Cancer treatments involving 3,5-disubstituted benzenealkynyl compounds and immune checkpoint inhibitors

Abstract

To provide a novel combination therapy that exhibits excellent antitumor effects. [Solution] An antitumor agent containing futivatinib or a salt thereof as the active ingredient (not containing pembrolizumab as the active ingredient) administered in combination to cancer patients with an immune checkpoint inhibitor (excluding CD155 / TIGIT pathway antagonists) and at least one other antitumor agent.

Description

[Technical Field]

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

[0002] Fibroblast growth factor (FGF) is expressed in a wide range of tissues and is one of the growth factors that govern cell proliferation and differentiation. The physiological activity of FGF is mediated by a specific cell surface receptor, the fibroblast growth factor receptor (FGFR). FGFR belongs to the receptor protein tyrosine kinase family and consists of an extracellular ligand-binding domain, a single-pass transmembrane domain, and an intracellular tyrosine kinase domain. Four types of FGFR have been identified to date (FGFR1, FGFR2, FGFR3, and FGFR4). FGFR forms a dimer upon binding to FGF and is activated by phosphorylation. Receptor activation induces the recruitment and activation of specific downstream signaling molecules, thereby expressing physiological functions. Abnormalities in FGF / FGFR signaling have been reported to be associated with various human tumors. Abnormal activation of the FGF / FGFR signaling pathway in human tumors is thought to be due to autocrine or paracrine mechanisms resulting from FGFR overexpression and / or gene amplification, gene mutations, chromosomal translocations, insertions, inversions, gene fusions, or overproduction of its ligand, FGF (Non-Patent Documents 1, 2, 3, and 4).

[0003] Meanwhile, cancer immunotherapy is being developed as one of the new cancer treatment methods.

[0004] The 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 defined by costimulation or coinhibition through the binding between the B7 family, which are co-stimulatory molecules, and the CD28 family, which are their receptors. That is, for T cells to be antigen-specifically activated, two characteristic signal transduction events are required. T cells that receive only antigen stimulation without costimulation from the B7 family become anergic, and immune tolerance is induced.

[0005] Cancer cells utilize this mechanism to suppress the activation of antigen-specific T cells, evade the immune surveillance mechanism, and continue to proliferate. Therefore, it is considered effective in cancer treatment to induce an anti-tumor immune response in the body of cancer patients by enhancing costimulation or blocking coinhibition, and controlling tumor immune escape. Various cancer immunotherapies targeting costimulatory molecules (stimulatory co-stimulatory molecules) or coinhibitory molecules (inhibitory co-stimulatory molecules) have been proposed (Non-Patent Document 5). For example, nivolumab (a humanized IgG4 monoclonal antibody against human PD-1), an immune checkpoint inhibitor that activates T cells by inhibiting the binding of PD-1 to its ligands (PD-L1 and PD-L2), is used in the treatment of malignant melanoma and the like (Patent Document 1, Non-Patent Document 6). Also, zimberelimab (AB122) is known as a new immune checkpoint inhibitor and is used in the treatment of Hodgkin lymphoma and the like (Non-Patent Document 7).

[0006] (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"), which is a 3,5-disubstituted benzene alkynyl compound, or a salt thereof is known as an FGFR inhibitor, and combinations of FGFR inhibitors with other antitumor agents have been reported so far (Patent Documents 2 and 3). In addition, a clinical trial (jRCT number: jRCT2011210020) regarding the combined administration of futibatinib and dimberelimab to non-small cell lung cancer patients has been conducted (Non-Patent Document 8).

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Non-Patent Documents

[0008]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

[0009] The objective of this invention is to provide a novel combination therapy that exhibits excellent antitumor effects in cancer patients. [Means for solving the problem]

[0010] In view of the current situation, the inventors have found that the above problems can be solved by further combining futivatinib or a salt thereof with a specific immune checkpoint inhibitor, and by adding another antitumor agent.

[0011] Therefore, the present invention provides the following items 1 to 55.

[0012] Item 1. The antitumor agents described in Item 1-1 below, the pharmaceutical compositions described in Item 1-2, the uses described in Item 1-3, the compounds or salts thereof for use described in Item 1-4, the uses described in Item 1-5, the commercial packaging described in Item 1-6, or the methods described in Item 1-7: Section 1-1. Any of the following antitumor agents (i) to (iii) (excluding antitumor agents containing pembrolizumab as the active ingredient and antitumor agents used in combination with pembrolizumab). (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with an immune checkpoint inhibitor and at least one other antitumor agent to cancer patients. (ii) The antitumor agent comprising an immune checkpoint inhibitor as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and at least one other antitumor agent for use in cancer patients. (iii) an antitumor agent comprising at least one other antitumor agent as an active ingredient, which is used in combination with futivatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor for use in cancer patients; Section 1-2. Pharmaceutical compositions for the prevention or treatment of any of the following cancers (i) to (iii) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and pharmaceutical compositions used in combination with pembrolizumab). (i) A pharmaceutical composition comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with an immune checkpoint inhibitor and at least one other antitumor agent in cancer patients. (ii) A pharmaceutical composition comprising an immune checkpoint inhibitor as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with futivatinib or a pharmaceutically acceptable salt thereof and at least one other antitumor agent in patients with cancer. (iii) A pharmaceutical composition comprising at least one other antitumor agent as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with futivatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor in patients with cancer; Section 1-3. Any of the following uses (i) to (iii) (excluding use for manufacturing antitumor agents containing pembrolizumab as an active ingredient and use for manufacturing antitumor agents intended to be administered in combination with pembrolizumab): (i) Use of futivatinib or a pharmaceutically acceptable salt thereof for manufacturing an antitumor agent to be used in combination with an immune checkpoint inhibitor and at least one other antitumor agent for use in cancer patients. (ii) Use of immune checkpoint inhibitors to manufacture antitumor agents to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and at least one other antitumor agent for administration to cancer patients. (iii) Use of at least one other antitumor agent to manufacture an antitumor agent to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor for use in cancer patients; Section 1-4. Compounds or salts thereof for use as described in any of (i) to (iii) below (excluding compounds used in combination with pembrolizumab and pembrolizumab for use). (i) Futivatinib or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of cancer, to be administered in combination with an immune checkpoint inhibitor and at least one other antitumor agent to cancer patients. (ii) An immune checkpoint inhibitor for use in the prevention or treatment of cancer, to be administered to cancer patients in combination with futivatinib or a pharmaceutically acceptable salt thereof and at least one other antitumor agent. (iii) at least one other antitumor agent for use in the prevention or treatment of cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor to cancer patients; Section 1-5. Use of any of the following (i) to (iii) (excluding the use of pembrolizumab and the use of compounds used in combination with pembrolizumab). (i) Use of futivatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of cancer, to be used in combination with an immune checkpoint inhibitor and at least one other antitumor agent in patients with cancer. (ii) Use of an immune checkpoint inhibitor for the prevention or treatment of cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof and at least one other antitumor agent to cancer patients. (iii) Use of at least one other antitumor agent for the prevention or treatment of cancer, used in combination with futivatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor in patients with cancer; Section 1-6. Any of the following commercial packages (i) to (iii) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and commercial packages intended for use in combination with pembrolizumab). (i) A commercial package comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, along with instructions for its use in preventing or treating cancer in a subject, to be used in combination with an immune checkpoint inhibitor and at least one other antitumor agent in a patient with cancer. (ii) A commercial package comprising an immune checkpoint inhibitor as an active ingredient, along with instructions for its use in preventing or treating cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and at least one other antitumor agent in a patient with cancer. (iii) A commercial package containing, as an active ingredient, an antitumor agent other than "futibatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor" (another antitumor agent), along with instructions for its use in preventing or treating cancer in a subject, which is intended to be administered in combination with futibatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor to a cancer patient; Section 1-7. Methods according to any of the following (i) to (iii) (excluding methods involving the administration of pembrolizumab and methods involving the administration of an antitumor agent to a subject who has received, is receiving, or is scheduled to receive pembrolizumab). (i) A method for preventing or treating cancer, comprising administering an effective amount of futivatinib or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has been, is, or is scheduled to be, administered an immune checkpoint inhibitor, and has been, is, or is scheduled to be, administered at least one other antitumor agent. (ii) A method for preventing or treating cancer, comprising administering an effective dose of an immune checkpoint inhibitor to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered futivatinib or a pharmaceutically acceptable salt thereof, and the subject has been, is, or is scheduled to be administered at least one other antitumor agent. (ii) A method for preventing or treating cancer, comprising administering an effective dose of at least one antitumor agent (other antitumor agent) other than "futivatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor" to a subject in need thereof, wherein the subject has been administered, is administered concurrently with, or is scheduled to be administered futivatinib or a pharmaceutically acceptable salt thereof, and the subject has been administered, is administered concurrently with, or is scheduled to be administered 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 anti-PD-1 antibody, anti-PD-L1 antibody and 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, semiprimab, spartalizumab, tislerizumab, BI754091, dostarizumab, sasamrimab, MGA-012, cetrelimab, AGEN-2034, zimberelimab, camrelizumab, buzigalimab and valstilimab.

[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 zimberelimab.

[0017] Item 6. An 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-based agents, and immune checkpoint inhibitors.

[0020] Item 9. Chemotherapy agents include 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, and eriburi. An antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method, according to item 6, which is at least one selected from the group consisting of n, irinotecan, nogitecan (topotecan), etoposide, teniposide, vinorelbine, vincristine, vinblastine, cisplatin, carboplatin, oxaliplatin, nedaplatin, domvanarimab, AB308, vivostrimab, osipermab, 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, dombanalimab 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-bound paclitaxel, cisplatin, carboplatin, and dombanarimab.

[0023] Item 12. An 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 selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, duodenal cancer, liver cancer, hepatocellular carcinoma, biliary tract cancer, pancreatic cancer, colorectal cancer, breast cancer, uterine cancer, ovarian cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, 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. An 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 selected from the group consisting of pancreatic cancer, lung cancer, esophageal cancer, biliary tract cancer, and head and neck cancer.

[0025] Item 14. An 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 prior history of treatment for advanced cancer or has a prior history of one line of chemotherapy.

[0026] Item 15. An antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method according to any one of items 1 to 14, characterized by repeating a 21-day or 28-day administration cycle once or more times.

[0027] Item 16. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method described in Item 15, comprising administering futivatinib once daily on each day of a 21-day or 28-day administration cycle.

[0028] Item 17. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial packaging or method described in Item 15, comprising administering zimberelimab for 1 to 2 days within a 21-day or 28-day administration cycle.

[0029] Item 18. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial packaging or method described in Item 15, comprising administering another antitumor agent for 1 to 5 days within a 21-day or 28-day administration cycle.

[0030] Item 19. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial packaging or method described in Item 15, wherein another antitumor agent is administered once on Day 1 of a 21-day or 28-day administration cycle.

[0031] Item 20. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method described in Item 15, wherein another antitumor agent is administered once on Day 1 and once on Day 8 of a 21-day or 28-day administration cycle.

[0032] Item 21. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method described in Item 15, wherein another antitumor agent is administered once each on Day 1, Day 8, and Day 15 of a 21-day or 28-day administration cycle.

[0033] Item 22. An antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method, as described in Item 15, wherein another antitumor agent is administered once each on Day 1, 2, 3, and 4 of a 21-day or 28-day administration cycle.

[0034] Item 23. An antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method as described in Item 15, wherein another antitumor agent is administered once each on Day 1, 2, 3, 4, and 5 of a 21-day or 28-day administration cycle.

[0035] Item 24. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method described in Item 16, wherein the dose of futivatinib 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 dose of futivatinib 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 packaging or method, as described in Item 16, wherein the dose of futivatinib is 20 mg / dose.

[0038] Item 27. The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial packaging or method, according to Item 17, wherein the dose of zimberelimab is 240 mg / dose to 360 mg / dose.

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

[0040] Section 28-2. Any of the following pharmaceutical compositions (i) to (iv) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and pharmaceutical compositions used in combination with pembrolizumab). (i) A pharmaceutical composition comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with zimbererimab, cisplatin, and 5-fluorouracil in patients with esophageal cancer. (ii) A pharmaceutical composition comprising zimberemab as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with futivatinib or a pharmaceutically acceptable salt thereof, cisplatin, and 5-fluorouracil in patients with esophageal cancer. (iii) A pharmaceutical composition comprising cisplatin as an active ingredient and further comprising a pharmaceutical carrier, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab and 5-fluorouracil for use in patients with esophageal cancer. (iv) A pharmaceutical composition comprising 5-fluorouracil as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab and cisplatin in patients with esophageal cancer.

[0041] Section 28-3. Any of the following uses (i) to (iv) (excluding use for manufacturing antitumor agents containing pembrolizumab as an active ingredient and use for manufacturing antitumor agents intended to be administered in combination with pembrolizumab): (i) Use of futivatinib or a pharmaceutically acceptable salt thereof for the manufacture of an antitumor agent to be used in combination with zimbererimab, cisplatin, and 5-fluorouracil for patients with esophageal cancer. (ii) Use of zimberelimab to manufacture an antitumor agent to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, cisplatin and 5-fluorouracil for use in patients with esophageal cancer. (iii) Use of cisplatin to manufacture an antitumor agent to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab and 5-fluorouracil for use in patients with esophageal cancer. (iv) Use of 5-fluorouracil to manufacture an antitumor agent to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab and cisplatin for use in patients with esophageal cancer.

[0042] Section 28-4. Compounds or salts thereof for use as described in any of (i) to (iv) below (excluding compounds used in combination with pembrolizumab and pembrolizumab for use). (i) Futivatinib or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of esophageal cancer, to be administered in combination with zimbererimab, cisplatin, and 5-fluorouracil to patients with esophageal cancer. (ii) Zimberemab for use in the prevention or treatment of esophageal cancer, to be administered in combination with futivatinib 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 futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab and 5-fluorouracil to patients with esophageal cancer. (iv) 5-fluorouracil for use in the prevention or treatment of esophageal cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab and cisplatin to patients with esophageal cancer.

[0043] Section 28-5. Use of any of the following (i) to (iv) (excluding the use of pembrolizumab and the use of compounds used in combination with pembrolizumab). (i) Use of futivatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of esophageal cancer, to be used in combination with zimbererimab, cisplatin, and 5-fluorouracil in patients with esophageal cancer. (ii) Use of zimberemab for the prevention or treatment of esophageal cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof, cisplatin and 5-fluorouracil to patients with esophageal cancer. (iii) Use of cisplatin to prevent or treat esophageal cancer in patients with esophageal cancer, in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab and 5-fluorouracil. (iv) Use of 5-fluorouracil for the prevention or treatment of esophageal cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab and cisplatin to patients with esophageal cancer.

[0044] Section 28-6. Any of the following commercial packages (i) to (iv) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and commercial packages intended for use in combination with pembrolizumab). (i) A commercial package comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, along with instructions for its use in a subject to prevent or treat esophageal cancer, to be used in combination with zimberemab, cisplatin, and 5-fluorouracil in patients with esophageal cancer. (ii) A commercial package comprising zimbererimab as an active ingredient, along with instructions for its use in preventing or treating esophageal cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, cisplatin and 5-fluorouracil in patients with esophageal cancer. (iii) A commercial package comprising cisplatin as an active ingredient, along with instructions for its use in preventing or treating esophageal cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab and 5-fluorouracil in patients with esophageal cancer. (iv) A commercial package comprising 5-fluorouracil as an active ingredient, along with instructions for its use in preventing or treating esophageal cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab and cisplatin in patients with esophageal cancer.

[0045] Section 28-7. Any method described in (i) to (iv) below (excluding methods involving the administration of pembrolizumab and methods involving the administration of an antitumor agent to a subject who has received, is receiving, or is scheduled to receive pembrolizumab). (i) A method for preventing or treating esophageal cancer, comprising administering an effective amount of futivatinib or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered zimbererimab, has been, is, or is scheduled to be administered cisplatin, and has been, is, or is scheduled to be administered 5-fluorouracil. (ii) A method for preventing or treating esophageal cancer, comprising administering an effective dose of zimberemab to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered futivatinib or a pharmaceutically acceptable salt thereof, has been, is, or is scheduled to be administered cisplatin, or has been, is, or is scheduled to be administered 5-fluorouracil. (iii) A method for preventing or treating esophageal cancer, comprising administering an effective dose of cisplatin to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered futivatinib or a pharmaceutically acceptable salt thereof, has been, is, or is scheduled to be administered zimbererimab, or has been, is, or is scheduled to be administered 5-fluorouracil. (iv) A method for preventing or treating esophageal cancer, comprising administering an effective dose of 5-fluorouracil to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered futivatinib or a pharmaceutically acceptable salt thereof, has been, is, or is scheduled to be administered zimbererimab, or has been, is, or is scheduled to be administered cisplatin.

[0046] Administer futivacinib at doses of 29.12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, and administer zimbererimab at a single dose of 360 mg / dose, and 80 mg / m². 2 Administer cisplatin once, 800 mg / m². 2 The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method according to item 28, characterized by administering 5-fluorouracil at a dose of / day daily for 5 consecutive days, repeating a 21-day administration cycle once or more times.

[0047] Administer futivacinib at doses of 30.12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, and administer 360 mg / dose of zimbererimab once on Day 1, and 80 mg / m². 2 Administer cisplatin once on Day 1, at a dose of 800 mg / m². 2 The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method according to item 28, characterized by administering 5-fluorouracil at a dose of / day daily from Day 1 to 5 for 21 days, repeated once or more times.

[0048] Item 31. An antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method as described in any one of items 28-30, wherein the cancer patient is an esophageal cancer patient with no prior treatment history for advanced cancer.

[0049] Item 32. An antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method described in any one of items 1 to 27, which is an antitumor agent described in item 32-1, a pharmaceutical composition described in item 32-2, a use described in item 32-3, a compound or salt thereof for use described in item 32-4, a use described in item 32-5, a commercial package described in item 32-6, or a method described in item 32-7 below: Section 32-1. Any of the following antitumor agents (i) to (iii) (excluding antitumor agents containing pembrolizumab as the active ingredient and antitumor agents used in combination with pembrolizumab). (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimbererimab and dombanarimab for patients with esophageal cancer. (ii) The antitumor agent comprising zimbererimab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and dombanarimab in patients with esophageal cancer. (iii) The antitumor agent comprising dombanalimab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and zimbererimab in patients with esophageal cancer.

[0050] Section 32-2. Pharmaceutical compositions for the prevention or treatment of any of the following esophageal cancers (i) to (iii) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and pharmaceutical compositions used in combination with pembrolizumab). (i) A pharmaceutical composition comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with zimbererimab and dombanarimab in patients with esophageal cancer. (ii) A pharmaceutical composition comprising zimbererimab as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with futivatinib or a pharmaceutically acceptable salt thereof and dombanarimab in patients with esophageal cancer. (iii) A pharmaceutical composition comprising dombanarimab as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with futivatinib or a pharmaceutically acceptable salt thereof and zimbererimab in patients with esophageal cancer.

[0051] Section 32-3. Any of the following uses (i) to (iii) (excluding use for manufacturing antitumor agents containing pembrolizumab as an active ingredient and use for manufacturing antitumor agents to be used in combination with pembrolizumab): (i) Use of futivatinib or a pharmaceutically acceptable salt thereof for the manufacture of an antitumor agent to be used in combination with zimberemab and dombanarimab for patients with esophageal cancer. (ii) Use of zimbererimab to manufacture an antitumor agent to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and dombanarimab for patients with esophageal cancer. (iii) Use of dombanarimab to manufacture an antitumor agent to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and zimbererimab for use in patients with esophageal cancer.

[0052] Section 32-4. Compounds or salts thereof for use as described in any of (i) to (iii) below (excluding compounds used in combination with pembrolizumab and pembrolizumab for use). (i) Futivatinib or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of esophageal cancer, to be used in combination with zimbererimab and dombanarimab in patients with esophageal cancer. (ii) Zimberelimab for use in the prevention or treatment of esophageal cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof and dombanarimab to patients with esophageal cancer. (iii) Dombanarimab for use in the prevention or treatment of esophageal cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof and zimbererimab to patients with esophageal cancer.

[0053] Section 32-5. Use of any of the following (i) to (iii) (excluding the use of pembrolizumab and the use of compounds used in combination with pembrolizumab). (i) Use of futivatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of esophageal cancer, to be used in combination with zimbererimab and dombanarimab in patients with esophageal cancer. (ii) Use of zimberemab for the prevention or treatment of esophageal cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof and dombanarimab to patients with esophageal cancer. (iii) Use of dombanarimab for the prevention or treatment of esophageal cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof and zimbererimab to patients with esophageal cancer.

[0054] Section 32-6. Any of the following commercial packages (i) to (iii) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and commercial packages intended for use in combination with pembrolizumab). (i) A commercial package comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, along with instructions for its use in preventing or treating esophageal cancer in a subject, to be used in combination with zimberelimab and dombanarimab in patients with esophageal cancer. (ii) A commercial package comprising zimberelimab as an active ingredient, along with instructions for its use in preventing or treating esophageal cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and dombanalimab in a patient with esophageal cancer. (iii) A commercial package comprising dombanalimab as an active ingredient, along with instructions for its use in preventing or treating esophageal cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and zimbererimab in patients with esophageal cancer.

[0055] Section 32-7. Methods according to any of the following (i) to (iii) (excluding methods involving the administration of pembrolizumab and methods involving the administration of an antitumor agent to a subject who has received, is receiving, or is scheduled to receive pembrolizumab). (i) A method for preventing or treating esophageal cancer, comprising administering an effective dose of futivatinib or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered zimbererimab, and has been, is, or is scheduled to be administered dombanarimab. (ii) A method for preventing or treating esophageal cancer, comprising administering an effective dose of zimbererimab to a subject in need thereof, wherein the subject has been, is, or is scheduled to be, administered futivatinib or a pharmaceutically acceptable salt thereof, and has been, is, or is scheduled to be administered dombanarimab. (iii) A method for preventing or treating esophageal cancer, comprising administering an effective dose of dombanarimab to a subject in need thereof, wherein the subject has been, is, or is scheduled to be, administered futivatinib or a pharmaceutically acceptable salt thereof, and has been, is, or is scheduled to be administered zimbererimab.

[0056] Item 33. An antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method according to Item 32, characterized by administering futivatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, administering 360 mg / dose of zimberelimab once, and administering 1200 mg / dose of domvanarimab once or more times in a 21-day administration cycle.

[0057] Item 34. An antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method according to Item 32, characterized by administering futivatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, administering 360 mg / dose of zimberelimab once on Day 1, and administering 1200 mg / dose of domvanarimab once on Day 1, repeating this 21-day administration cycle once or twice or more.

[0058] Item 35. An antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method as described in any one of items 32-34, wherein the cancer patient is an esophageal cancer patient with no prior treatment history for advanced cancer or with a prior treatment history of one line of chemotherapy.

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

[0060] Section 36-2. Pharmaceutical compositions for the prevention or treatment of any of the following head and neck cancers (i) to (iv) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and pharmaceutical compositions used in combination with pembrolizumab). (i) A pharmaceutical composition comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimbererimab, 5-fluorouracil, and carboplatin or cisplatin for patients with head and neck cancer, and further comprising a pharmaceutical carrier. (ii) A pharmaceutical composition comprising zimbererimab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil, and carboplatin or cisplatin for patients with head and neck cancer, and further comprising a pharmaceutical carrier. (iii) A pharmaceutical composition comprising 5-fluorouracil as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and carboplatin or cisplatin, for use in patients with head and neck cancer. (iv) A pharmaceutical composition comprising carboplatin or cisplatin as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and 5-fluorouracil, for use in patients with head and neck cancer.

[0061] Section 36-3. Any of the following uses (i) to (iv) (excluding use for manufacturing antitumor agents containing pembrolizumab as an active ingredient and use for manufacturing antitumor agents intended to be administered in combination with pembrolizumab): (i) Use of futivatinib or a pharmaceutically acceptable salt thereof for the manufacture of an antitumor agent to be used in combination with zimberemab, 5-fluorouracil, and carboplatin or cisplatin for patients with head and neck cancer. (ii) Use of zimberelimab to manufacture an antitumor agent to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil, and carboplatin or cisplatin for patients with head and neck cancer. (iii) Use of 5-fluorouracil to manufacture an antitumor agent to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and carboplatin or cisplatin for patients with head and neck cancer. (iv) Use of carboplatin or cisplatin to manufacture an antitumor agent to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and 5-fluorouracil for patients with head and neck cancer.

[0062] Section 36-4. Compounds or salts thereof for use as described in any of (i) to (iv) below (excluding compounds used in combination with pembrolizumab and pembrolizumab for use). (i) Futivatinib or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of head and neck cancer, to be administered in combination with zimbererimab, 5-fluorouracil, and carboplatin or cisplatin to patients with head and neck cancer. (ii) Zimberemab for use in the prevention or treatment of head and neck cancer, to be administered in combination with futivatinib 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 futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, 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 futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and 5-fluorouracil to patients with head and neck cancer.

[0063] Section 36-5. Use of any of the following (i) to (iv) (excluding the use of pembrolizumab and the use of compounds used in combination with pembrolizumab). (i) Use of futivatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of head and neck cancer, to be used in combination with zimberemab, 5-fluorouracil, and carboplatin or cisplatin in patients with head and neck cancer. (ii) Use of zimberemab for the prevention or treatment of head and neck cancer, to be administered in combination with futivatinib 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 the prevention or treatment of head and neck cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and carboplatin or cisplatin to patients with head and neck cancer. (iv) Use of carboplatin or cisplatin for the prevention or treatment of head and neck cancer, used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and 5-fluorouracil in patients with head and neck cancer.

[0064] Section 36-6. Any of the following commercial packages (i) to (iv) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and commercial packages intended for use in combination with pembrolizumab). (i) A commercial package comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, along with instructions for its use in a subject for the prevention or treatment of head and neck cancer, to be used in combination with zimberemab, 5-fluorouracil, and carboplatin or cisplatin in patients with head and neck cancer. (ii) A commercial package comprising zimberelimab as an active ingredient, along with instructions for its use in preventing or treating head and neck cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil, and carboplatin or cisplatin in patients with head and neck cancer. (iii) A commercial package comprising 5-fluorouracil as an active ingredient, along with instructions for its use in preventing or treating head and neck cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and carboplatin or cisplatin in patients with head and neck cancer. (iv) A commercial package comprising carboplatin or cisplatin as an active ingredient, along with instructions for its use in preventing or treating head and neck cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimberelimab, and 5-fluorouracil in patients with head and neck cancer.

[0065] Section 36-7. Any method described in (i) to (iv) below (excluding methods involving the administration of pembrolizumab and methods involving the administration of an antitumor agent to a subject who has received, is receiving, or is scheduled to receive pembrolizumab). (i) A method for preventing or treating head and neck cancer, comprising administering an effective amount of futivatinib or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered zimbererimab, has been, is, or is scheduled to be administered 5-fluorouracil, and has been, is, or is scheduled to be administered carboplatin or cisplatin. (ii) A method for preventing or treating head and neck cancer, comprising administering an effective dose of zimbererimab to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered futivatinib or a pharmaceutically acceptable salt thereof, has been, is, or is scheduled to be administered 5-fluorouracil, and has been, is, or is scheduled to be administered carboplatin or cisplatin. (iii) A method for preventing or treating head and neck cancer, comprising administering an effective dose of 5-fluorouracil to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered futivatinib or a pharmaceutically acceptable salt thereof, has been, is, or is scheduled to be administered zimbererimab, or has been, is, or is scheduled to be administered carboplatin or cisplatin. (iv) A method for preventing or treating head and neck cancer, comprising administering an effective dose of carboplatin or cisplatin to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered futivatinib or a pharmaceutically acceptable salt thereof, has been, is, or is scheduled to be administered zimbererimab, or has been, is, or is scheduled to be administered 5-fluorouracil.

[0066] 37. Administer futivatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, administer 360 mg / dose of zimbererimab once, and then add carboplatin with an AUC of 5 or 100 mg / m². 2 Administer cisplatin once, 1000 mg / m². 2 The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method according to item 36, characterized by administering 5-fluorouracil at a dose of / day daily for 4 consecutive days for 21 days, repeated once or more times.

[0067] 38. Administer futivatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, and administer 360 mg / dose of zimberemab once on Day 1, along with carboplatin with an AUC of 5 or 100 mg / m². 2 Administer cisplatin once on Day 1, at a dose of 1000 mg / m². 2 The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method according to item 36, characterized by administering 5-fluorouracil at a dose of / day daily from Day 1 to 4 for 21 days, and repeating this cycle once or more times.

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

[0069] Item 40. An antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method described in any one of items 1 to 27, which is an antitumor agent described in item 40-1, a pharmaceutical composition described in item 40-2, a use described in item 40-3, a compound or salt thereof for use described in item 40-4, a use described in item 40-5, a commercial package described in item 40-6, or a method described in item 40-7 below: Section 40-1. Any of the following antitumor agents (i) to (iii) (excluding antitumor agents containing pembrolizumab as the active ingredient and antitumor agents used in combination with pembrolizumab). (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimberemab and dombanarimab for patients with head and neck cancer. (ii) The antitumor agent comprising zimbererimab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and dombanarimab for patients with head and neck cancer. (iii) The antitumor agent comprising dombanalimab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and zimbererimab for patients with head and neck cancer.

[0070] Section 40-2. Pharmaceutical compositions for the prevention or treatment of any of the following head and neck cancers (i) to (iii) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and pharmaceutical compositions used in combination with pembrolizumab). (i) A pharmaceutical composition comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with zimberemab and dombanarimab in patients with head and neck cancer. (ii) A pharmaceutical composition comprising zimbererimab as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with futivatinib or a pharmaceutically acceptable salt thereof and dombanarimab in patients with head and neck cancer. (iii) A pharmaceutical composition comprising dombanarimab as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with futivatinib or a pharmaceutically acceptable salt thereof and zimbererimab in patients with head and neck cancer.

[0071] Section 40-3. Any of the following uses (i) to (iii) (excluding use for manufacturing antitumor agents containing pembrolizumab as an active ingredient and use for manufacturing antitumor agents to be used in combination with pembrolizumab): (i) Use of futivatinib or a pharmaceutically acceptable salt thereof for the manufacture of an antitumor agent to be used in combination with zimberemab and dombanarimab for patients with head and neck cancer. (ii) Use of zimbererimab to manufacture antitumor agents to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and dombanarimab for patients with head and neck cancer. (iii) Use of dombanarimab to manufacture an antitumor agent to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and zimbererimab for use in patients with head and neck cancer.

[0072] Section 40-4. Compounds or salts thereof for use as described in any of (i) to (iii) below (excluding compounds used in combination with pembrolizumab and pembrolizumab for use). (i) Futivatinib or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of head and neck cancer, to be used in combination with zimberemab and dombanalimab in patients with head and neck cancer. (ii) Zimberemab for use in the prevention or treatment of head and neck cancer, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and dombanarimab in patients with head and neck cancer. (iii) Dombanarimab for use in the prevention or treatment of head and neck cancer, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and zimbererimab in patients with head and neck cancer.

[0073] Section 40-5. Use of any of the following (i) to (iii) (excluding the use of pembrolizumab and the use of compounds used in combination with pembrolizumab). (i) Use of futivatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of head and neck cancer, to be used in combination with zimberemab and dombanarimab in patients with head and neck cancer. (ii) Use of zimberemab for the prevention or treatment of head and neck cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof and dombanarimab to patients with head and neck cancer. (iii) Use of dombanarimab for the prevention or treatment of head and neck cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof and zimbererimab to patients with head and neck cancer.

[0074] Section 40-6. Any of the following commercial packages (i) to (iii) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and commercial packages intended for use in combination with pembrolizumab). (i) A commercial package comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, along with instructions for its use in preventing or treating head and neck cancer in a subject, to be used in combination with zimberemab and dombanarimab in patients with head and neck cancer. (ii) A commercial package comprising zimberelimab as an active ingredient, along with instructions for its use in preventing or treating head and neck cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and dombanalimab in patients with head and neck cancer. (iii) A commercial package comprising dombanalimab as an active ingredient, along with instructions for its use in preventing or treating head and neck cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and zimbererimab in patients with head and neck cancer.

[0075] Section 40-7. Any method described in (i) to (iii) below (excluding methods involving the administration of pembrolizumab and methods involving the administration of an antitumor agent to a subject who has been administered, is simultaneously administered, or is scheduled to be administered pembrolizumab). (i) A method for preventing or treating head and neck cancer, comprising administering an effective amount of futivatinib or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered zimbererimab, and has been, is, or is scheduled to be administered dombanarimab. (ii) A method for preventing or treating head and neck cancer, comprising administering an effective dose of zimbererimab to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered futivatinib or a pharmaceutically acceptable salt thereof, and the subject has been, is, or is scheduled to be administered dombanarimab. (iii) A method for preventing or treating head and neck cancer, comprising administering an effective dose of dombanarimab to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered futivatinib or a pharmaceutically acceptable salt thereof, and the subject has been, is, or is scheduled to be administered zimbererimab.

[0076] Item 41. An antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method according to Item 40, characterized by administering futivatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, followed by a single dose of 360 mg / dose of zimberelimab and a single dose of 1200 mg / dose of domvanarimab, repeated once or more times in a 21-day administration cycle.

[0077] The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method according to item 40, characterized by administering futivatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, administering 360 mg / dose of zimberelimab once on Day 1, and administering 1200 mg / dose of domvanarimab once on Day 1, repeating this 21-day administration cycle once or twice or more.

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

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

[0080] Section 44-2. Pharmaceutical compositions for the prevention or treatment of any of the following non-small cell lung cancers (i) to (iv) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and pharmaceutical compositions used in combination with pembrolizumab). (i) A pharmaceutical composition comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with zimbererimab, albumin-bound paclitaxel, and carboplatin in patients with non-small cell lung cancer. (ii) A pharmaceutical composition comprising zimbererimab as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with futivatinib or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and carboplatin in patients with non-small cell lung cancer. (iii) A pharmaceutical composition comprising albumin-bound paclitaxel as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and carboplatin in patients with non-small cell lung cancer. (iv) A pharmaceutical composition comprising carboplatin as an active ingredient and further comprising a pharmaceutical carrier, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and albumin-bound paclitaxel for patients with non-small cell lung cancer.

[0081] Section 44-3. Any of the following uses (i) to (iv) (excluding use for manufacturing antitumor agents containing pembrolizumab as an active ingredient and use for manufacturing antitumor agents to be administered in combination with pembrolizumab): (i) Use of futivatinib or a pharmaceutically acceptable salt thereof for the manufacture of an antitumor agent to be used in combination with zimbererimab, albumin-bound paclitaxel, and carboplatin for patients with non-small cell lung cancer. (ii) Use of zimberelimab to manufacture an antitumor agent to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and carboplatin for patients with non-small cell lung cancer. (iii) Use of albumin-bound paclitaxel to manufacture an antitumor agent to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and carboplatin for patients with non-small cell lung cancer. (iv) Use of carboplatin to manufacture an antitumor agent to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and albumin-bound paclitaxel for patients with non-small cell lung cancer.

[0082] Section 44-4. Compounds or salts thereof for use as described in any of (i) to (iv) below (excluding compounds used in combination with pembrolizumab and pembrolizumab for use). (i) Futivatinib 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 zimbererimab, albumin-bound paclitaxel, and carboplatin to patients with non-small cell lung cancer. (ii) Zimberemab for use in the prevention or treatment of non-small cell lung cancer, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and carboplatin in 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 futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, 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 futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and albumin-bound paclitaxel to patients with non-small cell lung cancer.

[0083] Section 44-5. Use of any of the following (i) to (iv) (excluding the use of pembrolizumab and the use of compounds used in combination with pembrolizumab). (i) Use of futivatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of non-small cell lung cancer, to be administered in combination with zimbererimab, albumin-bound paclitaxel, and carboplatin to patients with non-small cell lung cancer. (ii) Use of zimberemab for the prevention or treatment of non-small cell lung cancer, to be administered in combination with futivatinib 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 prevention or treatment of non-small cell lung cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and carboplatin to patients with non-small cell lung cancer. (iv) Use of carboplatin for the prevention or treatment of non-small cell lung cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and albumin-bound paclitaxel to patients with non-small cell lung cancer.

[0084] Section 44-6. Any of the following commercial packages (i) to (iv) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and commercial packages intended for use in combination with pembrolizumab). (i) A commercial package comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, along with instructions for its use in preventing or treating non-small cell lung cancer in a subject, to be used in combination with zimberemab, albumin-bound paclitaxel, and carboplatin in patients with non-small cell lung cancer. (ii) A commercial package comprising zimberelimab as an active ingredient, along with instructions for its use in preventing or treating non-small cell lung cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and carboplatin in patients with non-small cell lung cancer. (iii) A commercial package comprising albumin-bound paclitaxel as an active ingredient, along with instructions for its use in preventing or treating non-small cell lung cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimberelimab, and carboplatin in patients with non-small cell lung cancer. (iv) A commercial package comprising carboplatin as an active ingredient, along with instructions for its use in preventing or treating non-small cell lung cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and albumin-bound paclitaxel in patients with non-small cell lung cancer.

[0085] Section 44-7. Any method described in (i) to (iv) below (excluding methods involving the administration of pembrolizumab and methods involving the administration of an antitumor agent to a subject who has received, is receiving, or is scheduled to receive 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 who needs it, wherein the subject has been administered gemberlimab, is to be administered simultaneously, or is scheduled to be administered, has been administered albumin-bound paclitaxel, is to be administered simultaneously, or is scheduled to be administered, and has been administered carboplatin, is to be administered simultaneously, or is scheduled to be administered. (ii) A method for preventing or treating non-small cell lung cancer, comprising administering an effective amount of gemberlimab to a subject who needs it, wherein the subject has been administered futibatinib or a pharmaceutically acceptable salt thereof, is to be administered simultaneously, or is scheduled to be administered, has been administered albumin-bound paclitaxel, is to be administered simultaneously, or is scheduled to be administered, and has been administered carboplatin, is to be administered simultaneously, or is scheduled to be administered. (iii) A method for preventing or treating non-small cell lung cancer, comprising administering an effective amount of albumin-bound paclitaxel to a subject who needs it, wherein the subject has been administered futibatinib or a pharmaceutically acceptable salt thereof, is to be administered simultaneously, or is scheduled to be administered, has been administered gemberlimab, is to be administered simultaneously, or is scheduled to be administered, and has been administered carboplatin, is to be administered simultaneously, or is scheduled to be administered. (iv) A method for preventing or treating non-small cell lung cancer, comprising administering an effective amount of carboplatin to a subject who needs it, wherein the subject has been administered futibatinib or a pharmaceutically acceptable salt thereof, is to be administered simultaneously, or is scheduled to be administered, has been administered gemberlimab, is to be administered simultaneously, or is scheduled to be administered, and has been administered albumin-bound paclitaxel, is to be administered simultaneously, or is scheduled to be administered.

[0086] Item 45. Futibatinib at 12 mg per dose, 16 mg per dose, or 20 mg per dose is administered once daily for consecutive days, gemberlimab at 360 mg per dose is administered once, 100 mg / m 2The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method according to item 44, characterized by administering three doses of albumin-suspended paclitaxel and one dose of carboplatin with an AUC of 6 over a 21-day period, repeated one or more times.

[0087] 46. ​​Administer futivatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, and administer 360 mg / dose of zimbererimab on Day 1, along with 100 mg / m². 2 The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method according to item 44, characterized by administering albumin-suspended paclitaxel once each on Day 1, Day 8, and Day 15, and repeating a 21-day administration cycle once or more times, in which carboplatin with an AUC of 6 is administered on Day 1.

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

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

[0090] Section 48-2. Pharmaceutical compositions for the prevention or treatment of any of the following biliary tract cancers (i) to (iv) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and pharmaceutical compositions used in combination with pembrolizumab). (i) A pharmaceutical composition comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with zimberemab, cisplatin, and gemcitabine in patients with biliary tract cancer. (ii) A pharmaceutical composition comprising zimbererimab as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with futivatinib or a pharmaceutically acceptable salt thereof, cisplatin, and gemcitabine in patients with biliary tract cancer. (iii) A pharmaceutical composition comprising gemcitabine as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and cisplatin in patients with biliary tract cancer. (iv) A pharmaceutical composition comprising cisplatin as an active ingredient and further comprising a pharmaceutical carrier, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and gemcitabine for use in patients with biliary tract cancer.

[0091] Section 48-3. Any of the following uses (i) to (iv) (excluding use for manufacturing antitumor agents containing pembrolizumab as an active ingredient and use for manufacturing antitumor agents to be used in combination with pembrolizumab): (i) Use of futivatinib or a pharmaceutically acceptable salt thereof for the manufacture of an antitumor agent to be used in combination with zimberemab, cisplatin, and gemcitabine for patients with biliary tract cancer. (ii) Use of zimbererimab to manufacture an antitumor agent to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, cisplatin, and gemcitabine for patients with biliary tract cancer. (iii) Use of gemcitabine for manufacturing antitumor agents to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and cisplatin for patients with biliary tract cancer. (iv) Use of cisplatin to manufacture antitumor agents to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and gemcitabine for patients with biliary tract cancer.

[0092] Section 48-4. Compounds or salts thereof for use as described in any of (i) to (iv) below (excluding compounds used in combination with pembrolizumab and pembrolizumab for use). (i) Futivacinib or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of biliary tract cancer, to be administered in combination with zimberemab, cisplatin, and gemcitabine to patients with biliary tract cancer. (ii) Zimberelimab for use in the prevention or treatment of biliary tract cancer, to be administered in combination with futivatinib 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 futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and cisplatin to patients with biliary tract cancer. (iv) Cisplatin for use in the prevention or treatment of biliary tract cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and gemcitabine to patients with biliary tract cancer.

[0093] Section 48-5. Use of any of the following (i) to (iv) (excluding the use of pembrolizumab and the use of compounds used in combination with pembrolizumab). (i) Use of futivatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of biliary tract cancer, to be used in combination with zimberemab, cisplatin, and gemcitabine in patients with biliary tract cancer. (ii) Use of zimberemab for the prevention or treatment of biliary tract cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof, cisplatin, and gemcitabine to patients with biliary tract cancer. (iii) Use of gemcitabine for the prevention or treatment of biliary tract cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and cisplatin to patients with biliary tract cancer. (iv) Use of cisplatin to prevent or treat biliary tract cancer in patients with biliary tract cancer, in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and gemcitabine.

[0094] Section 48-6. Any of the following commercial packages (i) to (iv) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and commercial packages intended for use in combination with pembrolizumab). (i) A commercial package comprising futibatinib or a pharmaceutically acceptable salt thereof as an active ingredient, along with instructions for its use in preventing or treating biliary tract cancer in a subject, to be used in combination with zimberemab, cisplatin, and gemcitabine in patients with biliary tract cancer. (ii) A commercial package comprising zimberelimab as an active ingredient, along with instructions for its use in preventing or treating biliary tract cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, cisplatin, and gemcitabine in patients with biliary tract cancer. (iii) A commercial package comprising gemcitabine as an active ingredient, along with instructions for its use in preventing or treating biliary tract cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimberelimab, and cisplatin in patients with biliary tract cancer. (iv) A commercial package comprising cisplatin as an active ingredient, along with instructions for its use in preventing or treating biliary tract cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and gemcitabine in patients with biliary tract cancer.

[0095] Section 48-7. Any method described in (i) to (iv) below (excluding methods involving the administration of pembrolizumab and methods involving the administration of an antitumor agent to a subject who has received, is receiving, or is scheduled to receive pembrolizumab). (i) A method for preventing or treating biliary tract cancer, comprising administering an effective amount of futivatinib or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered zimbererimab, has been, is, or is scheduled to be administered cisplatin, has been, is, or is scheduled to be administered gemcitabine. (ii) A method for preventing or treating biliary tract cancer, comprising administering an effective dose of zimbererimab to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered futivatinib or a pharmaceutically acceptable salt thereof, has been, is, or is scheduled to be administered cisplatin, or has been, is, or is scheduled to be administered gemcitabine. (iii) A method for preventing or treating biliary tract cancer, comprising administering an effective dose of gemcitabine to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered futivatinib or a pharmaceutically acceptable salt thereof, has been, is, or is scheduled to be administered zimbererimab, or has been, is, or is scheduled to be administered cisplatin. (iv) A method for preventing or treating biliary tract cancer, comprising administering an effective dose of cisplatin to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered futivatinib or a pharmaceutically acceptable salt thereof, has been, is, or is scheduled to be administered zimbererimab, or has been, is, or is scheduled to be administered gemcitabine.

[0096] 49. Administer futivacinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, and administer 360 mg / dose of zimbererimab once, plus 25 mg / m². 2 Administer cisplatin twice, 1000 mg / m². 2 The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method according to item 48, characterized by administering gemcitabine twice over a 21-day period, repeated once or more times.

[0097] Administer 50.12 mg, 16 mg, or 20 mg of futivatinib once daily, and 360 mg of zimbererimab on Day 1, followed by 25 mg / m². 2Administer cisplatin once on Day 1 and once on Day 8, at a dose of 1000 mg / m². 2 The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method according to item 48, characterized by administering gemcitabine once on Day 1 and once on Day 8 for 21 days, and repeating this cycle one or more times.

[0098] Item 51. An antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method as described in any one of items 48-50, wherein the cancer patient is a biliary tract cancer patient with no prior treatment history for advanced cancer.

[0099] Item 52. An antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method described in any one of items 1 to 27, which is an antitumor agent described in item 52-1, a pharmaceutical composition described in item 52-2, a use described in item 52-3, a compound or salt thereof for use described in item 52-4, a use described in item 52-5, a commercial package described in item 52-6, or a method described in item 52-7 below: Section 52-1. Any of the following antitumor agents (i) to (iv) (excluding antitumor agents containing pembrolizumab as the active ingredient and antitumor agents used in combination with pembrolizumab). (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimberemab, albumin-bound paclitaxel, and gemcitabine in patients with pancreatic cancer. (ii) The antitumor agent comprising zimberemab as the active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and gemcitabine for patients with pancreatic cancer. (iii) The antitumor agent comprising gemcitabine as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and albumin-bound paclitaxel for patients with pancreatic cancer. (iv) The antitumor agent comprising albumin-bound paclitaxel as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and gemcitabine in patients with pancreatic cancer.

[0100] Section 52-2. Pharmaceutical compositions for the prevention or treatment of any of the following pancreatic cancers (i) to (iv) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and pharmaceutical compositions used in combination with pembrolizumab). (i) A pharmaceutical composition comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with zimberemab, albumin-bound paclitaxel, and gemcitabine in patients with pancreatic cancer. (ii) A pharmaceutical composition comprising zimbererimab as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with futivatinib or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and gemcitabine in patients with pancreatic cancer. (iii) A pharmaceutical composition comprising gemcitabine as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and albumin-bound paclitaxel in patients with pancreatic cancer. (iv) A pharmaceutical composition comprising albumin-bound paclitaxel as an active ingredient, and further comprising a pharmaceutical carrier, for use in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and gemcitabine in patients with pancreatic cancer.

[0101] Section 52-3. Any of the following uses (i) to (iv) (excluding use for manufacturing antitumor agents containing pembrolizumab as an active ingredient and use for manufacturing antitumor agents intended to be administered in combination with pembrolizumab): (i) Use of futivatinib or a pharmaceutically acceptable salt thereof for the manufacture of an antitumor agent to be used in combination with zimberemab, albumin-bound paclitaxel, and gemcitabine in patients with pancreatic cancer. (ii) Use of zimbererimab to manufacture antitumor agents to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and gemcitabine for patients with pancreatic cancer. (iii) Use of gemcitabine to manufacture an antitumor agent to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and albumin-bound paclitaxel for patients with pancreatic cancer. (iv) Use of albumin-bound paclitaxel to manufacture an antitumor agent to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and gemcitabine for use in patients with pancreatic cancer.

[0102] Section 52-4. Compounds or salts thereof for use as described in any of (i) to (iv) below (excluding compounds used in combination with pembrolizumab and pembrolizumab for use). (i) Futivatinib or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of pancreatic cancer, to be administered in combination with zimberemab, albumin-bound paclitaxel, and gemcitabine to patients with pancreatic cancer. (ii) Zimberelimab for use in the prevention or treatment of pancreatic cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and gemcitabine to patients with pancreatic cancer. (iii) Gemcitabine for use in the prevention or treatment of pancreatic cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and albumin-bound paclitaxel to patients with pancreatic cancer. (iv) Albumin-bound paclitaxel for use in the prevention or treatment of pancreatic cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and gemcitabine to patients with pancreatic cancer.

[0103] Section 52-5. Use of any of the following (i) to (iv) (excluding the use of pembrolizumab and the use of compounds used in combination with pembrolizumab). (i) Use of futivatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of pancreatic cancer, to be administered in combination with zimberemab, albumin-bound paclitaxel, and gemcitabine to patients with pancreatic cancer. (ii) Use of zimberemab for the prevention or treatment of pancreatic cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and gemcitabine to patients with pancreatic cancer. (iii) Use of gemcitabine for the prevention or treatment of pancreatic cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and albumin-bound paclitaxel to patients with pancreatic cancer. (iv) Use of albumin-bound paclitaxel for the prevention or treatment of pancreatic cancer, to be administered in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and gemcitabine to patients with pancreatic cancer.

[0104] Section 52-6. Any of the following commercial packages (i) to (iv) (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient and commercial packages intended for use in combination with pembrolizumab). (i) A commercial package comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, along with instructions for its use in preventing or treating pancreatic cancer in a subject, to be used in combination with zimberemab, albumin-bound paclitaxel, and gemcitabine in patients with pancreatic cancer. (ii) A commercial package comprising zimberelimab as an active ingredient, along with instructions for its use in preventing or treating pancreatic cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and gemcitabine in patients with pancreatic cancer. (iii) A commercial package comprising gemcitabine as an active ingredient, along with instructions for its use in preventing or treating pancreatic cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and albumin-bound paclitaxel in patients with pancreatic cancer. (iv) A commercial package comprising albumin-bound paclitaxel as an active ingredient, along with instructions for its use in preventing or treating pancreatic cancer in a subject, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and gemcitabine in patients with pancreatic cancer.

[0105] Section 52-7. Methods according to any of the following (i) to (iv) (excluding methods involving the administration of pembrolizumab and methods involving the administration of an antitumor agent to a subject who has received, is receiving, or is scheduled to receive pembrolizumab). (i) A method for preventing or treating pancreatic cancer, comprising administering an effective amount of futivatinib or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered zimbererimab, has been, is, or is scheduled to be administered albumin-bound paclitaxel, and has been, is, or is scheduled to be administered gemcitabine. (ii) A method for preventing or treating pancreatic cancer, comprising administering an effective dose of zimbererimab to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered futivatinib or a pharmaceutically acceptable salt thereof, has been, is, or is scheduled to be administered albumin-bound paclitaxel, or has been, is, or is scheduled to be administered gemcitabine. (iii) A method for preventing or treating pancreatic cancer, comprising administering an effective dose of gemcitabine to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered futivatinib or a pharmaceutically acceptable salt thereof, has been, is, or is scheduled to be administered zimbererimab, or has been, is, or is scheduled to be administered albumin-bound paclitaxel. (iv) A method for preventing or treating pancreatic cancer, comprising administering an effective dose of albumin-bound paclitaxel to a subject in need thereof, wherein the subject has been, is, or is scheduled to be administered futivatinib or a pharmaceutically acceptable salt thereof, has been, is, or is scheduled to be administered zimbererimab, or has been, is, or is scheduled to be administered gemcitabine.

[0106] 53. Administer futivacinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, and administer 240 mg / dose of zimbererimab twice, or 125 mg / m². 2 Administer albumin-suspended paclitaxel three times, at a dose of 1000 mg / m². 2 The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method according to item 52, characterized by administering gemcitabine three times over a 28-day period, repeated once or more times.

[0107] 54. Administer futivatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, and administer 240 mg / dose of zimbererimab on Day 1 and Day 15, and 125 mg / m². 2 Paclitaxel in albumin-suspended form is administered once on Day 1, Day 8, and Day 15, at a dose of 1000 mg / m². 2 The antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method according to item 52, characterized by administering gemcitabine once on Day 1, Day 8, and Day 15, in a 28-day administration cycle, repeated once or more times.

[0108] Item 55. An antitumor agent, pharmaceutical composition, use, compound or salt thereof for use, commercial package or method as described in any one of items 52-54, wherein the cancer patient is a pancreatic cancer patient with no prior treatment history for advanced cancer. [Effects of the Invention]

[0109] According to the present invention, it is possible to provide a novel combination therapy that exhibits excellent antitumor effects (e.g., tumor reduction effect, survival extension effect, etc.) in cancer patients. In particular, the combination therapy of the present invention is effective for patients with lung cancer, esophageal cancer, biliary tract cancer, or head and neck cancer who have not received prior treatment. [Brief explanation of the drawing]

[0110] [Figure 1] This document outlines the clinical trial design for combination therapy including futivatinib. [Modes for carrying out the invention]

[0111] The present invention relates to providing futivatinib or its salts, immune checkpoint inhibitors (excluding pembrolizumab and CD155 / TIGIT pathway antagonists), and combinations with at least one other antitumor agent.

[0112] In the present invention, futibatinib, which provides excellent antitumor effects when used in combination with immune checkpoint inhibitors, is a disubstituted benzenealkynyl compound having the structure described below. Futibatinib is described as Example Compound 2 in the above-mentioned Patent Document 2. Futibatinib or its salts have been reported to have excellent FGFR inhibitory activity, inhibiting the phosphorylation ability of tyrosine in the substrate peptide sequences of the FGFR1, FGFR3, and FGFR4 receptor protein tyrosine kinases, respectively (Patent Document 2).

[0113] [ka]

[0114] The futibatinib or pharmaceutically acceptable salt thereof in the present invention described above is not particularly limited, but can be synthesized, for example, based on the manufacturing method described in Patent Document 2.

[0115] In the present invention, futibatinib can be used as is or in the form of a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts of futibatinib are, but are not limited to, addition salts with inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as acetic acid, citric acid, tartaric acid and maleic acid, salts with alkali metals such as potassium and sodium, salts with alkaline earth metals such as calcium and magnesium, and salts with organic bases such as ammonium salts, ethylamine salts and arginine salts.

[0116] The immune checkpoint inhibitors in this invention, excluding pembrolizumab and anti-TIGIT antibodies, act on immune checkpoint molecules to induce an antitumor immune response in the target organism and control the immune evasion of tumors.

[0117] Examples of such substances include those that promote the function of costimulatory molecules (stimulative co-stimulatory molecules) or those that suppress the function of coinhibitory molecules (inhibitory co-stimulatory molecules). Examples of immune checkpoint molecules include the B7 family (B7-1, B7-2, PD-L1, PD-L2, etc.), the CD28 family (CTLA-4, PD-1, etc.), the TNF superfamily (4-1BBL, OX40L), and the TNF receptor superfamily (4-1BB, OX40). Immune checkpoint inhibitors can utilize substances that target immune checkpoint molecules. Examples include PD-1 pathway antagonists, ICOS pathway agonists, CTLA-4 pathway antagonists, CD28 pathway agonists, BTLA pathway antagonists, 4-1BB pathway agonists, and CD155 / TIGIT pathway antagonists.

[0118] In the present invention, preferably, at least one selected from PD-1 pathway antagonists, ICOS pathway agonists, CTLA-4 pathway antagonists, CD28 pathway agonists, and CD155 / TIGIT pathway antagonists; more preferably, at least one selected from PD-1 pathway antagonists, CTLA-4 pathway antagonists, and CD155 / TIGIT pathway antagonists; more preferably, at least one selected from PD-1 pathway antagonists and CD155 / TIGIT pathway antagonists; and even more preferably, a PD-1 pathway antagonist.

[0119] PD-1 pathway antagonists inhibit immunosuppressive signals mediated by PD-1 expressed on T cells and its ligands, PD-L1 or PD-L2. Examples include, but are not limited to, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, PD-1 extracellular domains, PD-L1 extracellular domains, PD-L2 extracellular domains, 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. Preferably, they are anti-PD-1 antibodies, anti-PD-L1 antibodies, or anti-PD-L2 antibodies, and more preferably, anti-PD-1 antibodies or anti-PD-L1 antibodies. Among these, anti-PD-1 antibodies are particularly preferred.

[0120] Furthermore, CTLA-4 pathway antagonists inhibit immunosuppressive signals mediated by CTLA-4 expressed on T cells and its ligands, B7-1(CD80) and B7-2(CD86). Preferably, these are anti-CTLA-4 antibodies, CTLA-4 extracellular domains, CTLA-4-Ig (a fusion protein of the CTLA-4 extracellular domain and the FC region of Ig), anti-B7-1(CD80) antibodies, or anti-B7-2(CD86) antibodies, and more preferably anti-CTLA-4 antibodies or CTLA-4-Ig. Among these, anti-CTLA-4 antibodies are particularly preferred.

[0121] Furthermore, CD155 / TIGIT pathway antagonists inhibit immunosuppressive signals mediated by TIGIT expressed on T cells and its ligand, CD155. Examples include, but are not limited to, anti-CD155 antibodies and anti-TIGIT antibodies. Preferably, anti-CD155 antibodies or anti-TIGIT antibodies are used, and particularly preferably anti-TIGIT antibodies.

[0122] 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, Diabody, etc. (Nat. Rev. Immunol., 6:343-357, 2006), and these include monoclonal antibodies 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 preferred. In the present invention, monoclonal antibodies are preferred.

[0123] Preferably, it is a humanized IgG monoclonal antibody or a human IgG monoclonal antibody.

[0124] In the present invention, preferred anti-PD-1 antibodies include nivolumab, cemiplimab, spartalizumab, tislerizumab, BI754091, dostarlimab, sasanlimab, MGA-012, cetrelimab, AGEN-2034, zimberelimab, cemrelizumab, budigalimab, and balstilimab, with nivolumab or zimberelimab being preferred, and zimberelimab being particularly preferred.

[0125] Preferred anti-PD-L1 antibodies in the present invention include atezolizumab, durvalumab, avelumab, lodapolimab, and BGB-A333.

[0126] Preferred anti-CTLA-4 antibodies in the present invention include ipilimumab and tremelimumab.

[0127] In the present invention, preferred CTLA-4-Ig include abatacept and the like.

[0128] In the present invention, preferred anti-TIGIT antibodies include domvanalimab (AB154), AB308, vibostolimab, ociperlimab, tilagolumab, AGEN-1777, HB-0036, HLX-301, ONO-4686, M-6223, PM-1022, Etigilimab, ZG-005, AZD-2936, Belrestotug, or JS-006. Domvanalimab, AB308, vibostolimab, ociperlimab, or tilagolumab are preferred, domvanalimab or AB308 are more preferred, and domvanalimab is particularly preferred.

[0129] These agonists or antagonists can be manufactured by commonly known methods.

[0130] Furthermore, anti-PD-1 antibodies are already marketed or are scheduled to be marketed as nivolumab or zimbererimab, anti-PD-L1 antibodies as atezolizumab, durvalumab, or avelumab, anti-CTLA-4 antibodies as ipilimumab or tremelimumab, CTLA-4-Ig as abatacept, and anti-TIGIT antibodies as domvanarimab, and these can also be used.

[0131] In the present invention, immune checkpoint inhibitors may be used individually or in combination of two or more.

[0132] In the present invention, when using two or more immune checkpoint inhibitors, 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 × CTLA-4).

[0133] In the present invention, preferred immune checkpoint inhibitors are PD-1 pathway antagonists, more preferably anti-PD-1 antibodies, even more preferably nivolumab or zimberelimab, and particularly preferably zimberelimab.

[0134] The present invention achieves excellent antitumor effects by combining futivatinib or a pharmaceutically acceptable salt thereof with at least one immune checkpoint inhibitor, and adding an "additional antitumor agent" to create a combination of at least three agents. Therefore, the additional antitumor agent in the present invention is not particularly limited as long as it is an agent having antitumor activity other than futivatinib or a pharmaceutically acceptable salt thereof and the selected immune checkpoint inhibitor (except pembrolizumab). Here, "other than the selected immune checkpoint inhibitor" means, for example, that if A is selected as the "immune checkpoint inhibitor" in the antitumor agent of the present invention, then A is not selected as the "additional antitumor agent." In the present invention, the additional antitumor agent may take the form of a small molecule 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.

[0135] In the present invention, other preferred antitumor agents are chemotherapeutic agents. Here, the chemotherapeutic agent in the present invention is preferably at least one selected from the group consisting of antimetabolites (purine antimetabolites, pyrimidine antimetabolites, folic acid antimetabolites, 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 (small molecular targeted drugs, antibody-targeted drugs, etc.), antitumor antibiotics, and alkylating agents. At least one selected from the group consisting of ion-based antitumor agents, platinum-based preparations, and immune checkpoint inhibitors is more preferable; at least one selected from the group consisting of antimetabolites (purine-based antimetabolites, pyrimidine-based antimetabolites, folic acid antimetabolites, etc.), alkaloid-based antitumor agents, platinum-based preparations, and CD155 / TIGIT pathway antagonists is even more preferable; and at least one selected from the group consisting of antimetabolites (purine-based antimetabolites, pyrimidine-based antimetabolites, folic acid antimetabolites, etc.), alkaloid-based antitumor agents, platinum-based preparations, and anti-TIGIT antibodies is even more preferable. Furthermore, in an exemplary preferred embodiment of the present invention, at least one agent other than the above-mentioned immune checkpoint inhibitors may be used as the chemotherapeutic agent. In such embodiments, at least one selected from the group consisting of antimetabolites (purine antimetabolites, pyrimidine antimetabolites, folic acid antimetabolites, etc.), alkaloid antitumor agents, platinum preparations, molecular targeted drugs (small molecular targeted drugs, antibody-targeted drugs, etc.), antitumor antibiotics, and alkylating agents can be used as the chemotherapeutic agent.

[0136] More specifically, Purine antimetabolites such as fludarabine, cladribine, and nelarabine; 5-Fluorouracil (5-FU), tegafur / gimeracil / oteracil potassium combination preparations (TS-1 or S-1, trade name: "TS-1"), tegafur / uracil combination preparations (UFT, trade name: "UFT"), trifluridine / tipiracil hydrochloride combination preparations (TAS-102, trade name: "Lonsurf"), capecitabine, doxifluridine, 5-fluoro-2'-deoxyuridine (FdUrd), gemcitabine, cytarabine, and other pyrimidine antimetabolites; Folic acid antagonists such as pemetrexed and methotrexate; Alkaloid antitumor agents such as paclitaxel (marketed under trade names such as "Taxol" and "Abraxane," and including derivatives such as albumin-bound paclitaxel (e.g., ABI-007) and PEG-bound paclitaxel), docetaxel (marketed under trade name such as "Taxotere"), cabazitaxel, eribulin, irinotecan, nogitecan, etoposide, vinorelbine, vincristine, and vinblastine; Platinum-based drugs such as cisplatin, carboplatin, oxaliplatin, and nedaplatin; PD-1 pathway antagonists such as nivolumab, semiprimab, spartalizumab, tislerizumab, BI754091, dostarizumab, sasamrimab, MGA-012, cetrerimab, AGEN-2034, zimbererimab, camrelizumab, buzigalimab, valstilimab, atezolizumab, durvalumab, avelumab, rhodapolimab, or BGB-A333; CTLA-4 pathway antagonists such as ipilimumab, tremelimumab, or abatacept; CD155 / TIGIT pathway antagonists such as dombanarimab, AB308, vivostrimab, osperirumab, tilagolumab, 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, bertuzumab, rituximab, and ramucirumab; Antitumor antibiotics such as doxorubicin, daunorubicin, epirubicin, actinomycin D, and mitomycin C; and Preferably, at least one selected from the group consisting of alkylating agents such as cyclophosphamide, dacarbazine, temozolomide, nimustine, busulfan, procarbazine, and melphalan, Fludarabine, cladribine, nelarabine, 5-fluorouracil (5-FU), tegafur / gimeracil / oteracil potassium combination (TS-1 or S-1, trade name: "TS-1"), tegafur / uracil combination (UFT, trade name: "UFT"), trifluridine / tipiracil hydrochloride combination (TAS-102, trade name: "Lonsurf"), capecitabine, doxifluridine, 5-fluoro-2'-deoxyuridine (FdUrd), gemcitabine At least one selected from the group consisting of vin, cytarabine, pemetrexed, methotrexate, paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel, eribulin, irinotecan, nogitecan, etoposide, vinorelbine, vincristine, vinblastine, cisplatin, carboplatin, oxaliplatin, nedaplatin, dombanarimab, AB308, vivostrimab, osperirumab, and tilagorumab is more preferably selected. At least one selected from the group consisting of 5-fluorouracil, gemcitabine, albumin-bound paclitaxel, irinotecan, cisplatin, carboplatin, dombanarimab, and AB308 is more preferably used. At least one selected from the group consisting of 5-fluorouracil, gemcitabine, albumin-bound paclitaxel, cisplatin, carboplatin, and dombanarimab is more preferably, A combination of 5-fluorouracil and cisplatin, a combination of 5-fluorouracil and carboplatin, a combination of carboplatin and albumin-bound paclitaxel, a combination of cisplatin and gemcitabine, a combination of albumin-bound paclitaxel and gemcitabine, or dombanarimab is particularly preferred.

[0137] Suitable antitumor agents in the present invention include any of the following antitumor agents (i) to (iii) that do not contain pembrolizumab as an active ingredient. (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with an anti-PD-1 antibody and at least one other antitumor agent to cancer patients. (ii) The antitumor agent comprising an anti-PD-1 antibody as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and at least one other antitumor agent for use in cancer patients. (iii) The antitumor agent comprising at least one other antitumor agent as an active ingredient, which is used in combination with futivatinib or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody for administration to cancer patients.

[0138] More preferably, an antitumor agent is one of the following (i) to (iii) that does not contain pembrolizumab as an active ingredient. (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimbererimab and at least one other antitumor agent for use in cancer patients. (ii) The antitumor agent comprising zimbererimab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and at least one other antitumor agent for use in cancer patients. (iii) The antitumor agent comprising at least one other antitumor agent as an active ingredient, which is used in combination with futivatinib or a pharmaceutically acceptable salt thereof and zimbererimab for administration to cancer patients.

[0139] The administration schedule for the various active ingredients in 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 21-day or 28-day administration cycle once or twice or more.

[0140] In the present invention, the preferred administration schedule for futivatinib or its salt is once daily on each day of a 21-day or 28-day administration cycle.

[0141] In the present invention, the administration schedule for immune checkpoint inhibitors can be set as appropriate, but it is preferable to administer them at a frequency of once a day to once every four weeks. In the case of zimberelimab, for example, an administration frequency of once every three weeks or once every two weeks is preferred. Specifically, it is preferable to administer it once within a 21-day administration cycle, or twice within a 28-day administration cycle.

[0142] In the present invention, the administration schedule for other antitumor agents can be set as appropriate, but administration for 1 to 5 days within a 21-day administration cycle is preferred, and administration for 1, 2, 3, 4, or 5 days is more preferred. In another embodiment of the present invention, for example, the administration schedule for other antitumor agents is preferred, for example, administration for 1 to 5 days within a 28-day administration cycle, and administration for 1, 2, 3, 4, or 5 days is more preferred.

[0143] Preferred daily doses of futivatinib or its salts on administration days 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 daily doses and frequencies on administration days include, once daily, 4 mg / dose, 8 mg / dose, 12 mg / dose, 16 mg / dose, and 20 mg / dose. In another embodiment, preferred daily doses and frequencies on administration days include, once daily, 8 mg / dose, 12 mg / dose, 16 mg / dose, and 20 mg / dose. In yet another embodiment, preferred daily doses and frequencies on administration days include, once daily, 12 mg / dose, 16 mg / dose, and 20 mg / dose. In yet another embodiment, preferred daily doses and frequencies on administration days include, once daily, and 20 mg / dose.

[0144] In one embodiment, the present invention includes the fact that, in cases of cancer types where a stronger effect is desired (e.g., brain tumors), the dose of futivatinib or a salt thereof is greater than 20 mg once daily.

[0145] In the present invention, the daily dose of an immune checkpoint inhibitor on the day of administration is set appropriately depending on the drug, but in the case of nivolumab, preferred daily doses on the day of administration include 40-480 mg / dose, 80 mg / dose, 240 mg / dose, 360 mg / dose, or 480 mg / dose. Furthermore, the administration interval for nivolumab is preferably every 2-4 weeks, more preferably every 2-3 weeks, and even more preferably every 2 weeks. In the case of zimberelimab, preferred daily doses on the day of administration include 240-480 mg / dose, 240 mg / dose, 360 mg / dose, or 480 mg / dose, with 240 mg / dose or 360 mg / dose being preferred, and 360 mg / dose being more preferred. Furthermore, the administration interval for zimberelimab is preferably every 2-4 weeks, more preferably every 2 weeks or 3 weeks, and even more preferably every 2 weeks. In one embodiment of the present invention, the administration interval and dosage of zimberelimab is 360 mg once every three weeks. In one embodiment of the present invention, the administration interval and dosage of zimberelimab are 240 mg once every two weeks.

[0146] In this invention, "cancer" or "tumor" refers to a physiological state in mammals characterized by uncontrolled cell proliferation. "Cancer" and "tumor" are synonymous and interchangeable in this specification. Cancer includes solid tumors and hematological cancers. Examples include, but are not limited to, carcinomas, lymphomas, leukemias, blastomas, sarcomas, and borderline malignant tumors (carcinoids).

[0147] The cancers targeted by 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, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer (hepatocellular carcinoma), biliary tract cancer (gallbladder and bile duct cancer, etc.), pancreatic cancer, small intestine cancer, colorectal cancer (colon and rectal 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 include mesothelioma, testicular mesothelioma, etc., breast cancer, reproductive organ cancers (ovarian cancer, uterine cancer (cervical cancer, uterine body cancer, endometrial cancer, etc.)), kidney cancer, bladder cancer, urothelial carcinoma, prostate cancer, testicular tumors, skin cancers (malignant melanoma, epidermal carcinoma, etc.), hematological cancers (multiple myeloma, malignant lymphoma, leukemia, etc.), bone and soft tissue tumors, rhabdomyosarcoma, brain tumors, malignant schwannomas, neuroendocrine tumors, and thyroid cancer. Here, cancer includes not only the primary tumor but also cancers that have metastasized to other organs (such as the liver) and cancers of unknown primary origin. Furthermore, the antitumor agent of the present invention may be used in adjuvant chemotherapy performed after surgical removal of a tumor to prevent recurrence, or in adjuvant chemotherapy performed before surgical removal of a tumor.

[0148] In the present invention, preferred cancers are lung cancer, esophageal cancer, gastric cancer, duodenal cancer, liver cancer, hepatocellular carcinoma, biliary tract cancer, pancreatic cancer, colorectal 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 tumors, more preferably pancreatic cancer, lung cancer, esophageal cancer, biliary tract cancer, head and neck cancer, and even more preferably More preferably pancreatic cancer, lung cancer, esophageal cancer, biliary tract cancer, or head and neck cancer, more preferably pancreatic cancer, non-small cell lung cancer, esophageal cancer, biliary tract cancer, or head and neck cancer, even more preferably pancreatic cancer, non-small cell lung cancer, esophageal cancer, biliary tract cancer, or head and neck cancer with no prior treatment history for advanced cancer or with a history of one line of chemotherapy, and particularly preferably pancreatic cancer, non-small cell lung cancer, esophageal cancer, biliary tract cancer, or head and neck cancer with no prior treatment history for advanced cancer.

[0149] One embodiment of the present invention targets esophageal cancer patients who have no prior history of treatment for advanced cancer. One embodiment of the present invention targets esophageal cancer patients who have no prior treatment history for advanced cancer or who have a history of prior treatment with one line of chemotherapy. One embodiment of the present invention targets patients with head and neck cancer who have no prior treatment history for advanced cancer. One embodiment of the present invention targets patients with non-small cell lung cancer who have no prior treatment history for advanced cancer. One embodiment of the present invention targets patients with biliary tract cancer who have no prior history of treatment for advanced cancer. One embodiment of the present invention targets pancreatic cancer patients who have no prior treatment history for advanced cancer.

[0150] Suitable antitumor agents in the present invention include, but are not limited to, the following.

[0151] One of the following antitumor agents (i) to (iv) is preferred: (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimbererimab, cisplatin, and 5-fluorouracil for patients with esophageal cancer. (ii) The antitumor agent comprising zimbererimab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, cisplatin, and 5-fluorouracil for patients with esophageal cancer. (iii) The antitumor agent comprising cisplatin as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab and 5-fluorouracil for patients with esophageal cancer. (iv) The antitumor agent comprising 5-fluorouracil as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab and cisplatin for patients with esophageal cancer.

[0152] One of the antitumor agents described in (i) to (iv) above, futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose, administered once daily, and zimberemab at a dose of 360 mg / dose, and 80 mg / m². 2 Administer cisplatin once, 800 mg / m². 2 More preferably, an antitumor agent is characterized by administering 5-fluorouracil at a dose of / day daily for 5 consecutive days, repeating this 21-day administration cycle once or twice or more. One of the antitumor agents described in (i) to (iv) above, futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose, administered daily, and 360 mg / dose of zimbererimab administered once on Day 1, with 80 mg / m² being used. 2 Administer cisplatin once on Day 1, at a dose of 800 mg / m². 2 An antitumor agent is particularly preferred, characterized by administering 5-fluorouracil at a dose of / day daily from Day 1 to Day 5, in a 21-day administration cycle that is repeated once or more times. One embodiment of the present invention is an antitumor agent of any of (i) to (iv) above, administered as follows: 12 mg / dose of futivatinib once daily, 360 mg / dose of zimbererimab once on Day 1, and 80 mg / m² 2 Administer cisplatin once on Day 1, at a dose of 800 mg / m². 2An antitumor agent is described as one in which a 21-day administration cycle is repeated once or more times, in which 5-fluorouracil at a dose of / day is administered daily from Day 1 to Day 5. In this invention, "mg / m 2 " / dose" means the amount of body surface area (m²) per dose. 2 The dosage (mg) per unit is shown. One embodiment of the present invention is an antitumor agent of any of (i) to (iv) above, administered as follows: 16 mg / dose of futivatinib once daily, 360 mg / dose of zimbererimab once on Day 1, and 80 mg / m² 2 Administer cisplatin once on Day 1, at a dose of 800 mg / m². 2 An antitumor agent is described as one in which a 21-day administration cycle is repeated once or more times, in which 5-fluorouracil at a dose of / day is administered daily from Day 1 to Day 5. One embodiment of the present invention is an antitumor agent of any of (i) to (iv) above, administered as follows: 20 mg / dose of futivatinib once daily, 360 mg / dose of zimbererimab once on Day 1, and 80 mg / m² 2 Administer cisplatin once on Day 1, at a dose of 800 mg / m². 2 An antitumor agent is described as one in which a 21-day administration cycle is repeated once or more times, in which 5-fluorouracil at a dose of / day is administered daily from Day 1 to Day 5.

[0153] One of the following antitumor agents (i) to (iii) is preferred: (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimbererimab and dombanarimab for patients with esophageal cancer. (ii) The antitumor agent comprising zimbererimab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and dombanarimab in patients with esophageal cancer. (iii) The antitumor agent comprising dombanalimab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and zimbererimab in patients with esophageal cancer.

[0154] More preferably, an antitumor agent according to any of (i) to (iii) above, characterized by administering futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, administering 360 mg / dose of zimbererimab once, and administering 1200 mg / dose of dombanarimab once, repeating this 21-day administration cycle one or more times. An antitumor agent of any of the above (i) to (iii) is particularly preferred, characterized by administering futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, administering 360 mg / dose of zimberelimab once on Day 1, and administering 1200 mg / dose of dombanarimab once on Day 1, repeating this 21-day administration cycle once or twice or more. One embodiment of the present invention is an antitumor agent according to any of (i) to (iii) above, characterized in that a 21-day administration cycle is repeated once or twice, in which 12 mg / dose of futivatinib is administered once daily, 360 mg / dose of zimberelimab is administered once on Day 1, and 1200 mg / dose of dombanarimab is administered once on Day 1. One embodiment of the present invention is an antitumor agent according to any of (i) to (iii) above, characterized in that a 21-day administration cycle is repeated once or twice or more, in which 16 mg / dose of futivatinib is administered once daily, 360 mg / dose of zimberelimab is administered once on Day 1, and 1200 mg / dose of dombanarimab is administered once on Day 1. One embodiment of the present invention is an antitumor agent according to any of (i) to (iii) above, characterized in that a 21-day administration cycle is repeated once or twice or more, in which 20 mg / dose of futivatinib is administered once daily, 360 mg / dose of zimberelimab is administered once on Day 1, and 1200 mg / dose of dombanarimab is administered once on Day 1.

[0155] One of the following antitumor agents (i) to (iv) is preferred: (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimbererimab, 5-fluorouracil, and carboplatin or cisplatin for patients with head and neck cancer. (ii) The antitumor agent comprising zimberemab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil, and carboplatin or cisplatin for patients with head and neck cancer. (iii) The antitumor agent comprising 5-fluorouracil as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and carboplatin or cisplatin for patients with head and neck cancer. (iv) The antitumor agent comprising carboplatin or cisplatin as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and 5-fluorouracil for patients with head and neck cancer.

[0156] The following antitumor agents are used: futivatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, followed by a single dose of 360 mg / dose of zimberemab, and carboplatin with an AUC of 5 or 100 mg / m². 2 Administer cisplatin once, 1000 mg / m². 2 More preferably, the antitumor agent is characterized by administering 5-fluorouracil at a dose of / day daily for 4 consecutive days, repeating this 21-day administration cycle once or twice or more. The following antitumor agents are used: futivatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, zimberemab at 360 mg / dose once on Day 1, and carboplatin with an AUC of 5 or 100 mg / m². 2 Administer cisplatin once on Day 1, at a dose of 1000 mg / m². 2 An antitumor agent is particularly preferred, characterized by administering 5-fluorouracil at a dose of / day daily from Day 1 to Day 4, in a 21-day administration cycle that is repeated once or more times. One embodiment of the present invention is an antitumor agent of any of (i) to (iv) above, administered as follows: 12 mg / dose of futivatinib once daily, 360 mg / dose of zimberemab once on Day 1, and carboplatin with an AUC of 5 or 100 mg / m². 2 Administer cisplatin once on Day 1, at a dose of 1000 mg / m². 2 An antitumor agent is described as one in which a 21-day administration cycle is repeated once or more times, in which 5-fluorouracil at a dose of / day is administered daily from Day 1 to Day 4. One embodiment of the present invention is an antitumor agent of any of (i) to (iv) above, administered as follows: 16 mg / dose of futivatinib once daily, 360 mg / dose of zimberemab once on Day 1, and carboplatin with an AUC of 5 or 100 mg / m². 2 Administer cisplatin once on Day 1, at a dose of 1000 mg / m². 2 An antitumor agent is described as one in which a 21-day administration cycle is repeated once or more times, in which 5-fluorouracil at a dose of / day is administered daily from Day 1 to Day 4. One embodiment of the present invention is an antitumor agent of any of (i) to (iv) above, administered as follows: 20 mg / dose of futivatinib once daily, 360 mg / dose of zimberemab once on Day 1, and carboplatin with an AUC of 5 or 100 mg / m². 2 Administer cisplatin once on Day 1, at a dose of 1000 mg / m². 2 An antitumor agent is described as one in which a 21-day administration cycle is repeated once or more times, in which 5-fluorouracil at a dose of / day is administered daily from Day 1 to Day 4.

[0157] One of the following antitumor agents (i) to (iii) is preferred: (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimberemab and dombanarimab for patients with head and neck cancer. (ii) The antitumor agent comprising zimbererimab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and dombanarimab for patients with head and neck cancer. (iii) The antitumor agent comprising dombanalimab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and zimbererimab for patients with head and neck cancer.

[0158] More preferably, an antitumor agent according to any of (i) to (iii) above, characterized by administering futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, administering 360 mg / dose of zimbererimab once, and administering 1200 mg / dose of dombanarimab once, repeating this 21-day administration cycle one or more times. An antitumor agent of any of the above (i) to (iii) is particularly preferred, characterized by administering futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, administering 360 mg / dose of zimberelimab once on Day 1, and administering 1200 mg / dose of dombanarimab once on Day 1, repeating this 21-day administration cycle once or twice or more. One embodiment of the present invention is an antitumor agent according to any of (i) to (iii) above, characterized in that a 21-day administration cycle is repeated once or twice, in which 12 mg / dose of futivatinib is administered once daily, 360 mg / dose of zimberelimab is administered once on Day 1, and 1200 mg / dose of dombanarimab is administered once on Day 1. One embodiment of the present invention is an antitumor agent according to any of (i) to (iii) above, characterized in that a 21-day administration cycle is repeated once or twice or more, in which 16 mg / dose of futivatinib is administered once daily, 360 mg / dose of zimberelimab is administered once on Day 1, and 1200 mg / dose of dombanarimab is administered once on Day 1. One embodiment of the present invention is an antitumor agent according to any of (i) to (iii) above, characterized in that a 21-day administration cycle is repeated once or twice or more, in which 20 mg / dose of futivatinib is administered once daily, 360 mg / dose of zimberelimab is administered once on Day 1, and 1200 mg / dose of dombanarimab is administered once on Day 1.

[0159] One of the following antitumor agents (i) to (iv) is preferred: (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimbererimab, albumin-bound paclitaxel, and carboplatin in patients with non-small cell lung cancer. (ii) The antitumor agent comprising zimberemab as the active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and carboplatin for patients with non-small cell lung cancer. (iii) The antitumor agent comprising albumin-bound paclitaxel as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and carboplatin in patients with non-small cell lung cancer. (iv) The antitumor agent comprising carboplatin as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and albumin-bound paclitaxel for patients with non-small cell lung cancer.

[0160] One of the antitumor agents described in (i) to (iv) above, futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose, administered once daily, and zimberemab at a dose of 360 mg / dose, and 100 mg / m². 2 A more preferable antitumor agent is one characterized by administering albumin-suspended paclitaxel three times and carboplatin with an AUC of 6 once, repeating this 21-day administration cycle one or more times. One of the antitumor agents described in (i) to (iv) above, futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose is administered once daily for several days, and 360 mg / dose of zimbererimab is administered on Day 1, with 100 mg / m² being the other option. 2 An antitumor agent is particularly preferred, characterized by administering albumin-suspended paclitaxel once on Day 1, Day 8, and Day 15, and repeating a 21-day administration cycle once or more times, in which carboplatin with an AUC of 6 is administered on Day 1. One embodiment of the present invention is an antitumor agent of any of (i) to (iv) above, administered as follows: 12 mg / dose of futivatinib once daily for several days, 360 mg / dose of zimbererimab on Day 1, and 100 mg / m² 2 An antitumor agent is characterized by administering albumin-suspended paclitaxel once on Day 1, Day 8, and Day 15, and administering carboplatin with an AUC of 6 on Day 1, repeating this 21-day administration cycle once or more times. One embodiment of the present invention is an antitumor agent of any of (i) to (iv) above, administered as follows: 16 mg / dose of futivatinib once daily for several days, 360 mg / dose of zimbererimab on Day 1, and 100 mg / m² 2 An antitumor agent is characterized by administering albumin-suspended paclitaxel once on Day 1, Day 8, and Day 15, and administering carboplatin with an AUC of 6 on Day 1, repeating this 21-day administration cycle once or more times. One embodiment of the present invention is an antitumor agent of any of (i) to (iv) above, administered as follows: 20 mg / dose of futivatinib once daily for several days, 360 mg / dose of zimberemab on Day 1, and 100 mg / m² 2 An antitumor agent is characterized by administering albumin-suspended paclitaxel once on Day 1, Day 8, and Day 15, and administering carboplatin with an AUC of 6 on Day 1, repeating this 21-day administration cycle once or more times.

[0161] One of the following antitumor agents (i) to (iv) is preferred: (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimberemab, cisplatin, and gemcitabine for patients with biliary tract cancer. (ii) The antitumor agent comprising zimberemab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, cisplatin, and gemcitabine for patients with biliary tract cancer. (iii) The antitumor agent comprising gemcitabine as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and cisplatin for patients with biliary tract cancer. (iv) The antitumor agent comprising cisplatin as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and gemcitabine for patients with biliary tract cancer.

[0162] One of the antitumor agents described in (i) to (iv) above, futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose, administered once daily, and zimberemab at a dose of 360 mg / dose, and 100 mg / m². 2 A more preferable antitumor agent is one characterized by administering albumin-suspended paclitaxel three times and carboplatin with an AUC of 6 once, repeating this 21-day administration cycle one or more times. One of the antitumor agents described in (i) to (iv) above, futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose is administered once daily for several days, and 360 mg / dose of zimbererimab is administered on Day 1, with 100 mg / m² being the other option. 2 An antitumor agent is particularly preferred, characterized by administering albumin-suspended paclitaxel once on Day 1, Day 8, and Day 15, and repeating a 21-day administration cycle once or more times, in which carboplatin with an AUC of 6 is administered on Day 1. One embodiment of the present invention is an antitumor agent of any of (i) to (iv) above, administered as follows: 12 mg / dose of futivatinib once daily for several days, 360 mg / dose of zimbererimab on Day 1, and 100 mg / m² 2The anti-tumor agent is characterized in that the albumin-conjugated paclitaxel is administered once each on Day 1, Day 8, and Day 15, and the carboplatin with an AUC of 6 is administered on Day 1, and the 21-day administration cycle is repeated one or more times. As one embodiment of the present invention, any of the anti-tumor agents (i) to (iv) above, wherein 16 mg of futibatinib per dose is administered daily once a day, 360 mg of zimberelimab is administered on Day 1, and 100 mg / m 2 The anti-tumor agent is characterized in that the albumin-conjugated paclitaxel is administered once each on Day 1, Day 8, and Day 15, and the carboplatin with an AUC of 6 is administered on Day 1, and the 21-day administration cycle is repeated one or more times. As one embodiment of the present invention, any of the anti-tumor agents (i) to (iv) above, wherein 20 mg of futibatinib per dose is administered daily once a day, 360 mg of zimberelimab is administered on Day 1, and 100 mg / m 2 The anti-tumor agent is characterized in that the albumin-conjugated paclitaxel is administered once each on Day 1, Day 8, and Day 15, and the carboplatin with an AUC of 6 is administered on Day 1, and the 21-day administration cycle is repeated one or more times.

[0163] Any of the following anti-tumor agents (i) to (iv) is preferred. (i) The anti-tumor agent containing, as an active ingredient, futibatinib or a pharmaceutically acceptable salt thereof, which is used for combined administration with zimberelimab, albumin-conjugated paclitaxel, and gemcitabine to a pancreatic cancer patient. (ii) The anti-tumor agent containing, as an active ingredient, zimberelimab, which is used for combined administration with futibatinib or a pharmaceutically acceptable salt thereof, albumin-conjugated paclitaxel, and gemcitabine to a pancreatic cancer patient. (iii) The anti-tumor agent containing, as an active ingredient, gemcitabine, which is used for combined administration with futibatinib or a pharmaceutically acceptable salt thereof, zimberelimab, and albumin-conjugated paclitaxel to a pancreatic cancer patient. (iv) The antitumor agent comprising albumin-bound paclitaxel as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and gemcitabine in patients with pancreatic cancer.

[0164] One of the antitumor agents described in (i) to (iv) above, futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose, administered once daily for consecutive days, and zimbererimab at a dose of 240 mg / dose, administered twice, totaling 125 mg / m². 2 Administer albumin-suspended paclitaxel three times, at a dose of 1000 mg / m². 2 More preferably, the antitumor agent is characterized by administering gemcitabine three times per dose over a 28-day period, and repeating this cycle one or more times. One of the antitumor agents described in (i) to (iv) above, futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose is administered once daily for consecutive days, and zimberemab at a dose of 240 mg / dose is administered on Day 1 and Day 15, with 125 mg / m² being the other option. 2 Paclitaxel in albumin-suspended form is administered once on Day 1, Day 8, and Day 15, at a dose of 1000 mg / m². 2 An antitumor agent is particularly preferred, characterized by administering gemcitabine once on Day 1, Day 8, and Day 15, in a 28-day administration cycle repeated once or more times. One embodiment of the present invention is an antitumor agent of any of (i) to (iv) above, administered as follows: futivatinib at a dose of 12 mg / dose once daily, and zimberemab at a dose of 240 mg / dose on Day 1 and Day 15, totaling 125 mg / m². 2 Paclitaxel in albumin-suspended form is administered once on Day 1, Day 8, and Day 15, at a dose of 1000 mg / m². 2 An antitumor agent is characterized by administering gemcitabine once on Day 1, Day 8, and Day 15, in a 28-day administration cycle, which is repeated once or more times. One embodiment of the present invention is an antitumor agent of any of (i) to (iv) above, administered as follows: 16 mg / dose of futivatinib once daily for consecutive days, and 240 mg / dose of zimbererimab on Day 1 and Day 15, totaling 125 mg / m². 2 Paclitaxel in albumin-suspended form is administered once on Day 1, Day 8, and Day 15, at a dose of 1000 mg / m². 2 An antitumor agent is characterized by administering gemcitabine once on Day 1, Day 8, and Day 15, in a 28-day administration cycle, which is repeated once or more times. One embodiment of the present invention is an antitumor agent of any of (i) to (iv) above, administered as follows: 20 mg / dose of futivatinib once daily for consecutive days, and 240 mg / dose of zimbererimab on Day 1 and Day 15, totaling 125 mg / m². 2 Paclitaxel in albumin-suspended form is administered once on Day 1, Day 8, and Day 15, at a dose of 1000 mg / m². 2 An antitumor agent is characterized by administering gemcitabine once on Day 1, Day 8, and Day 15, in a 28-day administration cycle, which is repeated once or more times.

[0165] As used herein, the term “combination (therapy)” is intended to define a therapy involving the use of a combination of two or more compounds / agents (as defined above). Therefore, the use of compounds / agents in “combination (therapy),” “combination,” and “combined” in this application may mean compounds / agents administered as part of the same overall treatment regimen. The dosages of each of the two or more compounds / agents may differ: each may be administered simultaneously or at different times. Thus, it is understood that the compounds / agents in a combination may be administered sequentially (e.g., before or after) or simultaneously in either the same pharmaceutical formulation (i.e., together) or different pharmaceutical formulations (i.e., separately). Simultaneously in the same formulation, they are administered as a single formulation, but simultaneously in different pharmaceutical formulations, they are administered non-integrated.

[0166] There are no particular restrictions on the administration form of the antitumor agent of the present invention, and it can be appropriately selected according to the therapeutic purpose. Specifically, examples include oral preparations (tablets, coated tablets, powders, granules, capsules, liquids, etc.), injections, suppositories, patches, ointments, etc. In the case of futivatinib or its salt, oral preparations are preferred. In the case of immune checkpoint inhibitors and other antitumor agents, the above-mentioned administration forms are examples, with injections being preferred. In the case of zimberelimab, domvanarimab, carboplatin, cisplatin, 5-fluorouracil, albumin-bound paclitaxel, and gemcitabine, injections are preferred.

[0167] The antitumor agent of the present invention may be an immune checkpoint inhibitor and futivatinib or a salt thereof as the active ingredients, or it may be a pharmaceutical composition prepared by a commonly known method using a pharmaceutically acceptable carrier, depending on the form of administration. Examples of such carriers include various types commonly used in conventional drugs, such as excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, isotonic agents, pH adjusters, buffers, stabilizers, colorants, flavoring agents, and odorants.

[0168] The antitumor agent of the present invention may be formulated by dividing each active ingredient into multiple dosage forms, or by combining them into a single dosage form, based on the administration form and administration schedule of each active ingredient. Furthermore, each formulation may be manufactured and sold together in a single package suitable for concomitant administration, or each formulation may be manufactured and sold in separate packages. The same applies to embodiments of the pharmaceutical composition. Therefore, "a pharmaceutical composition containing an immune checkpoint inhibitor and futivatinib or a salt thereof as active ingredients" includes formulations in which each active ingredient is divided into multiple dosage forms, as well as formulations in which each active ingredient is combined into a single dosage form. The pharmaceutical composition in which each active ingredient is divided into multiple dosage forms includes formulations in which each formulation is combined into a single package suitable for concomitant administration, as well as formulations in which each formulation is separated into separate packages.

[0169] The present invention relates to an antitumor agent comprising futivatinib or a salt thereof, and a kit formulation that includes instructions for use describing the co-administration of futivatinib or a salt thereof with an immune checkpoint inhibitor to cancer patients. Here, "instructions for use" refers to any document that describes the above dosage, and does not need to be legally binding, but it is preferable that the above dosage is recommended. Specifically, examples include package inserts and brochures. Furthermore, a kit formulation that includes instructions for use may be one in which the instructions for use are printed and attached to the package of the kit formulation, or one in which the instructions for use are enclosed together with the antitumor agent in the package of the kit formulation.

[0170] In this invention, "treatment" includes procedures performed for the purpose of curing or relieving a disease, or for the purpose of suppressing disease progression or relapse or alleviating symptoms. Treatment includes the administration of drugs before or after surgical procedures, or the administration of drugs during or before or after radiation therapy.

[0171] The antitumor agent of the present invention can be used in the treatment of cancer. When referring to cancer patients receiving treatment with the combination therapy or other treatment regimens described herein, "antitumor effect" means at least one evaluation such as PFS (progression-free survival), DCR (disease control rate), DOR (duration of response), OS (overall survival), ORR (objective response rate), DCR (disease control rate), TTR (time to first response), PROs (patient-reported outcomes). In one embodiment, when targeting solid tumors, the tumor evaluation for the combination therapy described herein is evaluated according to the RECIST 1.1 criteria (criteria for evaluating the effectiveness of solid tumors), and the antitumor effect is indicated as SD (stable), PR (partial response), CR (complete response), or PD (progression). In the case of brain tumor evaluation, it can also be performed by Gd-MRI (standard brain tumor MRI including pre- and post-enhancement using gadolium (Gd) chelate contrast agent). [Examples]

[0172] Example: Phase 1a / b clinical trial of AB122 combination therapy in patients with advanced solid tumors. Objectives and evaluation criteria:

[0173]

Table 1

[0174] Method: This is a Phase 1, non-randomized, non-blinded, multi-center, platform trial to evaluate the tolerance and safety of AB122 in patients with malignant tumors. This trial consists of two phases (Phase 1a and Phase 1b). In Phase 1a, the purpose is to evaluate the safety and tolerance of the combination therapy based on AB122 in patients with advanced solid cancer, determine the recommended dose (RD) of each regimen, and evaluate the efficacy at the RD. In Phase 1b, the purpose is to add patients to an appropriate cohort and evaluate the safety and efficacy of the treatment method based on AB122.

[0175]

Table 2

[0176] Phase 1a When the tumor shrinkage effect based on RECIST v1.1 is determined in the first 5 patients, and the probability that the number of responders required in another 5 patients is observed according to the binomial distribution of the response rate is 20% or less, the enrollment may be stopped.

[0177] Dose-limiting toxicity (DLT): Define the following adverse events related to the investigational drug that occurred in Cycle 1 as DLT. The following grades follow the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 of the National Cancer Institute (NCI) of the United States.

[0178] The principal investigator and the sponsor of the trial will determine whether abnormal clinical laboratory values (excluding the following blood toxicities and non-blood toxicities) and transient signs or symptoms are applicable to DLT. · Grade 4 neutropenia lasting more than 7 days • Febrile neutropenia [absolute neutrophil count (ANC) of 1000 / mm³] 3 [Less than 38°C, AND body temperature exceeds 38.3°C at least once, or remains 38°C or higher for more than one hour.] • Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding requiring blood transfusion. • Grade 4 anemia or Grade 3 anemia requiring blood transfusion • Non-hematological adverse events of grade 3 or higher are considered DLTs. However, this excludes grade 3 fatigue with a duration of 3 days or less, grade 3 diarrhea, nausea or vomiting regardless of the use of antiemetics or antidiarrheals based on standard treatment, and grade 3 rash without the use of corticosteroids or anti-inflammatory drugs based on standard treatment. • Grade 2 or higher elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) accompanied by a total bilirubin increase exceeding twice the upper limit of normal (ULN), provided there are no early signs of cholestasis [alkaline phosphatase (ALP) elevation less than twice the ULN] and no other reason to explain these increases. • Toxicity associated with the investigational drug that prevents completion of Cycle 1 [defined as the period during which at least 75% of the prescribed number of oral doses of the investigational drug are administered, and the full doses of AB122 and AB154 (Cohort D-3 only) are administered], or that prevents the start of Cycle 2 (defined as administration interruption for more than two weeks). • Hyperphosphatemia: An increase in serum phosphorus levels of 10 mg / dL or more, Despite 7 days of phosphate-lowering therapy, serum phosphorus levels of 7 mg / dL or higher persist for more than 7 days.

[0179] Phase 1b The Phase 1b part will commence after tolerability and preliminary efficacy have been determined based on the results of the Phase 1a part. The cohorts to be expanded to the Phase 1b part will be determined through consultation between the Data Monitoring Committee (DMC) and the sponsor.

[0180] Target number of cases (planned): Cohort D-2 The target number of patients is a maximum of 52 for Phase 1a and a maximum of 30 for Phase 1b. Cohort D-3 The target number of patients is a maximum of 52 for Phase 1a and a maximum of 30 for Phase 1b. Cohort D-4 The target number of patients is 40 for Phase 1a and a maximum of 30 for Phase 1b. Cohort D-5 The target number of patients is 40 for Phase 1a and a maximum of 30 for Phase 1b. Cohort D-6 The target number of patients is a maximum of 52 for Phase 1a and a maximum of 30 for Phase 1b. Cohort D-7 The target number of patients is a maximum of 52 for Phase 1a and a maximum of 30 for Phase 1b. Cohort D-8 The target number of patients is a maximum of 52 for Phase 1a and a maximum of 30 for Phase 1b.

[0181] Diagnostic and main inclusion criteria: Patients with advanced solid tumors who are 18 years of age or older at the time of obtaining consent.

[0182] Dosage and administration method: Phase 1a Method of administration: The administration methods for each cohort are as follows.

[0183] [Table 3] JPEG2026089702000006.jpg132169

[0184] The experimental treatments to be conducted in each cohort are as follows: Cohort D-2: AB122 360 mg / body is administered intravenously over 60 minutes on Day 1. Cisplatin 80 mg / m² is administered on Day 1. 2 Administer intravenously. 5-fluorouracil 800 mg / m² from Day 1 to Day 5. 2Administer / day by continuous intravenous infusion. Administer futivatinib orally once daily on an empty stomach, at least one hour before or two hours after a meal. Cohort D-3: AB122 360 mg / body is administered by intravenous infusion over 60 minutes on Day 1. AB154 1200 mg / body is administered by intravenous infusion over 60 minutes on Day 1. Futivatinib is administered orally once daily on an empty stomach at least one hour before or two hours after a meal. Cohort D-4: AB122 360 mg / body is administered by intravenous infusion over 60 minutes on Day 1. Carboplatin AUC 5 or cisplatin 100 mg / m² is administered on Day 1. 2 Administer intravenously. 5-fluorouracil 1000 mg / m² from Day 1 to Day 4. 2 Administer / day by continuous intravenous infusion. Administer futivatinib orally once daily on an empty stomach, at least one hour before or two hours after a meal. Cohort D-5: AB122 360 mg / body is administered by intravenous infusion over 60 minutes on Day 1. AB154 1200 mg / body is administered by intravenous infusion over 60 minutes on Day 1. Futivatinib is 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 is administered intravenously over 60 minutes on Day 1. Albumin-bound paclitaxel 100 mg / m² 2 Administer intravenously on Day 1, Day 8, and Day 15, and administer carboplatin AUC6 intravenously on Day 1. Administer futivatinib orally once daily on an empty stomach, at least one hour before or two hours after a meal. Cohort D-7: AB122 360 mg / body is administered intravenously over 60 minutes on Day 1. Cisplatin 25 mg / m² 2 and gemcitabine 1000 mg / m² 2 Administer intravenously on Day 1 and Day 8. Administer futivatinib orally once daily on an empty stomach, at least one hour before or two hours after a meal. Cohort D-8: AB122 240 mg / body is administered by intravenous infusion over 60 minutes on Day 1 and Day 15. Albumin-bound paclitaxel 125 mg / m²2 and gemcitabine 1000 mg / m² 2 Administer intravenously on Day 1, Day 8, and Day 15. Administer futivatinib orally once daily on an empty stomach, at least one hour before or two hours after a meal.

[0185] If toxicity occurs at the start of the cycle or during the cycle, the dosage may be gradually changed according to the table below. The dosages of AB122 and AB154 should not be changed during the administration period.

[0186] [Table 4] JPEG2026089702000008.jpg120169

[0187] Phase 1b The dose level will be determined based on the tolerability of each cohort in Phase 1a.

[0188] Treatment period: Cohort D-8: One cycle is defined as 28 days. Cohort D-2 to D-7: One cycle is defined as 21 days. The experimental treatment will continue until any of the criteria for discontinuation are met.

[0189] Evaluation criteria: Effectiveness RECIST (v1.1, 2009) will be used for tumor assessment during the study period. Computed tomography (CT) scans will be performed at baseline, every four weeks after enrollment, every six weeks from Week 12 onward, and at discontinuation.

[0190] safety Standard safety monitoring and grading using NCI CTCAE v5.0 will be performed.

[0191] Statistical methods: The populations analyzed in this study are defined for each phase and cohort, but DLT-evaluable cases are defined for each cohort in Phase 1a.

[0192] [Table 5] JPEG2026089702000010.jpg77169

[0193] Analysis of primary endpoints Phase 1a: For DLT-evaluable cases, the incidence rate of DLTs is calculated for each level. All DLTs are listed by patient.

[0194] Phase 1b: For the combined FAS population from phases 1a and 1b, an ORR analysis based on RECIST v1.1 will be performed. The best overall effect based on RECIST v1.1 will be compiled, and the ORR and 95% CI will be estimated using the Clopper-Pearson method. Figure 1 shows an overview of the experimental design.

[0195] result For cohorts D-2, D-3, and D-7, the tolerability assessment confirmed that no dose-limiting toxicity was observed at level 1 doses. Furthermore, the expansion phase is ongoing, and the interim results for Cohort D-2 are shown in the table below. The objective response rate (ORR) was 58.5% and the disease control rate (DCR) was 92.7% in patients in the tolerability phase (N=3, level 1) and the expansion phase (N=38). These ORR and DCR values ​​exceed those of the combination therapy of pembrolizumab, 5-fluorouracil, and cisplatin, which is currently recommended as the first-line treatment for unresectable advanced or recurrent esophageal cancer (ORR (45.0%), DCR (79.4%)) (Lancet. 2021;398(10302):759-771.).

[0196] [Table 6] JPEG2026089702000012.jpg78169JPEG2026089702000013.jpg255166

Claims

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

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, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

4. The antitumor agent according to claim 2, wherein the anti-PD-1 antibody is at least one selected from the group consisting of nivolumab, semiprimab, spartalizumab, tislerizumab, BI754091, dostarizumab, sasamrimab, MGA-012, cetrelimab, AGEN-2034, zimberelimab, camrelizumab, buzigalimab, and valstilimab.

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

6. The antitumor agent according to claim 1, 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 antimetabolites, alkaloid antitumor agents, platinum-based drugs, immune checkpoint inhibitors, molecularly 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 antimetabolites, alkaloid antitumor agents, platinum-based agents, and immune checkpoint inhibitors.

9. The chemotherapy agents include 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, nogitecan (topotecan), etoposide, teniposide, vinorelbine, vincristine, vinblastine, cisplatin, carboplatin, oxaliplatin, nedaplatin, dombanarimab, AB308, vivostrimab, osperirumab, and tilagorumab.

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-bound paclitaxel, irinotecan, cisplatin, carboplatin, dombanalimab, 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-bound paclitaxel, cisplatin, carboplatin, and dombanarimab.

12. The antitumor agent according to claim 1, 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, colorectal 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.

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

15. The antitumor agent according to claim 1, characterized in that an administration cycle of 21 days or 28 days is repeated once or two or more times.

16. The antitumor agent according to claim 15, wherein futivatinib is administered once daily on each day of a 21-day or 28-day administration cycle.

17. The antitumor agent according to claim 15, wherein zimberelimab is administered for 1 to 2 days within a 21-day or 28-day administration cycle.

18. The antitumor agent according to claim 15, wherein another antitumor agent is administered for 1 to 5 days within a 21-day or 28-day administration cycle.

19. The antitumor agent according to claim 15, wherein another antitumor agent is administered once on Day 1 of a 21-day or 28-day administration cycle.

20. The antitumor agent according to claim 15, wherein another antitumor agent is administered once on Day 1 and once on Day 8 of a 21-day or 28-day administration cycle.

21. The antitumor agent according to claim 15, wherein another antitumor agent is administered once each on Day 1, Day 8, and Day 15 of a 21-day or 28-day administration cycle.

22. The antitumor agent according to claim 15, wherein other antitumor agents are administered once each on Day 1, 2, 3, and 4 of a 21-day or 28-day administration cycle.

23. The antitumor agent according to claim 15, wherein another antitumor agent is administered once each on Day 1, 2, 3, 4, and 5 of a 21-day or 28-day administration cycle.

24. The antitumor agent according to claim 16, wherein the dose of futivatinib is 8 mg / dose to 24 mg / dose.

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

26. The antitumor agent according to claim 16, wherein the dose of futivatinib is 20 mg / dose.

27. The antitumor agent according to claim 17, wherein the dose of zimbererimab is 240 mg / dose or 360 mg / dose.

28. An antitumor agent according to any one of claims 1 to 27, which is any of the antitumor agents listed in (i) to (iv) below. (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimbererimab, cisplatin, and 5-fluorouracil for patients with esophageal cancer. (ii) The antitumor agent comprising zimberemab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, cisplatin, and 5-fluorouracil for patients with esophageal cancer. (iii) The antitumor agent comprising cisplatin as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab and 5-fluorouracil for patients with esophageal cancer. (iv) The antitumor agent comprising 5-fluorouracil as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and cisplatin for patients with esophageal cancer.

29. Administer futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, and administer zimbererimab at a single dose of 360 mg / dose, and 80 mg / m². ２ Administer cisplatin once, 800 mg / m². ２ The antitumor agent according to claim 28, characterized in that a 21-day administration cycle of administering 5-fluorouracil at a dose of / day for 5 consecutive days is repeated once or twice or more.

30. Futivatinib is administered once daily at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose, and zimbererimab is administered once on Day 1 at a dose of 80 mg / m². ２ Administer cisplatin once on Day 1, at a dose of 800 mg / m². ２ The antitumor agent according to claim 28, characterized in that a 21-day administration cycle in which 5-fluorouracil at a dose of / day is administered daily from Day 1 to Day 5 is repeated once or twice or more.

31. The antitumor agent according to claim 28, wherein the cancer patient is an esophageal cancer patient with no prior treatment history for advanced cancer.

32. An antitumor agent according to any one of claims 1 to 27, which is any of the antitumor agents listed in (i) to (iii) below. (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimbererimab and dombanarimab for patients with esophageal cancer. (ii) The antitumor agent comprising zimberemab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and dombanarimab in patients with esophageal cancer. (iii) The antitumor agent comprising dombanalimab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and zimbererimab in patients with esophageal cancer.

33. The antitumor agent according to claim 32, characterized by administering futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, administering 360 mg / dose of zimberelimab once, and administering 1200 mg / dose of dombanarimab once, repeating this 21-day administration cycle one or more times.

34. The antitumor agent according to claim 32, characterized by administering futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, administering 360 mg / dose of zimberelimab once on Day 1, and administering 1200 mg / dose of domvanarimab once on Day 1, repeating this 21-day administration cycle once or twice or more.

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

36. An antitumor agent according to any one of claims 1 to 27, which is any of the antitumor agents listed in (i) to (iv) below. (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimberemab, 5-fluorouracil, and carboplatin or cisplatin for patients with head and neck cancer. (ii) The antitumor agent comprising zimberemab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil, and carboplatin or cisplatin for patients with head and neck cancer. (iii) The antitumor agent comprising 5-fluorouracil as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and carboplatin or cisplatin for patients with head and neck cancer. (iv) The antitumor agent comprising carboplatin or cisplatin as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and 5-fluorouracil for patients with head and neck cancer.

37. Administer futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, followed by a single dose of 360 mg / dose of zimbererimab, and then add carboplatin at an AUC of 5 or 100 mg / m². ２ Administer cisplatin once, 1000 mg / m². ２ The antitumor agent according to claim 36, characterized by administering 5-fluorouracil at a dose of / day for four consecutive days for a 21-day administration cycle, repeated once or twice or more times.

38. Futivatinib is administered once daily at a dose of 12 mg, 16 mg, or 20 mg, and zimberelimab is administered once on Day 1 at a dose of 360 mg, along with carboplatin at an AUC of 5 or 100 mg / m². ２ Administer cisplatin once on Day 1, at a dose of 1000 mg / m². ２ The antitumor agent according to claim 36, characterized in that a 21-day administration cycle in which 5-fluorouracil at a dose of / day is administered daily from Day 1 to Day 4 is repeated once or two or more times.

39. The antitumor agent according to claim 36, wherein the cancer patient is a head and neck cancer patient with no prior treatment history for advanced cancer.

40. An antitumor agent according to any one of claims 1 to 27, which is any of the antitumor agents listed in (i) to (iii) below. (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimberelimab and dombanalimab for patients with head and neck cancer. (ii) The antitumor agent comprising zimbererimab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and dombanarimab for patients with head and neck cancer. (iii) The antitumor agent comprising dombanalimab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof and zimbererimab for patients with head and neck cancer.

41. The antitumor agent according to claim 40, characterized by administering futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, administering 360 mg / dose of zimberelimab once, and administering 1200 mg / dose of dombanarimab once, repeating this 21-day administration cycle one or more times.

42. The antitumor agent according to claim 40, characterized by administering futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, administering 360 mg / dose of zimberelimab once on Day 1, and administering 1200 mg / dose of dombanarimab once on Day 1, repeating this 21-day administration cycle once or twice or more.

43. The antitumor agent according to claim 40, wherein the cancer patient is a head and neck cancer patient with no prior treatment history for advanced cancer.

44. An antitumor agent according to any one of claims 1 to 27, which is any of the antitumor agents listed in (i) to (iv) below. (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimbererimab, albumin-bound paclitaxel, and carboplatin for patients with non-small cell lung cancer. (ii) The antitumor agent comprising zimberemab as the active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and carboplatin for patients with non-small cell lung cancer. (iii) The antitumor agent comprising albumin-bound paclitaxel as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and carboplatin in patients with non-small cell lung cancer. (iv) The antitumor agent comprising carboplatin as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and albumin-bound paclitaxel for patients with non-small cell lung cancer.

45. Administering 12 mg per dose, 16 mg per dose, or 20 mg per dose of futibatinib once daily for consecutive days, administering 360 mg per dose of gembelinumab once, administering 100 mg / m ２ / dose of albumin suspension paclitaxel three times, and repeating once or more a 21-day dosing cycle of administering once carboplatin with an AUC of 6, the anti-tumor agent according to claim 44, characterized by this.

46. Futivatinib is administered once daily at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose, and zimbererimab is administered at a dose of 360 mg / dose on Day 1, with a dose of 100 mg / m². ２ The antitumor agent according to claim 44, characterized by administering albumin-suspended paclitaxel once on Day 1, Day 8, and Day 15, and administering carboplatin with an AUC of 6 on Day 1, and repeating this 21-day administration cycle once or twice or more.

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

48. An antitumor agent according to any one of claims 1 to 27, which is any of the antitumor agents listed in (i) to (iv) below. (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimberemab, cisplatin, and gemcitabine for patients with biliary tract cancer. (ii) The antitumor agent comprising zimberemab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, cisplatin, and gemcitabine for patients with biliary tract cancer. (iii) The antitumor agent comprising gemcitabine as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and cisplatin for patients with biliary tract cancer. (iv) The antitumor agent comprising cisplatin as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and gemcitabine for patients with biliary tract cancer.

49. Administer futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, and administer zimbererimab at a single dose of 360 mg / dose, followed by 25 mg / m². ２ Administer cisplatin twice, at a dose of 1000 mg / m². ２ The antitumor agent according to claim 48, characterized by administering gemcitabine twice per dose over a 21-day period, repeated once or more times.

50. Futivatinib is administered once daily at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose, and zimbererimab is administered at a dose of 360 mg / dose on Day 1, followed by 25 mg / m². ２ Administer cisplatin once on Day 1 and once on Day 8, at a dose of 1000 mg / m². ２ The antitumor agent according to claim 48, characterized by administering gemcitabine once on Day 1 and once on Day 8, in a 21-day administration cycle, repeated once or twice or more times.

51. The antitumor agent according to claim 48, wherein the cancer patient is a biliary tract cancer patient with no prior treatment history for advanced cancer.

52. An antitumor agent according to any one of claims 1 to 27, which is any of the antitumor agents listed in (i) to (iv) below. (i) The antitumor agent comprising futivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, to be used in combination with zimberelimab, albumin-bound paclitaxel, and gemcitabine for patients with pancreatic cancer. (ii) The antitumor agent comprising zimberemab as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, albumin-bound paclitaxel, and gemcitabine for patients with pancreatic cancer. (iii) The antitumor agent comprising gemcitabine as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and albumin-bound paclitaxel for patients with pancreatic cancer. (iv) The antitumor agent comprising albumin-bound paclitaxel as an active ingredient, to be used in combination with futivatinib or a pharmaceutically acceptable salt thereof, zimbererimab, and gemcitabine for patients with pancreatic cancer.

53. Futivatinib is administered once daily at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose, followed by two doses of 240 mg / dose of zimbererimab, and 125 mg / m². ２ Administer albumin-bound paclitaxel three times, at a dose of 1000 mg / m². ２ The antitumor agent according to claim 52, characterized by administering gemcitabine three times per dose over a 28-day period, repeated once or twice or more.

54. Administer futivatinib at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose once daily, and administer 240 mg / dose of zimbererimab on Day 1 and Day 15, with a dose of 125 mg / m². ２ Administer albumin-bound paclitaxel once on Day 1, Day 8, and Day 15, at a dose of 1000 mg / m². ２ The antitumor agent according to claim 52, characterized in that a 28-day administration cycle in which gemcitabine is administered once on Day 1, Day 8, and Day 15 is repeated once or more times.

55. The antitumor agent according to claim 52, wherein the cancer patient is a pancreatic cancer patient with no prior treatment history for advanced cancer.

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