by continuous intravenous injection over 46 hours. This can also be repeated every two weeks. When the anticancer drug is a combination of fluorouracil and irinotecan, and is administered in combination with FOLFIRI therapy (combination administration of fluorouracil, leucovorin, and irinotecan), the dose is 150 mg / m². ２ Administer irinotecan in an amount equal to (body surface area) via intravenous drip infusion over 90 minutes, resulting in a dose of 200 mg / m². ２ Administer leucovorin in an amount equal to (body surface area) via intravenous drip infusion over 120 minutes, resulting in a dose of 400 mg / m². ２ After rapidly administering fluorouracil in an amount equal to (body surface area), 2400 mg / m² is administered. ２ Fluorouracil in an amount equal to (body surface area) can be administered by continuous intravenous injection over 46 hours. For example, levofolinate (200 mg / m²) ２ ) and irinotecan (150 mg / m²) ２ Simultaneously start an intravenous infusion of fluorouracil (400 mg / m²). ２ After rapidly administering ) intravenously, fluorouracil (2400 mg / m²) is administered. ２ ) is administered by continuous intravenous injection. If the anticancer drug is cetuximab, 500 mg / m² of cetuximab (recombinant is also acceptable) is administered to adults. ２The dosage can be administered intravenously over a two-hour period at two-week intervals, based on the body surface area. The dosage can be reduced as appropriate depending on the patient's condition.

[0069] For example, if the cancer is pancreatic cancer, the settings can be configured as follows: If the anticancer drug is gemcitabine, for example, 1000 mg / m² per dose. ２ The drug (body surface area) is administered by intravenous drip infusion over 30 minutes, once a week for three consecutive weeks, with a rest period in the fourth week. This can be repeated as one course. If the anticancer drug is a combination of gemcitabine and nab-paclitaxel, for example, a 60-90 minute drip infusion is administered once a week for three consecutive weeks, with a rest period in the fourth week. This can be repeated as one 4-week course. If the anticancer drug is fluorouracil, oxaliplatin, and irinotecan, and is administered in combination with FOLFOFINOX therapy (combination administration of fluorouracil, leucovorin, oxaliplatin, and irinotecan), the adult dose is 85 mg / m². ２ After administering oxaliplatin in an amount equal to (body surface area) via intravenous infusion over 120 minutes, levofolinate is administered at a dose of 200 mg / m². ２ (Body surface area) can be administered by intravenous infusion over 120 minutes. Additionally, 180 mg / m² of levofolinate can be administered 30 minutes after intravenous infusion. ２ Irinotecan can be administered intravenously in an amount equal to (body surface area) over 90 minutes. Immediately after the completion of the intravenous infusion of levofolinate and irinotecan, 400 mg / m² of fluorouracil can be administered. ２ In addition to intravenous injection of (body surface area), 2400-3000 mg / m² of fluorouracil is administered. ２ (Body surface area) can be injected via continuous intravenous injection over 46 hours. This can also be repeated every two weeks.

[0070] The combination of dosages for the pharmaceutical containing the first active ingredient and the second active ingredient (anticancer drug) may be such that, per kg of body weight of the recipient, the dosage of the pharmaceutical containing the first active ingredient is 0.0001 to 1000 mg / kg body weight / day, and the dosage of the anticancer drug is 0.005 to 100 mg / kg body weight / day, or 0.01 to 75 mg / kg body weight / day, or 0.02 to 30 mg / kg body weight / day. When each dosage combination falls within these ranges, the therapeutic or preventive effect of cancer is enhanced. The dosage and administration method can be adjusted as appropriate while observing the pharmacokinetics of the drug (e.g., area under the curve of blood concentration profile AUC, maximum blood concentration Cmax, etc.) and the patient's condition.

[0071] The dosage and / or administration interval of the pharmaceutical product containing the first active ingredient and the second active ingredient (anticancer drug) shall be determined as necessary, using the area under the curve of the blood concentration profile (AUC), the maximum blood concentration (Cmax), the time to reach the maximum blood concentration (Tmax), and the elimination half-life (t). １／２ The information may be changed based on the health condition of the subject, etc.

[0072] The administration period can be, for example, 7 days per cycle, and can consist of one or more cycles, two or more cycles, three or more cycles, or four or more cycles. Each cycle may be performed consecutively, or there may be a rest period between cycles. A rest period may also be included in the middle of a cycle. During the rest period, administration of only the drug containing the first active ingredient may be stopped, administration of only the second active ingredient may be stopped, or administration of both may be stopped. Compound 1 and other anticancer drugs can be administered simultaneously, sequentially, or intermittently. In the case of sequential administration, compound 1 may be administered first, or the other anticancer drugs may be administered first.

[0073] The pharmaceutical product according to this embodiment is suitable for the prevention or treatment of cancer. Target cancers include lung cancer, gastrointestinal cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, head and neck cancer, kidney cancer, prostate cancer, and malignant melanoma.

[0074] In certain embodiments, preferred cancers to target are gastrointestinal cancers. Gastrointestinal cancers include esophageal cancer, gastric cancer, colorectal cancer (e.g., colon cancer, rectal cancer), anal cancer, small intestine cancer, and biliary tract cancer. In certain embodiments, a more preferred cancer to target is colorectal cancer.

[0075] In certain embodiments, the preferred cancer to target is lung cancer. Lung cancer includes non-small cell lung cancer (e.g., adenocarcinoma, squamous cell carcinoma, large cell carcinoma) and small cell lung cancer.

[0076] When the target cancer is colorectal cancer, it is preferable to use cetuximab as the concomitant anticancer drug, or to use it in combination with the FOLFOX therapy or FOLFIRI therapy regimen.

[0077] When the target cancer is pancreatic cancer, it is preferable that the anticancer drug used in combination is gemcitabine and / or nab-paclitaxel.

[0078] In certain embodiments, preferred cancers are those associated with abnormalities in the RAS gene (particularly the KRAS gene). Cancers associated with RAS gene abnormalities are, for example, cancers in which cancer cells have mutations in the coding region of the RAS gene and / or an amplification of the copy number of the RAS gene, resulting in increased RAS activity (including increased production of RAS protein). Mutations in the coding region of the RAS gene refer to, for example, one or more base deletions, additions, or substitutions in the coding region of the RAS gene. Amplification of the copy number of the RAS gene refers to the presence of more copies of the RAS gene than normally present on a chromosome. More copies means more than in normal cells, and a copy number of four or more can be considered to be an amplification of the copy number.

[0079] In this specification, "abnormality" refers to a state in which various chromosomes, genes, proteins, and signaling cascades within a cell deviate from their normal function or regulation, and is usually triggered by the constitutive activation of these components. For example, a gene mutation may cause various chromosomes, genes, proteins, and signaling cascades within a cell to be more activated than in normal cells (Cancer Metastasis Rev. 2013, 32, 147-162). To directly and quantitatively evaluate the involvement of mutants in cells, cell activation can be measured, for example, by LC / MS-MS based assays (Cancer Discov. 2016, 6, 316-329).

[0080] Amplification of RAS proteins (e.g., KRAS, NRAS, HRAS) refers to the synthesis and amplification of proteins in living cells. Protein amplification can be confirmed by measuring it using methods such as Western blotting or comparative genome hybridization (CGH) and comparing it with proteins in normal cells (Nat. Rev. Drug Discov. 2020, 19, 533-552, MolecularCytogenetics, 2015, 8:103).

[0081] Whether a cancer is related to an abnormality in the RAS gene can be determined by (1) confirming whether the subject with cancer has an abnormality in the RAS gene, and / or (2) confirming whether the subject with cancer has an amplification of the copy number of the RAS gene. In method (1), for example, by identifying a mutation in the base sequence of the coding region of the RAS gene in a biological sample obtained from a subject with cancer, and further confirming that the mutated RAS protein is expressed, it can be determined that the cancer is related to an abnormality in the RAS gene. In method (2), for example, by confirming that the copy number of the RAS gene is amplified and / or that the production of the RAS protein is increased in a biological sample obtained from a subject with cancer, it can be determined that the cancer is related to an abnormality in the RAS gene. An increase in the production of the RAS protein can also be called overexpression of the RAS protein. Whether or not RAS protein production is increased can be confirmed, for example, by comparing it with the expression level of a typical RAS protein, the expression level of a RAS protein in a subject without the cancer, or the expression level of a RAS protein in a subject before developing cancer.

[0082] The discrimination method (1) or (2) can be any method that can detect mutations in the coding region of the RAS gene or amplification of the copy number of the RAS gene in a biological sample of a subject with cancer, and can be carried out by methods known to those skilled in the art. For example, the RAS gene may be isolated from a biological sample obtained from a subject with cancer, amplified by PCR or the like, and its base sequence may be directly determined by a sequencer or the like. Alternatively, for example, a commercially available in vitro diagnostic agent that can detect mutations in the RAS gene may be used.

[0083] Three isoforms of the RAS protein are known: KRAS protein, NRAS protein, and HRAS protein. In a particular embodiment, the RAS gene exhibiting a genetic abnormality is one or more RAS genes selected from the group consisting of KRAS gene, NRAS gene, and HRAS gene. In a particular embodiment, the RAS gene exhibiting a genetic abnormality is the KRAS gene.

[0084] In certain embodiments, the cancers of interest include cancers associated with the production of mutant RAS proteins and / or increased production of RAS proteins. The production of mutant RAS proteins and / or increased production of RAS proteins is typically due to abnormalities in the RAS genes described above. Mutant RAS proteins include mutant KRAS proteins, mutant NRAS proteins, and mutant HRAS proteins.

[0085] In certain embodiments, the mutant RAS protein has a mutation at at least one amino acid position selected from the group consisting of glycine at position 12 (G), glycine at position 13 (G), and glutamine at position 61 (Q) in the amino acid sequence of the human wild-type KRAS, NRAS, or HRAS protein. For example, "G12C," a commonly used notation for a mutation in the amino acid sequence, means a mutation in which glycine at position 12 (G) is replaced with cysteine ​​(C).

[0086] In certain embodiments, the mutation in the mutant KRAS protein includes a mutation at at least one amino acid position selected from the group consisting of G12, G13, Q61, and A146 in the amino acid sequence of the wild-type KRAS protein. In certain embodiments, the mutant KRAS protein is a protein having at least one mutation selected from the group consisting of G12A, G12C, G12D, G12S, G12V, G13D, Q61H, Q61K, and A146T compared to the amino acid sequence of the wild-type KRAS protein. Cancers associated with abnormalities in the KRAS gene may be cancers in which a protein having at least one mutation selected from the group consisting of G12A, G12C, G12D, G12S, G12V, G13D, Q61H, Q61K, and A146T is detected compared to the amino acid sequence of the wild-type KRAS protein.

[0087] In certain embodiments, the mutation in the mutant NRAS protein includes a mutation at at least one amino acid position selected from the group consisting of G12, G13, and Q61 in the amino acid sequence of the wild-type NRAS protein. In certain embodiments, the mutant NRAS protein is a protein having at least one mutation selected from the group consisting of G12C, G12D, G13D, G13V, Q61K, and Q61L compared to the amino acid sequence of the wild-type NRAS protein. Cancers associated with abnormalities in the NRAS gene may be cancers in which a protein having at least one mutation selected from the group consisting of G12C, G12D, G13D, G13V, Q61K, and Q61L compared to the amino acid sequence of the wild-type NRAS protein is detected.

[0088] In certain embodiments, the mutant HRAS protein contains a mutation at the G13 amino acid position in the amino acid sequence of the wild-type HRAS protein. In certain embodiments, the mutant HRAS protein is a protein having the G13R mutation compared to the amino acid sequence of the wild-type HRAS protein. Cancers associated with abnormalities in the HRAS gene may be cancers in which a protein having the G13R mutation is detected compared to the amino acid sequence of the wild-type HRAS protein.

[0089] Another aspect of this embodiment is a method for treating or preventing cancer, comprising administering a first active ingredient and a second active ingredient to a target, wherein the first active ingredient is compound 1 or a salt thereof or a solvate thereof, and the second active ingredient is an anticancer agent.

[0090] Another aspect of this embodiment is a first active ingredient for use in the treatment or prevention of cancer, used in combination with a second active ingredient, wherein the first active ingredient is compound 1 or a salt thereof or a solvate thereof, and the second active ingredient is an anticancer agent.

[0091] Another aspect of this embodiment is the use of the first active ingredient for the manufacture of a pharmaceutical product for the treatment or prevention of cancer, used in combination with a second active ingredient, wherein the first active ingredient is compound 1 or a salt thereof or a solvate thereof, and the second active ingredient is an anticancer agent.

[0092] [Second Embodiment] One embodiment of the present invention is a pharmaceutical for the treatment or prevention of cancer, comprising a first active ingredient used in combination with a second active ingredient. In this embodiment, the first active ingredient is an anticancer agent, and the second active ingredient is a compound represented by the following formula (1), a salt thereof, or a solvate thereof.

[0093] In describing this embodiment, for convenience, the "compound represented by formula (1)" may be referred to as "compound 1," and the "compound represented by formula (1), its salt, or its solvates" may be referred to as the "second active ingredient." The second active ingredient includes the compound represented by formula (1), salts of the compound represented by formula (1), solvates of the compound represented by formula (1), and solvates of salts of the compound represented by formula (1).

[0094] In this embodiment, the second active ingredient compound 1 or its salt or solvate is not included in the first active ingredient anticancer agent.

[0095] In this embodiment, the "first active ingredient" can refer to the definition and description of the "second active ingredient" in the first embodiment.

[0096] Furthermore, the "second active ingredient" in this embodiment may refer to the definition and description of the "first active ingredient" as described in the first embodiment.

[0097] In this embodiment, the pharmaceutical product containing the first active ingredient (anticancer agent) may further contain a pharmaceutically acceptable carrier. Examples of pharmaceutically acceptable carriers include excipients, binders, lubricants, colorants, flavorings, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, and antioxidants that are commonly used in formulation. The pharmaceutical product containing the first active ingredient may contain the above carriers individually or in any combination, depending on the form of the formulation.

[0098] In this embodiment, the pharmaceutical formulation containing the first active ingredient (anticancer agent) and the second active ingredient can each be administered independently by methods such as oral, rectal, parenteral (intravenous, intramuscular, subcutaneous, transdermal), intracisional, intravaginal, intraperitoneal, intravesical, topical administration, and inhalation. Forms of the formulation include, for example, tablets, capsules, granules, powders, pills, injections, infusions, patches, ointments, lotions, creams, gels, aqueous and non-aqueous oral solutions and suspensions, eye drops, dry syrups, lozenges, suppositories, and parenteral solutions filled in containers suitable for individual doses. Furthermore, the administration method can be adapted to various administration methods, including controlled-release formulations such as subcutaneous implantation. Those skilled in the art can select a suitable form of formulation depending on the method of administration and / or purpose of administration of the pharmaceutical.

[0099] When administering a pharmaceutical product containing the first active ingredient (anticancer drug) by any of the above methods, the second active ingredient may be administered by the same method or by a different method. Specifically, the pharmaceutical product containing the first active ingredient (anticancer drug) may be administered orally, and the second active ingredient may be administered by injection or intravenous infusion. Alternatively, the pharmaceutical product containing the first active ingredient (anticancer drug) may be administered orally, and the second active ingredient may be administered orally. The interval between the administration of the pharmaceutical product containing the first active ingredient (anticancer drug) and the administration of the second active ingredient can be, for example, 0 to 14 days, 0 to 10 days, or 0 to 7 days. When the administration interval is 0 days, it means that the pharmaceutical product containing the first active ingredient and the second active ingredient are administered on the same day. The administration interval is, for example, measured by the area under the curve of the blood concentration profile (AUC), the maximum blood concentration (Cmax), the time to reach the maximum blood concentration (Tmax), and the elimination half-life (t). １／２ The decision can be made considering the health condition of the individual, etc.

[0100] In administering a pharmaceutical product containing the first active ingredient (anticancer drug), known dosages and / or administration schedules depending on the type of anticancer drug can be applied. The dosage of the first active ingredient (anticancer drug) may be set to 0.005 to 100 mg per kg of body weight of the recipient. The dosage of the anticancer drug may be 0.005 to 100 mg / kg body weight / day, 0.01 to 75 mg / kg body weight / day, 0.02 to 50 mg / kg body weight / day, or 5 to 40 mg / kg body weight / day per kg of body weight of the recipient. When the dosage of the anticancer drug falls within these ranges, the therapeutic or preventive effect of cancer is enhanced. The number of times the pharmaceutical product containing the first active ingredient (anticancer drug) is administered may be, for example, once or twice a week.

[0101] The number of times a drug containing the first active ingredient (anticancer drug) is administered can be set to any number of times, for example, once every two weeks (14 days), once every week (7 days), once every six days, once every five days, once every four days, once every three days, once every two days, once every day (24 hours), twice a day, or three times a day. When determining the appropriate dosage and number of administrations (administration frequency), you may refer to the package insert for the anticancer drug.

[0102] The dosage of the second active ingredient can be 0.0001 to 1000 mg per kg of body weight per dose. Alternatively, the dosage can be selected within the range of 0.001 to 100,000 mg / body per patient, but it is not necessarily limited to these values. The dosage and method of administration will vary depending on the patient's weight, age, symptoms, etc., but those skilled in the art can select them appropriately. When the dosage of the second active ingredient falls within these ranges, the therapeutic or preventive effect of cancer is enhanced.

[0103] The number of times the second active ingredient is administered can be set to any number of times, for example, once every two weeks (14 days), once every week (7 days), once every six days, once every five days, once every four days, once every three days, once every two days, once every day (24 hours), twice a day, or three times a day.

[0104] The combination of dosages for the first active ingredient (anticancer drug) and the second active ingredient may be such that, per kg of body weight of the recipient, the dosage of the first active ingredient (anticancer drug) is 0.005 to 100 mg / kg body weight / day and the dosage of the second active ingredient is 0.0001 to 1000 mg / kg body weight / day, or the dosage of the first active ingredient (anticancer drug) is 0.01 to 75 mg / kg body weight / day and the dosage of the second active ingredient (anticancer drug) is 0.02 to 30 mg / kg body weight / day. When each dosage combination falls within these ranges, the therapeutic or preventive effect of cancer is enhanced. The dosage and administration method can be adjusted as appropriate while observing the pharmacokinetics of the drug (e.g., area under the curve of blood concentration profile AUC, maximum blood concentration Cmax, etc.) and the patient's condition.

[0105] The dosage and / or administration interval of the pharmaceutical product containing the first active ingredient (anticancer drug) and the second active ingredient shall be determined as necessary, using the area under the curve of the blood concentration profile (AUC), the maximum blood concentration (Cmax), the time to reach the maximum blood concentration (Tmax), and the elimination half-life (t). １／２ The information may be changed based on the health condition of the subject, etc.

[0106] The administration period can be, for example, 7 days per cycle, and can consist of one or more cycles, two or more cycles, three or more cycles, or four or more cycles. Each cycle may be performed consecutively, or there may be a rest period between cycles. A rest period may also be included in the middle of a cycle. During the rest period, administration of only the drug containing the first active ingredient may be stopped, administration of only the second active ingredient may be stopped, or administration of both may be stopped.

[0107] The pharmaceutical product according to this embodiment is suitable for the prevention or treatment of cancer. Target cancers include lung cancer, gastrointestinal cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, head and neck cancer, kidney cancer, prostate cancer, and malignant melanoma.

[0108] In certain embodiments, preferred cancers to target are gastrointestinal cancers. Gastrointestinal cancers include esophageal cancer, gastric cancer, colorectal cancer (e.g., colon cancer, rectal cancer), anal cancer, small intestine cancer, and biliary tract cancer. In certain embodiments, a more preferred cancer to target is colorectal cancer.

[0109] In certain embodiments, the preferred cancer to target is lung cancer. Lung cancer includes non-small cell lung cancer (e.g., adenocarcinoma, squamous cell carcinoma, large cell carcinoma) and small cell lung cancer.

[0110] In certain embodiments, preferred cancers are those associated with abnormalities in the KRAS gene. Cancers associated with abnormalities in the KRAS gene are, for example, cancers in which cancer cells have mutations in the coding region of the KRAS gene and / or an amplification of the KRAS gene copy number, resulting in increased KRAS activity (including increased production of KRAS protein). A mutation in the coding region of the KRAS gene refers to, for example, one or more base deletions, additions, or substitutions in the KRAS gene coding region. An amplification of the KRAS gene copy number means the presence of more KRAS genes than are normally present on a chromosome. A "larger copy number" means a number greater than that of normal cells; a copy number of four or more can be considered an amplification.

[0111] A method for determining whether a cancer is related to an abnormality in the KRAS gene can be found by referring to the description in the first embodiment.

[0112] Another aspect of this embodiment is a method for treating or preventing cancer, comprising administering a first active ingredient and a second active ingredient to a target, wherein the first active ingredient is an anticancer agent and the second active ingredient is compound 1 or a salt thereof or a solvate thereof.

[0113] Another aspect of this embodiment is a first active ingredient for use in the treatment or prevention of cancer, used in combination with a second active ingredient, wherein the first active ingredient is an anticancer agent and the second active ingredient is compound 1 or a salt thereof or a solvate thereof.

[0114] Another aspect of this embodiment is the use of the first active ingredient for the manufacture of a pharmaceutical product for the treatment or prevention of cancer, used in combination with a second active ingredient, wherein the first active ingredient is an anticancer agent and the second active ingredient is compound 1 or a salt thereof or a solvate thereof.

[0115] The following describes preferred specific embodiments of the present invention as examples, but the present invention is not limited thereto.

[0116] [Synthesis Example 1: Method for synthesizing compound 1] Compound 1 was synthesized by the same method as described in Patent Document 9, and the final product was obtained as a dried product. Specifically, compound PP2320 in Patent Document 9 corresponds to compound 1. Compound (1) is (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 ４，８ . 0 ２６，３０ It is also called pentatetraconta-42-ene-23,1'-cyclobutane-17-carboxamide.

[0117] Example 1: Efficacy study of combination therapy with compound 1 and cetuximab in cancer with KRAS activating mutations 1. Materials and methods LoVo cell lines cultured in vitro were treated with Hanks' Balanced Salt solution (Sigma-Aldrich, product code: H9269) in 5 × 10⁻¹⁴⁻¹ ７ The cells were suspended to a concentration of cells / mL. The prepared cell suspension was then used to feed BALB / c-nu / nu mice (CAnN.Cg-Foxn1). <nu>0.1 mL of CrlCrlj (manufactured by Jackson Laboratory Japan Co., Ltd.) was transplanted subcutaneously into the right ventral region. The drug was administered to mice (LoVo cancer-bearing mice) in which tumor (cancer cell) engraftment was confirmed.

[0118] Compound 1 was dissolved in a mixture of 10% DMSO (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., product code: 043-07216) and 5% Cremophor EL (manufactured by Sigma-Aldrich, product code: C5135), and administered orally at a dose of 4 mg / kg once daily for 10 days. Cetuximab was diluted with physiological saline (manufactured by Otsuka Pharmaceutical Factory Co., Ltd.) and administered intravenously at a dose of 40 mg / kg twice a week. In the combination therapy group, Compound 1 suspended in the mixture was administered orally in the same manner as above, and cetuximab diluted with physiological saline was administered intravenously. Eight tumor-bearing mice were used in each group.

[0119] Administration of various drugs was started on day 34 post-transplant, and tumor volume and body weight were measured until day 44. The short and long diameters of the tumor were measured using electronic calipers, and the tumor volume was calculated by multiplying the long diameter by the short diameter by the short diameter and dividing by 1 / 2. Similarly, tumor volume and body weight were measured for LoVo tumor-bearing mice (drug-free group) that did not receive any drugs. Body weight was calculated as the percentage change from day 34 post-transplant.

[0120] At 44 days post-transplant, a two-sided Student's t-test was performed to determine whether there was a difference in tumor volume between the group administered compound 1 alone and the group administered compound 1 and cetuximab in combination. The p-value (significance level: 5%) was calculated. Figure 1A shows the time course of tumor volume after LoVo transplantation in the drug-free group, the compound 1 monotherapy group, the cetuximab monotherapy group, and the combination therapy group, and Figure 1B shows the relative time course of body weight. Based on the p-value, an asterisk is indicated in Figure 1. ※※※ :p<0.001).

[0121] 2. Results Efficacy study of combination therapy with compound 1 and cetuximab in LoVo tumor-bearing mice As shown in Figure 1, in an in vivo efficacy study using LoVo tumor-bearing mice with KRAS activating mutations, the combination therapy group had significantly smaller tumor volume compared to the compound 1 monotherapy group.

[0122] Example 2: Evaluation of KRAS signaling inhibitory activity by combination of compound 1 and cetuximab in cancer with KRAS activating mutations 1. Materials and methods After the completion of Example 1, compound 1 (4 mg / kg) and cetuximab (40 mg / kg) were re-administered to nude mice (n=3), respectively. After 4 hours, the tumors were collected, frozen in liquid nitrogen, and stored at -80°C. Subsequently, under cooling with liquid nitrogen, the collected tumors were crushed using a multi-bead shocker (Yasui Kikai) and dissolved in lysis buffer (ThermoFisher Scientific, product code: 16117) containing a protease / phosphatase inhibitor (ThermoFisher Scientific, product code: 78447). The concentration of the protein solution was measured using a DirectDetect spectrometer, and protein solution 1 was prepared by adding 5× Fluorescent Master Mix (protein simple, product code: PS-ST01-8) to a concentration of 1 mg / mL, and incubated at 95°C for 5 minutes. From the remaining protein solution, 80 μg was used to recover the activated form, RAS-GTP, using the Active Ras Pull-Down and Detection Kit (ThermoFisher Scientific, product code: 16117), and protein solution 2 was prepared and incubated at 95°C for 5 minutes. Protein solutions 1 and 2 were applied to a 12-230 kDa Jess or Wes Separation Module (proteinsimple, product code: SM-W004), and the protein was detected. The primary and secondary antibodies used, and their dilution concentrations, are shown in Tables 1 and 2. The results of Western blotting to evaluate KRAS signal inhibitory activity are shown in Figure 2. "KRAS-GTP" represents "KRAS bound to GTP," and "perk" and "pEGFR" represent "phosphorylated ERK" and "phosphorylated EGFR," respectively. Compared to the use of compound 1 or cetuximab as a monotherapy, the combination of compound 1 and cetuximab showed a decrease in KRAS-GTP, perk, and DUSP4, and enhanced suppression of KRAS signaling.

[0123]

[0124]

[0125] Example 3: Combination anticancer activity test of KRAS inhibitors against various anticancer drugs 1. Experimental materials and methods (1) For the cell line test, LS180 (colorectal cancer cell line with KRAS-G12D mutation (ATCC)), GP2d (colorectal cancer cell line with KRAS-G12D mutation (ECACC)), and SK-CO-1 (colorectal cancer cell line with KRAS-G12V mutation (ATCC)) were used.

[0126] (2) Cytotoxicity tests of various anticancer drugs when KRAS inhibitors are added. 5-FU (Selleck Biotech, product code: S1209), oxaliplatin (Fujifilm Wako Pure Chemical Industries, Ltd., product code: 156-02691), and SN-38 (active metabolite of irinotecan, topoisomerase I inhibitor, Selleck Biotech, product code: S4908) were used for evaluation as anticancer drugs.

[0127] Using Echo (Beckman Coulter), 5-FU (final concentration in the system: 2.5 μM or 5 μM), oxaliplatin (final concentration in the system: 0.3 μM), and SN-38 (final concentration in the system: 1.25 μM or 2.5 nM) were added to each well of a Prime Surface® plate 384U white (Sumitomo Bakelite Co., Ltd., product code: MS-9384W). DMSO or distilled water was added as a control.

[0128] Compound 1 (final system concentration of 2 nM, 4 nM, or 7.5 nM) was added to each well of a Prime Surface® plate 384U white (Sumitomo Bakelite Co., Ltd., product code: MS-9384W) using Echo (Beckman Coulter). DMSO was added as a control.

[0129] As a background signal, DMSO or distilled water was added, and wells containing only culture medium were prepared.

[0130] Various cells cultured under the conditions summarized in Table 3 were seeded at a rate of 500 cells per well on the above-mentioned plates and incubated at 37°C. After incubation under 3D conditions for 7 days, CellTiter-Glo2.0 Cell Viability Assay (Promega, product code: G9243) was added, and the luminescence intensity was measured using a Multimode Plate Reader EnVision Xcite (PerkinElmer) to monitor the cell count. Cell viability was calculated by subtracting the background signal value from the signal value of each seeded well, with the signal value of the control well set to 100%. Evaluations were performed for each condition with N=10.

[0131] NEAA: Non-essential amino acids; FBS: Fetal bovine serum

[0132] In colorectal cancer cell lines containing KRAS-activating mutations, cells were treated with compound 1 and / or 5-FU, compound 1 and / or oxaliplatin, or compound 1 and / or SN-38. Cell viability after each treatment is shown in Figures 3-5. Tukey HSD tests were performed to determine if there was a difference in cell viability between each treatment condition, and p-values ​​were calculated. An asterisk is indicated in each figure based on the p-value (****: p < 0.0001).

[0133] 2. Results (1) 5-FU As shown in Figure 3, in all colorectal cancer cell lines LS180, GP2d, and SK-CO-1, the group treated with compound 1 and 5-FU together showed a significantly lower cell viability compared to both the group treated with compound 1 alone and the group treated with 5-FU alone. These results suggest that the combination of compound 1 and 5-FU in colorectal cancer cell lines enhances the cell proliferation inhibitory activity of compound 1.

[0134] (2) Oxaliplatin As shown in Figure 4, in all colorectal cancer cell lines LS180, GP2d, and SK-CO-1, the group treated with compound 1 and oxaliplatin showed a significantly lower cell viability compared to both the group treated with compound 1 alone and the group treated with oxaliplatin alone. These results suggest that the combination of compound 1 and oxaliplatin in colorectal cancer cell lines enhances the cell proliferation inhibitory activity of compound 1.

[0135] (3) SN-38 As shown in Figure 5, in all colorectal cancer cell lines LS180, GP2d, and SK-CO-1, the group treated with compound 1 and SN-38 showed a significantly lower cell viability compared to both the group treated with compound 1 alone and the group treated with SN-38 alone. These results suggest that the combination of compound 1 and SN-38 in colorectal cancer cell lines enhances the cell proliferation inhibitory activity of compound 1.

[0136] Example 4: Combination anticancer activity test of KRAS inhibitors against RAS(ON) inhibitors 1. Experimental materials and methods (1) Cell line tests included NCI-H1373 (lung cancer cell line with KRAS-G12C mutation (ATCC)), NCI-H2122 (lung cancer cell line with KRAS-G12C mutation (ATCC)), A-427 (lung cancer cell line with KRAS-G12D mutation (ATCC)), NCI-H1944 (lung cancer cell line with KRAS-G13D mutation (ATCC)), AsPC-1 (pancreatic cancer cell line with KRAS-G12D mutation (ATCC)), HPAC (KRAS- The following cell lines were used: pancreatic cancer cell line with G12D mutation (ATCC), PANC-1 (pancreatic cancer cell line with KRAS-G12D mutation (ATCC)), LS180 (colorectal cancer cell line with KRAS-G12D mutation (ATCC)), GP2d (colorectal cancer cell line with KRAS-G12D mutation (ECACC)), SW620 (colorectal cancer cell line with KRAS-G12V mutation (ATCC)), and HCT-116 (colorectal cancer cell line with KRAS-G13D mutation (ATCC)).

[0137] (2) Cytotoxicity test of RAS(ON) inhibitors when KRAS inhibitors are added As the RAS(ON) inhibitor, compound number A99 ((1S,2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 Compound H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-phenylcyclopropane-1-carboxamide was used for evaluation. Compound 1 was used for evaluation as a KRAS inhibitor. RMC-6236 was synthesized by the same method as described in Patent Document 14. The structure of the obtained compounds was confirmed by purity by liquid chromatography-mass spectrometry (LCMS), measurement of optical purity by chiral SFC or chiral HPLC, and DMSO-d ６ or CDCl ３ It was used as a solvent. １ This was confirmed by 1H NMR spectral analysis.

[0138] A matrix was created using Echo (Beckman Coulter) to prepare serial dilution series of the RAS(ON) inhibitor and compound 1. Nine serial dilution series were prepared by 3-fold serial dilutions of the RAS(ON) inhibitor and compound 1 dissolved in 100% DMSO. The maximum concentration of the RAS(ON) inhibitor ranged from 0.05 μM to 1 μM depending on the cell line. The maximum concentration of compound 1 ranged from 0.1 μM to 1 μM depending on the cell line. The RAS(ON) inhibitor and compound 1 were added to each well of a Prime Surface® plate 384U white (Sumitomo Bakelite Co., Ltd., product code: MS-9384W) at a concentration 1000 times the final concentration. DMSO was added as a control. Wells with DMSO added and wells with only culture medium added were prepared as background signals.

[0139] Various cultured cells were seeded onto the plates described above and incubated at 37°C. The culture conditions and the number of seeded cells per well are shown in Table 4. After incubation under 3D conditions for 7 days, CellTiter-Glo2.0 Cell Viability Assay (Promega, product code: G9243) was added, and the luminescence intensity was measured using a Multimode Plate Reader EnVision Xcite (PerkinElmer) to monitor the cell count. FBS: Fetal Bovine Serum; EGF: Epidermal Growth Factor; NEAA: Non-Essential Amino Acids

[0140] (3) Data Analysis The cell proliferation inhibition rate was calculated by subtracting the background signal value from the signal value of each seeded cell well, and then standardizing the result by subtracting the background signal value from the signal value of the control well. Evaluation was performed for each condition with N=2. The Loewe additive model was used as a mathematical model analysis to determine whether the two drugs exhibited a synergistic effect, and the Combination Index (CI) and Synergy Score (SS) for a 50 percent cell proliferation inhibition rate were calculated (Chou TC, Talalay P. A simple generalized equation for the analysis of multiple inhibitions of Michaelis-Menten kinetic systems J Biol Chem. 1977Sep 25;252(18):6438-42.; Lehar J, Krueger A, Avery W, et al. Synergistic drug combinations tend to improve therapeutically relevant selectivity. NatBiotechnol 27, 659-666 (2009). https: / / doi.org / 10.1038 / nbt.1549). In addition, isobologram visualization was performed to confirm whether the two drugs exhibited a synergistic effect. The software used for these analyses and visualizations was Genedata Screener® (manufactured by Genedata). A CI value less than 1 can be interpreted as indicating a synergistic effect between the two drugs. Furthermore, a smaller CI value indicates a stronger synergistic effect. A positive SS value can be interpreted as indicating a synergistic effect between the two drugs. Furthermore, a larger SS value indicates a stronger synergistic effect.

[0141] 2. The results of CI and SS between compound 1 and compound A99 or RMC-6236 are shown in Table 5. The isobolograms at 50 percent cell proliferation inhibition are shown in Figures 6 and 7. In each graph, the horizontal axis represents the concentration of compound 1, and the vertical axis represents the concentration of compound A99 or RMC-6236. The solid line represents the IC ratio when compound 1 and compound A99 or RMC-6236 are used in combination. ５０ The combination of values ​​is shown. The dotted line represents the IC of compound 1 and compound A99 or RMC-6236 as a single agent. ５０ A straight line is shown connecting the values. IC of a single agent. ５０ IC is obtained by using a combination of methods rather than drawing a straight line connecting the values. ５０ If the solid line of the value curves downward, it is determined that the compound used in combination has a synergistic effect. The results in Figures 6 and 7 suggest that there is a synergistic effect in inhibiting cell proliferation between compound A99 or RMC-6236 and compound 1. Furthermore, the results in Table 5 suggest that, for both the CI and SS indices, the combination of RAS(ON) inhibitors and compound 1 has a synergistic effect in inhibiting cell proliferation in cancer cell lines with KRAS mutations. < / nu>

Claims

1. A pharmaceutical product for the treatment or prevention of cancer, comprising a first active ingredient and used in combination with a second active ingredient, wherein the first active ingredient is a compound represented by the following formula (1), a salt thereof, or a solvate thereof, and the second active ingredient is an anticancer agent.

2. A pharmaceutical product for the treatment or prevention of cancer, comprising a first active ingredient and used in combination with a second active ingredient, wherein the first active ingredient is an anticancer agent and the second active ingredient is a compound represented by the following formula (1), a salt thereof, or a solvate thereof.

3. The pharmaceutical product according to claim 1 or 2, wherein the first active ingredient and the second active ingredient are used simultaneously or separately.

4. The pharmaceutical product according to any one of claims 1 to 3, wherein the first active ingredient and the second active ingredient are provided as a kit or used in combination as a compound.

5. The pharmaceutical product according to any one of claims 1 to 4, wherein the anticancer agent is at least one selected from the group consisting of chemotherapeutic agents, molecular targeted drugs, and immune checkpoint inhibitors.

6. The pharmaceutical product according to claim 5, wherein the molecularly targeted drug is a RAS(ON) inhibitor, a RAS(OFF) inhibitor, or an EGFR inhibitor.

7. The pharmaceutical product according to claim 6, wherein the EGFR inhibitor is cetuximab, panitumumab, gefitinib or a salt thereof or its solvate, erlotinib or a salt thereof or its solvate, afatinib or a salt thereof or its solvate, osimertinib or a salt thereof or its solvate, or lapatinib or a salt thereof or its solvate.

8. The pharmaceutical product according to claim 6, wherein the RAS(ON) inhibitor is at least one selected from the group consisting of daraxone rasib, erylon rasib, RMC-7977, ERAS-0015, GFH547, ERAS-4001, PF-07934040, PF-07985045, BBO-8520, FMC-376, zoldon rasib, GFH375, RMC-5127, ALTA3263, RAS-F, and AN-9025.

9. The pharmaceutical product according to claim 5, wherein the chemotherapeutic agent is at least one selected from the group consisting of antimetabolites, platinum preparations, topoisomerase inhibitors, and taxane-based anticancer agents.

10. The pharmaceutical product according to claim 9, wherein the antimetabolite is fluorouracil, capecitabine, gemcitabine, methotrexate, pemetrexed, or a salt thereof or a solvate thereof, or a tegafur / gimeracil / oteracil potassium combination.

11. The pharmaceutical product according to claim 9, wherein the platinum preparation is oxaliplatin, cisplatin, carboplatin, nedaplatin, or a salt thereof or a solvate thereof.

12. The pharmaceutical product according to claim 9, wherein the topoisomerase inhibitor is irinotecan, topotecan, etoposide, or doxorubicin, or a salt thereof or a solvate thereof.

13. The pharmaceutical product according to claim 5, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

14. The pharmaceutical product according to any one of claims 1 to 5, wherein the combination with the anticancer agent is incorporated into a FOLFOX therapy or FOLFIRI therapy regimen, or the anticancer agent is at least one selected from the group consisting of cetuximab, pembrolizumab, cisplatin, carboplatin, pemetrexed, gemcitabine, and nab-paclitaxel.

15. The pharmaceutical product according to any one of claims 1 to 14, wherein the cancer is at least one selected from the group consisting of lung cancer, gastrointestinal cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, head and neck cancer, kidney cancer, prostate cancer, and malignant melanoma.

16. The pharmaceutical product according to any one of claims 1 to 15, wherein the cancer is a cancer associated with an abnormality in the KRAS gene.

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