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

Abstract

The problem to be solved by the present invention is to provide a novel combination therapy exhibiting an excellent antitumor effect. The present invention provides an antitumor agent (that does not contain pemblolizumab as an active ingredient) that contains, as an active ingredient, futibatinib or a salt thereof that is administered to a cancer patient in combination with an immune checkpoint inhibitor (excluding CD155 / TIGIT pathway antagonist) and at least one or more other antitumor agents.

Description

Cancer treatment methods including 3,5-disubstituted benzenealkynyl compounds and immune checkpoint inhibitors

[0001] The present invention relates to an antitumor agent, an antitumor effect enhancer, and a kit preparation.

[0002] Fibroblast growth factors (FGFs) are expressed in a wide range of tissues and are one of the growth factors responsible for cell proliferation and differentiation. The physiological activity of FGFs is mediated by specific cell surface receptors, called fibroblast growth factor receptors (FGFRs). FGFRs belong to the receptor-type protein tyrosine kinase family and consist of an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain. Four types of FGFRs have been identified to date (FGFR1, FGFR2, FGFR3, and FGFR4). FGFRs form dimers upon binding with FGF and are activated by phosphorylation. Receptor activation induces the recruitment and activation of specific downstream signaling molecules, resulting in physiological functions. Abnormalities in FGF / FGFR signaling have been reported to be associated with various human tumors. Abnormal activation of FGF / FGFR signaling in human tumors is believed to be caused by autocrine or paracrine mechanisms due to overexpression of FGFR and / or gene amplification, gene mutation, chromosomal translocation, insertion, or inversion, gene fusion, or overproduction of its ligand, FGF (Non-Patent Documents 1, 2, 3, and 4).

[0003] On the other hand, cancer immunotherapy is being developed as a new cancer treatment method.

[0004] Activation of the adaptive immune response begins with the binding of an antigen peptide-MHC complex to a T cell receptor (TCR). This binding is further determined by costimulation or coinhibition due to binding between the costimulatory molecule B7 family and its receptor CD28 family. In other words, two characteristic signaling events are required for T cells to be activated in an antigen-specific manner. T cells that are stimulated only by antigen without costimulation from the B7 family become unresponsive (anergy), and immune tolerance is induced.

[0005] Cancer cells exploit this mechanism to suppress the activation of antigen-specific T cells, thereby evading immune surveillance and continuing to proliferate. Therefore, enhancing costimulation or blocking coinhibition to induce antitumor immune responses in cancer patients and suppress tumor immune escape are thought to be effective cancer treatments. Various cancer immunotherapies targeting costimulatory molecules (stimulatory costimulatory molecules) or coinhibitory molecules (inhibitory costimulatory molecules) have been proposed (Non-Patent Document 5). For example, nivolumab (a human IgG4 monoclonal antibody against human PD-1) is an immune checkpoint inhibitor that activates T cells by inhibiting the binding of PD-1 to its ligands (PD-L1 and PD-L2), and is used in the treatment of malignant melanoma and other diseases (Patent Document 1, Non-Patent Document 6). Furthermore, zimberelimab (AB122) is known as a new immune checkpoint inhibitor and is used to treat Hodgkin's lymphoma and the like (Non-Patent Document 7).

[0006] The 3,5-disubstituted benzenealkynyl compound (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (hereinafter referred to as "futibatinib") or a salt thereof is known as an FGFR inhibitor, and combinations of FGFR inhibitors with other antitumor agents have been reported (Patent Documents 2 and 3). In addition, a clinical trial (jRCT Number: jRCT2011210020) on the combined administration of futibatinib and zimbelelimab in patients with non-small cell lung cancer is being conducted (Non-Patent Document 8).

[0007] International Publication No. 2004 / 004771, International Publication No. 2013 / 108809, International Publication No. 2017 / 150725, International Publication No. 2016 / 161239

[0008] Nat. Rev. Cancer 10:116-129 (2010) J. Clin. Oncol. 24, 3664-3671 (2006) Mol. Cancer Res. 3, 655-667 (2005) Cancer Res. 70, 2085-2094 (2010) Nat. Rev. Cancer, 12:252-264 (2012) N. Engl. J. Med. , 366:2443-2454 (2012) Drugs. 81(17):2063-2068(2021) https: / / jrct. niph. go. jp / latest-detail / jRCT2011210020

[0009] An objective of the present invention is to provide a novel combination therapy that exhibits excellent antitumor effects for cancer patients.

[0010] In view of the current situation, the present inventors have discovered that the above-mentioned problems can be solved by combining futibatinib or a salt thereof with a specific immune checkpoint inhibitor and further combining it with another antitumor agent.

[0011] Therefore, the present invention provides the following items 1 to 51.

[0012] Item 1. The antitumor agent according to Item 1-1 below, the pharmaceutical composition according to Item 1-2, the use according to Item 1-3, the compound or salt thereof for the use according to Item 1-4, the use according to Item 1-5, the commercial package according to Item 1-6, or the method according to Item 1-7: Item 1-1. Any of the following antitumor agents (i) to (iii) (excluding antitumor agents containing pembrolizumab as an active ingredient and antitumor agents used in combination with pembrolizumab): (i) The antitumor agent comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with an immune checkpoint inhibitor and at least one or more other antitumor agents to cancer patients. (ii) The antitumor agent comprising an immune checkpoint inhibitor as an active ingredient, which is used in combination with futibatinib or a pharmaceutically acceptable salt thereof and at least one or more other antitumor agents to cancer patients. (iii) An antitumor agent comprising as an active ingredient at least one or more other antitumor agents, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor to a cancer patient; Items 1-2. A pharmaceutical composition for preventing or treating any of the following cancers (i) to (iii) (excluding pharmaceutical compositions comprising pembrolizumab as an active ingredient and pharmaceutical compositions used to be administered in combination with pembrolizumab): (i) A pharmaceutical composition comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used to be administered in combination with an immune checkpoint inhibitor and at least one or more other antitumor agents to a cancer patient, and further comprising a pharmaceutical carrier. (ii) A pharmaceutical composition comprising as an active ingredient an immune checkpoint inhibitor, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and at least one or more other antitumor agents to a cancer patient, and further comprising a pharmaceutical carrier.(iii) A pharmaceutical composition comprising as an active ingredient at least one or more other antitumor agents, and further comprising a pharmaceutical carrier, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor to a cancer patient; Item 1-3. Any of the following uses (i) to (iii) (excluding, however, use for producing an antitumor agent comprising pembrolizumab as an active ingredient and use for producing an antitumor agent to be administered in combination with pembrolizumab): (i) Use of futibatinib or a pharmaceutically acceptable salt thereof for producing an antitumor agent to be administered in combination with an immune checkpoint inhibitor and at least one or more other antitumor agents to a cancer patient. (ii) Use of an immune checkpoint inhibitor for producing an antitumor agent to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and at least one or more other antitumor agents to a cancer patient. (iii) Use of at least one or more other anti-tumor agents for the manufacture of an anti-tumor agent used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor to cancer patients; Items 1-4. A compound or a salt thereof for use according to any of the following (i) to (iii) (excluding a compound used to be administered in combination with pembrolizumab and pembrolizumab for use). (i) Futibatinib or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of cancer, used to be administered in combination with an immune checkpoint inhibitor and at least one or more other anti-tumor agents to cancer patients. (ii) An immune checkpoint inhibitor for use in the prevention or treatment of cancer, used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and at least one or more other anti-tumor agents to cancer patients. (iii) at least one or more other antitumor agents for use in the prevention or treatment of cancer, which are used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor to cancer patients; Item 1-5. Use of any of the following (i) to (iii) (excluding the use of pembrolizumab and the use of a compound to be administered in combination with pembrolizumab):(i) Use of futibatinib or a pharmaceutically acceptable salt thereof to be administered in combination with an immune checkpoint inhibitor and at least one or more other anti-tumor agents to cancer patients for the prevention or treatment of cancer. (ii) Use of an immune checkpoint inhibitor to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and at least one or more other anti-tumor agents to cancer patients for the prevention or treatment of cancer. (iii) Use of at least one or more other anti-tumor agents to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor to cancer patients for the prevention or treatment of cancer. Items 1-6. Any of the following commercial packages (i) to (iii) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and commercial packages used to be administered in combination with pembrolizumab). (i) A commercial package comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient together with instructions for use thereof to prevent or treat cancer in a subject, the commercial package being used to be administered in combination with an immune checkpoint inhibitor and at least one or more other anti-tumor agents to a cancer patient. (ii) A commercial package comprising an immune checkpoint inhibitor as an active ingredient together with instructions for use thereof to prevent or treat cancer in a subject, the commercial package being used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and at least one or more other anti-tumor agents to a cancer patient.(iii) A commercial package comprising an antitumor agent (other antitumor agent) other than "futibatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor" as an active ingredient, together with instructions for its use to prevent or treat cancer in a subject, said commercial package being used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor to a cancer patient; Items 1-7. A method according to any of the following (i) to (iii) (excluding methods comprising administering pembrolizumab and methods comprising administering an antitumor agent to a subject who has been administered, is being administered simultaneously with, or will be administered with pembrolizumab). (i) A method for preventing or treating cancer, comprising administering an effective amount of futibatinib or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has been administered, is being administered simultaneously with, or will be administered with, an immune checkpoint inhibitor, and the subject has been administered, is being administered simultaneously with, or will be administered with, at least one or more other anti-tumor agents. (ii) A method for preventing or treating cancer, comprising administering an effective amount of an immune checkpoint inhibitor to a subject in need thereof, wherein the subject has been administered, is being administered simultaneously with, or will be administered with, futibatinib or a pharmaceutically acceptable salt thereof, and the subject has been administered, is being administered simultaneously with, or will be administered with, at least one or more other anti-tumor agents. (ii) A method for preventing or treating cancer, comprising administering to a subject in need thereof an effective amount of at least one or more antitumor agents (other antitumor agents) other than "futibatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor", wherein the subject has been administered, is or will be administered simultaneously with futibatinib or a pharmaceutically acceptable salt thereof, and the subject has been administered, is or will be administered simultaneously with an immune checkpoint inhibitor.

[0013] Item 2. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 1, wherein the immune checkpoint inhibitor is at least one selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-PD-L2 antibody.

[0014] Item 3. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 1 or 2, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0015] Item 4. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 2 or 3, wherein the anti-PD-1 antibody is at least one selected from the group consisting of nivolumab, cemiplimab, spartalizumab, tislelizumab, BI754091, dostarizumab, sasanlimab, MGA-012, cetrelimab, AGEN-2034, zimverelimab, camrelizumab, budigalimab, and balstilimab.

[0016] Item 5. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 4, wherein the anti-PD-1 antibody is dimverelimab.

[0017] Item 6. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to any one of Items 1 to 5, wherein the other antitumor agent is a chemotherapeutic agent.

[0018] Item 7. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 6, wherein the chemotherapeutic agent is at least one selected from the group consisting of antimetabolites, alkaloid antitumor agents, platinum preparations, immune checkpoint inhibitors, molecularly targeted drugs, antitumor antibiotics, and alkylating agents.

[0019] Item 8. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 6, wherein the chemotherapeutic agent is at least one selected from the group consisting of antimetabolites, alkaloid antitumor agents, platinum preparations, and immune checkpoint inhibitors.

[0020] Item 9. The chemotherapeutic agent is fludarabine, cladribine, nelarabine, 5-fluorouracil, tegafur / gimeracil / oteracil potassium, tegafur / uracil, trifluridine / tipiracil hydrochloride, capecitabine, doxifluridine, 5-fluoro-2'-deoxyuridine, gemcitabine, cytarabine, pemetrexed, methotrexate, paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel, or eribulin. Item 7. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 6, wherein the compound is at least one selected from the group consisting of irinotecan, nogitecan (topotecan), etoposide, teniposide, vinorelbine, vincristine, vinblastine, cisplatin, carboplatin, oxaliplatin, nedaplatin, domvanalimab, AB308, vibostolimab, osipellimab, and tiragolumab.

[0021] Item 10. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 6, wherein the chemotherapeutic agent is at least one selected from the group consisting of 5-fluorouracil, gemcitabine, albumin-bound paclitaxel, irinotecan, cisplatin, carboplatin, domvanalimab, and AB308.

[0022] Item 11. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 6, wherein the chemotherapeutic agent is at least one selected from the group consisting of 5-fluorouracil, gemcitabine, albumin-suspended paclitaxel, cisplatin, carboplatin, and domvanalimab.

[0023] Item 12. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to any one of Items 1 to 11, wherein the cancer is at least one type selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, duodenal cancer, liver cancer, hepatocellular carcinoma, biliary tract cancer, pancreatic cancer, colon cancer, breast cancer, uterine cancer, ovarian cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumor, thyroid cancer, bone and soft tissue tumor, leukemia, malignant lymphoma, multiple myeloma, head and neck cancer, brain tumor, mesothelioma, skin cancer, and cancer of unknown primary origin.

[0024] Item 13. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to any one of Items 1 to 11, wherein the cancer is at least one type selected from the group consisting of pancreatic cancer, lung cancer, esophageal cancer, biliary tract cancer, and head and neck cancer.

[0025] Item 14. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to any one of Items 1 to 13, wherein the cancer patient is a cancer patient who has no history of prior treatment for advanced cancer or has a history of prior treatment with one line of chemotherapy.

[0026] Item 15. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to any one of Items 1 to 14, wherein a 21-day administration cycle is repeated once or twice or more times.

[0027] Item 16. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 15, wherein futibatinib is administered once daily on each day of a 21-day administration cycle.

[0028] Item 17. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 15, wherein dimverelimab is administered once on Day 1 of a 21-day administration cycle.

[0029] Item 18. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 15, wherein the other antitumor agent is administered for 1 to 5 days during a 21-day administration cycle.

[0030] Item 19. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 15, wherein the other antitumor agent is administered once on Day 1 of a 21-day administration cycle.

[0031] Item 20. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 15, wherein the other antitumor agent is administered once on Day 1 and once on Day 8 of a 21-day administration cycle.

[0032] Item 21. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 15, wherein the other antitumor agent is administered once on Day 1, once on Day 8, and once on Day 15 of a 21-day administration cycle.

[0033] Item 22. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 15, wherein the other antitumor agent is administered once each on Day 1, 2, 3, and 4 of a 21-day administration cycle.

[0034] Item 23. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 15, wherein the other antitumor agent is administered once each on Day 1, 2, 3, 4, and 5 of a 21-day administration cycle.

[0035] Item 24. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 16, wherein the dose of futibatinib is 8 mg / dose to 24 mg / dose.

[0036] Item 25. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 16, wherein the dosage of futibatinib is 12 mg / dose, 16 mg / dose, or 20 mg / dose.

[0037] Item 26. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 16, wherein the dose of futibatinib is 20 mg / dose.

[0038] Item 27. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 17, wherein the dose of dimverelimab is 360 mg / dose.

[0039] Item 28. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to any one of Items 1 to 27, which is the antitumor agent according to Item 28-1 below, the pharmaceutical composition according to Item 28-2, the use according to Item 28-3, the compound or salt thereof for the use according to Item 28-4, the use according to Item 28-5, the commercial package according to Item 28-6, or the method according to Item 28-7: Item 28-1. Any of the following antitumor agents (i) to (iv): (i) The antitumor agent comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with jimverelimab, cisplatin, and 5-fluorouracil to patients with esophageal cancer. (ii) The antitumor agent comprising jimverelimab as an active ingredient, which is used in combination with jimverelimab or a pharmaceutically acceptable salt thereof, cisplatin, and 5-fluorouracil to patients with esophageal cancer. (iii) The antitumor agent comprising cisplatin as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimblerimab, and 5-fluorouracil to patients with esophageal cancer. (iv) The antitumor agent comprising 5-fluorouracil as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimblerimab, and cisplatin to patients with esophageal cancer.

[0040] Item 28-2. Any of the following pharmaceutical compositions (i) to (iv) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and pharmaceutical compositions used for combination administration with pembrolizumab): (i) A pharmaceutical composition containing futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient and further comprising a pharmaceutical carrier, which is used for combination administration with jimverelimab, cisplatin, and 5-fluorouracil to patients with esophageal cancer. (ii) A pharmaceutical composition containing jimverelimab as an active ingredient and further comprising a pharmaceutical carrier, which is used for combination administration with futibatinib or a pharmaceutically acceptable salt thereof, cisplatin, and 5-fluorouracil to patients with esophageal cancer. (iii) A pharmaceutical composition containing cisplatin as an active ingredient and further comprising a pharmaceutical carrier, which is used for combination administration with futibatinib or a pharmaceutically acceptable salt thereof, jimverelimab, and 5-fluorouracil to patients with esophageal cancer. (iv) A pharmaceutical composition comprising 5-fluorouracil as an active ingredient and a pharmaceutical carrier, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, dimverelimab, and cisplatin to a patient with esophageal cancer.

[0041] Item 28-3. Use of any of the following (i) to (iv) (excluding use for producing an antitumor agent containing pembrolizumab as an active ingredient and use for producing an antitumor agent to be administered in combination with pembrolizumab): (i) Use of futibatinib or a pharmaceutically acceptable salt thereof for producing an antitumor agent to be administered in combination with zimverelimab, cisplatin, and 5-fluorouracil to patients with esophageal cancer. (ii) Use of zimverelimab for producing an antitumor agent to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, cisplatin, and 5-fluorouracil to patients with esophageal cancer. (iii) Use of cisplatin for producing an antitumor agent to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimverelimab, and 5-fluorouracil to patients with esophageal cancer. (iv) Use of 5-fluorouracil for the manufacture of an antitumor agent to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimverelimab, and cisplatin to patients with esophageal cancer.

[0042] Item 28-4. A compound or salt thereof for use according to any of (i) to (iv) below (excluding a compound used in combination with pembrolizumab and pembrolizumab for use): (i) futibatinib or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of esophageal cancer, to be administered in combination with zimverelimab, cisplatin, and 5-fluorouracil to patients with esophageal cancer. (ii) zimverelimab for use in the prevention or treatment of esophageal cancer, to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, cisplatin, and 5-fluorouracil to patients with esophageal cancer. (iii) cisplatin for use in the prevention or treatment of esophageal cancer, to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimverelimab, and 5-fluorouracil to patients with esophageal cancer. (iv) 5-fluorouracil for use in the prevention or treatment of esophageal cancer, wherein the 5-fluorouracil is administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, dimverelimab, and cisplatin to patients with esophageal cancer.

[0043] Item 28-5. Use of any of the following (i) to (iv) (excluding the use of pembrolizumab and the use of a compound used in combination with pembrolizumab): (i) Use of futibatinib or a pharmaceutically acceptable salt thereof, to be administered in combination with zimverelimab, cisplatin, and 5-fluorouracil to patients with esophageal cancer, for the prevention or treatment of esophageal cancer. (ii) Use of zimverelimab, to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, cisplatin, and 5-fluorouracil to patients with esophageal cancer, for the prevention or treatment of esophageal cancer. (iii) Use of cisplatin, to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimverelimab, and 5-fluorouracil to patients with esophageal cancer, for the prevention or treatment of esophageal cancer. (iv) Use of 5-fluorouracil for preventing or treating esophageal cancer, wherein the 5-fluorouracil is administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, dimverelimab, and cisplatin to patients with esophageal cancer.

[0044] Item 28-6. Any of the commercial packages (i) to (iv) below (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and commercial packages used for administration in combination with pembrolizumab): (i) A commercial package containing futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient together with instructions for use thereof for preventing or treating esophageal cancer in a subject, the commercial package being used for administration in combination with zimverelimab, cisplatin, and 5-fluorouracil to patients with esophageal cancer. (ii) A commercial package containing futibatinib as an active ingredient together with instructions for use thereof for preventing or treating esophageal cancer in a subject, the commercial package being used for administration in combination with zimverelimab or a pharmaceutically acceptable salt thereof, cisplatin, and 5-fluorouracil to patients with esophageal cancer. (iii) A commercial package comprising cisplatin as an active ingredient together with instructions for use thereof to prevent or treat esophageal cancer in a subject, wherein the commercial package is used to administer in combination with fuchibatinib or a pharmaceutically acceptable salt thereof, zimblerimab, and 5-fluorouracil to a patient with esophageal cancer. (iv) A commercial package comprising 5-fluorouracil as an active ingredient together with instructions for use thereof to prevent or treat esophageal cancer in a subject, wherein the commercial package is used to administer in combination with fuchibatinib or a pharmaceutically acceptable salt thereof, zimblerimab, and cisplatin to a patient with esophageal cancer.

[0045] Item 28-7. A method according to any of the following (i) to (iv) (excluding methods comprising administering pembrolizumab and methods comprising administering an antitumor agent to a subject who has been administered, is being administered simultaneously with, or is to be administered with pembrolizumab): (i) A method for preventing or treating esophageal cancer, comprising administering an effective amount of futibatinib or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has been administered, is being administered simultaneously with, or is to be administered with gimvelelimab, has been administered, is being administered simultaneously with, or is to be administered with cisplatin, and has been administered, is being administered simultaneously with, or is to be administered with 5-fluorouracil. (ii) A method for preventing or treating esophageal cancer, comprising administering an effective amount of gimverelimab to a subject in need thereof, wherein the subject has been administered, is being administered simultaneously with, or will be administered with futibatinib or a pharmaceutically acceptable salt thereof, has been administered, is being administered simultaneously with, or will be administered with cisplatin, and has been administered, is being administered simultaneously with, or will be administered with 5-fluorouracil. (iii) A method for preventing or treating esophageal cancer, comprising administering an effective amount of cisplatin to a subject in need thereof, wherein the subject has been administered, is being administered simultaneously with, or will be administered with futibatinib or a pharmaceutically acceptable salt thereof, has been administered, is being administered simultaneously with, or will be administered with gimverelimab, and has been administered, is being administered simultaneously with, or will be administered with 5-fluorouracil. (iv) A method for preventing or treating esophageal cancer, comprising administering an effective amount of 5-fluorouracil to a subject in need thereof, wherein the subject has been administered, is being administered concomitantly with, or will be administered with futibatinib or a pharmaceutically acceptable salt thereof, has been administered, is being administered concomitantly with, or will be administered with zimverelimab, and has been administered, is being administered concomitantly with, or will be administered with cisplatin.

[0046] Item 29. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 28, characterized in that a 21-day administration cycle comprising daily administration of 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib, a single administration of 360 mg / dose of dimverelimab, a single administration of 80 mg / m2 / dose of cisplatin, and 5-fluorouracil at 800 mg / m2 / day for 5 consecutive days is repeated once or twice or more times.

[0047] Item 30. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 28, characterized in that a 21-day administration cycle comprising administering 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib once daily, administering 360 mg / dose of dimverelimab once on Day 1, administering 80 mg / m2 / dose of cisplatin once on Day 1, and administering 800 mg / m2 / day of 5-fluorouracil daily on Days 1 to 5 is repeated once or twice or more times.

[0048] Item 31. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to any one of Items 28 to 30, wherein the cancer patient is an esophageal cancer patient with no history of prior treatment for advanced cancer.

[0049] Item 32. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to any one of Items 1 to 27, which is the antitumor agent according to Item 32-1 below, the pharmaceutical composition according to Item 32-2, the use according to Item 32-3, the compound or salt thereof for the use according to Item 32-4, the use according to Item 32-5, the commercial package according to Item 32-6, or the method according to Item 32-7: Item 32-1. Any of the following antitumor agents (i) to (iii) (excluding antitumor agents containing pembrolizumab as an active ingredient and antitumor agents used in combination with pembrolizumab): (i) The antitumor agent comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with zimblerimab and domvanalimab to treat esophageal cancer patients. (ii) The antitumor agent comprising zimbelelimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and domvanalimab to patients with esophageal cancer. (iii) The antitumor agent comprising domvanalimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and zimbelelimab to patients with esophageal cancer.

[0050] Item 32-2. A pharmaceutical composition for preventing or treating esophageal cancer, any of the following (i) to (iii) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and pharmaceutical compositions used for combination administration with pembrolizumab): (i) A pharmaceutical composition containing futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient and further comprising a pharmaceutical carrier, used for combination administration with zimverelimab and domvanalimab to patients with esophageal cancer. (ii) A pharmaceutical composition containing zimverelimab as an active ingredient and further comprising a pharmaceutical carrier, used for combination administration with futibatinib or a pharmaceutically acceptable salt thereof and domvanalimab to patients with esophageal cancer. (iii) A pharmaceutical composition containing domvanalimab as an active ingredient and further comprising a pharmaceutical carrier, used for combination administration with futibatinib or a pharmaceutically acceptable salt thereof and zimverelimab to patients with esophageal cancer.

[0051] Item 32-3. Use of any of the following (i) to (iii) (excluding use for producing an antitumor agent containing pembrolizumab as an active ingredient and use for producing an antitumor agent to be administered in combination with pembrolizumab): (i) Use of futibatinib or a pharmaceutically acceptable salt thereof for producing an antitumor agent to be administered in combination with zimverelimab and domvanalimab to patients with esophageal cancer. (ii) Use of zimverelimab for producing an antitumor agent to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, and domvanalimab to patients with esophageal cancer. (iii) Use of domvanalimab for producing an antitumor agent to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, and zimverelimab to patients with esophageal cancer.

[0052] Item 32-4. A compound or salt thereof for use according to any of the following (i) to (iii) (excluding a compound used in combination with pembrolizumab and pembrolizumab for use): (i) futibatinib or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of esophageal cancer, to be administered in combination with zimverelimab and domvanalimab to patients with esophageal cancer. (ii) zimverelimab for use in the prevention or treatment of esophageal cancer, to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and domvanalimab to patients with esophageal cancer. (iii) domvanalimab for use in the prevention or treatment of esophageal cancer, to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and zimverelimab to patients with esophageal cancer.

[0053] Item 32-5. Use of any of the following (i) to (iii) (excluding the use of pembrolizumab and the use of a compound used in combination with pembrolizumab): (i) Use of futibatinib or a pharmaceutically acceptable salt thereof, used in combination with zimverelimab and domvanalimab, to prevent or treat esophageal cancer in patients with esophageal cancer. (ii) Use of zimverelimab, used in combination with futibatinib or a pharmaceutically acceptable salt thereof, and domvanalimab, to prevent or treat esophageal cancer in patients with esophageal cancer. (iii) Use of domvanalimab, used in combination with futibatinib or a pharmaceutically acceptable salt thereof, and zimverelimab, to prevent or treat esophageal cancer in patients with esophageal cancer.

[0054] Item 32-6. Any of the following commercial packages (i) to (iii) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and commercial packages used for administration in combination with pembrolizumab): (i) A commercial package containing futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient together with instructions for use thereof for preventing or treating esophageal cancer in a subject, the commercial package being used for administration in combination with zimverelimab and domvanalimab to patients with esophageal cancer. (ii) A commercial package containing zimbelelimab as an active ingredient together with instructions for use thereof for preventing or treating esophageal cancer in a subject, the commercial package being used for administration in combination with futibatinib or a pharmaceutically acceptable salt thereof and domvanalimab to patients with esophageal cancer. (iii) A commercial package comprising domvanalimab as an active ingredient together with instructions for its use to prevent or treat esophageal cancer in a subject, the commercial package being used to administer in combination with futibatinib or a pharmaceutically acceptable salt thereof and zimbelelimab to a patient with esophageal cancer.

[0055] Item 32-7. A method according to any of the following (i) to (iii) (excluding methods comprising administering pembrolizumab and methods comprising administering an antitumor agent to a subject who has been administered, is being administered simultaneously with, or is to be administered with pembrolizumab): (i) A method for preventing or treating esophageal cancer, comprising administering an effective amount of futibatinib or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has been administered, is administered simultaneously with, or will be administered with zimverelimab, and has been administered, is administered simultaneously with, or will be administered with domvanalimab. (ii) A method for preventing or treating esophageal cancer, comprising administering an effective amount of zimverelimab to a subject in need thereof, wherein the subject has been administered, is administered simultaneously with, or will be administered with zimverelimab or a pharmaceutically acceptable salt thereof, and has been administered, is administered simultaneously with, or will be administered with domvanalimab. (iii) A method for preventing or treating esophageal cancer, comprising administering an effective amount of domvanalimab to a subject in need thereof, wherein the subject has been administered, is being administered concomitantly with, or will be administered futibatinib or a pharmaceutically acceptable salt thereof, and has been administered, is being administered concomitantly with, or will be administered zimverelimab.

[0056] Item 33. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 32, characterized in that a 21-day administration cycle of 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib is administered once daily, 360 mg / dose of dimverelimab is administered once, and 1200 mg / dose of domvanalimab is administered once, is repeated once or twice or more times.

[0057] Item 34. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 32, characterized in that a 21-day administration cycle in which 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib is administered once daily, 360 mg / dimverelimab is administered once on Day 1, and 1200 mg / dose of domvanalimab is administered once on Day 1 is repeated once or twice or more times.

[0058] Item 35. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to any one of Items 32 to 34, wherein the cancer patient is an esophageal cancer patient who has no history of prior treatment for advanced cancer or has a history of prior treatment with one line of chemotherapy.

[0059] Item 36. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to any one of Items 1 to 27, which is the antitumor agent according to Item 36-1 below, the pharmaceutical composition according to Item 36-2, the use according to Item 36-3, the compound or salt thereof for the use according to Item 36-4, the use according to Item 36-5, the commercial package according to Item 36-6, or the method according to Item 36-7: Item 36-1. Any of the following antitumor agents (i) to (iv) (excluding antitumor agents containing pembrolizumab as an active ingredient and antitumor agents used in combination with pembrolizumab): (i) The antitumor agent comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with dimvelelimab, 5-fluorouracil, and carboplatin or cisplatin to be administered to patients with head and neck cancer. (ii) The antitumor agent comprising jimverelimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil, and carboplatin or cisplatin to patients with head and neck cancer. (iii) The antitumor agent comprising 5-fluorouracil as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, jimverelimab, and carboplatin or cisplatin to patients with head and neck cancer. (iv) The antitumor agent comprising carboplatin or cisplatin as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, jimverelimab, and 5-fluorouracil to patients with head and neck cancer.

[0060] Item 36-2. A pharmaceutical composition for preventing or treating head and neck cancer, selected from any of (i) to (iv) below (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and pharmaceutical compositions used to be administered in combination with pembrolizumab): (i) A pharmaceutical composition containing futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient and further comprising a pharmaceutical carrier, which is used to be administered in combination with futibatinib, 5-fluorouracil, and carboplatin or cisplatin to patients with head and neck cancer. (ii) A pharmaceutical composition containing futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient and further comprising a pharmaceutical carrier, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil, and carboplatin or cisplatin to patients with head and neck cancer. (iii) A pharmaceutical composition comprising 5-fluorouracil as an active ingredient and a pharmaceutical carrier, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimblerimab, and carboplatin or cisplatin to patients with head and neck cancer. (iv) A pharmaceutical composition comprising carboplatin or cisplatin as an active ingredient and a pharmaceutical carrier, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimblerimab, and 5-fluorouracil to patients with head and neck cancer.

[0061] Item 36-3. Use of any of the following (i) to (iv) (excluding use for producing an antitumor agent containing pembrolizumab as an active ingredient and use for producing an antitumor agent to be administered in combination with pembrolizumab): (i) Use of futibatinib or a pharmaceutically acceptable salt thereof for producing an antitumor agent to be administered in combination with zimverelimab, 5-fluorouracil, and carboplatin or cisplatin to patients with head and neck cancer. (ii) Use of zimverelimab for producing an antitumor agent to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil, and carboplatin or cisplatin to patients with head and neck cancer. (iii) Use of 5-fluorouracil for producing an antitumor agent to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimverelimab, and carboplatin or cisplatin to patients with head and neck cancer. (iv) Use of carboplatin or cisplatin for producing an antitumor agent to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, dimverelimab, and 5-fluorouracil to patients with head and neck cancer.

[0062] Item 36-4. A compound or salt thereof for use according to any of the following (i) to (iv) (excluding a compound used in combination with pembrolizumab and pembrolizumab for use): (i) futibatinib or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of head and neck cancer, to be administered in combination with gimverelimab, 5-fluorouracil, and carboplatin or cisplatin to patients with head and neck cancer. (ii) gimverelimab for use in the prevention or treatment of head and neck cancer, to be administered in combination with gimverelimab or a pharmaceutically acceptable salt thereof, 5-fluorouracil, and carboplatin or cisplatin to patients with head and neck cancer. (iii) 5-fluorouracil for use in the prevention or treatment of head and neck cancer, to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimblerimab, and carboplatin or cisplatin to patients with head and neck cancer. (iv) Carboplatin or cisplatin for use in the prevention or treatment of head and neck cancer, to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimblerimab, and 5-fluorouracil to patients with head and neck cancer.

[0063] Item 36-5. Use of any of the following (i) to (iv) (excluding the use of pembrolizumab and the use of a compound used in combination with pembrolizumab): (i) Use of futivatinib or a pharmaceutically acceptable salt thereof, used in combination with zimverelimab, 5-fluorouracil, and carboplatin or cisplatin to prevent or treat head and neck cancer in patients with head and neck cancer. (ii) Use of zimverelimab, used in combination with futivatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil, and carboplatin or cisplatin to prevent or treat head and neck cancer in patients with head and neck cancer. (iii) Use of 5-fluorouracil, used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimverelimab, and carboplatin or cisplatin to prevent or treat head and neck cancer in patients with head and neck cancer. (iv) Use of carboplatin or cisplatin to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, dimverelimab, and 5-fluorouracil to patients with head and neck cancer for preventing or treating head and neck cancer.

[0064] Item 36-6. Any of the commercial packages (i) to (iv) below (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and commercial packages used for administration in combination with pembrolizumab): (i) A commercial package containing futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient together with instructions for use thereof for preventing or treating head and neck cancer in a subject, the commercial package being used for administration in combination with dimverelimab, 5-fluorouracil, and carboplatin or cisplatin to head and neck cancer patients. (ii) A commercial package containing dimverelimab as an active ingredient together with instructions for use thereof for preventing or treating head and neck cancer in a subject, the commercial package being used for administration in combination with dimverelimab or a pharmaceutically acceptable salt thereof, 5-fluorouracil, and carboplatin or cisplatin to head and neck cancer patients. (iii) A commercial package comprising 5-fluorouracil as an active ingredient together with instructions for use thereof to prevent or treat head and neck cancer in a subject, the commercial package being used to administer in combination with fuchibatinib or a pharmaceutically acceptable salt thereof, zimblerimab, and carboplatin or cisplatin to a patient with head and neck cancer. (iv) A commercial package comprising carboplatin or cisplatin as an active ingredient together with instructions for use thereof to prevent or treat head and neck cancer in a subject, the commercial package being used to administer in combination with fuchibatinib or a pharmaceutically acceptable salt thereof, zimblerimab, and 5-fluorouracil to a patient with head and neck cancer.

[0065] Item 36-7. A method according to any of the following (i) to (iv) (excluding methods comprising administering pembrolizumab and methods comprising administering an antitumor agent to a subject who has been administered, is being administered simultaneously with, or is to be administered with pembrolizumab): (i) A method for preventing or treating head and neck cancer, comprising administering an effective amount of futibatinib or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has been administered, is being administered simultaneously with, or is to be administered with gimverelimab, has been administered, is being administered simultaneously with, or is to be administered with 5-fluorouracil, and has been administered, is being administered simultaneously with, or is to be administered with carboplatin or cisplatin. (ii) A method for preventing or treating head and neck cancer, comprising administering an effective amount of gimverelimab to a subject in need thereof, wherein the subject has been administered, is being administered simultaneously with, or will be administered with futibatinib or a pharmaceutically acceptable salt thereof, has been administered, is being administered simultaneously with, or will be administered with 5-fluorouracil, and has been administered, is being administered simultaneously with, or will be administered with carboplatin or cisplatin. (iii) A method for preventing or treating head and neck cancer, comprising administering an effective amount of 5-fluorouracil to a subject in need thereof, wherein the subject has been administered, is being administered simultaneously with, or will be administered with futibatinib or a pharmaceutically acceptable salt thereof, has been administered, is being administered simultaneously with, or will be administered with gimverelimab, and has been administered, is being administered simultaneously with, or will be administered with carboplatin or cisplatin. (iv) A method for preventing or treating head and neck cancer, comprising administering an effective amount of carboplatin or cisplatin to a subject in need thereof, wherein the subject has been administered, is being administered concomitantly with, or will be administered with futibatinib or a pharmaceutically acceptable salt thereof, has been administered, is being administered concomitantly with, or will be administered with dimverelimab, and has been administered, is being administered concomitantly with, or will be administered with 5-fluorouracil.

[0066] Item 37. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 36, characterized in that a 21-day administration cycle comprising daily administration of 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib, a single administration of 360 mg / dose of dimverelimab, a single administration of carboplatin with an AUC of 5 or 100 mg / m2 / dose of cisplatin, and 4 consecutive days of daily administration of 1000 mg / m2 / day of 5-fluorouracil is repeated once or twice or more times.

[0067] Item 38. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 36, characterized in that a 21-day administration cycle comprising administering 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib once daily, administering 360 mg / dose of dimverelimab once on Day 1, administering carboplatin at an AUC of 5 or 100 mg / m2 / dose of cisplatin once on Day 1, and administering 1000 mg / m2 / day of 5-fluorouracil daily on Days 1 to 4 is repeated once or twice or more times.

[0068] Item 39. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to any one of Items 37 to 38, wherein the cancer patient is a head and neck cancer patient with no history of prior treatment for advanced cancer.

[0069] Item 40. The antitumor agent, pharmaceutical composition, use, compound for use or a salt thereof, commercial package, or method according to any one of Items 1 to 27, which is the antitumor agent according to Item 40-1 below, the pharmaceutical composition according to Item 40-2, the use according to Item 40-3, the compound or a salt thereof for the use according to Item 40-4, the use according to Item 40-5, the commercial package according to Item 40-6, or the method according to Item 40-7: Item 40-1. Any of the following antitumor agents (i) to (iii) (excluding antitumor agents containing pembrolizumab as an active ingredient and antitumor agents used in combination with pembrolizumab): (i) The antitumor agent comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with zimblerimab and domvanalimab to treat head and neck cancer patients. (ii) The antitumor agent comprising zimbelelimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and domvanalimab to patients with head and neck cancer. (iii) The antitumor agent comprising domvanalimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and zimbelelimab to patients with head and neck cancer.

[0070] Item 40-2. A pharmaceutical composition for preventing or treating head and neck cancer, which is any of the following (i) to (iii) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and pharmaceutical compositions used to be administered in combination with pembrolizumab): (i) A pharmaceutical composition containing futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient and further comprising a pharmaceutical carrier, which is used to be administered in combination with zimverelimab and domvanalimab to patients with head and neck cancer. (ii) A pharmaceutical composition containing zimbelelimab as an active ingredient and further comprising a pharmaceutical carrier, which is used to be administered in combination with zimverelimab or a pharmaceutically acceptable salt thereof and domvanalimab to patients with head and neck cancer. (iii) A pharmaceutical composition comprising domvanalimab as an active ingredient and a pharmaceutical carrier, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and zimverelimab to a patient with head and neck cancer.

[0071] Item 40-3. Use of any of the following (i) to (iii) (excluding use for producing an antitumor agent containing pembrolizumab as an active ingredient and use for producing an antitumor agent to be administered in combination with pembrolizumab): (i) Use of futibatinib or a pharmaceutically acceptable salt thereof for producing an antitumor agent to be administered in combination with zimverelimab and domvanalimab to patients with head and neck cancer. (ii) Use of zimverelimab for producing an antitumor agent to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, and domvanalimab to patients with head and neck cancer. (iii) Use of domvanalimab for producing an antitumor agent to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, and zimverelimab to patients with head and neck cancer.

[0072] Item 40-4. A compound or salt thereof for use according to any of the following (i) to (iii) (excluding a compound used in combination with pembrolizumab and pembrolizumab for use): (i) futibatinib or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of head and neck cancer, to be administered in combination with zimverelimab and domvanalimab to patients with head and neck cancer. (ii) zimverelimab for use in the prevention or treatment of head and neck cancer, to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and domvanalimab to patients with head and neck cancer. (iii) domvanalimab for use in the prevention or treatment of head and neck cancer, to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and zimverelimab to patients with head and neck cancer.

[0073] Item 40-5. Use of any of the following (i) to (iii) (excluding the use of pembrolizumab and the use of a compound used in combination with pembrolizumab): (i) Use of futibatinib or a pharmaceutically acceptable salt thereof, used in combination with zimverelimab and domvanalimab, to prevent or treat head and neck cancer in patients with head and neck cancer. (ii) Use of zimverelimab, used in combination with futibatinib or a pharmaceutically acceptable salt thereof, and domvanalimab, to prevent or treat head and neck cancer in patients with head and neck cancer. (iii) Use of domvanalimab, used in combination with futibatinib or a pharmaceutically acceptable salt thereof, and zimverelimab, to prevent or treat head and neck cancer in patients with head and neck cancer.

[0074] Item 40-6. Any of the commercial packages (i) to (iii) below (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and commercial packages used for combination administration with pembrolizumab): (i) A commercial package containing futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient together with instructions for use thereof for preventing or treating head and neck cancer in a subject, the commercial package being used for combination administration with zimverelimab and domvanalimab to head and neck cancer patients. (ii) A commercial package containing zimbelelimab as an active ingredient together with instructions for use thereof for preventing or treating head and neck cancer in a subject, the commercial package being used for combination administration with futibatinib or a pharmaceutically acceptable salt thereof and domvanalimab to head and neck cancer patients. (iii) A commercial package comprising domvanalimab as an active ingredient together with instructions for its use to prevent or treat head and neck cancer in a subject, the commercial package being used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and zimbelelimab to a patient with head and neck cancer.

[0075] Item 40-7. A method according to any of the following (i) to (iii) (excluding methods comprising administering pembrolizumab and methods comprising administering an antitumor agent to a subject who has been administered, is being administered simultaneously with, or is to be administered with pembrolizumab): (i) A method for preventing or treating head and neck cancer, comprising administering an effective amount of futibatinib or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has been administered, is being administered simultaneously with, or is to be administered with zimverelimab, and the subject has been administered, is being administered simultaneously with, or is to be administered with domvanalimab. (ii) A method for preventing or treating head and neck cancer, comprising administering an effective amount of gimverelimab to a subject in need thereof, wherein the subject has been administered, is being administered simultaneously with, or will be administered with futibatinib or a pharmaceutically acceptable salt thereof, and the subject has been administered, is being administered simultaneously with, or will be administered with domvanalimab. (iii) A method for preventing or treating head and neck cancer, comprising administering an effective amount of domvanalimab to a subject in need thereof, wherein the subject has been administered, is being administered simultaneously with, or will be administered with futibatinib or a pharmaceutically acceptable salt thereof, and the subject has been administered, is being administered simultaneously with, or will be administered with domvanalimab.

[0076] Item 41. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 40, characterized in that a 21-day administration cycle of 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib is administered once daily, 360 mg / dose of dimverelimab is administered once, and 1200 mg / dose of domvanalimab is administered once, is repeated once or twice or more times.

[0077] Item 42. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 40, characterized in that a 21-day administration cycle in which 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib is administered once daily, 360 mg / dimverelimab is administered once on Day 1, and 1200 mg / dose of domvanalimab is administered once on Day 1 is repeated once or twice or more times.

[0078] Item 43. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to any one of Items 40 to 42, wherein the cancer patient is a head and neck cancer patient with no history of prior treatment for advanced cancer.

[0079] Item 44. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to any one of Items 1 to 27, which is the antitumor agent according to Item 44-1 below, the pharmaceutical composition according to Item 44-2, the use according to Item 44-3, the compound or salt thereof for the use according to Item 44-4, the use according to Item 44-5, the commercial package according to Item 44-6, or the method according to Item 44-7: Item 44-1. Any of the following antitumor agents (i) to (iv) (excluding antitumor agents containing pembrolizumab as an active ingredient and antitumor agents used in combination with pembrolizumab): (i) The antitumor agent comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with dimvelelimab, albumin-bound paclitaxel, and carboplatin to patients with non-small cell lung cancer. (ii) The antitumor agent comprising zimverelimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, albumin-suspended paclitaxel, and carboplatin to patients with non-small cell lung cancer. (iii) The antitumor agent comprising zimverelimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimverelimab, and carboplatin to patients with non-small cell lung cancer. (iv) The antitumor agent comprising carboplatin as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimverelimab, and albumin-suspended paclitaxel to patients with non-small cell lung cancer.

[0080] Item 44-2. A pharmaceutical composition for preventing or treating non-small cell lung cancer, selected from any of (i) to (iv) below (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and pharmaceutical compositions used to be administered in combination with pembrolizumab): (i) A pharmaceutical composition containing futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient and further comprising a pharmaceutical carrier, which is used to be administered in combination with futibatinib, albumin-bound paclitaxel, and carboplatin to patients with non-small cell lung cancer. (ii) A pharmaceutical composition containing futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient and further comprising a pharmaceutical carrier, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and carboplatin to patients with non-small cell lung cancer. (iii) A pharmaceutical composition comprising albumin-suspended paclitaxel as an active ingredient and a pharmaceutical carrier, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimbelelimab, and carboplatin to patients with non-small cell lung cancer. (iv) A pharmaceutical composition comprising carboplatin as an active ingredient and a pharmaceutical carrier, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimbelelimab, and albumin-suspended paclitaxel to patients with non-small cell lung cancer.

[0081] Item 44-3. Use of any of the following (i) to (iv) (excluding use for producing an antitumor agent containing pembrolizumab as an active ingredient and use for producing an antitumor agent to be administered in combination with pembrolizumab): (i) Use of futibatinib or a pharmaceutically acceptable salt thereof for producing an antitumor agent to be administered in combination with zimverelimab, albumin-bound paclitaxel, and carboplatin to patients with non-small cell lung cancer. (ii) Use of zimverelimab for producing an antitumor agent to be administered in combination with zimverelimab or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and carboplatin to patients with non-small cell lung cancer. (iii) Use of albumin-bound paclitaxel for the manufacture of an antitumor agent to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimblerimab, and carboplatin to patients with non-small cell lung cancer. (iv) Use of carboplatin for the manufacture of an antitumor agent to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimblerimab, and albumin-bound paclitaxel to patients with non-small cell lung cancer.

[0082] Item 44-4. A compound or salt thereof for use according to any of the following (i) to (iv) (excluding a compound used in combination with pembrolizumab and pembrolizumab for use): (i) futibatinib or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of non-small cell lung cancer, to be administered in combination with zimvelelimab, albumin-bound paclitaxel, and carboplatin to patients with non-small cell lung cancer. (ii) zimvelelimab for use in the prevention or treatment of non-small cell lung cancer, to be administered in combination with zimvelelimab or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and carboplatin to patients with non-small cell lung cancer. (iii) Albumin-bound paclitaxel for use in the prevention or treatment of non-small cell lung cancer, to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimbelelimab, and carboplatin to patients with non-small cell lung cancer. (iv) Carboplatin for use in the prevention or treatment of non-small cell lung cancer, to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimbelelimab, and albumin-bound paclitaxel to patients with non-small cell lung cancer.

[0083] Item 44-5. Use of any of the following (i) to (iv) (excluding the use of pembrolizumab and the use of a compound used in combination with pembrolizumab): (i) Use of futibatinib or a pharmaceutically acceptable salt thereof, used in combination with zimvelerimab, albumin-bound paclitaxel, and carboplatin to prevent or treat non-small cell lung cancer in patients with non-small cell lung cancer. (ii) Use of zimvelerimab, used in combination with zimvelerimab or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and carboplatin to prevent or treat non-small cell lung cancer in patients with non-small cell lung cancer. (iii) Use of albumin-bound paclitaxel in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimblerimab, and carboplatin to prevent or treat non-small cell lung cancer in patients with non-small cell lung cancer. (iv) Use of carboplatin in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimblerimab, and albumin-bound paclitaxel to prevent or treat non-small cell lung cancer in patients with non-small cell lung cancer.

[0084] Item 44-6. Any of the following commercial packages (i) to (iv) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and commercial packages used for administration in combination with pembrolizumab): (i) A commercial package containing futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient together with instructions for use thereof for preventing or treating non-small cell lung cancer in a subject, wherein the commercial package is used for administration in combination with jimverelimab, albumin-bound paclitaxel, and carboplatin to patients with non-small cell lung cancer. (ii) A commercial package containing jimverelimab as an active ingredient together with instructions for use thereof for preventing or treating non-small cell lung cancer in a subject, wherein the commercial package is used for administration in combination with jimverelimab or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and carboplatin to patients with non-small cell lung cancer. (iii) A commercial package comprising albumin-bound paclitaxel as an active ingredient together with instructions for use thereof to prevent or treat non-small cell lung cancer in a subject, wherein the commercial package is used to administer in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimbelelimab, and carboplatin to patients with non-small cell lung cancer. (iv) A commercial package comprising carboplatin as an active ingredient together with instructions for use thereof to prevent or treat non-small cell lung cancer in a subject, wherein the commercial package is used to administer in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimbelelimab, and albumin-bound paclitaxel to patients with non-small cell lung cancer.

[0085] Item 44-7. A method according to any of the following (i) to (iv) (excluding methods comprising administering pembrolizumab and methods comprising administering an antitumor agent to a subject who has been administered, is being administered concomitantly with, or is to be administered pembrolizumab): (i) A method for preventing or treating non-small cell lung cancer, comprising administering an effective amount of futibatinib or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has been administered, is being administered concomitantly with, or is to be administered with gimverelimab, has been administered, is being administered concomitantly with, or is to be administered with albumin-bound paclitaxel, and has been administered, is being administered concomitantly with, or is to be administered with carboplatin. (ii) A method for preventing or treating non-small cell lung cancer, comprising administering an effective amount of gimverelimab to a subject in need thereof, wherein the subject has been administered, is being administered simultaneously with, or will be administered with futibatinib or a pharmaceutically acceptable salt thereof, has been administered, is being administered simultaneously with, or will be administered with albumin-bound paclitaxel, and has been administered, is being administered simultaneously with, or will be administered with carboplatin. (iii) A method for preventing or treating non-small cell lung cancer, comprising administering an effective amount of albumin-bound paclitaxel to a subject in need thereof, wherein the subject has been administered, is being administered simultaneously with, or will be administered with futibatinib or a pharmaceutically acceptable salt thereof, has been administered, is being administered simultaneously with, or will be administered with gimverelimab, and has been administered, is being administered simultaneously with, or will be administered with carboplatin. (iv) A method for preventing or treating non-small cell lung cancer, comprising administering an effective amount of carboplatin to a subject in need thereof, wherein the subject has been administered, is being administered concomitantly with, or will be administered with futibatinib or a pharmaceutically acceptable salt thereof, has been administered, is being administered concomitantly with, or will be administered with dimverelimab, and has been administered, is being administered concomitantly with, or will be administered with albumin-bound paclitaxel.

[0086] Item 45. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 44, characterized in that a 21-day administration cycle comprising daily administration of 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib, one administration of 360 mg / dose of dimverelimab, three administrations of 100 mg / m2 / dose of albumin-bound paclitaxel, and one administration of carboplatin with an AUC of 6 is repeated once or twice or more times.

[0087] Item 46. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 44, characterized in that a 21-day administration cycle comprising administering 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib once daily, administering 360 mg / dose of dimverelimab on Day 1, administering 100 mg / m2 / dose of albumin-bound paclitaxel once each on Day 1, Day 8, and Day 15, and administering carboplatin at an AUC of 6 on Day 1, is repeated once or twice or more times.

[0088] Item 47. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to any one of Items 44 to 46, wherein the cancer patient is a non-small cell lung cancer patient with no history of prior treatment for advanced cancer.

[0089] Item 48. The antitumor agent, pharmaceutical composition, use, compound for use or a salt thereof, commercial package, or method according to any one of Items 1 to 27, which is the antitumor agent according to Item 48-1 below, the pharmaceutical composition according to Item 48-2, the use according to Item 48-3, the compound or a salt thereof for the use according to Item 48-4, the use according to Item 48-5, the commercial package according to Item 48-6, or the method according to Item 48-7: Item 48-1. Any of the following antitumor agents (i) to (iv) (excluding antitumor agents containing pembrolizumab as an active ingredient and antitumor agents used in combination with pembrolizumab): (i) The antitumor agent comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with zimblerimab, cisplatin, and gemcitabine to be administered to patients with biliary tract cancer. (ii) The antitumor agent comprising jimverelimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, cisplatin, and gemcitabine to patients with biliary tract cancer. (iii) The antitumor agent comprising gemcitabine as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, jimverelimab, and cisplatin to patients with biliary tract cancer. (iv) The antitumor agent comprising cisplatin as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, jimverelimab, and gemcitabine to patients with biliary tract cancer.

[0090] Item 48-2. A pharmaceutical composition for preventing or treating biliary tract cancer, any of the following (i) to (iv) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and pharmaceutical compositions used to be administered in combination with pembrolizumab): (i) A pharmaceutical composition containing futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient and further comprising a pharmaceutical carrier, which is used to be administered in combination with futibatinib, cisplatin, and gemcitabine to patients with biliary tract cancer. (ii) A pharmaceutical composition containing futibatinib or a pharmaceutically acceptable salt thereof, cisplatin, and gemcitabine to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, cisplatin, and gemcitabine to patients with biliary tract cancer, which is used to be administered in combination with futibatinib, cisplatin, and gemcitabine ... (iii) A pharmaceutical composition comprising gemcitabine as an active ingredient and a pharmaceutical carrier, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimblerimab, and cisplatin to patients with biliary tract cancer. (iv) A pharmaceutical composition comprising cisplatin as an active ingredient and a pharmaceutical carrier, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimblerimab, and gemcitabine to patients with biliary tract cancer.

[0091] Item 48-3. Use of any of the following (i) to (iv) (excluding use for producing an antitumor agent containing pembrolizumab as an active ingredient and use for producing an antitumor agent to be administered in combination with pembrolizumab): (i) Use of futibatinib or a pharmaceutically acceptable salt thereof for producing an antitumor agent to be administered in combination with zimverelimab, cisplatin, and gemcitabine to patients with biliary tract cancer. (ii) Use of zimverelimab for producing an antitumor agent to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, cisplatin, and gemcitabine to patients with biliary tract cancer. (iii) Use of gemcitabine for producing an antitumor agent to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimverelimab, and cisplatin to patients with biliary tract cancer. (iv) Use of cisplatin for the manufacture of an antitumor agent to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, dimverelimab, and gemcitabine to patients with biliary tract cancer.

[0092] Item 48-4. A compound or salt thereof for use according to any of (i) to (iv) below (excluding a compound used in combination with pembrolizumab and pembrolizumab for use): (i) futibatinib or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of biliary tract cancer, to be administered in combination with zimverelimab, cisplatin, and gemcitabine to patients with biliary tract cancer. (ii) zimverelimab for use in the prevention or treatment of biliary tract cancer, to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, cisplatin, and gemcitabine to patients with biliary tract cancer. (iii) gemcitabine for use in the prevention or treatment of biliary tract cancer, to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimverelimab, and cisplatin to patients with biliary tract cancer. (iv) Cisplatin for use in the prevention or treatment of biliary tract cancer, wherein the cisplatin is administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimverelimab, and gemcitabine to patients with biliary tract cancer.

[0093] Item 48-5. Use of any of the following (i) to (iv) (excluding the use of pembrolizumab and the use of a compound used in combination with pembrolizumab): (i) Use of futibatinib or a pharmaceutically acceptable salt thereof, used in combination with zimverelimab, cisplatin, and gemcitabine to prevent or treat biliary tract cancer in patients with biliary tract cancer. (ii) Use of zimverelimab, used in combination with futibatinib or a pharmaceutically acceptable salt thereof, cisplatin, and gemcitabine to prevent or treat biliary tract cancer in patients with biliary tract cancer. (iii) Use of gemcitabine, used in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimverelimab, and cisplatin to prevent or treat biliary tract cancer in patients with biliary tract cancer. (iv) Use of cisplatin for preventing or treating biliary tract cancer, wherein the cisplatin is administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimverelimab, and gemcitabine to patients with biliary tract cancer.

[0094] Item 48-6. Any of the commercial packages (i) to (iv) below (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and commercial packages used for administration in combination with pembrolizumab): (i) A commercial package containing futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient together with instructions for use thereof for preventing or treating biliary tract cancer in a subject, wherein the commercial package is used for administration in combination with zimblerimab, cisplatin, and gemcitabine to patients with biliary tract cancer. (ii) A commercial package containing zimblerimab as an active ingredient together with instructions for use thereof for preventing or treating biliary tract cancer in a subject, wherein the commercial package is used for administration in combination with futibatinib or a pharmaceutically acceptable salt thereof, cisplatin, and gemcitabine to patients with biliary tract cancer. (iii) A commercial package comprising gemcitabine as an active ingredient together with instructions for use thereof to prevent or treat biliary tract cancer in a subject, wherein the commercial package is used to administer in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimbelelimab, and cisplatin to a patient with biliary tract cancer. (iv) A commercial package comprising cisplatin as an active ingredient together with instructions for use thereof to prevent or treat biliary tract cancer in a subject, wherein the commercial package is used to administer in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimbelelimab, and gemcitabine to a patient with biliary tract cancer.

[0095] Item 48-7. A method according to any of the following (i) to (iv) (excluding methods comprising administering pembrolizumab and methods comprising administering an antitumor agent to a subject who has been administered, is being administered simultaneously with, or is to be administered with pembrolizumab): (i) A method for preventing or treating biliary tract cancer, comprising administering an effective amount of futibatinib or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has been administered, is being administered simultaneously with, or is to be administered with gimverelimab, has been administered, is being administered simultaneously with, or is to be administered with cisplatin, and has been administered, is being administered simultaneously with, or is to be administered with gemcitabine. (ii) A method for preventing or treating biliary tract cancer, comprising administering an effective amount of gimverelimab to a subject in need thereof, wherein the subject has been administered, is being administered simultaneously with, or will be administered with futibatinib or a pharmaceutically acceptable salt thereof, has been administered, is being administered simultaneously with, or will be administered with cisplatin, and has been administered, is being administered simultaneously with, or will be administered with gemcitabine. (iii) A method for preventing or treating biliary tract cancer, comprising administering an effective amount of gemcitabine to a subject in need thereof, wherein the subject has been administered, is being administered simultaneously with, or will be administered with futibatinib or a pharmaceutically acceptable salt thereof, has been administered, is being administered simultaneously with, or will be administered with gimverelimab, and has been administered, is being administered simultaneously with, or will be administered with cisplatin. (iv) A method for preventing or treating biliary tract cancer, comprising administering an effective amount of cisplatin to a subject in need thereof, wherein the subject has been administered, is being administered simultaneously with, or will be administered futibatinib or a pharmaceutically acceptable salt thereof, has been administered, is being administered simultaneously with, or will be administered zimbelelimab, and has been administered, is being administered simultaneously with, or will be administered gemcitabine.

[0096] Item 49. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 48, characterized in that a 21-day administration cycle comprising administering 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib once daily, administering 360 mg / dose of dimverelimab once, administering 25 mg / m2 / dose of cisplatin twice, and administering 1000 mg / m2 / dose of gemcitabine twice is repeated once or twice or more times.

[0097] Item 50. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to Item 48, characterized in that a 21-day administration cycle of 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib is administered once daily, 360 mg / dose of dimverelimab is administered on Day 1, 25 mg / m2 / dose of cisplatin is administered once on Day 1 and once on Day 8, and 1000 mg / m2 / dose of gemcitabine is administered once on Day 1 and once on Day 8 is repeated once or twice or more.

[0098] Item 51. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package, or method according to any one of Items 48 to 52, wherein the cancer patient is a biliary tract cancer patient with no history of previous treatment for advanced cancer.

[0099] According to the present invention, it is possible to provide a new combination therapy that shows excellent antitumor effects (e.g., tumor reduction effect, survival time extension effect, etc.) in cancer patients. The combination therapy of the present invention is particularly effective for patients with lung cancer, esophageal cancer, biliary tract cancer, or head and neck cancer who have not received prior treatment.

[0100] An outline of the clinical trial design for combination therapy including futibatinib is shown below.

[0101] The present invention provides futibatinib or a salt thereof, an immune checkpoint inhibitor (excluding pembrolizumab and CD155 / TIGIT pathway antagonists), and a combination thereof with at least one other antitumor agent.

[0102] In the present invention, futibatinib, which brings about an excellent antitumor effect when used in combination with an immune checkpoint inhibitor, is a disubstituted benzenealkynyl compound having the following structure: Futibatinib is described as Example Compound 2 in the above-mentioned Patent Document 2. It has been reported that futibatinib or a salt thereof has an excellent FGFR inhibitory effect, and inhibits the phosphorylation ability of the receptor protein tyrosine kinases FGFR1, FGFR3, and FGFR4 to tyrosine in the substrate peptide sequence (Patent Document 2).

[0103]

[0104] The above-mentioned futibatinib or a pharmaceutically acceptable salt thereof in the present invention is not particularly limited, but can be synthesized based on the production method described in Patent Document 2, for example.

[0105] In the present invention, futibatinib can be used as it is or in the form of pharmaceutically acceptable salt.The pharmaceutically acceptable salt of futibatinib is not particularly limited, but can be exemplified by the addition salt with inorganic acid such as hydrochloric acid, sulfuric acid, etc., organic acid such as acetic acid, citric acid, tartaric acid, maleic acid, etc., the salt with alkali metal such as potassium, sodium, etc., the salt with alkaline earth metal such as calcium, magnesium, etc., the salt with organic base such as ammonium salt, ethylamine salt, arginine salt, etc.

[0106] The immune checkpoint inhibitor of the present invention acts on immune checkpoint molecules, excluding pembrolizumab and anti-TIGIT antibodies, and has the effect of inducing an anti-tumor immune response in the living body of a subject and suppressing tumor immune escape.

[0107] Examples of such immune checkpoint inhibitors include substances that promote the function of costimulatory molecules (stimulatory costimulatory molecules) or substances that suppress the function of coinhibitory molecules (inhibitory costimulatory molecules). Examples of immune checkpoint molecules include B7 family (B7-1, B7-2, PD-L1, PD-L2, etc.), CD28 family (CTLA-4, PD-1, etc.), TNF superfamily (4-1BBL, OX40L), and TNF receptor superfamily (4-1BB, OX40) molecules, and substances that target immune checkpoint molecules can be used as immune checkpoint inhibitors. Examples include PD-1 pathway antagonists, ICOS pathway agonists, CTLA-4 pathway antagonists, CD28 pathway agonists, BTLA pathway antagonists, 4-1BB pathway agonists, CD155 / TIGIT pathway antagonists, and the like.

[0108] In the present invention, the antagonist is preferably at least one selected from a PD-1 pathway antagonist, an ICOS pathway agonist, a CTLA-4 pathway antagonist, a CD28 pathway agonist, and a CD155 / TIGIT pathway antagonist, more preferably at least one selected from a PD-1 pathway antagonist, a CTLA-4 pathway antagonist, and a CD155 / TIGIT pathway antagonist, more preferably at least one selected from a PD-1 pathway antagonist and a CD155 / TIGIT pathway antagonist, and even more preferably a PD-1 pathway antagonist.

[0109] PD-1 pathway antagonists inhibit immunosuppressive signals mediated by PD-1 expressed on T cells or its ligands PD-L1 or PD-L2. Examples of PD-1 pathway antagonists include, but are not limited to, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, PD-1 extracellular domain, PD-L1 extracellular domain, PD-L2 extracellular domain, PD-1-Ig (a fusion protein of the PD-1 extracellular domain and the Fc region of Ig), PD-L1-Ig, PD-L2-Ig, PD-1 siRNA, PD-L1 siRNA, and PD-L2 siRNA. Anti-PD-1 antibodies, anti-PD-L1 antibodies, or anti-PD-L2 antibodies are preferred, and anti-PD-1 antibodies or anti-PD-L1 antibodies are more preferred. Of these, anti-PD-1 antibodies are particularly preferred.

[0110] Furthermore, the CTLA-4 pathway antagonist inhibits immunosuppressive signals from CTLA-4 expressed on T cells or its ligands, B7-1 (CD80) and B7-2 (CD86), and is preferably an anti-CTLA-4 antibody, a CTLA-4 extracellular domain, CTLA-4-Ig (a fusion protein of the CTLA-4 extracellular domain and the Fc region of Ig), an anti-B7-1 (CD80) antibody, or an anti-B7-2 (CD86) antibody, more preferably an anti-CTLA-4 antibody or CTLA-4-Ig. Of these, an anti-CTLA-4 antibody is particularly preferred.

[0111] Furthermore, the CD155 / TIGIT pathway antagonist inhibits immunosuppressive signals mediated by TIGIT expressed on T cells or its ligand CD155, and examples thereof include, but are not limited to, anti-CD155 antibodies and anti-TIGIT antibodies. Preferred are anti-CD155 antibodies and anti-TIGIT antibodies, and particularly preferred is anti-TIGIT antibody.

[0112] These antibodies include immunoglobulins (IgA, IgD, IgE, IgG, IgM, IgY, etc.), Fab fragments, F(ab')2 fragments, single-chain antibody fragments (scFv), single-domain antibodies, diabodies, etc. (Nat. Rev. Immunol., 6:343-357, 2006), and these include monoclonal or polyclonal antibodies such as human antibodies, humanized antibodies, chimeric antibodies, mouse antibodies, llama antibodies, and chicken antibodies. In the present invention, immunoglobulins (preferably IgG, etc.) are preferred. In the present invention, human antibodies or humanized antibodies are also preferred. In the present invention, monoclonal antibodies are preferred.

[0113] Preferably, the antibody is a humanized IgG monoclonal antibody or a human IgG monoclonal antibody.

[0114] Preferred anti-PD-1 antibodies in the present invention include nivolumab, cemiplimab, spartalizumab, tislelizumab, BI754091, dostarlimab, sasanlimab, MGA-012, and cetrelimab. b), AGEN-2034, Zimberelimab, Camrelizumab, Budigalimab, Balstilimab and the like are included, with Nivolumab or Zimberelimab being preferred, and Zimberelimab being particularly preferred.

[0115] Preferred anti-PD-L1 antibodies in the present invention include atezolizumab, durvalumab, avelumab, lodapolimab, BGB-A333, and the like.

[0116] Preferred anti-CTLA-4 antibodies in the present invention include ipilimumab, tremelimumab, and the like.

[0117] In the present invention, preferred CTLA-4-Ig includes abatacept and the like.

[0118] Preferred anti-TIGIT antibodies in the present invention include domvanalimab (AB154), AB308, vibostolimab, osiperlimab, tiragolumab, AGEN-1777, HB-0036, HLX-301, and ONO-4. 686, M-6223, PM-1022, Etigilimab, ZG-005, AZD-2936, Belrestotug, or JS-006, among which domvanalimab, AB308, vibostolimab, osipellimab, or tiragolumab is preferred, domvanalimab or AB308 is more preferred, and domvanalimab is particularly preferred.

[0119] These agonists or antagonists can be produced by conventionally known production methods.

[0120] In addition, anti-PD-1 antibodies such as nivolumab or zimverelimab, anti-PD-L1 antibodies such as atezolizumab, durvalumab, or avelumab, anti-CTLA-4 antibodies such as ipilimumab or tremelimumab, CTLA-4-Ig such as abatacept, and anti-TIGIT antibodies such as domvanalimab are already on the market or are scheduled to be on the market, and these can also be used.

[0121] In the present invention, the immune checkpoint inhibitors may be used alone or in combination of two or more.

[0122] In the present invention, when two or more immune checkpoint inhibitors are used, for example, immune checkpoint inhibitors such as anti-PD-1 antibodies and anti-CTLA-4 antibodies can be used in combination, or bispecific antibodies capable of binding to different immune checkpoint molecules can be used. An example of a bispecific antibody capable of binding to both PD-1 and CTLA-4 is XmAb20717 (PD-1 x CTLA-4).

[0123] In the present invention, a preferred immune checkpoint inhibitor is a PD-1 pathway antagonist, more preferably an anti-PD-1 antibody, more preferably nivolumab or zimberelimab, and particularly preferably zimberelimab.

[0124] The present invention achieves excellent antitumor effects by adding an "additional antitumor agent" to a combination of at least three drugs, namely, futibatinib or a pharmaceutically acceptable salt thereof and at least one or more immune checkpoint inhibitors. Therefore, the additional antitumor agent in the present invention is not particularly limited as long as it is a drug having antitumor activity other than futibatinib or a pharmaceutically acceptable salt thereof or the selected immune checkpoint inhibitor (excluding pembrolizumab). Here, the term "other antitumor agent" as used herein means, for example, that if A is selected as the "immune checkpoint inhibitor" for the antitumor agent of the present invention, A is not selected as the "other antitumor agent." The additional antitumor agent in the present invention may take the form of a low molecular weight compound, an antibody, or a nucleic acid. In the present invention, the additional antitumor agent may be used alone or in combination of two or more.

[0125] Another preferred antitumor agent in the present invention is a chemotherapeutic agent. Here, the chemotherapeutic agent in the present invention is preferably at least one selected from the group consisting of antimetabolites (purine antimetabolites, pyrimidine antimetabolites, antifolates, etc.), alkaloid antitumor agents, platinum preparations, immune checkpoint inhibitors (PD-1 pathway antagonists, CTLA-4 pathway antagonists, CD155 / TIGIT pathway antagonists, etc.), molecular targeted drugs (low-molecular targeted drugs, antibody-targeted drugs, etc.), antitumor antibiotics, and alkylating agents. At least one selected from the group consisting of antimetabolites (purine antimetabolites, pyrimidine antimetabolites, folate antagonists, etc.), alkaloid antumor agents, platinum agents, and CD155 / TIGIT pathway antagonists is even more preferred, and at least one selected from the group consisting of antimetabolites (purine antimetabolites, pyrimidine antimetabolites, folate antagonists, etc.), alkaloid antumor agents, platinum agents, and anti-TIGIT antibodies is even more preferred.

[0126] More specifically, purine antimetabolites such as fludarabine, cladribine, nelarabine, etc.; pyrimidine antimetabolites such as 5-fluorouracil (5-FU), tegafur / gimeracil / oteracil potassium combination drug (TS-1 or S-1, trade name: "TS-1"), tegafur / uracil combination drug (UFT, trade name: "UFT"), trifluridine / tipiracil hydrochloride combination drug (TAS-102, trade name: "Lonsurf"), capecitabine, doxifluridine, 5-fluoro-2'-deoxyuridine (FdUrd), gemcitabine, cytarabine, etc.; folate antimetabolites such as pemetrexed, methotrexate, etc.; Alkaloid antitumor agents such as paclitaxel (marketed under the trade names "Taxol" and "Abraxane", and paclitaxel includes derivatives such as albumin-suspended paclitaxel (e.g., ABI-007) and PEG-bound paclitaxel), docetaxel (trade name "Taxotere", etc.), cabazitaxel, eribulin, irinotecan, nogitecan, etoposide, vinorelbine, vincristine, and vinblastine; platinum preparations such as cisplatin, carboplatin, oxaliplatin, and nedaplatin; PD-1 pathway antagonists such as nivolumab, cemiplimab, spartalizumab, tislelizumab, BI754091, dostalizumab, sasanlimab, MGA-012, cetrelimab, AGEN-2034, zimverelimab, camrelizumab, budigalimab, balstilimab, atezolizumab, durvalumab, avelumab, rodapolimab, or BGB-A333; CTLA-4 pathway antagonists such as ipilimumab, tremelimumab, or abatacept; CD155 / TIGIT pathway antagonists such as domvanalimab, AB308, vibostolimab, osipellimab, tiragolumab, AGEN-1777, HB-0036, HLX-301, ONO-4686, M-6223, PM-1022, Etigilimab, ZG-005, AZD-2936, Belrestotug or JS-006;Small molecule targeted drugs such as imatinib, gefitinib, erlotinib, lapatinib, sunitinib, dasatinib, everolimus, temsirolimus, selumetinib, trametinib, sorafenib, afatinib, regorafenib, dabrafenib, vemurafenib, and MK2206; antibody molecular targeted drugs such as trastuzumab, cetuximab, bevacizumab, panitumumab, veltuzumab, rituximab, and ramucirumab; antitumor antibiotics such as doxorubicin, daunorubicin, epirubicin, actinomycin D, and mitomycin C;and at least one selected from the group consisting of alkylating agents such as cyclophosphamide, dacarbazine, temozolomide, nimustine, busulfan, procarbazine, and melphalan is preferred, and fludarabine, cladribine, nelarabine, 5-fluorouracil (5-FU), tegafur / gimeracil / oteracil potassium combination drug (TS-1 or S-1, trade name: "TS-1"), tegafur / uracil combination drug (UFT, trade name: "UFT"), trifluridine / tipiracil hydrochloride combination drug (TAS-102, trade name: "Lonsurf"), capecitabine, doxifluridine, 5-fluoro-2'-deoxyuridine (FdUrd), gemcitabine, more preferably at least one selected from the group consisting of vinorelbine, cytarabine, pemetrexed, methotrexate, paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel, eribulin, irinotecan, topotecan, etoposide, vinorelbine, vincristine, vinblastine, cisplatin, carboplatin, oxaliplatin, nedaplatin, domvanalimab, AB308, vibostolimab, osipellimab, and tiragolumab; At least one selected from the group consisting of 5-fluorouracil, gemcitabine, albumin-suspended paclitaxel, irinotecan, cisplatin, carboplatin, domvanalimab, and AB308 is more preferred, at least one selected from the group consisting of 5-fluorouracil, gemcitabine, albumin-suspended paclitaxel, cisplatin, carboplatin, and domvanalimab is even more preferred, and a combination of 5-fluorouracil and cisplatin, a combination of 5-fluorouracil and carboplatin, a combination of carboplatin and albumin-suspended paclitaxel, a combination of cisplatin and gemcitabine, or domvanalimab is particularly preferred;

[0127] Suitable antitumor agents of the present invention include any of the following antitumor agents (i) to (iii), which do not contain pembrolizumab as an active ingredient: (i) the antitumor agent containing futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used to be administered in combination with an anti-PD-1 antibody and at least one or more other antitumor agents to cancer patients. (ii) the antitumor agent containing an anti-PD-1 antibody as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and at least one or more other antitumor agents to cancer patients. (iii) the antitumor agent containing at least one or more other antitumor agents as active ingredients, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody to cancer patients.

[0128] More preferably, the antitumor agent is any one of the following (i) to (iii), which does not contain pembrolizumab as an active ingredient. (i) The antitumor agent contains futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used to be administered in combination with jimverelimab and at least one or more other antitumor agents to cancer patients. (ii) The antitumor agent contains jimverelimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and at least one or more other antitumor agents to cancer patients. (iii) The antitumor agent contains at least one or more other antitumor agents as active ingredients, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and jimverelimab to cancer patients.

[0129] The administration schedule for the various active ingredients of the present invention can be set as appropriate as long as the effects of the present invention are achieved, but it is preferable to repeat the administration cycle of 21 days once or twice or more times.

[0130] In the present invention, the administration schedule of futibatinib or a salt thereof is preferably once a day on each day of a 21-day administration cycle.

[0131] In the present invention, the administration schedule of the immune checkpoint inhibitor can be set as appropriate, but is preferably administered at an administration frequency of once a day to once every four weeks. In the case of dimvelelimab, for example, it is preferably administered once in a 21-day administration cycle.

[0132] In the present invention, the administration schedule for other antitumor agents can be set as appropriate, but administration for 1 to 5 days in a 21-day administration cycle is preferred, and administration for 1, 2, 3, 4, or 5 days is more preferred.

[0133] Preferred daily doses of futibatinib or a salt thereof on the day of administration include, for example, 4 mg to 160 mg, 4 mg to 24 mg, 12 to 24 mg, 16 to 24 mg, and 20 mg. More specifically, preferred frequency of administration and dosages on the day of administration include once a day, 4 mg / dose, 8 mg / dose, 12 mg / dose, 16 mg / dose, and 20 mg / dose. In another aspect, preferred frequency of administration and dosages on the day of administration include once a day, 8 mg / dose, 12 mg / dose, 16 mg / dose, and 20 mg / dose. In another aspect, preferred frequency of administration and dosages on the day of administration include once a day, 12 mg / dose, 16 mg / dose, and 20 mg / dose. In another aspect, preferred frequency of administration and dosages on the day of administration include once a day, 20 mg / dose.

[0134] In one embodiment, the present invention includes that in the case of cancer types for which a stronger effect is desired (for example, brain tumors), the dose of futibatinib or a salt thereof is more than 20 mg / dose once a day.

[0135] In the present invention, the daily dose of the immune checkpoint inhibitor on the day of administration is set appropriately depending on the drug, and in the case of nivolumab, preferred daily doses on the day of administration include 40 to 480 mg / dose, 80 mg / dose, 240 mg / dose, 360 mg / dose, or 480 mg / dose. The administration interval for nivolumab is preferably every 2 to 4 weeks, more preferably every 2 to 3 weeks, and even more preferably every 2 weeks. In the case of dimvelelimab, preferred daily doses on the day of administration include 240 to 480 mg / dose, 240 mg / dose, 360 mg / dose, or 480 mg / dose, with 360 mg / dose being more preferred.

[0136] As used herein, "cancer" or "tumor" refers to a physiological condition in mammals characterized by unregulated cell growth. "Cancer" and "tumor" have the same meaning and are used interchangeably herein. Cancer includes solid tumors and hematological cancers. Examples include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma, sarcoma, and borderline malignant tumors (carcinoid).

[0137] Cancers that can be treated with the combined method of the present invention include, regardless of the presence or absence of abnormalities in the FGFR pathway, for example, head and neck cancer, digestive cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer (hepatocellular carcinoma), biliary tract cancer (gallbladder / bile duct cancer, etc.), pancreatic cancer, small intestine cancer, large intestine cancer (colorectal cancer, colon cancer, rectal cancer, etc.)), lung cancer (non-small cell lung cancer, small cell lung cancer), mesothelioma (malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, Examples of cancers that can be treated include mesothelioma, testicular mesothelioma, etc.), breast cancer, reproductive cancer (ovarian cancer, uterine cancer (cervical cancer, uterine cancer, endometrial cancer, etc.), kidney cancer, bladder cancer, urothelial cancer, prostate cancer, testicular tumor, skin cancer (malignant melanoma, epidermal cancer, etc.), blood cancer (multiple myeloma, malignant lymphoma, leukemia, etc.), bone and soft tissue tumor, rhabdomyosarcoma, brain tumor, malignant neurilemmoma, neuroendocrine tumor, thyroid cancer, etc. Here, cancer includes not only primary tumor but also cancer that has metastasized to other organs (liver, etc.) and cancer of unknown primary origin. Furthermore, the antitumor agent of the present invention may be used for postoperative adjuvant chemotherapy performed to prevent recurrence after surgical removal of a tumor, or for neoadjuvant chemotherapy performed before surgical removal of a tumor.

[0138] In the present invention, preferred cancers are lung cancer, esophageal cancer, gastric cancer, duodenal cancer, liver cancer, hepatocellular carcinoma, biliary tract cancer, pancreatic cancer, colon cancer, breast cancer, uterine cancer, ovarian cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumor, thyroid cancer, bone and soft tissue tumor, leukemia, malignant lymphoma, multiple myeloma, head and neck cancer, brain tumor, mesothelioma, skin cancer, and cancer of unknown primary origin, more preferably solid cancer, more preferably pancreatic cancer, lung cancer, esophageal cancer, biliary tract cancer, and head and neck cancer. More preferably, the cancer is lung cancer, esophageal cancer, biliary tract cancer, or head and neck cancer, even more preferably non-small cell lung cancer, esophageal cancer, biliary tract cancer, or head and neck cancer, even more preferably non-small cell lung cancer, esophageal cancer, biliary tract cancer, or head and neck cancer that has no history of previous treatment for advanced cancer or has a history of previous treatment with one line of chemotherapy, and particularly preferably non-small cell lung cancer, esophageal cancer, biliary tract cancer, or head and neck cancer that has no history of previous treatment for advanced cancer.

[0139] In one embodiment of the present invention, the subject is an esophageal cancer patient who has no history of prior treatment for advanced cancer. In one embodiment of the present invention, the subject is an esophageal cancer patient who has no history of prior treatment for advanced cancer or who has a history of prior treatment with one line of chemotherapy. In one embodiment of the present invention, the subject is a head and neck cancer patient who has no history of prior treatment for advanced cancer. In one embodiment of the present invention, the subject is a non-small cell lung cancer patient who has no history of prior treatment for advanced cancer. In one embodiment of the present invention, the subject is a biliary tract cancer patient who has no history of prior treatment for advanced cancer.

[0140] Suitable antitumor agents in the present invention include, but are not limited to, the following:

[0141] Any of the following antitumor agents (i) to (iv) is preferred: (i) the antitumor agent comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used to be administered in combination with jimverelimab, cisplatin, and 5-fluorouracil to patients with esophageal cancer. (ii) the antitumor agent comprising jimverelimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, cisplatin, and 5-fluorouracil to patients with esophageal cancer. (iii) the antitumor agent comprising cisplatin as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, jimverelimab, and 5-fluorouracil to patients with esophageal cancer. (iv) The antitumor agent comprising 5-fluorouracil as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimverelimab, and cisplatin to patients with esophageal cancer.

[0142] In the case of any of the antitumor agents (i) to (iv), futibatinib is administered at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, and dimvelelimab is administered at a dose of 360 mg / dose once, and dimvelelimab is administered at a dose of 80 mg / m ２ cisplatin was administered once at 800 mg / m ２ More preferred is an antitumor agent characterized in that a 21-day administration cycle in which 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib is administered once daily, 360 mg / dose of zimbelelimab is administered once on Day 1, and 80 mg / m ２ Cisplatin was administered once on Day 1 at a dose of 800 mg / m ２ Particularly preferred is an antitumor agent characterized in that a 21-day administration cycle in which 5-fluorouracil is administered on Days 1 to 5 of each treatment is repeated once or twice or more times.

[0143] Any of the following antitumor agents (i) to (iii) is preferred: (i) the antitumor agent comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used to be administered in combination with zimvelerimab and domvanalimab to patients with esophageal cancer. (ii) the antitumor agent comprising zimvelerimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and domvanalimab to patients with esophageal cancer. (iii) the antitumor agent comprising domvanalimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and zimvelerimab to patients with esophageal cancer.

[0144] More preferred is any of the antitumor agents (i) to (iii) above, characterized in that a 21-day administration cycle of 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib is administered once daily, 360 mg / dose of zimbelelimab is administered once, and 1200 mg / dose of domvanalimab is administered once, repeated once or twice or more times; and particularly preferred is any of the antitumor agents (i) to (iii) above, characterized in that a 21-day administration cycle of 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib is administered once daily, 360 mg / dose of zimbelelimab is administered once on Day 1, and 1200 mg / dose of domvanalimab is administered once or twice or more times.

[0145] Any of the following antitumor agents (i) to (iv) is preferred: (i) the antitumor agent comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used to be administered in combination with jimverelimab, 5-fluorouracil, and carboplatin or cisplatin to patients with head and neck cancer. (ii) the antitumor agent comprising jimverelimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil, and carboplatin or cisplatin to patients with head and neck cancer. (iii) the antitumor agent comprising 5-fluorouracil as an active ingredient, which is used to be administered in combination with jimverelimab or a pharmaceutically acceptable salt thereof, jimverelimab, and carboplatin or cisplatin to patients with head and neck cancer. (iv) The antitumor agent comprising carboplatin or cisplatin as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, dimverelimab, and 5-fluorouracil to patients with head and neck cancer.

[0146] More preferred is any of the antitumor agents (i) to (iv) above, characterized in that a 21-day administration cycle in which 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib is administered once daily, 360 mg / dose of zimbelelimab is administered once, and 1200 mg / dose of domvanalimab is administered once, is repeated once or twice or more times; and particularly preferred is any of the antitumor agents (i) to (iv) above, characterized in that a 21-day administration cycle in which 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib is administered once daily, 360 mg / dose of zimbelelimab is administered once on Day 1, and 1200 mg / dose of domvanalimab is administered once or twice or more times.

[0147] Any of the following antitumor agents (i) to (iii) is preferred: (i) the antitumor agent comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used to be administered in combination with zimverelimab and domvanalimab to patients with head and neck cancer. (ii) the antitumor agent comprising zimbelelimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and domvanalimab to patients with head and neck cancer. (iii) the antitumor agent comprising domvanalimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and zimverelimab to patients with head and neck cancer.

[0148] More preferred is any of the antitumor agents (i) to (iii) above, characterized in that a 21-day administration cycle of 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib is administered once daily, 360 mg / dose of zimbelelimab is administered once, and 1200 mg / dose of domvanalimab is administered once, repeated once or twice or more times; and particularly preferred is any of the antitumor agents (i) to (iii) above, characterized in that a 21-day administration cycle of 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib is administered once daily, 360 mg / dose of zimbelelimab is administered once on Day 1, and 1200 mg / dose of domvanalimab is administered once or twice or more times.

[0149] Any of the following antitumor agents (i) to (iv) is preferred: (i) the antitumor agent comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used to be administered in combination with jimvelerimab, albumin-suspended paclitaxel, and carboplatin to patients with non-small cell lung cancer. (ii) the antitumor agent comprising jimvelerimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, albumin-suspended paclitaxel, and carboplatin to patients with non-small cell lung cancer. (iii) the antitumor agent comprising albumin-suspended paclitaxel as an active ingredient, which is used to be administered in combination with jimvelerimab or a pharmaceutically acceptable salt thereof, jimvelerimab, and carboplatin to patients with non-small cell lung cancer. (iv) The antitumor agent comprising carboplatin as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimverelimab, and albumin-bound paclitaxel to patients with non-small cell lung cancer.

[0150] In the case of any one of the antitumor agents (i) to (iv), futibatinib is administered at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, and dimvelelimab is administered at a dose of 360 mg / dose once, and dimvelelimab is administered at a dose of 100 mg / m ２ More preferred is an antitumor agent characterized in that a 21-day administration cycle in which 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib is administered once daily, 360 mg / dose of zimbelelimab is administered on Day 1, and 100 mg / m ２

[0039] An antitumor agent characterized in that a 21-day administration cycle in which albumin-suspended paclitaxel is administered once each on Day 1, Day 8, and Day 15 and carboplatin at an AUC of 6 is administered on Day 1 is repeated once or twice or more times is particularly preferred.

[0151] Any of the following antitumor agents (i) to (iv) is preferred: (i) the antitumor agent comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used to be administered in combination with jimverelimab, cisplatin, and gemcitabine to patients with biliary tract cancer. (ii) the antitumor agent comprising jimverelimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, cisplatin, and gemcitabine to patients with biliary tract cancer. (iii) the antitumor agent comprising gemcitabine as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, jimverelimab, and cisplatin to patients with biliary tract cancer. (iv) The antitumor agent comprising cisplatin as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, zimverelimab, and gemcitabine to patients with biliary tract cancer.

[0152] In the case of any one of the antitumor agents (i) to (iv), futibatinib is administered at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, and dimvelelimab is administered at a dose of 360 mg / dose once, and dimvelelimab is administered at a dose of 100 mg / m ２ More preferred is an antitumor agent characterized in that a 21-day administration cycle in which 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib is administered once daily, 360 mg / dose of zimbelelimab is administered on Day 1, and 100 mg / m ２

[0039] An antitumor agent characterized in that a 21-day administration cycle in which albumin-suspended paclitaxel is administered once each on Day 1, Day 8, and Day 15 and carboplatin at an AUC of 6 is administered on Day 1 is repeated once or twice or more times is particularly preferred.

[0153] As used herein, the term "combination therapy" is intended to define a therapy that includes the use of a combination of two or more compounds / agents (as defined above). Accordingly, the use of "combination therapy," "combination," and "in combination" compounds / agents in this application can refer to compounds / agents that are administered as part of the same overall treatment regimen. The respective posology of the two or more compounds / agents can vary; each can be administered simultaneously or at different times. Thus, it is understood that the compounds / agents of a combination can be administered sequentially (e.g., before or after) or simultaneously, either in the same pharmaceutical formulation (i.e., together) or in different pharmaceutical formulations (i.e., separately). Simultaneously in the same formulation, as a single formulation, but simultaneously in different pharmaceutical formulations, non-integrally.

[0154] The dosage form of the antitumor agent of the present invention is not particularly limited and can be appropriately selected depending on the purpose of treatment. Specific examples include oral preparations (tablets, coated tablets, powders, granules, capsules, liquids, etc.), injections, suppositories, patches, ointments, etc. In the case of futibatinib or a salt thereof, oral preparations are preferred. In the case of immune checkpoint inhibitors and other antitumor agents, the above-mentioned dosage forms can be mentioned, with injections being preferred. In the case of dimverelimab, domvanalimab, carboplatin, cisplatin, 5-fluorouracil, albumin-suspended paclitaxel, and gemcitabine, injections are preferred.

[0155] The antitumor agent of the present invention may be an immune checkpoint inhibitor and futibatinib or a salt thereof, which are the active ingredients, themselves used as an antitumor agent, or may be a pharmaceutical composition prepared by a commonly known method using a pharmaceutically acceptable carrier depending on the administration form. Examples of such carriers include various substances commonly used in conventional pharmaceuticals, such as excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, isotonicity agents, pH adjusters, buffers, stabilizers, colorants, flavoring agents, and odorants.

[0156] The antitumor agent of the present invention may be formulated by dividing each active ingredient into multiple dosage forms, or may be formulated together into a single dosage form, depending on the dosage form and administration schedule of each active ingredient. Furthermore, each formulation may be manufactured and sold together in a single package suitable for combined administration, or each formulation may be manufactured and sold separately in separate packages. The same applies to the pharmaceutical composition embodiment. Therefore, a "pharmaceutical composition comprising an immune checkpoint inhibitor and futibatinib or a salt thereof as active ingredients" includes both formulations in which each active ingredient is divided into multiple dosage forms and formulations in which each active ingredient is divided into a single dosage form. The pharmaceutical composition in which each active ingredient is divided into multiple dosage forms includes both formulations in which each formulation is divided into a single package suitable for combined administration and formulations in which each formulation is divided into separate packages.

[0157] The present invention relates to a kit formulation comprising an antitumor agent containing futibatinib or a salt thereof and instructions for use that describe the combined administration of futibatinib or a salt thereof and an immune checkpoint inhibitor to a cancer patient. Here, the "instructions" may be any instructions that describe the dosage, regardless of whether they are legally binding, but preferably recommend the dosage. Specific examples include package inserts, pamphlets, etc. Furthermore, the kit formulation including instructions for use may be one in which the instructions for use are printed and attached to the package of the kit formulation, or one in which the instructions for use are enclosed in the package of the kit formulation together with the antitumor agent.

[0158] In the present invention, "treatment" includes treatment performed with the aim of curing or relieving a disease, or suppressing the progression or recurrence of the disease, or alleviating symptoms. Treatment also includes administration of a drug before or after a surgical procedure, or administration of a drug during, before or after radiation therapy.

[0159] The antitumor agent of the present invention can be used to treat cancer. When referring to a cancer patient receiving treatment with a therapeutic regimen, such as the combination therapy described herein, "antitumor effect" refers to at least one evaluation, such as PFS (progression-free survival), DCR (disease control rate), DOR (duration of response), OS (overall survival), ORR (objective response rate), DCR (disease control rate), TTR (time to first response), or PROs (patient-reported outcomes). In one embodiment, when a solid tumor is targeted, tumor evaluation for the combination therapy described herein is evaluated according to the RECIST 1.1 criteria (Solid Tumor Response Evaluation Criteria), and the antitumor effect is expressed as SD (stable disease), PR (partial response), CR (complete response), or PD (progression). Tumor evaluation of brain tumors can also be performed by standard brain tumor MRI, including pre- and post-enhancement using a gadolinium (Gd) chelate contrast agent.

[0160] Example Phase 1a / b Clinical Trial of AB122 Combination Therapy in Patients with Advanced Solid Tumors Objectives and Endpoints:

[0161]

[0162] Methods: This is a Phase 1, non-randomized, open-label, multicenter, platform study evaluating the tolerability and safety of AB122 in patients with malignancies. The study consists of two phases (Phase 1a and Phase 1b). Phase 1a aims to evaluate the safety and tolerability of AB122-based combination therapy in patients with advanced solid tumors, determine the recommended dose (RD) of each regimen, and evaluate efficacy at the RD. Phase 1b aims to accrue patients to appropriate cohorts and evaluate the safety and efficacy of AB122-based therapy.

[0163]

[0164] Phase 1a: Once tumor response based on RECIST v1.1 has been determined in the first 5 patients, enrollment may be halted if there is a 20% or lower probability of observing the required number of responses in another 5 patients according to the binomial response rate distribution.

[0165] Dose-limiting toxicity (DLT): The following adverse events related to the investigational drug that occurred in Cycle 1 will be defined as DLT. The following grades will be based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0:

[0166] The investigator and sponsor will determine whether laboratory abnormalities (excluding hematologic and non-hematologic toxicities listed below) and transient signs or symptoms constitute DLTs: Grade 4 neutropenia lasting more than 7 days Febrile neutropenia (absolute neutrophil count (ANC) 1000 / mm ３ - Temperature less than 38.3°C even once or sustained for more than 1 hour: - Grade 4 thrombocytopenia or Grade 3 thrombocytopenia accompanied by bleeding and requiring transfusion - Grade 4 anemia or Grade 3 anemia requiring transfusion - Non-hematological adverse events of Grade 3 or greater are considered DLTs, except for Grade 3 fatigue lasting 3 days or less, Grade 3 diarrhea, nausea, or vomiting with or without standard-of-care antiemetics or antidiarrheals, and Grade 3 rash without the use of standard-of-care corticosteroids or anti-inflammatory medications. - Grade 2 or greater increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) accompanied by an increase in total bilirubin greater than 2 times the upper limit of normal (ULN), in the absence of early signs of cholestasis (an increase in alkaline phosphatase (ALP) less than 2 times the ULN) and no other explanation for these increases. - Study drug-related toxicity that prevents the completion of Cycle 1 (defined as the period during which at least 75% of the prescribed oral study drug doses are administered and the full dose of AB122 and AB154 (Cohort D-3 only) is administered) or prevents the initiation of Cycle 2 (defined as a dose interruption of more than 2 weeks). Hyperphosphatemia: - An increase in serum phosphorus of 10 mg / dL or more, or - An increase in serum phosphorus of 7 mg / dL or more that lasts for 7 days or more despite phosphate-lowering therapy.

[0167] Phase 1b Phase 1b will begin after tolerability and preliminary efficacy have been determined based on the results of Phase 1a. The cohorts to be expanded into Phase 1b will be determined in consultation with the Data Monitoring Committee (DMC) and the sponsor.

[0168] Target number of cases (planned): Cohort D-2 The target number of cases will be a maximum of 32 for Phase 1a and a maximum of 30 for Phase 1b. Cohort D-3 The target number of cases will be a maximum of 32 for Phase 1a and a maximum of 30 for Phase 1b. Cohort D-4 The target number of cases will be 20 for Phase 1a and a maximum of 30 for Phase 1b. Cohort D-5 The target number of cases will be 20 for Phase 1a and a maximum of 30 for Phase 1b. Cohort D-6 The target number of cases will be a maximum of 32 for Phase 1a and a maximum of 30 for Phase 1b. Cohort D-7 The target number of cases will be a maximum of 32 for Phase 1a and a maximum of 30 for Phase 1b.

[0169] Diagnosis and main inclusion criteria: Patients with advanced solid cancer aged 18 years or older at the time of consent.

[0170] Dosage and Administration Method: Phase 1a Administration Method: The administration method for each cohort is shown below.

[0171]

[0172] The study treatments for each cohort will be as follows: Cohort D-2: AB122 360 mg / body will be administered by intravenous infusion over 60 minutes on Day 1. Cisplatin 80 mg / m ２ 5-fluorouracil 800 mg / m was administered intravenously from Day 1 to Day 5. ２ AB154 1200 mg / body will be administered intravenously over 60 minutes on Day 1. Futibatinib will be administered orally once daily on an empty stomach, at least 1 hour before or 2 hours after a meal. Cohort D-3: AB122 360 mg / body will be administered intravenously over 60 minutes on Day 1. AB154 1200 mg / body will be administered intravenously over 60 minutes on Day 1. Futibatinib will be administered orally once daily on an empty stomach, at least 1 hour before or 2 hours after a meal. Cohort D-4: AB122 360 mg / body will be administered intravenously over 60 minutes on Day 1. Carboplatin AUC 5 or cisplatin 100 mg / m on Day 1.２ 5-fluorouracil 1000 mg / m was administered intravenously from Day 1 to Day 4. ２ AB154 1200 mg / body will be administered intravenously over 60 minutes on Day 1. Futibatinib will be administered orally once daily on an empty stomach, at least 1 hour before or 2 hours after a meal. Cohort D-5: AB122 360 mg / body will be administered intravenously over 60 minutes on Day 1. AB154 1200 mg / body will be administered intravenously over 60 minutes on Day 1. Futibatinib will be administered orally once daily on an empty stomach, at least 1 hour before or 2 hours after a meal. Cohort D-6: AB122 360 mg / body will be administered intravenously over 60 minutes on Day 1. Albumin-bound paclitaxel 100 mg / m ２ Cohort D-7: AB122 360 mg / body is administered intravenously over 60 minutes on Day 1. Cisplatin 25 mg / m ２ and gemcitabine 1000 mg / m ２ will be administered intravenously on Day 1 and Day 8. Futibatinib will be administered orally once daily on an empty stomach at least 1 hour before or 2 hours after a meal.

[0173] If toxicity occurs at the start of or during the cycle, the dose of futibatinib, 5-fluorouracil, or cisplatin may be gradually changed according to the table below. The doses of AB122 and AB154 will not be changed during the administration period.

[0174]

[0175] Phase 1b dose levels will be determined based on tolerability in each Phase 1a cohort.

[0176] Treatment period: One cycle is 21 days. Study treatment will be continued until any of the discontinuation criteria is met.

[0177] Evaluation criteria: Efficacy Tumor assessment during the study will be performed using RECIST (v1.1, 2009). Computed tomography (CT) scans will be performed at baseline, every 4 weeks after enrollment, every 6 weeks from Week 12 onwards, and at discontinuation.

[0178] Safety Standard safety monitoring and grading using NCI CTCAE v5.0 will be performed.

[0179] Statistical methods: The analysis population for this study will be defined by phase and cohort, with DLT-evaluable patients defined by Phase 1a cohort.

[0180]

[0181] Analysis of primary endpoints Phase 1a: For DLT-evaluable patients, the incidence of DLT will be calculated for each level. All DLTs will be listed by patient.

[0182] Phase 1b: ORR analysis based on RECIST v1.1 will be performed on the combined population of Phase 1a and Phase 1b FAS. Best overall response based on RECIST v1.1 will be compiled, and ORR and 95% CI will be estimated using the Clopper-Pearson method. An overview of the study design is shown in Figure 1.

Claims

1. Any of the following antitumor agents (i) to (iii) (excluding antitumor agents containing pembrolizumab as an active ingredient and antitumor agents used to be administered in combination with pembrolizumab): (i) The antitumor agent containing futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used to be administered in combination with an immune checkpoint inhibitor and at least one or more other antitumor agents to cancer patients. (ii) The antitumor agent containing an immune checkpoint inhibitor as an active ingredient, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and at least one or more other antitumor agents to cancer patients. (iii) The antitumor agent containing at least one or more other antitumor agents as active ingredients, which is used to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and at least one or more other antitumor agents to cancer patients.

2. The antitumor agent according to claim 1, wherein the immune checkpoint inhibitor is at least one selected from the group consisting of anti-PD-1 antibody, anti-PD-L1 antibody, and anti-PD-L2 antibody.

3. The antitumor agent according to claim 1 or 2, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

4. The antitumor agent according to claim 2 or 3, wherein the anti-PD-1 antibody is at least one selected from the group consisting of nivolumab, cemiplimab, spartalizumab, tislelizumab, BI754091, dostalizumab, sasanlimab, MGA-012, cetrelimab, AGEN-2034, dimverelimab, camrelizumab, budigalimab, and balstilimab.

5. The antitumor agent according to claim 4, wherein the anti-PD-1 antibody is dimverelimab.

6. The antitumor agent according to any one of claims 1 to 5, wherein the other antitumor agent is a chemotherapeutic agent.

7. The antitumor agent according to claim 6, wherein the chemotherapeutic agent is at least one selected from the group consisting of metabolic antagonists, alkaloid antitumor agents, platinum preparations, immune checkpoint inhibitors, molecular targeted drugs, antitumor antibiotics, and alkylating agents.

8. The antitumor agent according to claim 6, wherein the chemotherapeutic agent is at least one selected from the group consisting of metabolic antagonists, alkaloid antitumor agents, platinum preparations, and immune checkpoint inhibitors.

9. The chemotherapy agent is fludarabine, cladribine, nelarabine, 5-fluorouracil, tegafur / gimeracil / oteracil potassium, tegafur / uracil, trifluridine / tipiracil hydrochloride, capecitabine, doxifluridine, 5-fluoro-2'-deoxyuridine, gemcitabine, cytarabine, pemetrexed, methotrexate, paclitaxel, albumin-bound paclitaxel, The antitumor agent according to claim 6, which is at least one selected from the group consisting of docetaxel, cabazitaxel, eribulin, irinotecan, topotecan, etoposide, teniposide, vinorelbine, vincristine, vinblastine, cisplatin, carboplatin, oxaliplatin, nedaplatin, dombanalimab, AB308, vibostolimab, osiperlimab and tiragolumab.

10. The antitumor agent according to claim 6, wherein the chemotherapeutic agent is at least one selected from the group consisting of 5-fluorouracil, gemcitabine, albumin-suspended paclitaxel, irinotecan, cisplatin, carboplatin, domvanalimab and AB308.

11. The antitumor agent according to claim 6, wherein the chemotherapeutic agent is at least one selected from the group consisting of 5-fluorouracil, gemcitabine, albumin-suspended paclitaxel, cisplatin, carboplatin, and domvanalimab.

12. The antitumor agent according to any one of claims 1 to 11, wherein the cancer is at least one selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, duodenal cancer, liver cancer, hepatocellular carcinoma, biliary tract cancer, pancreatic cancer, colon cancer, breast cancer, uterine cancer, ovarian cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, thyroid cancer, bone and soft tissue tumor, leukemia, malignant lymphoma, multiple myeloma, head and neck cancer, brain tumor, mesothelioma, skin cancer, and cancer of unknown primary origin.

13. The antitumor agent according to any one of claims 1 to 11, wherein the cancer is at least one type selected from the group consisting of pancreatic cancer, lung cancer, esophageal cancer, biliary tract cancer, and head and neck cancer.

14. The antitumor agent according to any one of claims 1 to 13, wherein the cancer patient is a cancer patient who has no history of prior treatment for advanced cancer or who has a history of prior treatment with one line of chemotherapy.

15. The antitumor agent according to any one of claims 1 to 14, characterized in that a 21-day administration cycle is repeated once or twice or more times.

16. The antitumor agent of claim 15, wherein futibatinib is administered once daily on each day of a 21-day administration cycle.

17. The antitumor agent according to claim 15, wherein jimverelimab is administered once on Day 1 of a 21-day administration cycle.

18. The antitumor agent according to claim 15, wherein the other antitumor agent is administered for 1 to 5 days during a 21-day administration cycle.

19. The antitumor agent according to claim 15, wherein the other antitumor agent is administered once on Day 1 of the 21-day administration cycle.

20. The antitumor agent according to claim 15, wherein the other antitumor agent is administered once each on Day 1 and Day 8 of the 21-day administration cycle.

21. The antitumor agent according to claim 15, wherein the other antitumor agent is administered once each on Day 1, Day 8, and Day 15 of the 21-day administration cycle.

22. The antitumor agent according to claim 15, wherein the other antitumor agent is administered once each on days 1, 2, 3 and 4 of the 21-day administration cycle.

23. The antitumor agent according to claim 15, wherein the other antitumor agent is administered once each on days 1, 2, 3, 4 and 5 of the 21-day administration cycle.

24. The antitumor agent according to claim 16, wherein the dosage of futibatinib is 8 mg to 24 mg per administration.

25. The antitumor agent according to claim 16, wherein the dosage of futibatinib is 12 mg / dose, 16 mg / dose, or 20 mg / dose.

26. The antitumor agent according to claim 16, wherein the dosage of futibatinib is 20 mg per administration.

27. The antitumor agent according to claim 17, wherein the dosage of dimverelimab is 360 mg per administration.

28. The antitumor agent according to any one of claims 1 to 27, which is any one of the following antitumor agents (i) to (iv): (i) the antitumor agent comprising futibatinib or a pharma- ceutical acceptable salt thereof as an active ingredient, which is used to be administered in combination with jimvelerimab, cisplatin and 5-fluorouracil to patients with esophageal cancer. (ii) the antitumor agent comprising jimvelerimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharma-ceutical acceptable salt thereof, cisplatin and 5-fluorouracil to patients with esophageal cancer. (iii) the antitumor agent comprising cisplatin as an active ingredient, which is used to be administered in combination with futibatinib or a pharma-ceutical acceptable salt thereof, jimvelerimab and 5-fluorouracil to patients with esophageal cancer. (iv) The above antitumor agent, which contains 5-fluorouracil as an active ingredient and is used to be administered in combination with futibatinib or a pharma- ceutically acceptable salt thereof, zimverelimab and cisplatin to a patient with esophageal cancer.

29. 12 mg, 16 mg, or 20 mg of futibatinib administered once daily, 360 mg of dimverelimab administered once, and 80 mg / m ２ Cisplatin was administered once at 800 mg / m ２ The antitumor agent according to claim 28, wherein a 21-day administration cycle of 5-fluorouracil / day is administered for 5 consecutive days is repeated once or twice or more.

30. 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib administered once daily, 360 mg / dose of dimvelelimab administered once on Day 1, and 80 mg / m ２ Cisplatin was administered once on Day 1 at a dose of 800 mg / m ２ The antitumor agent according to claim 28, wherein a 21-day administration cycle of 5-fluorouracil / day is administered daily on days 1 to 5 is repeated once or more than twice.

31. The antitumor agent according to any one of claims 28 to 30, wherein the cancer patient is an esophageal cancer patient with no history of previous treatment for advanced cancer.

32. The antitumor agent according to any one of claims 1 to 27, which is any one of the following antitumor agents (i) to (iii): (i) the antitumor agent comprising futibatinib or a pharma- ceutical acceptable salt thereof as an active ingredient, which is used to be administered in combination with zimvelerimab and domvanalimab to patients with esophageal cancer. (ii) the antitumor agent comprising zimvelerimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharma-ceutical acceptable salt thereof, and domvanalimab to patients with esophageal cancer. (iii) the antitumor agent comprising domvanalimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharma-ceutical acceptable salt thereof, and zimvelerimab to patients with esophageal cancer.

33. The antitumor agent described in claim 32, characterized in that a 21-day administration cycle of 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib administered once daily, 360 mg / dose of dimverelimab administered once, and 1200 mg / dose of domvanalimab administered once is repeated once or twice or more.

34. The antitumor agent described in claim 32, characterized in that a 21-day administration cycle of 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib administered once daily, 360 mg / dose of zimverelimab administered once on Day 1, and 1200 mg / dose of domvanalimab administered once on Day 1 is repeated once or twice or more.

35. The antitumor agent according to any one of claims 32 to 34, wherein the cancer patient is an esophageal cancer patient who has no history of prior treatment for advanced cancer or who has a history of prior treatment with one line of chemotherapy.

36. The antitumor agent according to any one of claims 1 to 27, which is any one of the following antitumor agents (i) to (iv): (i) the antitumor agent comprising, as an active ingredient, futibatinib or a pharmaceutically acceptable salt thereof, which is administered in combination with jimvelerimab, 5-fluorouracil, and carboplatin or cisplatin to patients with head and neck cancer. (ii) the antitumor agent comprising, as an active ingredient, jimvelerimab, which is administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil, and carboplatin or cisplatin to patients with head and neck cancer. (iii) the antitumor agent comprising, as an active ingredient, 5-fluorouracil, which is administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, jimvelerimab, and carboplatin or cisplatin to patients with head and neck cancer. (iv) The antitumor agent comprising carboplatin or cisplatin as an active ingredient, which is used to be administered in combination with futibatinib or a pharma- ceutically acceptable salt thereof, dimverelimab, and 5-fluorouracil to a patient with head and neck cancer.

37. Futibatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose administered once daily, dimverelimab at 360 mg / dose administered once, and carboplatin at AUC 5 or 100 mg / m ２ Cisplatin was administered once at 1000 mg / m ２ The antitumor agent according to claim 36, wherein a 21-day administration cycle of 5-fluorouracil / day is administered for 4 consecutive days is repeated once or twice or more.

38. 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib administered once daily, 360 mg / dose of dimverelimab administered once on Day 1, and 100 mg / m ２ Cisplatin was administered once on Day 1 at a dose of 1000 mg / m ２ The antitumor agent according to claim 36, wherein a 21-day administration cycle in which 5-fluorouracil is administered on Day 1 to Day 4 is repeated once or twice or more.

39. The antitumor agent according to any one of claims 36 to 38, wherein the cancer patient is a head and neck cancer patient with no history of previous treatment for advanced cancer.

40. The antitumor agent according to any one of claims 1 to 27, which is any one of the following antitumor agents (i) to (iii): (i) The antitumor agent comprising futibatinib or a pharma- ceutical acceptable salt thereof as an active ingredient, which is used to be administered in combination with zimverelimab and domvanalimab to patients with head and neck cancer. (ii) The antitumor agent comprising zimverelimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharma-ceutical acceptable salt thereof, and domvanalimab to patients with head and neck cancer. (iii) The antitumor agent comprising domvanalimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharma-ceutical acceptable salt thereof, and zimverelimab to patients with head and neck cancer.

41. The antitumor agent described in claim 40, characterized in that a 21-day administration cycle of 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib administered once daily, 360 mg / dose of dimverelimab administered once, and 1200 mg / dose of domvanalimab administered once is repeated once or more times.

42. The antitumor agent described in claim 40, characterized in that a 21-day administration cycle of 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib administered once daily, 360 mg / dose of zimverelimab administered once on Day 1, and 1200 mg / dose of domvanalimab administered once on Day 1 is repeated once or more than twice.

43. The antitumor agent according to any one of claims 40 to 42, wherein the cancer patient is a head and neck cancer patient with no history of previous treatment for advanced cancer.

44. The antitumor agent according to any one of claims 1 to 27, which is any one of the following antitumor agents (i) to (iv): (i) the antitumor agent comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is administered in combination with jimvelerimab, albumin-suspended paclitaxel, and carboplatin to non-small cell lung cancer patients; (ii) the antitumor agent comprising jimvelerimab as an active ingredient, which is administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, albumin-suspended paclitaxel, and carboplatin to non-small cell lung cancer patients; (iii) the antitumor agent comprising albumin-suspended paclitaxel as an active ingredient, which is administered in combination with futibatinib or a pharmaceutically acceptable salt thereof, jimvelerimab, and carboplatin to non-small cell lung cancer patients. (iv) The antitumor agent comprising carboplatin as an active ingredient, which is used to be administered in combination with futibatinib or a pharma- ceutically acceptable salt thereof, zimverelimab, and albumin-suspended paclitaxel to patients with non-small cell lung cancer.

45. 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib administered once daily, 360 mg / dose of dimverelimab administered once, and 100 mg / m ２ The antitumor agent according to claim 44, characterized in that a 21-day administration cycle of three doses of albumin-suspended paclitaxel / dose and one dose of carboplatin with an AUC of 6 is repeated once or more than twice.

46. ​​12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib administered once daily, 360 mg / dose of dimvelelimab administered on Day 1, and 100 mg / m ２ The antitumor agent according to claim 44, characterized in that a 21-day administration cycle in which albumin-suspended paclitaxel is administered once per day on Day 1, once per day on Day 8, and once per day on Day 15, and carboplatin at an AUC of 6 is administered on Day 1 is repeated once or twice or more.

47. The antitumor agent according to any one of claims 44 to 46, wherein the cancer patient is a non-small cell lung cancer patient with no history of prior treatment for advanced cancer.

48. The antitumor agent according to any one of claims 1 to 27, which is any one of the following antitumor agents (i) to (iv): (i) the antitumor agent comprising futibatinib or a pharma- ceutical acceptable salt thereof as an active ingredient, which is used to be administered in combination with jimvelerimab, cisplatin, and gemcitabine to patients with biliary tract cancer; (ii) the antitumor agent comprising jimvelerimab as an active ingredient, which is used to be administered in combination with futibatinib or a pharma-ceutical acceptable salt thereof, cisplatin, and gemcitabine to patients with biliary tract cancer; (iii) the antitumor agent comprising gemcitabine as an active ingredient, which is used to be administered in combination with futibatinib or a pharma-ceutical acceptable salt thereof, jimvelerimab, and cisplatin to patients with biliary tract cancer. (iv) The antitumor agent comprising cisplatin as an active ingredient, which is used to be administered in combination with futibatinib or a pharma- ceutically acceptable salt thereof, zimverelimab, and gemcitabine to patients with biliary tract cancer.

49. 12 mg, 16 mg, or 20 mg of futibatinib administered once daily, 360 mg of dimvelelimab administered once, and 25 mg / m ２ Cisplatin was administered twice at 1000 mg / m ２ The antitumor agent according to claim 48, characterized in that a 21-day administration cycle in which gemcitabine is administered twice per dose is repeated once or more than twice.

50. 12 mg / dose, 16 mg / dose, or 20 mg / dose of futibatinib administered once daily, 360 mg / dose of dimvelelimab administered on Day 1, and 25 mg / m ２ Cisplatin was administered once each on Day 1 and Day 8 at a dose of 1000 mg / m ２ The antitumor agent according to claim 48, characterized in that a 21-day administration cycle in which gemcitabine is administered once on Day 1 and once on Day 8 is repeated once or twice or more.

51. The antitumor agent according to any one of claims 48 to 50, wherein the cancer patient is a biliary tract cancer patient with no history of previous treatment for advanced cancer.

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