Cancer treatment comprising 3,5-disubstituted phenylalkynyl compounds and immune checkpoint inhibitors

Abstract

The present invention aims to solve the problem of providing a novel combination therapy with excellent antitumor effects. The present invention provides an antitumor agent (excluding pembrolizumab as an active ingredient) which includes as an active ingredient, fobamintib or a pharmaceutically acceptable salt thereof, to be administered in combination with an immune checkpoint inhibitor (excluding a CD155 / TIGIT pathway antagonist) and at least one or more other antitumor agents to a cancer patient.

Description

Technical Field

[0001] This invention relates to antitumor agents, antitumor efficacy enhancers, and reagent kit formulations. Background Technology

[0002] Fibroblast growth factors (FGF) are expressed in various tissues and are among the growth factors that regulate cell proliferation and differentiation. The physiological activity of FGF is mediated by fibroblast growth factor receptors (FGFRs), which are specific cell surface receptors. FGFRs belong to the receptor protein tyrosine kinase family, including an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain. Four FGFRs (FGFR1, FGFR2, FGFR3, and FGFR4) have been identified. FGFRs bind to FGF to form a dimer and are activated by phosphorylation. Receptor activation induces the mobilization and activation of specific downstream signal transduction molecules, thereby exerting their physiological functions. Several reports have been published regarding the relationship between abnormal FGF / FGFR signal transduction and various human tumors. Aberrant activation of FGF / FGFR signaling in human tumors is thought to be caused by autocrine or paracrine mechanisms resulting from FGFR overexpression and / or gene amplification, gene mutation, chromosomal translocation, insertion and inversion, gene fusion, or excessive production of FGF (ligand) (NPL 1, 2, 3 and 4).

[0003] On the other hand, there has been progress in developing cancer immunotherapy as a new treatment for cancer.

[0004] Activation of the adaptive immune response begins with the binding of the antigen peptide-MHC complex to T-cell receptors (TCRs). This binding is further limited by the costimulation or co-inhibition effects resulting from the binding of the B7 family of costimulatory molecules to their receptor CD28 family. In other words, for T cells to specifically activate antigens, two characteristic signal transduction events are required. T cells that receive only antigen stimulation without costimulation from the B7 family enter an unresponsive state, inducing immune tolerance.

[0005] By utilizing this mechanism to inhibit the activation of antigen-specific T cells, cancer cells evade the immune surveillance system and continue to grow. Therefore, inducing an anti-tumor immune response in cancer patients and preventing tumor immune escape by enhancing co-stimulation and blocking co-inhibition is considered an effective treatment for cancer. Various regimens targeting co-stimulatory molecules (stimulatory co-stimulatory molecules) or co-inhibitory molecules (inhibitory co-stimulatory molecules) exist for cancer immunotherapy (NPL 5). For example, nivolumab (a human IgG4 monoclonal antibody against human PD-1), as an immune checkpoint inhibitor that activates T cells by inhibiting the binding of PD-1 to its ligands (PD-L1 and PD-L2), has been used to treat malignant melanoma and other conditions (PTL 1 and NPL 6). Furthermore, zimberelimab (AB122), a novel immune checkpoint inhibitor, is known to be used to treat Hodgkin's lymphoma and other conditions (NPL 7).

[0006] (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-yl)prop-2-en-1-one (hereinafter referred to as "Fabatinib") is a 3,5-disubstituted benzoynyl compound or a salt thereof, known as an FGFR inhibitor, and there are currently reports of FGFR inhibitors being used in combination with other antitumor agents (PTL 2 and PTL 3). Furthermore, a clinical trial (jRCT number: jRCT2011210020) of fabatinib in combination with serpalimumab in patients with non-small cell lung cancer is underway (NPL 8).

[0007] Reference List Patent documents PTL 1: WO2004 / 004771 PTL 2: WO2013 / 108809 PTL 3: WO2017 / 150725 PTL 4: WO2016 / 161239 Non-patent literature NPL 1: Nat. Rev. Cancer 10: 116-129 (2010) NPL 2: J. Clin. Oncol. 24, 3664-3671 (2006) NPL 3: Mol. Cancer Res. 3, 655-667 (2005) NPL 4: Cancer Res.70, 2085-2094 (2010) NPL 5: Nat. Rev. Cancer, 12: 252-264 (2012) NPL 6: N. Engl. J. Med., 366: 2443-2454 (2012) NPL 7: Drugs. 81 (17): 2063-2068 (2021) NPL 8: https: / / jrct.niph.go.jp / latest-detail / jRCT2011210020 Summary of the Invention

[0008] Technical issues The purpose of this invention is to provide a new combination therapy with excellent anti-tumor effects for cancer patients.

[0009] Problem Solving Methods In view of the above, the inventors have discovered that the above problems can be solved by combining it with fubatinib or its salts and specific immune checkpoint inhibitors, and further by using other antitumor agents.

[0010] Therefore, the present invention provides the following items from 1 to 55.

[0011] Item 1. The following are examples of antitumor agents according to Item 1-1, pharmaceutical compositions according to Item 1-2, uses according to Item 1-3, compounds or salts thereof according to uses according to Item 1-4, uses according to Item 1-5, commercial packaging according to Item 1-6, or methods according to Item 1-7: Item 1-1. Any of the following (i) to (iii) antitumor agents (excluding antitumor agents containing pembrolizumab as an active ingredient, and antitumor agents used in combination with pembrolizumab): (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with immune checkpoint inhibitors and at least one or more other antitumor agents for use in cancer patients; (ii) The antitumor agents include immune checkpoint inhibitors as active ingredients, which are used in combination with fobatinib or a pharmaceutically acceptable salt thereof and at least one or more other antitumor agents in cancer patients; and (iii) The antitumor agent includes at least one or more other antitumor agents as active ingredients, which are used in combination with fubatinib or pharmaceutically acceptable salts and immune checkpoint inhibitors in cancer patients; Items 1-2. Any of the following (i) to (iii) pharmaceutical compositions for the prevention or treatment of cancer (excluding pharmaceutical compositions that include pembrolizumab as an active ingredient, and pharmaceutical compositions used in combination with pembrolizumab): (i) The pharmaceutical composition comprises fubatinib or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprises a drug carrier for use in combination with immune checkpoint inhibitors and at least one or more other antitumor agents in cancer patients; (ii) The pharmaceutical composition comprises an immune checkpoint inhibitor as an active ingredient and also includes a drug carrier for use in combination with fobatinib or a pharmaceutically acceptable salt thereof and at least one or more other antitumor agents in cancer patients; and (iii) The pharmaceutical composition comprises at least one or more other antitumor agents as active ingredients, and further comprises a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor in cancer patients; Items 1-3. Any of the following (i) to (iii) (excluding uses for manufacturing antitumor agents comprising pembrolizumab as an active ingredient, and uses for manufacturing antitumor agents to be administered in combination with pembrolizumab): (i) The use of fubatinib or a pharmaceutically acceptable salt thereof in the manufacture of an antitumor agent for use in combination with immune checkpoint inhibitors and at least one or more other antitumor agents in patients with cancer; (ii) Immune checkpoint inhibitors for the manufacture of an antitumor agent intended for use in combination with fobatinib or a pharmaceutically acceptable salt thereof and at least one or more other antitumor agents in patients with cancer; and (iii) At least one or more other antitumor agents are used to manufacture an antitumor agent for use in combination with fobatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor in patients with cancer; Items 1-4. Compounds or salts thereof used for any of the following (i) to (iii) (excluding compounds and pembrolizumab used for the purpose of administration): (i) Fubatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of cancer, which is administered in combination with immune checkpoint inhibitors and at least one or more other antitumor agents to cancer patients; (ii) Immune checkpoint inhibitors used for the prevention or treatment of cancer, administered in combination with fobatinib or a pharmaceutically acceptable salt thereof and at least one or more other antitumor agents to cancer patients; and (iii) At least one or more other antitumor agents for the prevention or treatment of cancer, which are administered in combination with fubatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor to cancer patients; Items 1-5. Any of the following (i) through (iii) (excluding the use of pembrolizumab and the use of compounds in combination with pembrolizumab): (i) The use of fubatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of cancer, in combination with immune checkpoint inhibitors and at least one or more other antitumor agents in patients with cancer; (ii) Use of immune checkpoint inhibitors for the prevention or treatment of cancer, in combination with fobatinib or a pharmaceutically acceptable salt thereof and at least one or more other antitumor agents in patients with cancer; and (iii) Use of at least one or more other antitumor agents for the prevention or treatment of cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor in a cancer patient; Items 1-6. Commercial packaging of any of (i) to (iii) below (excluding commercial packaging used in combination with pharmaceutical compositions containing pembrolizumab as an active ingredient and pembrolizumab): (i) The commercial packaging includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, together with instructions for use in the prevention or treatment of cancer in a subject, which is used in combination with immune checkpoint inhibitors and at least one or more other antitumor agents for use in cancer patients. (ii) The commercial packaging includes an immune checkpoint inhibitor as the active ingredient, along with instructions for its use in the prevention or treatment of cancer in a subject, intended for use in combination with fobatinib or a pharmaceutically acceptable salt thereof and at least one or more other antitumor agents in cancer patients; and (iii) The commercial packaging includes an antitumor agent (other antitumor agent) other than "fubatinib or its pharmaceutically acceptable salts and immune checkpoint inhibitors" as the active ingredient, together with instructions for use in the prevention or treatment of cancer in a subject, which is intended to be administered in combination with fubatinib or its pharmaceutically acceptable salts and immune checkpoint inhibitors to cancer patients.

[0012] Items 1-7. According to any one of the following (i) to (iii) (excluding methods including administration of pembrolizumab, and methods including administration of antitumor agents to subjects who have been, concurrently or are to be administered pembrolizumab): (i) A method of preventing or treating cancer, comprising administering an effective amount of fobatinib or a pharmaceutically acceptable salt thereof to a subject in need of such subject, wherein the subject has been, concurrently administered or is to be administered an immune checkpoint inhibitor, and the subject has been, concurrently administered or is to be administered at least one or more other antitumor agents. (ii) A method of preventing or treating cancer, comprising administering an effective amount of an immune checkpoint inhibitor to a subject in need, wherein the subject has been, concurrently administered, or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, and the subject has been, concurrently administered, or is to be administered at least one or more antitumor agents; and (ii) A method of preventing or treating cancer, comprising administering an effective amount of at least one or more antitumor agents (other antitumor agents) other than "fubatinib or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor" to a subject in need, wherein the subject has been, concurrently administered or is to be administered fubatinib or a pharmaceutically acceptable salt thereof, and the subject has been, concurrently administered or is to be administered an immune checkpoint inhibitor.

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

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

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

[0016] Item 5. The antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method as described in Item 4, wherein the antiPD-1 antibody is cepalimab.

[0017] Item 6. An antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to any one of items 1 to 5, wherein other antitumor agents are chemotherapeutic agents.

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

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

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

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

[0023] Item 12. An antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to any one of items 1 to 11, wherein the cancer is selected from at least one 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 or 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 for use or salt thereof, commercial packaging or method according to any one of items 1 to 11, wherein the cancer is at least one selected from pancreatic cancer, lung cancer, esophageal cancer, biliary tract cancer and head and neck cancer.

[0025] Item 14. An antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to any one of items 1 to 13, wherein the cancer patient is a cancer patient who has not previously received treatment for advanced cancer or has previously received first-line chemotherapy.

[0026] Item 15. An antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to any one of items 1 to 14, wherein the 21-day or 28-day administration cycle is repeated once or twice or more.

[0027] Item 16. The antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to Item 15, wherein fobatinib is administered once daily on each day of a 21-day or 28-day administration cycle.

[0028] Item 17. The antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to Item 15, wherein serpalimab is administered for 1 to 2 days in a 21-day or 28-day administration cycle.

[0029] Item 18. The antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to Item 15, wherein, during an administration cycle of 21 or 28 days, the other antitumor agent is administered for 1 to 5 days.

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

[0031] Item 20. The antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to Item 15, wherein, in a 21-day or 28-day administration cycle, the other antitumor agent is administered once on day 1 and once on day 8.

[0032] Item 21. The antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to Item 15, wherein, in a 21-day or 28-day administration cycle, the other antitumor agent is administered once each on day 1, day 8 and day 15.

[0033] Item 22. The antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to Item 15, wherein, in a 21-day or 28-day administration cycle, the other antitumor agent is administered once each on day 1, day 2, day 3 and day 4.

[0034] Item 23. The antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to Item 15, wherein, in a 21-day or 28-day administration cycle, the other antitumor agent is administered once each on day 1, day 2, day 3, day 4 and day 5.

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

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

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

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

[0039] Item 28. An antitumor agent, pharmaceutical composition, use, compound for use or a salt thereof, commercial packaging or method according to any one of items 1 to 27, wherein it is an antitumor agent according to item 28-1, a pharmaceutical composition according to item 28-2, a use according to item 28-3, a compound for use or a salt thereof according to item 28-4, a use according to item 28-5, a commercial packaging according to item 28-6, or a method according to item 28-7: Item 28-1. Any one of the following (i) to (iv) antitumor agents: (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, which is used in combination with cepalimumab, cisplatin and 5-fluorouracil for patients with esophageal cancer; (ii) The antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts, cisplatin and 5-fluorouracil in patients with esophageal cancer; (iii) The antitumor agent comprises cisplatin as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, serpalimumab, and 5-fluorouracil in patients with esophageal cancer; and (iv) The antitumor agent includes 5-fluorouracil as an active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and cisplatin for patients with esophageal cancer.

[0040] Item 28-2. Any of the following (i) to (iv) pharmaceutical compositions (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient, and pharmaceutical compositions used in combination with pembrolizumab): (i) The pharmaceutical composition comprises fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, and further comprises a drug carrier for use in combination with cepallimab, cisplatin and 5-fluorouracil in patients with esophageal cancer; (ii) The pharmaceutical composition comprises cepalimumab as the active ingredient and also includes a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cisplatin and 5-fluorouracil in patients with esophageal cancer; (iii) The pharmaceutical composition comprises cisplatin as the active ingredient and also includes a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, serpalimumab, and 5-fluorouracil in patients with esophageal cancer; and (iv) The pharmaceutical composition includes 5-fluorouracil as an active ingredient and also includes a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimab and cisplatin in patients with esophageal cancer.

[0041] Item 28-3. Any of the following (i) to (iv) (excluding uses for manufacturing antitumor agents comprising pembrolizumab as an active ingredient, and uses for manufacturing antitumor agents for use in combination with pembrolizumab): (i) The use of fubatinib or a pharmaceutically acceptable salt thereof in the manufacture of an antitumor agent for use in combination with cepalimumab, cisplatin and 5-fluorouracil in patients with esophageal cancer; (ii) Sepalimab is intended for use in the manufacture of an antitumor agent for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cisplatin and 5-fluorouracil in patients with esophageal cancer; (iii) Cisplatin for use in the manufacture of an antitumor agent administered in combination with fobatinib or a pharmaceutically acceptable salt thereof, serpalimumab, and 5-fluorouracil for patients with esophageal cancer; and (iv) 5-Fluorouracil for use in the manufacture of an antitumor agent for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and cisplatin in patients with esophageal cancer.

[0042] Item 28-4. Compounds or salts thereof used for any of the following (i) to (iv) (excluding compounds and pembrolizumab used for the purpose of administration): (i) Fabatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of esophageal cancer, which is used in combination with cepalimumab, cisplatin and 5-fluorouracil in patients with esophageal cancer; (ii) Sepalimab for the prevention or treatment of esophageal cancer, which is administered in combination with fubatinib or a pharmaceutically acceptable salt thereof, cisplatin and 5-fluorouracil in patients with esophageal cancer; (iii) Cisplatin for the prevention or treatment of esophageal cancer, administered in combination with fubatinib or a pharmaceutically acceptable salt thereof, serpalimumab, and 5-fluorouracil in patients with esophageal cancer; and (iv) 5-Fluorouracil for the prevention or treatment of esophageal cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and cisplatin in patients with esophageal cancer.

[0043] Item 28-5. Any of the following (i) to (iv) uses (excluding the use of pembrolizumab and the use of compounds in combination with pembrolizumab): (i) Use of fubatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of esophageal cancer, in combination with cepalimumab, cisplatin and 5-fluorouracil in patients with esophageal cancer; (ii) Use of serpalimumab for the prevention or treatment of esophageal cancer, in combination with fubatinib or its pharmaceutically acceptable salts, cisplatin and 5-fluorouracil in patients with esophageal cancer; (iii) Use of cisplatin for the prevention or treatment of esophageal cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof, serpalimumab and 5-fluorouracil in patients with esophageal cancer; and (iv) Use of 5-fluorouracil for the prevention or treatment of esophageal cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and cisplatin in patients with esophageal cancer.

[0044] Items 28-6. Commercial packaging of any of the following (i) to (iv) (excluding commercial packaging used in combination with pharmaceutical compositions containing pembrolizumab as an active ingredient and pembrolizumab): (i) The commercial packaging includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, together with instructions for use in the prevention or treatment of esophageal cancer in subjects, which is used in combination with cepalimumab, cisplatin and 5-fluorouracil in patients with esophageal cancer. (ii) The commercial packaging includes cepalimumab as the active ingredient, together with a manual for its use in the prevention or treatment of esophageal cancer in subjects, which is used in combination with fubatinib or its pharmaceutically acceptable salts, cisplatin and 5-fluorouracil in patients with esophageal cancer. (iii) The commercial packaging includes cisplatin as the active ingredient, along with instructions for use in the prevention or treatment of esophageal cancer in subjects, administered in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and 5-fluorouracil in patients with esophageal cancer; and (iv) The commercial packaging includes 5-fluorouracil as the active ingredient, together with instructions for its use in the prevention or treatment of esophageal cancer in subjects, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and cisplatin in patients with esophageal cancer.

[0045] Item 28-7. According to any one of the following (i) to (iv) (but excluding methods including administration of pembrolizumab, and methods including administration of antitumor agents to subjects who have been, concurrently or are to be administered pembrolizumab): (i) A method of preventing or treating esophageal cancer, comprising administering an effective amount of fobatinib or a pharmaceutically acceptable salt thereof to a subject in need of the subject, wherein the subject has been, concurrently administered or is to be administered cepalimab, has been, concurrently administered or is to be administered cisplatin, or has been, concurrently administered or is to be administered 5-fluorouracil. (ii) A method of preventing or treating esophageal cancer, comprising administering an effective amount of cepalimumab to a subject in need of it, wherein the subject has been, concurrently administered or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, has been, concurrently administered or is to be administered cisplatin, or has been, concurrently administered or is to be administered 5-fluorouracil. (iii) A method of preventing or treating esophageal cancer, comprising administering an effective amount of cisplatin to a subject in need, wherein the subject has been, concurrently administered, or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, has been, concurrently administered, or is to be administered cepalimab, or has been, concurrently administered, or is to be administered 5-fluorouracil; and (iv) A method of preventing or treating esophageal cancer, comprising administering an effective amount of 5-fluorouracil to a subject in need of it, wherein the subject has been, concurrently administered or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, has been, concurrently administered or is to be administered cepalimab, or has been, concurrently administered or is to be administered cisplatin.

[0046] Item 29. The antitumor agent, pharmaceutical composition, use, compound for use, or salt thereof, commercial packaging, or method according to Item 28, wherein a 21-day administration cycle is repeated once or twice or more, during said administration cycle, 12 mg / dose, 16 mg / dose, or 20 mg / dose of fobatinib is administered once daily, and 360 mg / dose of cepalimab is administered once daily, at 80 mg / m 2 A single dose of cisplatin, 800 mg / m². 2 5-Fluorouracil was administered daily for 5 days.

[0047] Item 30. An antitumor agent, pharmaceutical composition, use, compound for use, or salt thereof, commercial packaging, or method according to Item 28, wherein a 21-day administration cycle is repeated once or twice or more, during said administration cycle, 12 mg / dose, 16 mg / dose, or 20 mg / dose of fobatinib is administered once daily, and 360 mg / dose of cepalimab is administered once on day 1, at 80 mg / m 2 Cisplatin was administered once on day 1, at a dose of 800 mg / m². 2 5-Fluorouracil was administered daily from day 1 to day 5.

[0048] Item 31. An antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to any one of items 28 to 30, wherein the cancer patient is an esophageal cancer patient who has not previously received treatment for advanced cancer.

[0049] Item 32. An antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to any one of items 1 to 27, wherein the antitumor agent is according to item 32-1, a pharmaceutical composition is according to item 32-2, the use is according to item 32-3, the compound for use is according to item 32-4, the use is according to item 32-5, the commercial packaging is according to item 32-6, or the method is according to item 32-7. Item 32-1. Any of the following (i) to (iii) antitumor agents (excluding antitumor agents containing pembrolizumab as an active ingredient, and antitumor agents used in combination with pembrolizumab): (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, which is used in combination with cepallimab and dovanalimab for patients with esophageal cancer; (ii) The antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof and dovanalimab in patients with esophageal cancer; and (iii) The antitumor agents include dovanalimab as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof and cepalimumab in patients with esophageal cancer.

[0050] Item 32-2. Any of the following (i) to (iii) pharmaceutical compositions for the prevention or treatment of esophageal cancer (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient, and pharmaceutical compositions used in combination with pembrolizumab): (i) The pharmaceutical composition comprises fubatinib or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprises a drug carrier for use in combination with cepallimab and dovanalimab in patients with esophageal cancer; (ii) The pharmaceutical composition comprises cepalimumab as the active ingredient and also includes a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof and dovanalimab in patients with esophageal cancer; and (iii) The pharmaceutical composition includes dovanalimab as the active ingredient and also includes a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof and cepalimab in patients with esophageal cancer.

[0051] Item 32-3. Any of the following (i) to (iii) (excluding uses for manufacturing antitumor agents comprising pembrolizumab as an active ingredient, and uses for manufacturing antitumor agents for use in combination with pembrolizumab): (i) The use of fubatinib or a pharmaceutically acceptable salt thereof in the manufacture of an antitumor agent for use in combination with cepalimumab and dovanalimab in patients with esophageal cancer; (ii) The use of cepalimumab to manufacture an antitumor agent for use in combination with fubabatinib or a pharmaceutically acceptable salt thereof and dovanalimab in patients with esophageal cancer; and (iii) Dovanalimab is used to manufacture an antitumor agent for use in combination with fubatinib or a pharmaceutically acceptable salt thereof and cepalimumab in patients with esophageal cancer.

[0052] Items 32-4. Compounds or salts thereof intended for use according to any of the following (i) to (iii) (excluding compounds and pembrolizumab intended for use in combination with pembrolizumab): (i) Fubatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of esophageal cancer, which is used in combination with cepalimumab and dovanalimab in patients with esophageal cancer; (ii) Sepalimab for the prevention or treatment of esophageal cancer, administered in combination with fubabatinib or a pharmaceutically acceptable salt thereof and dovanalimab in patients with esophageal cancer; and (iii) Dovanalimab for the prevention or treatment of esophageal cancer, which is administered in combination with fubatinib or a pharmaceutically acceptable salt thereof and cepalimumab to patients with esophageal cancer.

[0053] Items 32-5. Any of the following (i) through (iii) (excluding the use of pembrolizumab and the use of compounds in combination with pembrolizumab): (i) Use of fubatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of esophageal cancer, in combination with cepalimumab and dovanalimab in patients with esophageal cancer; (ii) Use of cepalimumab for the prevention or treatment of esophageal cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof and dovanalimab in patients with esophageal cancer; and (iii) Use of dovanalimab for the prevention or treatment of esophageal cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof and cepalimumab in patients with esophageal cancer.

[0054] Items 32-6. Commercial packaging of any of the following (i) to (iii) (excluding commercial packaging used in combination with pharmaceutical compositions containing pembrolizumab as an active ingredient and pembrolizumab): (i) The commercial packaging includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, together with instructions for use in the prevention or treatment of esophageal cancer in subjects, which is intended to be administered in combination with cepalimumab and dovanalimab to patients with esophageal cancer. (ii) The commercial packaging comprises cepalimumab as the active ingredient, together with an instruction manual for its use in the prevention or treatment of esophageal cancer in subjects, which is intended for use in combination with fubatinib or its pharmaceutically acceptable salts and dovanalimab in patients with esophageal cancer; and (iii) The commercial packaging includes dovanalimab as the active ingredient, together with instructions for use in the prevention or treatment of esophageal cancer in subjects, which is intended to be administered in combination with fubatinib or a pharmaceutically acceptable salt thereof and cepalimumab to patients with esophageal cancer.

[0055] Items 32-7. According to any one of the following (i) to (iii) (but excluding methods including administration of pembrolizumab, and methods including administration of antitumor agents to subjects who have been, concurrently or are to be administered pembrolizumab): (i) A method of preventing or treating esophageal cancer, comprising administering an effective amount of fobatinib or a pharmaceutically acceptable salt thereof to a subject in need of the subject, wherein the subject has been, concurrently administered or is to be administered cepalimab, and has been, concurrently administered or is to be administered dovanalimab. (ii) A method of preventing or treating esophageal cancer, comprising administering an effective amount of cepalimumab to a subject in need, wherein the subject has been, concurrently administered, or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, and has been, concurrently administered, or is to be administered dovanalimab; and (iii) A method of preventing or treating esophageal cancer, comprising administering an effective amount of dovanalimab to a subject in need of the subject, wherein the subject has been, concurrently administered or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, and has been, concurrently administered or is to be administered cepalimab.

[0056] Item 33. The antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to Item 32, wherein the 21-day administration cycle is repeated once or twice or more, wherein fobatinib is administered once daily at a dose of 12 mg / dose, 16 mg / dose or 20 mg / dose, cepalimumab is administered once daily at a dose of 360 mg / dose, and dovanalimab is administered once daily at a dose of 1200 mg / dose.

[0057] Item 34. The antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to Item 32, wherein the 21-day administration cycle is repeated once or twice or more, wherein fobatinib at 12 mg / dose, 16 mg / dose or 20 mg / dose is administered once daily, cepalimab at 360 mg / dose is administered once on day 1, and dovanalimab at 1200 mg / dose is administered once on day 1.

[0058] Item 35. An antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to any one of items 32 to 34, wherein the cancer patient is an esophageal cancer patient who has not previously received treatment for advanced cancer or has previously received first-line chemotherapy.

[0059] Item 36. An antitumor agent, pharmaceutical composition, use, compound for use or a salt thereof, commercial packaging or method according to any one of items 1 to 27, wherein the antitumor agent is according to item 36-1, a pharmaceutical composition is according to item 36-2, the use is according to item 36-3, the compound for use is according to item 36-4, the use is according to item 36-5, the commercial packaging is according to item 36-6, or the method is according to item 36-7. Item 36-1. Any of the following (i) to (iv) antitumor agents (excluding antitumor agents containing pembrolizumab as an active ingredient, and antitumor agents used in combination with pembrolizumab): (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, which is used in combination with cepalimumab, 5-fluorouracil and carboplatin or cisplatin for patients with head and neck cancer; (ii) The antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil and carboplatin or cisplatin for patients with head and neck cancer; (iii) The antitumor agent comprises 5-fluorouracil as an active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimab, and carboplatin or cisplatin in patients with head and neck cancer; and (iv) The antitumor agents include carboplatin or cisplatin as active ingredients, which are used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and 5-fluorouracil for patients with head and neck cancer.

[0060] Item 36-2. Any of the following (i) to (iv) pharmaceutical compositions for the prevention or treatment of head and neck cancer (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient, and pharmaceutical compositions used in combination with pembrolizumab): (i) The pharmaceutical composition comprises fubatinib or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprises a drug carrier for use in combination with cepallimab, 5-fluorouracil and carboplatin or cisplatin in patients with head and neck cancer. (ii) The pharmaceutical composition comprises cepalimumab as the active ingredient and also includes a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil and carboplatin or cisplatin in patients with head and neck cancer. (iii) The pharmaceutical composition comprises 5-fluorouracil as the active ingredient and also includes a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimab, and carboplatin or cisplatin in patients with head and neck cancer; and (iv) The pharmaceutical composition includes carboplatin or cisplatin as an active ingredient and also includes a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimab and 5-fluorouracil in patients with head and neck cancer.

[0061] Item 36-3. Any of the following (i) to (iv) (excluding uses for manufacturing antitumor agents comprising pembrolizumab as an active ingredient, and uses for manufacturing antitumor agents for use in combination with pembrolizumab): (i) The use of fubatinib or a pharmaceutically acceptable salt thereof in the manufacture of an antitumor agent for use in combination with cepalimumab, 5-fluorouracil and carboplatin or cisplatin in patients with head and neck cancer; (ii) Sepalimab is intended for use in the manufacture of an antitumor agent for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil and carboplatin or cisplatin in patients with head and neck cancer; (iii) 5-Fluorouracil for use in the manufacture of an antitumor agent intended for use in combination with fobatinib or a pharmaceutically acceptable salt thereof, serpalimab, and carboplatin or cisplatin in patients with head and neck cancer; and (iv) Carboplatin or cisplatin is used to manufacture an antitumor agent for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and 5-fluorouracil in patients with head and neck cancer.

[0062] Item 36-4. Compounds or salts thereof used for any of the following (i) to (iv) (excluding compounds and pembrolizumab used for the purpose of administration): (i) Fubatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of head and neck cancer, which is used in combination with cepalimumab, 5-fluorouracil and carboplatin or cisplatin in patients with head and neck cancer; (ii) Sepalimab for the prevention or treatment of head and neck cancer, which is administered in combination with fubatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil and carboplatin or cisplatin in patients with head and neck cancer; (iii) 5-Fluorouracil for the prevention or treatment of head and neck cancer, administered in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and carboplatin or cisplatin in patients with head and neck cancer; and (iv) Carboplatin or cisplatin for the prevention or treatment of head and neck cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and 5-fluorouracil in patients with head and neck cancer.

[0063] Item 36-5. Any of the following (i) to (iv) uses (excluding the use of pembrolizumab and the use of compounds in combination with pembrolizumab): (i) Use of fubatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of head and neck cancer, in combination with cepalimumab, 5-fluorouracil and carboplatin or cisplatin in patients with head and neck cancer; (ii) Use of cepalimumab for the prevention or treatment of head and neck cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil and carboplatin or cisplatin in patients with head and neck cancer; (iii) Use of 5-fluorouracil for the prevention or treatment of head and neck cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and carboplatin or cisplatin in patients with head and neck cancer; and (iv) Use of carboplatin or cisplatin for the prevention or treatment of head and neck cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and 5-fluorouracil in patients with head and neck cancer.

[0064] Items 36-6. Commercial packaging of any of the following (i) to (iv) (excluding commercial packaging used in combination with pharmaceutical compositions containing pembrolizumab as an active ingredient and pembrolizumab): (i) The commercial packaging includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, together with instructions for use in the prevention or treatment of head and neck cancer in subjects, which is intended to be administered in combination with cepalimumab, 5-fluorouracil and carboplatin or cisplatin in patients with head and neck cancer. (ii) The commercial packaging includes cepalimumab as the active ingredient, together with instructions for use in the prevention or treatment of head and neck cancer in subjects, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil and carboplatin or cisplatin in patients with head and neck cancer. (iii) The commercial packaging includes 5-fluorouracil as the active ingredient, together with instructions for use in the prevention or treatment of head and neck cancer in a subject, which is intended for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and carboplatin or cisplatin in patients with head and neck cancer; and (iv) The commercial packaging includes carboplatin or cisplatin as the active ingredient, together with instructions for use in the prevention or treatment of head and neck cancer in subjects, which is intended to be administered in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and 5-fluorouracil to patients with head and neck cancer.

[0065] Items 36-7. According to any one of the following (i) to (iv) (excluding methods including administration of pembrolizumab, and methods including administration of antitumor agents to subjects who have been, concurrently or are to be administered pembrolizumab): (i) A method of preventing or treating head and neck cancer, comprising administering an effective amount of fobatinib or a pharmaceutically acceptable salt thereof to a subject in need of the subject, wherein the subject has been, concurrently administered or is to be administered cepalimab, has been, concurrently administered or is to be administered 5-fluorouracil, or has been, concurrently administered or is to be administered carboplatin or cisplatin. (ii) A method of preventing or treating head and neck cancer, comprising administering an effective amount of cepalimumab to a subject in need of it, wherein the subject has been, concurrently administered or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, has been, concurrently administered or is to be administered 5-fluorouracil, or has been, concurrently administered or is to be administered carboplatin or cisplatin; (iii) A method of preventing or treating head and neck cancer, comprising administering an effective amount of 5-fluorouracil to a subject in need, wherein the subject has been, concurrently administered, or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, has been, concurrently administered, or is to be administered cepalimab, or has been, concurrently administered, or is to be administered carboplatin or cisplatin; and (iv) A method of preventing or treating head and neck cancer, comprising administering an effective amount of carboplatin or cisplatin to a subject in need of such subject, wherein the subject has been, concurrently administered or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, has been, concurrently administered or is to be administered cepalimab, or has been, concurrently administered or is to be administered 5-fluorouracil.

[0066] Item 37. The antitumor agent, pharmaceutical composition, use, compound for use, or salt thereof, commercial packaging, or method according to Item 36, wherein a 21-day administration cycle is repeated once or twice or more, during said administration cycle, 12 mg / dose, 16 mg / dose, or 20 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once daily, and carboplatin with an AUC 5 or 100 mg / m² is administered. 2 A single dose of cisplatin, 1000 mg / m². 2 5-Fluorouracil was administered daily for 4 days.

[0067] Item 38. The antitumor agent, pharmaceutical composition, use, compound for use, or salt thereof, commercial packaging, or method according to Item 36, wherein a 21-day administration cycle is repeated once or twice or more, wherein fobatinib is administered once daily at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose, cepalimumab is administered once daily on day 1 at a dose of 360 mg / dose, and carboplatin or 100 mg / m² at an AUC 5. 2 Cisplatin was administered once on day 1, at a dose of 1000 mg / m². 2 5-Fluorouracil was administered daily from day 1 to day 4.

[0068] Item 39. An antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to any one of items 37 to 38, wherein the cancer patient is a head and neck cancer patient who has not previously received treatment for advanced cancer.

[0069] Item 40. An antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to any one of items 1 to 27, wherein the antitumor agent is according to item 40-1, a pharmaceutical composition is according to item 40-2, the use is according to item 40-3, the compound for use is according to item 40-4, the use is according to item 40-5, the commercial packaging is according to item 40-6, or the method is according to item 40-7. Item 40-1. Any of the following (i) to (iii) antitumor agents (excluding antitumor agents containing pembrolizumab as an active ingredient, and antitumor agents used in combination with pembrolizumab): (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with cepallimab and dovanalimab for patients with head and neck cancer; (ii) The antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof and dovanalimab in patients with head and neck cancer; and (iii) The antitumor agents include dovanalimab as an active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof and cepalimumab for patients with head and neck cancer.

[0070] Item 40-2. Any of the following (i) to (iii) pharmaceutical compositions for the prevention or treatment of head and neck cancer (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient, and pharmaceutical compositions used in combination with pembrolizumab): (i) The pharmaceutical composition comprises fubatinib or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprises a drug carrier for use in combination with cepallimab and dovanalimab in patients with head and neck cancer; (ii) The pharmaceutical composition comprises cepalimumab as the active ingredient and also includes a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof and dovanalimab in patients with head and neck cancer; and (iii) The pharmaceutical composition includes dovanalimab as the active ingredient and also includes a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof and cepalimumab in patients with head and neck cancer.

[0071] Item 40-3. Any of the following (i) to (iii) (excluding uses for manufacturing antitumor agents comprising pembrolizumab as an active ingredient, and uses for manufacturing antitumor agents for use in combination with pembrolizumab): (i) The use of fubatinib or a pharmaceutically acceptable salt thereof in the manufacture of an antitumor agent to be administered in combination with cepalimumab and dovanalimab for patients with head and neck cancer; (ii) The use of cepalimumab to manufacture an antitumor agent for use in combination with fubabatinib or a pharmaceutically acceptable salt thereof and dovanalimab in patients with head and neck cancer; and (iii) Dovanalimab is used to manufacture an antitumor agent for use in combination with fubatinib or a pharmaceutically acceptable salt thereof and cepalimumab in patients with head and neck cancer.

[0072] Item 40-4. Compounds or salts thereof intended for use according to any of the following (i) to (iii) (excluding compounds and pembrolizumab intended for use in combination with pembrolizumab): (i) Fubatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of head and neck cancer, which is used in combination with cepalimumab and dovanalimab in patients with head and neck cancer; (ii) Sepalimab for the prevention or treatment of head and neck cancer, administered in combination with fubabatinib or a pharmaceutically acceptable salt thereof and dovanalimab in patients with head and neck cancer; and (iii) Dovanalimab for the prevention or treatment of head and neck cancer, which is administered in combination with fubatinib or a pharmaceutically acceptable salt thereof and cepalimumab to patients with head and neck cancer.

[0073] Items 40-5. Any of the following (i) through (iii) (excluding the use of pembrolizumab and the use of compounds in combination with pembrolizumab): (i) Use of fubatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of head and neck cancer, in combination with cepalimumab and dovanalimab in patients with head and neck cancer; (ii) Use of cepalimumab for the prevention or treatment of head and neck cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof and dovanalimab in patients with head and neck cancer; and (iii) Use of dovanalimab for the prevention or treatment of head and neck cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof and cepalimumab in patients with head and neck cancer.

[0074] Items 40-6. Commercial packaging of any of the following (i) to (iii) (excluding commercial packaging used in combination with pharmaceutical compositions containing pembrolizumab as an active ingredient and pembrolizumab): (i) The commercial packaging includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, together with instructions for use in the prevention or treatment of head and neck cancer in subjects, which is intended to be administered in combination with cepalimumab and dovanalimab to patients with head and neck cancer. (ii) The commercial packaging comprises cepalimumab as the active ingredient, together with instructions for use in the prevention or treatment of head and neck cancer in a subject, intended for use in combination with fubatinib or a pharmaceutically acceptable salt thereof and dovanalimab in patients with head and neck cancer; and (iii) The commercial packaging includes dovanalimab as the active ingredient, together with instructions for use in the prevention or treatment of head and neck cancer in subjects, which is intended to be administered in combination with fubatinib or a pharmaceutically acceptable salt thereof and cepalimumab to patients with head and neck cancer.

[0075] Items 40-7. According to any one of the following (i) to (iii) (excluding methods including administration of pembrolizumab, and methods including administration of antitumor agents to subjects who have been, concurrently or are to be administered pembrolizumab): (i) A method of preventing or treating head and neck cancer, comprising administering an effective amount of fobatinib or a pharmaceutically acceptable salt thereof to a subject in need of the subject, wherein the subject has been, concurrently administered or is to be administered cepalimab, and the subject has been, concurrently administered or is to be administered dovanalimab. (ii) A method of preventing or treating head and neck cancer, comprising administering an effective amount of cepalimumab to a subject in need, wherein the subject has been, concurrently administered, or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, and the subject has been, concurrently administered, or is to be administered dovanalimab; and (iii) A method of preventing or treating head and neck cancer, comprising administering an effective amount of dovanalimab to a subject in need of it, wherein the subject has been, concurrently administered or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, and the subject has been, concurrently administered or is to be administered cepalimumab.

[0076] Item 41. The antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to Item 40, wherein the 21-day administration cycle is repeated once or twice or more, wherein fobatinib is administered once daily at a dose of 12 mg / dose, 16 mg / dose or 20 mg / dose, cepalimab is administered once daily at a dose of 360 mg / dose, and dovanalimab is administered once daily at a dose of 1200 mg / dose.

[0077] Item 42. The antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to Item 40, wherein the 21-day administration cycle is repeated once or twice or more, wherein fobatinib at 12 mg / dose, 16 mg / dose or 20 mg / dose is administered once daily, cepalimab at 360 mg / dose is administered once on day 1, and dovanalimab at 1200 mg / dose is administered once on day 1.

[0078] Item 43. An antitumor agent, pharmaceutical composition, use, compound for use or a salt thereof, commercial packaging or method according to any one of items 40 to 42, wherein the cancer patient is a head and neck cancer patient who has not previously received treatment for advanced cancer.

[0079] Item 44. An antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to any one of items 1 to 27, wherein it is an antitumor agent according to item 44-1, a pharmaceutical composition according to item 44-2, a use according to item 44-3, a compound for use or salt thereof according to item 44-4, a use according to item 44-5, a commercial packaging according to item 44-6, or a method according to item 44-7: Item 44-1. Any of the following (i) to (iv) antitumor agents (excluding antitumor agents containing pembrolizumab as an active ingredient, and antitumor agents used in combination with pembrolizumab): (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, which is used in combination with cepalimumab, albumin-bound paclitaxel and carboplatin for patients with non-small cell lung cancer; (ii) The antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salt, albumin-bound paclitaxel and carboplatin for patients with non-small cell lung cancer; (iii) The antitumor agent includes albumin-bound paclitaxel as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and carboplatin for patients with non-small cell lung cancer; and (iv) The antitumor agents include carboplatin as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and albumin-bound paclitaxel for patients with non-small cell lung cancer.

[0080] Item 44-2. Any of the following (i) to (iv) pharmaceutical compositions for the prevention or treatment of non-small cell lung cancer (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient, and pharmaceutical compositions used in combination with pembrolizumab): (i) The pharmaceutical composition comprises fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, and also comprises a drug carrier for use in combination with cepalimab, albumin-bound paclitaxel and carboplatin in patients with non-small cell lung cancer; (ii) The pharmaceutical composition comprises cepalimumab as the active ingredient and also includes a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt, albumin-bound paclitaxel and carboplatin for patients with non-small cell lung cancer; (iii) The pharmaceutical composition comprises albumin-bound paclitaxel as the active ingredient and further comprises a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimab, and carboplatin in patients with non-small cell lung cancer; and (iv) The pharmaceutical composition includes carboplatin as the active ingredient and also includes a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and albumin-bound paclitaxel in patients with non-small cell lung cancer.

[0081] Item 44-3. Any of the following (i) to (iv) (excluding uses for manufacturing antitumor agents comprising pembrolizumab as an active ingredient, and uses for manufacturing antitumor agents for use in combination with pembrolizumab): (i) Fubatinib or a pharmaceutically acceptable salt thereof is used to manufacture an antitumor agent for use in combination with cepalimumab, albumin-bound paclitaxel and carboplatin in patients with non-small cell lung cancer; (ii) Sepalimab is intended for use in the manufacture of an antitumor agent for use in combination with fubatinib or pharmaceutically acceptable salts, albumin-bound paclitaxel and carboplatin for patients with non-small cell lung cancer; (iii) Albumin-bound paclitaxel for use in the manufacture of an antitumor agent to be administered in combination with fubatinib or a pharmaceutically acceptable salt thereof, serpalimumab, and carboplatin for patients with non-small cell lung cancer; and (iv) Carboplatin is used to manufacture an antitumor agent for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and albumin-bound paclitaxel in patients with non-small cell lung cancer.

[0082] Item 44-4. Compounds or salts thereof used for any of the following (i) to (iv) (excluding compounds and pembrolizumab used for the purpose of administration): (i) Fubatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of non-small cell lung cancer, which is used in combination with cepalimumab, albumin-bound paclitaxel and carboplatin in patients with non-small cell lung cancer; (ii) Sepalimab for the prevention or treatment of non-small cell lung cancer, which is used in combination with fubatinib or pharmaceutically acceptable salt, albumin-bound paclitaxel and carboplatin in patients with non-small cell lung cancer; (iii) Albumin-bound paclitaxel for the prevention or treatment of non-small cell lung cancer, administered in combination with fubatinib or its pharmaceutically acceptable salts, cepalimumab, and carboplatin in patients with non-small cell lung cancer; and (iv) Carboplatin for the prevention or treatment of non-small cell lung cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and albumin-bound paclitaxel in patients with non-small cell lung cancer.

[0083] Items 44-5. Any of the following (i) to (iv) uses (excluding the use of pembrolizumab and the use of compounds in combination with pembrolizumab): (i) Use of fubatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of non-small cell lung cancer, in combination with cepalimumab, albumin-bound paclitaxel and carboplatin in patients with non-small cell lung cancer; (ii) Use of cepalimumab for the prevention or treatment of non-small cell lung cancer, in combination with fubatinib or pharmaceutically acceptable salt, albumin-bound paclitaxel and carboplatin in patients with non-small cell lung cancer; (iii) Use of albumin-bound paclitaxel for the prevention or treatment of non-small cell lung cancer, in combination with fubatinib or its pharmaceutically acceptable salts, cepalimumab, and carboplatin in patients with non-small cell lung cancer; and (iv) Use of carboplatin for the prevention or treatment of non-small cell lung cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and albumin-bound paclitaxel in patients with non-small cell lung cancer.

[0084] Items 44-6. Commercial packaging of any of the following (i) to (iv) (excluding commercial packaging used in combination with pharmaceutical compositions containing pembrolizumab as an active ingredient and pembrolizumab): (i) The commercial packaging includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, together with instructions for use in the prevention or treatment of non-small cell lung cancer in a subject, which is used in combination with cepalimumab, albumin-bound paclitaxel and carboplatin for patients with non-small cell lung cancer. (ii) The commercial packaging includes cepalimumab as the active ingredient, together with a manual for its use in the prevention or treatment of non-small cell lung cancer in a subject, which is used in combination with fubatinib or its pharmaceutically acceptable salt, albumin-bound paclitaxel and carboplatin for patients with non-small cell lung cancer. (iii) The commercial packaging comprises albumin-bound paclitaxel as the active ingredient, together with a brochure for its use in the prevention or treatment of non-small cell lung cancer in a subject, which is intended for use in combination with fubatinib or its pharmaceutically acceptable salts, cepalimumab, and carboplatin in patients with non-small cell lung cancer; and (iv) The commercial packaging includes carboplatin as the active ingredient, together with instructions for use in the prevention or treatment of non-small cell lung cancer in a subject, which is intended to be administered in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and albumin-bound paclitaxel in patients with non-small cell lung cancer.

[0085] Items 44-7. According to any one of the following (i) to (iv) (excluding methods including administration of pembrolizumab, and methods including administration of antitumor agents to subjects who have been, concurrently or are to be administered pembrolizumab): (i) A method of preventing or treating non-small cell lung cancer, comprising administering an effective amount of fobatinib or a pharmaceutically acceptable salt thereof to a subject in need of the subject, wherein the subject has been, concurrently administered or is to be administered cepalimab, has been, concurrently administered or is to be administered albumin-bound paclitaxel, or has been, concurrently administered or is to be administered carboplatin. (ii) A method of preventing or treating non-small cell lung cancer, comprising administering an effective amount of cepalimumab to a subject in need of it, wherein the subject has been, concurrently administered or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, has been, concurrently administered or is to be administered albumin-bound paclitaxel, or has been, concurrently administered or is to be administered carboplatin. (iii) A method for the prevention or treatment of non-small cell lung cancer, comprising administering an effective amount of albumin-bound paclitaxel to a subject in need, wherein the subject has been, concurrently administered, or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, has been, concurrently administered, or is to be administered cepalimab, or has been, concurrently administered, or is to be administered carboplatin; and (iv) A method for the prevention or treatment of non-small cell lung cancer, comprising administering an effective amount of carboplatin to a subject in need of it, wherein the subject has been, concurrently administered or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, has been, concurrently administered or is to be administered cepalimab, or has been, concurrently administered or is to be administered albumin-bound paclitaxel.

[0086] Item 45. The antitumor agent, pharmaceutical composition, use, compound for use, or salt thereof, commercial packaging, or method according to Item 44, wherein a 21-day administration cycle is repeated once or twice or more, during said administration cycle, 12 mg / dose, 16 mg / dose, or 20 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once daily, and 100 mg / m 2 The drug is administered three times with albumin-bound paclitaxel and once with carboplatin (AUC 6).

[0087] Item 46. The antitumor agent, pharmaceutical composition, use, compound for use, or salt thereof, commercial packaging, or method according to Item 44, wherein a 21-day administration cycle is repeated once or twice or more, during said administration cycle, 12 mg / dose, 16 mg / dose, or 20 mg / dose of fobatinib is administered once daily, and 360 mg / dose of cepalimumab is administered once on day 1, at a dose of 100 mg / m 2 The albumin-bound paclitaxel was administered once each on days 1, 8, and 15, while carboplatin with an AUC of 6 was administered on day 1.

[0088] Item 47. An antitumor agent, pharmaceutical composition, use, compound for use or a salt thereof, commercial packaging or method according to any one of items 44 to 46, wherein the cancer patient is a non-small cell lung cancer patient who has not previously received treatment for advanced cancer.

[0089] Item 48. An antitumor agent, pharmaceutical composition, use, compound for use or a salt thereof, commercial packaging or method according to any one of items 1 to 27, wherein it is an antitumor agent according to item 48-1, a pharmaceutical composition according to item 48-2, a use according to item 48-3, a compound for use or a salt thereof according to item 48-4, a use according to item 48-5, a commercial packaging according to item 48-6, or a method according to item 48-7: Item 48-1. Any of the following (i) to (iv) antitumor agents (excluding antitumor agents containing pembrolizumab as an active ingredient, and antitumor agents used in combination with pembrolizumab): (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, which is used in combination with cepalimumab, cisplatin and gemcitabine for patients with biliary tract cancer; (ii) The antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts, cisplatin and gemcitabine for patients with biliary tract cancer; (iii) The antitumor agent includes gemcitabine as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and cisplatin in patients with biliary tract cancer; and (iv) The antitumor agents include cisplatin as an active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and gemcitabine for patients with biliary tract cancer.

[0090] Item 48-2. Any of the following (i) to (iv) pharmaceutical compositions for the prevention or treatment of biliary tract cancer (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient, and pharmaceutical compositions used in combination with pembrolizumab): (i) The pharmaceutical composition comprises fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, and further comprises a drug carrier for use in combination with cepallimab, cisplatin and gemcitabine for patients with biliary tract cancer; (ii) The pharmaceutical composition comprises cepalimumab as the active ingredient and also includes a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cisplatin and gemcitabine in patients with biliary tract cancer. (iii) The pharmaceutical composition comprises gemcitabine as the active ingredient and also includes a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimab, and cisplatin in patients with biliary tract cancer; and (iv) The pharmaceutical composition includes cisplatin as the active ingredient and also includes a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimab and gemcitabine in patients with biliary tract cancer.

[0091] Item 48-3. Any of the following (i) to (iv) (excluding uses for manufacturing antitumor agents comprising pembrolizumab as an active ingredient, and uses for manufacturing antitumor agents for use in combination with pembrolizumab): (i) The use of fubatinib or a pharmaceutically acceptable salt thereof in the manufacture of an antitumor agent for use in combination with cepalimumab, cisplatin and gemcitabine in patients with biliary tract cancer; (ii) Sepalimab is intended for use in the manufacture of an antitumor agent for use in combination with fubatinib or pharmaceutically acceptable salts of it, cisplatin and gemcitabine in patients with biliary tract cancer; (iii) Gemcitabine for the manufacture of an antitumor agent to be administered in combination with fubabatinib or a pharmaceutically acceptable salt thereof, serpalimumab, and cisplatin for patients with biliary tract cancer; and (iv) Cisplatin is used in the manufacture of an antitumor agent for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and gemcitabine for patients with biliary tract cancer.

[0092] Item 48-4. Compounds or salts thereof used for any of the following (i) to (iv) (excluding compounds and pembrolizumab used for the purpose of administration): (i) Fabatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of biliary tract cancer, which is used in combination with cepalimumab, cisplatin and gemcitabine in patients with biliary tract cancer; (ii) Sepalimab for the prevention or treatment of biliary tract cancer, which is administered in combination with fubatinib or its pharmaceutically acceptable salts, cisplatin and gemcitabine to patients with biliary tract cancer; (iii) Gemcitabine for the prevention or treatment of biliary tract cancer, administered in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and cisplatin in patients with biliary tract cancer; and (iv) Cisplatin for the prevention or treatment of biliary tract cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and gemcitabine in patients with biliary tract cancer.

[0093] Item 48-5. Any of the following (i) to (iv) uses (excluding the use of pembrolizumab and the use of compounds in combination with pembrolizumab): (i) Use of fubatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of biliary tract cancer, in combination with cepalimumab, cisplatin and gemcitabine in patients with biliary tract cancer; (ii) Use of cepalimumab for the prevention or treatment of biliary tract cancer, in combination with fubatinib or its pharmaceutically acceptable salts, cisplatin and gemcitabine in patients with biliary tract cancer; (iii) Gemcitabine is used for the prevention or treatment of biliary tract cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and cisplatin in patients with biliary tract cancer; and (iv) Use of cisplatin for the prevention or treatment of biliary tract cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and gemcitabine in patients with biliary tract cancer.

[0094] Items 48-6. Commercial packaging of any of the following (i) to (iv) (excluding commercial packaging used in combination with pharmaceutical compositions containing pembrolizumab as an active ingredient and pembrolizumab): (i) The commercial packaging includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, together with instructions for use in the prevention or treatment of biliary tract cancer in subjects, which is used in combination with cepalimumab, cisplatin and gemcitabine in patients with biliary tract cancer. (ii) The commercial packaging includes cepalimumab as the active ingredient, together with a manual for its use in the prevention or treatment of biliary tract cancer in subjects, which is intended to be administered in combination with fubatinib or its pharmaceutically acceptable salts, cisplatin and gemcitabine to patients with biliary tract cancer. (iii) The commercial packaging includes gemcitabine as the active ingredient, together with instructions for use in the prevention or treatment of biliary tract cancer in a subject, which is intended for use in combination with fubabatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and cisplatin in patients with biliary tract cancer; and (iv) The commercial packaging includes cisplatin as the active ingredient, together with instructions for use in the prevention or treatment of biliary tract cancer in subjects, which is intended to be administered in combination with fubatinib or its pharmaceutically acceptable salts, cepalimumab and gemcitabine in patients with biliary tract cancer.

[0095] Item 48-7. According to any one of the following (i) to (iv) (excluding methods including administration of pembrolizumab, and methods including administration of antitumor agents to subjects who have been, concurrently or are to be administered pembrolizumab): (i) A method of preventing or treating biliary tract cancer, comprising administering an effective amount of fobatinib or a pharmaceutically acceptable salt thereof to a subject in need of the subject, wherein the subject has been, concurrently administered or is to be administered cepalimab, has been, concurrently administered or is to be administered cisplatin, or has been, concurrently administered or is to be administered gemcitabine. (ii) A method of preventing or treating biliary tract cancer, comprising administering an effective amount of cepalimumab to a subject in need of it, wherein the subject has been, concurrently administered or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, has been, concurrently administered or is to be administered cisplatin, or has been, concurrently administered or is to be administered gemcitabine. (iii) A method of preventing or treating biliary tract cancer, comprising administering an effective amount of gemcitabine to a subject in need, wherein the subject has been, concurrently administered, or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, has been, concurrently administered, or is to be administered cepalimab, or has been, concurrently administered, or is to be administered cisplatin; and (iv) A method of preventing or treating biliary tract cancer, comprising administering an effective amount of cisplatin to a subject in need of it, wherein the subject has been, concurrently administered or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, has been, concurrently administered or is to be administered cepalimab, or has been, concurrently administered or is to be administered gemcitabine.

[0096] Item 49. An antitumor agent, pharmaceutical composition, use, compound for use, or salt thereof, commercial packaging, or method according to Item 48, wherein a 21-day administration cycle is repeated once or twice or more, during said administration cycle, 12 mg / dose, 16 mg / dose, or 20 mg / dose of fobatinib is administered once daily, and 360 mg / dose of cepalimab is administered once daily, along with 25 mg / m 2Cisplatin was administered twice, 1000 mg / m². 2 Apply gemcitabine twice a day.

[0097] Item 50. An antitumor agent, pharmaceutical composition, use, compound for use, or salt thereof, commercial packaging, or method according to Item 48, wherein a 21-day administration cycle is repeated once or twice or more, during said administration cycle, 12 mg / dose, 16 mg / dose, or 20 mg / dose of fobatinib is administered once daily, and 360 mg / dose of cepalimumab is administered on day 1, 25 mg / m 2 Cisplatin was administered twice daily, on days 1 and 8, at a dose of 1000 mg / m². 2 Gemcitabine was administered once daily on day 1 and once daily on day 8.

[0098] Item 51. An antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to any one of items 48 to 50, wherein the cancer patient is a patient with biliary tract cancer who has not previously received treatment for advanced cancer.

[0099] Item 52. An antitumor agent, pharmaceutical composition, use, compound for use or salt thereof, commercial packaging or method according to any one of items 1 to 27, wherein it is an antitumor agent according to item 52-1, a pharmaceutical composition according to item 52-2, a use according to item 52-3, a compound for use or salt thereof according to item 52-4, a use according to item 52-5, a commercial packaging according to item 52-6, or a method according to item 52-7: Item 52-1. Any of the following (i) to (iv) antitumor agents (excluding antitumor agents containing pembrolizumab as an active ingredient, and antitumor agents used in combination with pembrolizumab): (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with cepalimumab, albumin-bound paclitaxel and gemcitabine for patients with pancreatic cancer; (ii) The antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salt, albumin-bound paclitaxel and gemcitabine for patients with pancreatic cancer; (iii) The antitumor agent includes gemcitabine as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and albumin-bound paclitaxel in patients with pancreatic cancer; and (iv) The antitumor agents include albumin-bound paclitaxel as an active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and gemcitabine for patients with pancreatic cancer.

[0100] Item 52-2. Any of the following (i) to (iv) pharmaceutical compositions for the prevention or treatment of pancreatic cancer (excluding pharmaceutical compositions containing pembrolizumab as an active ingredient, and pharmaceutical compositions used in combination with pembrolizumab): (i) The pharmaceutical composition comprises fubatinib or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprises a drug carrier for use in combination with cepalimab, albumin-bound paclitaxel and gemcitabine in patients with pancreatic cancer; (ii) The pharmaceutical composition comprises cepalimumab as the active ingredient and also includes a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt, albumin-bound paclitaxel and gemcitabine in patients with pancreatic cancer. (iii) The pharmaceutical composition comprises gemcitabine as the active ingredient and also includes a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and albumin-bound paclitaxel in patients with pancreatic cancer; and (iv) The pharmaceutical composition comprises albumin-bound paclitaxel as the active ingredient and also comprises a drug carrier for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimab and gemcitabine in patients with pancreatic cancer.

[0101] Item 52-3. Any of the following (i) to (iv) (excluding uses for manufacturing antitumor agents comprising pembrolizumab as an active ingredient, and uses for manufacturing antitumor agents for use in combination with pembrolizumab): (i) The use of fubatinib or a pharmaceutically acceptable salt thereof in the manufacture of an antitumor agent for use in combination with cepalimumab, albumin-bound paclitaxel and gemcitabine in patients with pancreatic cancer; (ii) Sepalimab is intended for use in the manufacture of an antitumor agent for use in combination with fubatinib or pharmaceutically acceptable salts, albumin-bound paclitaxel or gemcitabine in patients with pancreatic cancer; (iii) Gemcitabine for the manufacture of an antitumor agent intended for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and albumin-bound paclitaxel in patients with pancreatic cancer; and (iv) Albumin-bound paclitaxel is used to manufacture an antitumor agent for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and gemcitabine for patients with pancreatic cancer.

[0102] Item 52-4. Compounds or salts thereof used for any of the following (i) to (iv) (excluding compounds and pembrolizumab used for the purpose of administration): (i) Fubatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of pancreatic cancer, which is used in combination with cepalimumab, albumin-bound paclitaxel and gemcitabine in patients with pancreatic cancer; (ii) Sepalimab for the prevention or treatment of pancreatic cancer, which is used in combination with fubatinib or pharmaceutically acceptable salt, albumin-bound paclitaxel and gemcitabine in patients with pancreatic cancer; (iii) Gemcitabine for the prevention or treatment of pancreatic cancer, administered in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and albumin-bound paclitaxel in patients with pancreatic cancer; and (iv) Albumin-bound paclitaxel for the prevention or treatment of pancreatic cancer, in combination with fubatinib or its pharmaceutically acceptable salts, cepalimumab and gemcitabine in patients with pancreatic cancer.

[0103] Items 52-5. Any of the following (i) to (iv) uses (excluding the use of pembrolizumab and the use of compounds in combination with pembrolizumab): (i) Use of fubatinib or a pharmaceutically acceptable salt thereof for the prevention or treatment of pancreatic cancer, in combination with cepalimumab, albumin-bound paclitaxel and gemcitabine in patients with pancreatic cancer; (ii) Use of cepalimumab for the prevention or treatment of pancreatic cancer, in combination with fubatinib or pharmaceutically acceptable salt, albumin-bound paclitaxel and gemcitabine in patients with pancreatic cancer; (iii) Gemcitabine for the prevention or treatment of pancreatic cancer, in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and albumin-bound paclitaxel in patients with pancreatic cancer; and (iv) Use of albumin-bound paclitaxel for the prevention or treatment of pancreatic cancer, in combination with fubatinib or its pharmaceutically acceptable salts, cepalimumab and gemcitabine in patients with pancreatic cancer.

[0104] Items 52-6. Commercial packaging of any of the following (i) to (iv) (excluding commercial packaging used in combination with pharmaceutical compositions containing pembrolizumab as an active ingredient and pembrolizumab): (i) The commercial packaging includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, together with instructions for use in the prevention or treatment of pancreatic cancer in a subject, which is used in combination with cepalimumab, albumin-bound paclitaxel and gemcitabine in patients with pancreatic cancer. (ii) The commercial packaging includes cepalimumab as the active ingredient, together with a manual for its use in the prevention or treatment of pancreatic cancer in a subject, which is used in combination with fubatinib or its pharmaceutically acceptable salt, albumin-bound paclitaxel and gemcitabine in patients with pancreatic cancer. (iii) The commercial packaging includes gemcitabine as the active ingredient, together with instructions for use in the prevention or treatment of pancreatic cancer in a subject, which is intended for use in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and albumin-bound paclitaxel in patients with pancreatic cancer; and (iv) The commercial packaging includes albumin-bound paclitaxel as the active ingredient, together with instructions for use in the prevention or treatment of pancreatic cancer in subjects, which is intended to be administered in combination with fubatinib or its pharmaceutically acceptable salts, cepalimumab and gemcitabine to patients with pancreatic cancer.

[0105] Items 52-7. According to any one of the following (i) to (iv) (excluding methods including administration of pembrolizumab, and methods including administration of antitumor agents to subjects who have been, concurrently or are to be administered pembrolizumab): (i) A method of preventing or treating pancreatic cancer, comprising administering an effective amount of fobatinib or a pharmaceutically acceptable salt thereof to a subject in need of the subject, wherein the subject has been, concurrently administered or is to be administered cepalimab, has been, concurrently administered or is to be administered albumin-bound paclitaxel, or has been, concurrently administered or is to be administered gemcitabine. (ii) A method of preventing or treating pancreatic cancer, comprising administering an effective amount of cepalimumab to a subject in need of it, wherein the subject has been, concurrently administered or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, has been, concurrently administered or is to be administered albumin-bound paclitaxel, or has been, concurrently administered or is to be administered gemcitabine. (iii) A method of preventing or treating pancreatic cancer, comprising administering an effective amount of gemcitabine to a subject in need, wherein the subject has been, concurrently administered, or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, has been, concurrently administered, or is to be administered cepalimab, or has been, concurrently administered, or is to be administered albumin-bound paclitaxel; and (iv) A method of preventing or treating pancreatic cancer, comprising administering an effective amount of albumin-bound paclitaxel to a subject in need of it, wherein the subject has been, concurrently administered or is to be administered fobatinib or a pharmaceutically acceptable salt thereof, has been, concurrently administered or is to be administered cepalimab, or has been, concurrently administered or is to be administered gemcitabine.

[0106] Item 53. The antitumor agent, pharmaceutical composition, use, compound for use, or salt thereof, commercial packaging, or method according to Item 52, wherein a 28-day administration cycle is repeated once or twice or more, during said administration cycle, 12 mg / dose, 16 mg / dose, or 20 mg / dose of fobatinib is administered once daily, 240 mg / dose of cepalimumab is administered twice daily, and 125 mg / m 2 The albumin-bound paclitaxel was administered three times at a dose of 1000 mg / m². 2 / dose of gemcitabine was administered three times.

[0107] Item 54. The antitumor agent, pharmaceutical composition, use, compound for use, or salt thereof, commercial packaging, or method according to Item 52, wherein a 28-day administration cycle is repeated once or twice or more, wherein fobatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose is administered once daily, and cepalimumab at 240 mg / dose is administered on days 1 and 15, and 125 mg / m 2 The albumin-bound paclitaxel was administered once each on days 1, 8, and 15, at a dose of 1000 mg / m². 2 Gemcitabine was administered once each on day 1, day 8, and day 15.

[0108] Item 55. An antitumor agent, pharmaceutical composition, use, compound for use or a salt thereof, commercial packaging or method according to any one of items 52 to 54, wherein the cancer patient is a pancreatic cancer patient who has not previously received treatment for advanced cancer.

[0109] Beneficial effects of the invention According to the present invention, novel combination therapies with excellent anti-tumor effects (e.g., tumor reduction and survival prolongation) can be provided for cancer patients. In particular, the combination therapies of the present invention are especially effective for patients with previously untreated lung cancer, esophageal cancer, biliary tract cancer, or head and neck cancer. Attached Figure Description

[0110] Figure 1 This document outlines the clinical trial design for a combination therapy that includes fubatinib. Detailed Implementation

[0111] This invention relates to the provision of combined administration of, for example, fobatinib or its salts, immune checkpoint inhibitors (other than pembrolizumab and CD155 / TIGIT pathway antagonists) and at least one or more other antitumor agents.

[0112] In this invention, futibatinib is a disubstituted benzoyne compound having the following structure, which exhibits excellent antitumor effects when used in combination with immune checkpoint inhibitors. Futibatinib is described as compound 2 in PTL 2 above. It has been reported that futibatinib or its salts have excellent FGFR inhibitory effects, inhibiting the ability of FGFR1, FGFR3, and FGFR4 receptor protein tyrosine kinases to phosphorylate tyrosine residues in substrate peptide sequences (PTL 2). While there are no particular limitations on the fabatinib or its pharmaceutically acceptable salts described above in this invention, they may, for example, be synthesized based on the manufacturing method described in PTL 2.

[0113] In this invention, fubatinib can be used as is or in the form of pharmaceutically acceptable salts. There are no particular limitations on pharmaceutically acceptable salts of fubatinib, but examples include: addition salts formed with inorganic acids, such as hydrochloric acid and sulfuric acid, or organic acids, such as acetic acid, citric acid, tartaric acid, and maleic acid; salts formed with alkali metals, such as potassium and sodium; salts formed with alkaline earth metals, such as calcium and magnesium; and salts formed with organic bases, such as ammonium salts, ethylamine salts, and arginine salts.

[0114] In this invention, in addition to pembrolizumab and anti-TIGIT antibody, immune checkpoint inhibitors act on immune checkpoint molecules and have the effect of inducing anti-tumor immune responses and preventing tumor immune escape in the subject.

[0115] Examples of such immune checkpoint inhibitors include substances that promote the function of co-stimulatory molecules (stimulatory co-stimulatory molecules) and substances that inhibit the function of co-inhibitory 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) molecules. Substances targeting immune checkpoint molecules can be used as immune checkpoint inhibitors. Examples include PD-1 pathway antagonists, ICOS pathway agonists, CTLA-4 pathway antagonists, CD28 pathway agonists, BTLA pathway antagonists, 4-1BB pathway agonists, and CD155 / TIGIT pathway antagonists.

[0116] In this invention, at least one or more of the following are preferred: PD-1 pathway antagonists, ICOS pathway agonists, CTLA-4 pathway antagonists, CD28 pathway agonists, and CD155 / TIGIT pathway antagonists; more preferably, at least one or more of the following are preferred: PD-1 pathway antagonists, CTLA-4 pathway antagonists, and CD155 / TIGIT pathway antagonists; even more preferably, at least one or more of the following are preferred: PD-1 pathway antagonists and CD155 / TIGIT pathway antagonists; and even more preferably, PD-1 pathway antagonists.

[0117] PD-1 pathway antagonists inhibit the immunosuppressive signaling of PD-1 and its ligands PD-L1 or PD-L2 expressed on T cells. Examples include, but are not limited to, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, PD-1 extracellular domain, PD-L1 extracellular domain, PD-L2 extracellular domain, PD-1-Ig (a fusion protein of the PD-1 extracellular domain and the FC region of Ig), PD-L1-Ig, PD-L2-Ig, PD-1 siRNA, PD-L1 siRNA, PD-L2 siRNA, etc. Anti-PD-1 antibodies, anti-PD-L1 antibodies, or anti-PD-L2 antibodies are preferred, and anti-PD-1 antibodies or anti-PD-L1 antibodies are more preferred. Anti-PD-1 antibodies are particularly preferred.

[0118] Furthermore, CTLA-4 pathway antagonists inhibit the immunosuppressive signaling of CTLA-4 and its ligands B7-1 (CD80) and B7-2 (CD86) expressed on T cells. Preferably, 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 are preferred, with anti-CTLA-4 antibodies or CTLA-4-Ig being particularly preferred. Anti-CTLA-4 antibodies are especially preferred.

[0119] Furthermore, CD155 / TIGIT pathway antagonists inhibit the immunosuppressive signaling of TIGIT and its ligand CD155 expressed on T cells. Examples include, but are not limited to, anti-CD155 antibodies and anti-TIGIT antibodies. Anti-CD155 antibodies and anti-TIGIT antibodies are preferred, and anti-TIGIT antibodies are particularly preferred.

[0120] Examples of 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, and bispecific antibodies (Diabody, Nat. Rev. Immunol., 6: 343-357, 2006), and these antibodies include monoclonal and polyclonal antibodies, such as human antibodies, humanized antibodies, chimeric antibodies, mouse antibodies, alpaca antibodies, and chicken antibodies. In this invention, immunoglobulins (preferably IgG, etc.) are preferred. Furthermore, in this invention, human antibodies or humanized antibodies are preferred. In this invention, monoclonal antibodies are preferred.

[0121] Humanized IgG monoclonal antibodies or human IgG monoclonal antibodies are preferred.

[0122] In this invention, preferred anti-PD-1 antibodies include nivolumab, cemiplimab, spartalizumab, tislelizumab, BI754091, dostarlimab, sasanlimab, MGA-012, cetrelimab, AGEN-2034, zimberelimab, camrelizumab, budigalimab, and balstilimab, with nivolumab or cetrelimab being preferred, and cetrelimab being particularly preferred.

[0123] In this invention, preferred anti-PD-L1 antibodies include atezolizumab, durvalumab, avelumab, lodapolimab, BGB-A333, etc.

[0124] In this invention, preferred anti-CTLA-4 antibodies include ipilimumab, tremelimumab, etc.

[0125] In this invention, preferred CTLA-4-Ig includes abatacept, etc.

[0126] In this invention, preferred anti-TIGIT antibodies include domvanalimab (AB154), AB308, vibostolimab, ociperlimab, tiragolumab, AGEN-1777, HB-0036, HLX-301, ONO-4686, M-6223, PM-1022, etigilimab, ZG-005, AZD-2936, Belrestotug, or JS-006, etc.; domvanalimab, AB308, vibostolimab, ociperlimab, or tiragolumab are preferred, domvanalimab or AB308 are more preferred, and domvanalimab is especially preferred.

[0127] These agonists or antagonists can be manufactured using well-known methods.

[0128] In addition, the anti-PD-1 antibody has been or will be marketed as nivolumab or cepalimab; the anti-PD-L1 antibody has been or will be marketed as atezolizumab, durvalumab, or avelumab; the anti-CTLA-4 antibody has been or will be marketed as ipilimumab or tesimumab; the CTLA-4-Ig antibody has been or will be marketed as abatacept; and the anti-TIGIT antibody has been or will be marketed as dovanalimab.

[0129] In this invention, immune checkpoint inhibitors can be used alone or in combination of two or more.

[0130] In this invention, when two or more immune checkpoint inhibitors are used, for example, immune checkpoint inhibitors such as anti-PD-1 antibody and anti-CTLA-4 antibody can be used in combination, or bispecific antibodies that can bind to different immune checkpoint molecules can be used. Examples of bispecific antibodies include XmAb20717 (PD-1 × CTLA-4), which can bind to both PD-1 and CTLA-4.

[0131] In this invention, the immune checkpoint inhibitor is preferably a PD-1 pathway antagonist, more preferably an anti-PD-1 antibody, and even more preferably nivolumab or serpalimumab, especially serpalimumab.

[0132] By adding "other antitumor agents" (additional antitumor agents) to a combination of fobatinib or a pharmaceutically acceptable salt thereof and at least one or more immune checkpoint inhibitors, thereby using at least three or more agents in combination, the present invention exhibits excellent antitumor effects. Therefore, there are no particular limitations on the other antitumor agents in the present invention, as long as they are fobatinib or a pharmaceutically acceptable salt thereof, or agents with antitumor activity other than the selected immune checkpoint inhibitors (excluding pembrolizumab). It should be noted that the phrase "other antitumor agents other than the selected immune checkpoint inhibitors" means, for example, that when A is selected as the "immune checkpoint inhibitor" in the antitumor agents of the present invention, then A is not selected as the "other antitumor agent." In the present invention, the other antitumor agents can be in the form of any of low molecular weight compounds, antibodies, and nucleic acids. In the present invention, the other antitumor agents can be used alone or in combination of two or more.

[0133] In this invention, other preferred antitumor agents are chemotherapeutic agents. Here, in this invention, the chemotherapeutic agent is preferably selected from at least one 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.), molecularly targeted drugs (low molecular weight molecularly targeted drugs / antibody molecularly targeted drugs, etc.), antitumor antibiotics, and alkylating agents; more preferably, it is selected from antimetabolites (purine antimetabolites, pyrimidine antimetabolites, etc.). The chemotherapeutic agent is selected from at least one of the following: metabolites, folic acid antimetabolites, alkaloid antitumor agents, platinum preparations, and immune checkpoint inhibitors; more preferably, it is selected from at least one of the following: antimetabolites (purine antimetabolites, pyrimidine antimetabolites, folic acid antimetabolites, etc.), alkaloid antitumor agents, platinum preparations, and CD155 / TIGIT pathway antagonists; even more preferably, it is selected from at least one of the following: antimetabolites (purine antimetabolites, pyrimidine antimetabolites, folic acid antimetabolites, etc.), alkaloid antitumor agents, platinum preparations, and anti-TIGIT antibodies. Furthermore, in an exemplary preferred embodiment of the present invention, agents other than at least the aforementioned immune checkpoint inhibitors can be used as chemotherapeutic agents. In such embodiments, as chemotherapeutic agents, for example, at least one of the following can be used: antimetabolites (purine antimetabolites, pyrimidine antimetabolites, folic acid antimetabolites, etc.), alkaloid antitumor agents, platinum preparations, molecularly targeted drugs (low molecular weight molecularly targeted drugs / antibody molecularly targeted drugs, etc.), antitumor antibiotics, and alkylating agents.

[0134] More specifically, it is preferred to select at least one of the following: Purine antimetabolites, such as fludarabine, cladribine, or nelarabine. Pyrimidine antimetabolites, such as 5-fluorouracil (5-FU), tegafur / gimeracil / oteracil potassium (TS-1 or S-1, trade name: "TS-1"), tegafur / uracil (UFT, trade name: "UFT"), trifluridine / tipiracil hydrochloride (TAS-102, trade name: "LONSURF"), capecitabine, doxifluridine, 5-fluoro-2'-deoxyuridine (FdUrd), gemcitabine, or cytarabine. Folic acid antimetabolites, such as pemetrexed or methotrexate. Alkaloid antitumor agents, such as paclitaxel (sold under the trade names "Taxol" and "Abraxane," paclitaxel includes derivatives such as albumin-bound paclitaxel (e.g., ABI-007) and PEG-bound paclitaxel), docetaxel (trade name "Taxotere," etc.), cabazitaxel, eribulin, irinotecan, nogitecan, etoposide, vinorelbine, vincristine, or vinblastine; Platinum preparations, such as cisplatin, carboplatin, oxaliplatin, or nedaplatin. PD-1 pathway antagonists, such as nivolumab, cimiprimab, spartazolizumab, tislelizumab, BI754091, dotalimab, saxajub, MGA-012, cilizumab, AGEN-2034, cepalimumab, camrelizumab, bugglimab, batitilumab, atezolizumab, durvalumab, avelumab, lodalimab, or BGB-A333; CTLA-4 pathway antagonists, such as ipilimumab, texilimumab, or abatacept; CD155 / TIGIT pathway antagonists, such as dovanarimab, AB308, vimbrolizumab, osperimab, tirelimumab, AGEN-1777, HB-0036, HLX-301, ONO-4686, M-6223, PM-1022, atelimumab, ZG-005, AZD-2936, berisutramab, or JS-006; Low molecular weight targeted drugs, such as imatinib, gefitinib, erlotinib, lapatinib, sunitinib, dasatinib, everolimus, temsirolimus, selumetinib, trametinib, sorafenib, afatinib, regorafenib, dabrafenib, vemurafenib, or MK2206; Antibody molecular targeted drugs, such as trastuzumab, cetuximab, bevacizumab, panitumumab, veltuzumab, rituximab, or ramucirumab. Antitumor antibiotics, such as doxorubicin, daunorubicin, epirubicin, actinomycin D, or mitomycin C; and Alkylating agents, such as cyclophosphamide, dacarbazine, temozolomide, nimustine, busulfan, procarbazine, or melphalan. More preferably, the formulation is selected from fludarabine, cladribine, nerabine, 5-fluorouracil (5-FU), tegafur / gammidine / oteracil potassium compound formulations (TS-1 or S-1, trade name: "TS-1"), tegafur / uracil compound formulations (UFT, trade name: "UFT"), trifluorouridine / tipyrimidine hydrochloride compound formulations (TAS-102, trade name: "LONSURF"), capecitabine, deoxyfluorouracil, etc. At least one of the following: glycoside, 5-fluoro-2'-deoxyuridine (FdUrd), gemcitabine, cytarabine, pemetrexed, methotrexate, paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel, iribulin, irinotecan, notecan, etoposide, vinorelbine, vincristine, vinca alkaloid, cisplatin, carboplatin, oxaliplatin, nedaplatin, dovanalimab, AB308, vimbrolizumab, osperimab, and tislelizumab; More preferably, it is selected from at least one of 5-fluorouracil, gemcitabine, albumin-bound paclitaxel, irinotecan, cisplatin, carboplatin, dovanalimab, and AB308; More preferably, it is selected from at least one of 5-fluorouracil, gemcitabine, albumin-bound paclitaxel, cisplatin, carboplatin, and dovanalimab; and The combination of 5-fluorouracil and cisplatin, the combination of 5-fluorouracil and carboplatin, the combination of carboplatin and albumin-bound paclitaxel, the combination of cisplatin and gemcitabine, and the combination of albumin-bound paclitaxel and gemcitabine or dovanalimab are particularly preferred.

[0135] The antitumor agents applicable in this invention include any one of the following (i) to (iii), wherein the antitumor agents do not include pembrolizumab as the active ingredient: (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with an antiPD-1 antibody and at least one or more other antitumor agents for use in cancer patients; (ii) The antitumor agent comprises an antiPD-1 antibody as an active ingredient, which is used in combination with fobatinib or a pharmaceutically acceptable salt thereof and at least one or more other antitumor agents in cancer patients; and (iii) The antitumor agent includes at least one or more other antitumor agents as active ingredients, which are used in combination with fubatinib or a pharmaceutically acceptable salt thereof and an antiPD-1 antibody in cancer patients.

[0136] More preferably, the antitumor agent comprises any one of the following (i) to (iii), wherein the antitumor agent does not include pembrolizumab as the active ingredient: (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with cepalimumab and at least one or more other antitumor agents for use in cancer patients; (ii) The antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof and at least one or more other antitumor agents in cancer patients; and (iii) The antitumor agent includes at least one or more other antitumor agents as active ingredients, which are used in combination with fubatinib or a pharmaceutically acceptable salt thereof and cepalimumab in cancer patients.

[0137] The application schemes for various active ingredients in this invention can be appropriately set, as long as they can achieve the effects of this invention. However, it is preferred to repeat the application cycle of 21 days or 28 days once, twice, or more.

[0138] In this invention, the preferred administration regimen for fobatinib or its salts is once daily on each day of a 21-day or 28-day administration cycle.

[0139] In this invention, the administration regimen of immune checkpoint inhibitors can be appropriately set, but it is preferred to administer them at a frequency of once daily to once every four weeks. In the case of serpalimumab, for example, the preferred administration frequency is once every three weeks or once every two weeks. Specifically, it can be administered once within a 21-day administration cycle or twice within a 28-day administration cycle.

[0140] In this invention, the administration regimen of other antitumor agents can be appropriately set, but in a 21-day administration cycle, it is preferred to administer for 1 to 5 days, more preferably for 1, 2, 3, 4 or 5 days. In another embodiment of this invention, as an administration regimen of other antitumor agents, for example, in a 28-day administration cycle, it is preferred to administer for 1 to 5 days, more preferably for 1, 2, 3, 4 or 5 days.

[0141] Examples of preferred daily doses of fobatinib or its salts on the day of administration include: 4 mg to 160 mg, 4 mg to 24 mg, 12 mg to 24 mg, 16 mg to 24 mg, 20 mg, etc. More specifically, preferred frequency of administration and daily dose on the day of administration include: once daily, 4 mg / dose, 8 mg / dose, 12 mg / dose, 16 mg / dose, 20 mg / dose, etc. In another embodiment, preferred frequency of administration and daily dose on the day of administration include: once daily, 8 mg / dose, 12 mg / dose, 16 mg / dose, 20 mg / dose. In another embodiment, preferred frequency of administration and daily dose on the day of administration include: once daily, 12 mg / dose, 16 mg / dose, 20 mg / dose. In another embodiment, preferred frequency of administration and daily dose on the day of administration includes: once daily, 20 mg / dose.

[0142] In one embodiment, the invention includes, in cases where a stronger effect is required for cancer types such as brain tumors, a dose of fobatinib or a salt thereof exceeding 20 mg / dose, once daily.

[0143] In this invention, the daily dose of the immune checkpoint inhibitor on the administration date is appropriately set according to the drug, but in the case of nivolumab, preferred daily doses on the administration date include 40 to 480 mg / dose, 80 mg / dose, 240 mg / dose, 360 mg / dose, or 480 mg / dose. Furthermore, the administration interval for nivolumab is preferably 2 to 4 weeks, more preferably 2 to 3 weeks, and even more preferably 2 weeks. In the case of cepalimab, preferred daily doses on the administration date include 240 to 480 mg / dose, 240 mg / dose, 360 mg / dose, or 480 mg / dose, preferably 240 mg / dose or 360 mg / dose, and more preferably 360 mg / dose. Furthermore, the administration interval for cepalimab is preferably 2 to 4 weeks, more preferably 2 to 3 weeks, and even more preferably 2 weeks.

[0144] As one embodiment of the present invention, the administration interval and dosage of serpalimab is 360 mg / dose every 3 weeks.

[0145] As one embodiment of the present invention, the administration interval and dosage of serpalimab is 240 mg / dose every 2 weeks.

[0146] In this invention, "cancer" or "tumor" refers to a physiological condition in mammals characterized by uncontrolled cell growth. "Cancer" and "tumor" have the same meaning in this specification and can be used interchangeably. Cancer includes solid tumors and hematologic cancers. Examples include, but are not limited to: carcinoma, lymphoma, leukemia, blastoma, sarcoma, and borderline malignancy (carcinoid).

[0147] Examples of cancers targeted by the combined method of the present invention include, but are not limited to, head and neck cancer, digestive organ cancers (esophageal cancer, gastric cancer, duodenal cancer, liver cancer (hepatocellular carcinoma), biliary tract cancers (such as gallbladder cancer and bile duct cancer), pancreatic cancer, small bowel cancer, large colorectal cancer (such as colorectal cancer, colon cancer, and rectal cancer), lung cancer (such as non-small cell lung cancer and small cell lung cancer), mesothelioma (such as malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, and testicular mesothelioma), breast cancer, reproductive system cancers (ovarian cancer, uterine cancer (such as cervical cancer, endometrial cancer, and endometrial cancer), kidney cancer, bladder cancer, urothelial carcinoma, prostate cancer, testicular tumors, skin cancer (such as malignant melanoma and epidermal cancer), blood cancers (such as multiple myeloma, malignant lymphoma, leukemia), bone and soft tissue tumors, rhabdomyosarcoma, brain tumors, malignant schwannomas, neuroendocrine tumors, thyroid cancer, etc., regardless of whether the FGFR pathway is abnormal. It should be noted that the cancer mentioned here includes not only the primary lesion but also cancer that has metastasized to other organs (such as the liver). The antitumor agent of this invention can also be used as adjuvant chemotherapy after surgical removal of the tumor to prevent recurrence, or as adjuvant chemotherapy before surgical removal of the tumor.

[0148] In this invention, preferred cancers include 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 tumors, thyroid cancer, bone or soft tissue tumors, leukemia, malignant lymphoma, multiple myeloma, head and neck cancer, brain tumors, mesothelioma, skin cancer, and cancers of unknown primary origin; solid cancers are preferred; pancreatic cancer, lung cancer, esophageal cancer, biliary tract cancer, or head and neck cancer are more preferred; pancreatic cancer, lung cancer, esophageal cancer, biliary tract cancer, or head and neck cancer are even more preferred; pancreatic cancer, non-small cell lung cancer, esophageal cancer, biliary tract cancer, or head and neck cancer that have not previously received advanced cancer treatment or have previously received first-line chemotherapy are even more preferred; pancreatic cancer, non-small cell lung cancer, esophageal cancer, biliary tract cancer, or head and neck cancer that have not previously received advanced cancer treatment are particularly preferred.

[0149] In one embodiment of the present invention, the subjects were esophageal cancer patients who had not previously received treatment for advanced cancer.

[0150] In one embodiment of the present invention, the subjects were esophageal cancer patients who had not previously received treatment for advanced cancer or had previously received first-line chemotherapy.

[0151] In one embodiment of the present invention, the subjects were head and neck cancer patients who had not previously received treatment for advanced cancer.

[0152] In one embodiment of the present invention, the subjects were non-small cell lung cancer patients who had not previously received treatment for advanced cancer.

[0153] In one embodiment of the present invention, the subjects were patients with biliary tract cancer who had not previously received treatment for advanced cancer.

[0154] In one embodiment of the present invention, the subjects were pancreatic cancer patients who had not previously received treatment for advanced cancer.

[0155] Suitable antitumor agents in this invention include, but are not limited to, the following.

[0156] Preferred antitumor agents are any one of the following (i) to (iv): (i) Antitumor agents include fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, which is used in combination with cepalimumab, cisplatin and 5-fluorouracil for patients with esophageal cancer; (ii) Antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts, cisplatin and 5-fluorouracil for patients with esophageal cancer; (iii) Antitumor agents include cisplatin as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimab, and 5-fluorouracil in patients with esophageal cancer; and (iv) Antitumor agents include 5-fluorouracil as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts, cepalimumab and cisplatin for patients with esophageal cancer.

[0157] Further preferred are any one of the antitumor agents described in (i) to (iv) above, wherein the 21-day administration cycle is repeated once, twice, or more, during which fobatinib is administered once daily at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose, and cepalimumab is administered once daily at a dose of 360 mg / dose, 80 mg / m 2 A single dose of cisplatin, 800 mg / m². 25-Fluorouracil was administered daily for 5 days; particularly preferred were any of the antitumor agents described in (i) to (iv) above, wherein the 21-day administration cycle was repeated once or twice or more, during which fobatinib was administered once daily at doses of 12 mg, 16 mg, or 20 mg, and cepalimab was administered once daily at doses of 360 mg on day 1, 80 mg / m 2 Cisplatin was administered once on day 1, at a dose of 800 mg / m². 2 5-Fluorouracil was administered daily from day 1 to day 5.

[0158] One embodiment of the present invention comprises any one of (i) to (iv) above, wherein a 21-day administration cycle is repeated once, twice or more, wherein 12 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and 80 mg / m 2 Cisplatin was administered once on day 1, at a dose of 800 mg / m². 2 5-Fluorouracil was administered daily from day 1 to day 5.

[0159] In this invention, "mg / m 2 " / dosage" refers to the amount applied per unit body surface area (m²) per application. 2 The dosage (mg).

[0160] One embodiment of the present invention comprises any one of (i) to (iv) above, wherein a 21-day administration cycle is repeated once, twice or more, wherein 16 mg / dose of fobatinib is administered once daily, and 360 mg / dose of cepalimab is administered once on day 1, and 80 mg / m 2 Cisplatin was administered once on day 1, at a dose of 800 mg / m². 2 5-Fluorouracil was administered daily from day 1 to day 5.

[0161] One embodiment of the present invention comprises any one of the antitumor agents described in (i) to (iv) above, wherein a 21-day administration cycle is repeated once, twice, or more, wherein 20 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and 80 mg / m 2 Cisplatin was administered once on day 1, at a dose of 800 mg / m². 2 5-Fluorouracil was administered daily from day 1 to day 5.

[0162] Preferred antitumor agents are any one of (i) to (iii) below: (i) Antitumor agents include fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, which are used in combination with cepalimumab and dovanalimab for patients with esophageal cancer; (ii) Antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts and dovanalimab in patients with esophageal cancer; and (iii) Antitumor agents include dovanalimab as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts and cepalimumab for patients with esophageal cancer.

[0163] Further preferred are any of the antitumor agents described in (i) to (iii) above, wherein the 21-day administration cycle is repeated once or twice or more, wherein 12 mg / dose, 16 mg / dose or 20 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once, and 1200 mg / dose of domonalimumab is administered once; particularly preferred are any of the antitumor agents described in (i) to (iii) above, wherein the 21-day administration cycle is repeated once or twice or more, wherein 12 mg / dose, 16 mg / dose or 20 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and 1200 mg / dose of domonalimumab is administered once on day 1.

[0164] One embodiment of the present invention includes any one of (i) to (iii) above, wherein a 21-day administration cycle is repeated once, twice or more, wherein 12 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and 1200 mg / dose of dovanalimab is administered once on day 1.

[0165] One embodiment of the present invention includes any one of the antitumor agents (i) to (iii) above, wherein a 21-day administration cycle is repeated once, twice or more, wherein 16 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and 1200 mg / dose of dovanalimab is administered once on day 1.

[0166] One embodiment of the present invention includes any one of (i) to (iii) above, wherein a 21-day administration cycle is repeated once, twice or more, wherein 20 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and 1200 mg / dose of dovanalimab is administered once on day 1.

[0167] Preferred antitumor agents are any one of the following (i) to (iv): (i) Antitumor agents include fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, which is used in combination with cepalimumab, 5-fluorouracil and carboplatin or cisplatin for patients with head and neck cancer; (ii) Antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts, 5-fluorouracil and carboplatin or cisplatin for patients with head and neck cancer; (iii) Antitumor agents include 5-fluorouracil as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and carboplatin or cisplatin for patients with head and neck cancer; and (iv) Antitumor agents include carboplatin or cisplatin as active ingredients, which are used in combination with fubatinib or its pharmaceutically acceptable salts, cepalimumab and 5-fluorouracil for patients with head and neck cancer.

[0168] Further preferred are any one of the antitumor agents described in (i) to (iv) above, wherein the 21-day administration cycle is repeated once, twice, or more, during which fobatinib is administered once daily at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose, cepalimumab is administered once daily at a dose of 360 mg / dose, and carboplatin or 100 mg / mcg is administered at an AUC of 5. 2 A single dose of cisplatin, 1000 mg / m². 2 5-Fluorouracil was administered daily for 4 days; particularly preferred were any of the antitumor agents described in (i) to (iv) above, wherein the 21-day administration cycle was repeated once or twice or more, wherein fobatinib was administered once daily at doses of 12 mg, 16 mg, or 20 mg, cepalimab was administered once daily on day 1, and carboplatin or 100 mg / m² was administered at AUC 5. 2 Cisplatin was administered once on day 1, at a dose of 1000 mg / m². 2 5-Fluorouracil was administered daily from day 1 to day 4.

[0169] One embodiment of the present invention comprises any one of the antitumor agents described in (i) to (iv) above, wherein a 21-day administration cycle is repeated once, twice, or more, wherein 12 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and carboplatin with an AUC of 5 or 100 mg / m 2 Cisplatin was administered once on day 1, at a dose of 1000 mg / m². 2 5-Fluorouracil was administered daily from day 1 to day 4.

[0170] One embodiment of the present invention comprises any one of the antitumor agents described in (i) to (iv) above, wherein a 21-day administration cycle is repeated once, twice, or more, wherein 16 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and carboplatin with an AUC of 5 or 100 mg / m 2 Cisplatin was administered once on day 1, at a dose of 1000 mg / m². 2 5-Fluorouracil was administered daily from day 1 to day 4.

[0171] One embodiment of the present invention comprises any one of the antitumor agents described in (i) to (iv) above, wherein a 21-day administration cycle is repeated once, twice, or more, wherein 20 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and carboplatin with an AUC of 5 or 100 mg / m 2 Cisplatin was administered once on day 1, at a dose of 1000 mg / m². 2 5-Fluorouracil was administered daily from day 1 to day 4.

[0172] Preferred antitumor agents are any one of (i) to (iii) below: (i) Antitumor agents include fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, which is used in combination with cepalimumab and dovanalimab for patients with head and neck cancer; (ii) Antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts and dovanalimab in patients with head and neck cancer; and (iii) Antitumor agents include dovanalimab as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts and cepalimumab for patients with head and neck cancer.

[0173] Further preferred are any of the antitumor agents described in (i) to (iii) above, wherein the 21-day administration cycle is repeated once or twice or more, wherein 12 mg / dose, 16 mg / dose or 20 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once, and 1200 mg / dose of domonalimumab is administered once; particularly preferred are any of the antitumor agents described in (i) to (iii) above, wherein the 21-day administration cycle is repeated once or twice or more, wherein 12 mg / dose, 16 mg / dose or 20 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and 1200 mg / dose of domonalimumab is administered once on day 1.

[0174] One embodiment of the present invention includes any one of the antitumor agents (i) to (iii) above, wherein a 21-day administration cycle is repeated once or twice or more, wherein 12 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and 1200 mg / dose of dovanalimab is administered once on day 1.

[0175] One embodiment of the present invention includes any one of the antitumor agents (i) to (iii) above, wherein a 21-day administration cycle is repeated once, twice or more, wherein 16 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and 1200 mg / dose of dovanalimab is administered once on day 1.

[0176] One embodiment of the present invention includes any one of (i) to (iii) above, wherein a 21-day administration cycle is repeated once, twice or more, wherein 20 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and 1200 mg / dose of dovanalimab is administered once on day 1.

[0177] Preferred antitumor agents are any one of the following (i) to (iv): (i) Antitumor agents include fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, which is used in combination with cepalimumab, albumin-bound paclitaxel and carboplatin for patients with non-small cell lung cancer; (ii) Antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salt, albumin-bound paclitaxel and carboplatin for patients with non-small cell lung cancer; (iii) Antitumor agents include albumin-bound paclitaxel as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts, cepalimumab, and carboplatin for patients with non-small cell lung cancer; and (iv) Antitumor agents include carboplatin as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts, cepalimumab and albumin-bound paclitaxel for patients with non-small cell lung cancer.

[0178] Further preferred are any one of the antitumor agents described in (i) to (iv) above, wherein the 21-day administration cycle is repeated once, twice, or more, during which fobatinib is administered once daily at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose, cepalimumab is administered once daily at a dose of 360 mg / dose, and 100 mg / m 2 The drug is administered three times with albumin-bound paclitaxel and once with carboplatin at an AUC of 6; particularly preferred are any of the antitumor agents described in (i) to (iv) above, wherein the 21-day administration cycle is repeated once, twice or more, during which fobatinib is administered once daily at doses of 12 mg / dose, 16 mg / dose or 20 mg / dose, cepalimumab is administered once on day 1, and 100 mg / m 2 The albumin-bound paclitaxel was administered once each on days 1, 8, and 15, while carboplatin with an AUC of 6 was administered on day 1.

[0179] One embodiment of the present invention comprises any one of (i) to (iv) above, wherein a 21-day administration cycle is repeated once, twice or more, wherein 12 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and 100 mg / m 2 The albumin-bound paclitaxel was administered once each on days 1, 8, and 15, while carboplatin with an AUC of 6 was administered on day 1.

[0180] One embodiment of the present invention comprises any one of (i) to (iv) above, wherein a 21-day administration cycle is repeated once, twice or more, wherein 16 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and 100 mg / m 2 The albumin-bound paclitaxel was administered once each on days 1, 8, and 15, while carboplatin with an AUC of 6 was administered on day 1.

[0181] One embodiment of the present invention comprises any one of the antitumor agents described in (i) to (iv) above, wherein a 21-day administration cycle is repeated once, twice, or more times, wherein 20 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and 100 mg / m 2 The albumin-bound paclitaxel was administered once each on days 1, 8, and 15, while carboplatin with an AUC of 6 was administered on day 1.

[0182] Preferred antitumor agents are any one of the following (i) to (iv): (i) Antitumor agents include fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, which is used in combination with cepalimumab, cisplatin and gemcitabine for patients with biliary tract cancer; (ii) Antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts, cisplatin and gemcitabine for patients with biliary tract cancer; (iii) Antitumor agents include gemcitabine as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts, cepalimumab, and cisplatin for patients with biliary tract cancer; and (iv) Antitumor agents include cisplatin as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts, cepalimumab and gemcitabine for patients with biliary tract cancer.

[0183] Further preferred are any one of the antitumor agents described in (i) to (iv) above, wherein the 21-day administration cycle is repeated once, twice, or more, during which fobatinib is administered once daily at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose, cepalimumab is administered once daily at a dose of 360 mg / dose, and 100 mg / m 2 The drug is administered three times with albumin-bound paclitaxel and once with carboplatin at an AUC of 6; particularly preferred are any of the antitumor agents described in (i) to (iv) above, wherein the 21-day administration cycle is repeated once, twice or more, during which fobatinib is administered once daily at doses of 12 mg / dose, 16 mg / dose or 20 mg / dose, cepalimumab is administered once on day 1, and 100 mg / m 2 The albumin-bound paclitaxel was administered once each on days 1, 8, and 15, while carboplatin with an AUC of 6 was administered on day 1.

[0184] One embodiment of the present invention comprises any one of (i) to (iv) above, wherein a 21-day administration cycle is repeated once, twice or more, wherein 12 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and 100 mg / m 2 The albumin-bound paclitaxel was administered once each on days 1, 8, and 15, while carboplatin with an AUC of 6 was administered on day 1.

[0185] One embodiment of the present invention comprises any one of (i) to (iv) above, wherein a 21-day administration cycle is repeated once, twice or more, wherein 16 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and 100 mg / m 2 The albumin-bound paclitaxel was administered once each on days 1, 8, and 15, while carboplatin with an AUC of 6 was administered on day 1.

[0186] One embodiment of the present invention comprises any one of the antitumor agents described in (i) to (iv) above, wherein a 21-day administration cycle is repeated once, twice, or more times, wherein 20 mg / dose of fobatinib is administered once daily, 360 mg / dose of cepalimumab is administered once on day 1, and 100 mg / m 2 The albumin-bound paclitaxel was administered once each on days 1, 8, and 15, while carboplatin with an AUC of 6 was administered on day 1.

[0187] Preferred antitumor agents are any one of the following (i) to (iv): (i) Antitumor agents include fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, which is used in combination with cepalimumab, albumin-bound paclitaxel and gemcitabine for patients with pancreatic cancer; (ii) Antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salt, albumin-bound paclitaxel and gemcitabine for patients with pancreatic cancer; (iii) Antitumor agents include gemcitabine as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts, cepalimumab, and albumin-bound paclitaxel in patients with pancreatic cancer; and (iv) Antitumor agents include albumin-bound paclitaxel as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts, cepalimumab and gemcitabine for patients with pancreatic cancer.

[0188] Further preferred are any one of the antitumor agents described in (i) to (iv) above, wherein the 28-day administration cycle is repeated once, twice, or more, during which fobatinib is administered once daily at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose, cepalimumab is administered twice daily at a dose of 240 mg / dose, and 125 mg / m 2 The albumin-bound paclitaxel was administered three times at a dose of 1000 mg / m². 2 Gemcitabine is administered three times per dose; particularly preferred are any of the antitumor agents described in (i) to (iv) above, wherein the 28-day administration cycle is repeated once, twice or more, during which fobatinib is administered once daily at doses of 12 mg / dose, 16 mg / dose or 20 mg / dose, cepalimumab is administered on days 1 and 15, and 125 mg / m 2 The albumin-bound paclitaxel was administered once each on days 1, 8, and 15, at a dose of 1000 mg / m². 2 Gemcitabine was administered once each on day 1, day 8, and day 15.

[0189] One embodiment of the present invention comprises any one of the antitumor agents described in (i) to (iv) above, wherein a 28-day administration cycle is repeated once, twice, or more, wherein 12 mg / dose of fobatinib is administered once daily, 240 mg / dose of cepalimumab is administered on days 1 and 15, and 125 mg / m 2 The albumin-bound paclitaxel was administered once each on days 1, 8, and 15, at a dose of 1000 mg / m². 2 Gemcitabine was administered once each on day 1, day 8, and day 15.

[0190] One embodiment of the present invention comprises any one of the antitumor agents described in (i) to (iv) above, wherein a 28-day administration cycle is repeated once, twice, or more, wherein 16 mg / dose of fobatinib is administered once daily, 240 mg / dose of cepalimumab is administered on days 1 and 15, and 125 mg / m 2 The albumin-bound paclitaxel was administered once each on days 1, 8, and 15, at a dose of 1000 mg / m². 2 Gemcitabine was administered once each on day 1, day 8, and day 15.

[0191] One embodiment of the present invention comprises any one of the antitumor agents described in (i) to (iv) above, wherein a 28-day administration cycle is repeated once, twice, or more, wherein 20 mg / dose of fobatinib is administered once daily, 240 mg / dose of cepalimumab is administered on days 1 and 15, and 125 mg / m 2 The albumin-bound paclitaxel was administered once each on days 1, 8, and 15, at a dose of 1000 mg / m². 2 Gemcitabine was administered once each on day 1, day 8, and day 15.

[0192] As used in this specification, the term "combination (therapy)" is intended to define a therapy that includes the combined use of two or more compounds / drugs (as defined above). Therefore, "combination (therapy)," "combination," and the "combined" use of compounds / drugs in this application can mean the administration of compounds / drugs as part of the same overall treatment regimen. The dosage of each of the two or more compounds / drugs may be different; each compound / drug may be administered simultaneously or at different times. Therefore, it should be understood that combined compounds / drugs may be administered sequentially (e.g., before or after) or simultaneously, in the same pharmaceutical formulation (i.e., together) or in different pharmaceutical formulations (i.e., separately). The same formulation is a single formulation, but different pharmaceutical formulations are not a single entity.

[0193] The administration form of the antitumor agent of this invention is not particularly limited and can be appropriately selected according to the therapeutic purpose. Specific examples include oral formulations (tablets, coated tablets, powders, granules, capsules, solutions, etc.), injections, suppositories, patches, ointments, etc. In the case of fobatinib or its salts, oral formulations are preferred. In the case of immune checkpoint inhibitors and other antitumor agents, the above-mentioned administration forms can be cited, with injections being preferred. In the case of cepallimab, dovanalimab, carboplatin, cisplatin, 5-fluorouracil, albumin-bound paclitaxel, or gemcitabine, injections are preferred.

[0194] The antitumor agents, immune checkpoint inhibitors, and fobatinib or their salts (as active ingredients) according to the present invention can be used directly as antitumor agents, and the pharmaceutical compositions can be prepared by known methods using pharmaceutically acceptable carriers, depending on their form of administration. Examples of such carriers include various carriers commonly used in pharmaceuticals, such as excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, isotonic agents, pH adjusters, buffers, stabilizers, colorants, flavoring agents, masking agents, etc.

[0195] The antitumor agents of the present invention can be formulated into multiple dosage forms, or into a single dosage form, depending on the administration method and regimen of each active ingredient. Furthermore, the formulations can be manufactured and sold in a single package suitable for combined administration, or in separate packages. This also applies to embodiments of the pharmaceutical compositions. Therefore, "a pharmaceutical composition comprising an immune checkpoint inhibitor and fobatinib or a salt thereof as an active ingredient" includes pharmaceutical compositions prepared by separately formulating the active ingredients into multiple dosage forms, and pharmaceutical compositions prepared by separately formulating the active ingredients into a single dosage form. Pharmaceutical compositions prepared by separately formulating the active ingredients into multiple dosage forms include pharmaceutical compositions prepared by formulating the formulation into a single package suitable for combined administration, and pharmaceutical compositions prepared by formulating the formulation into separate packages.

[0196] This invention relates to a kit formulation comprising an antitumor agent and an instruction manual, wherein the antitumor agent includes fobatinib or a salt thereof, and the instruction manual indicates that fobatinib or a salt thereof is administered in combination with an immune checkpoint inhibitor for cancer patients. The term "instruction manual" as used herein can refer to a manual specifying the aforementioned dosage, whether or not it is legally binding; instruction manuals specifying the aforementioned dosage are preferred. Specific examples include package inserts, brochures, etc. The kit formulation including the instruction manual may have the instruction manual printed or attached to the kit formulation packaging, or the instruction manual may be included together with the antitumor agent within the kit formulation packaging.

[0197] The treatments in this invention include procedures aimed at curing or alleviating a disease, or at inhibiting disease progression or recurrence, or reducing symptoms. These treatments include administering medication before or after surgical procedures, or during, before, or after radiation therapy.

[0198] The antitumor agent of this invention can be used to treat cancer. When referring to cancer patients receiving treatment regimens, such as the combination therapies described in this specification, "antitumor efficacy" refers to at least one of the following assessments: progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), overall survival (OS), objective response rate (ORR), disease control rate (DCR), time to first response (TTR), patient-reported outcomes (PRO), etc. In one embodiment, the tumor assessment of solid tumors using the combination therapies described in this specification is based on the RECIST 1.1 criteria (Response Evaluation Criteria in Solid Cancers), and the antitumor efficacy is expressed as stable disease (SD), partial response (PR), complete response (CR), and progressive disease (PD). Tumor assessment of brain tumors can be performed using standard brain tumor MRI with a gadolinium (Gd) chelate contrast agent, including pre-contrast and post-contrast MRI.

[0199] Example Example: Phase 1a / b clinical trial of AB122 combination therapy in patients with advanced solid tumors Purpose and endpoint: Table 1 method: This trial is a phase 1, non-randomized, open-label, multicenter platform study to evaluate the tolerability and safety of AB122 in patients with malignant tumors.

[0200] This trial is divided into two phases (Phase 1a and Phase 1b). In Phase 1a, the objective was to evaluate the safety and tolerability of AB122-based combination therapies in patients with advanced solid tumors, determine the recommended dose (RD) for each regimen, and assess efficacy under RD. In Phase 1b, the objective was to enroll patients in an appropriate cohort and evaluate the safety and efficacy of AB122-based treatments.

[0201] Table 2 Phase 1a If a tumor reduction effect based on RECIST v1.1 is established in the first five patients, the enrollment may be terminated if the probability of observing the required number of response cases in the other five patients is 20% or lower, based on the binomial distribution of the response rate.

[0202] Dose-limiting toxicity (DLT): The following adverse events related to the study drug that occurred during cycle 1 are defined as DLTs. The following grades are based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

[0203] Researchers and sponsors will determine whether laboratory abnormalities (excluding hematologic and non-hematologic toxicities) and transient signs or symptoms are consistent with DLT.

[0204] Grade 4 neutropenia lasting more than 7 days Febrile neutropenia [absolute neutrophil count (ANC) less than 1000 / mm] 3 [And a body temperature higher than 38.3℃ at least once, or a temperature equal to or higher than 38℃ for more than 1 hour] Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding requiring blood transfusion. Grade 4 anemia or Grade 3 anemia requiring a blood transfusion Grade 3 or higher non-hematologic adverse events are considered DLT. The criteria are the exclusion of the following: Grade 3 fatigue lasting 3 days or less, Grade 3 diarrhea, nausea or vomiting with or without antiemetics or antidiarrheals based on standards of care, and Grade 3 rash without the use of corticosteroids or anti-inflammatory agents based on standards of care.

[0205] Grade 2 or higher elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT), accompanied by an increase in total bilirubin exceeding twice the upper limit of reference (ULN). This is conditional on the absence of preliminary findings of cholestasis (alkaline phosphatase (ALP) elevation less than twice the ULN) and the absence of other explanations for these elevations.

[0206] The period during which the completion of Cycle 1 (defined as the period during which 75% or more of the prescribed oral doses of the study drug have been administered, and all doses of AB122 and AB154 (cohort D-3 only) have been administered) and the commencement of Cycle 2 are hindered by study drug-related toxicities. Hyperphosphatemia: Serum phosphorus levels increased by 10 mg / dL or more, or Despite 7 days of phosphorus-lowering treatment, serum phosphorus levels remained elevated by 7 mg / dL or more for 7 days or longer. Phase 1b After determining tolerability and preliminary effectiveness based on the results of Phase 1a, Phase 1b will be initiated. The cohort extending to Phase 1b will be determined through consultation between the Data Monitoring Committee (DMC) and the sponsor.

[0207] Target number of cases (planned): Queue D-2 The target number of cases for Phase 1a is a maximum of 52, and for Phase 1b it is a maximum of 30.

[0208] Queue D-3 The target number of cases for Phase 1a is a maximum of 52, and for Phase 1b it is a maximum of 30.

[0209] Queue D-4 The target number of cases for Phase 1a is a maximum of 40, and for Phase 1b it is a maximum of 30.

[0210] Queue D-5 The target number of cases for Phase 1a is a maximum of 40, and for Phase 1b it is a maximum of 30.

[0211] Queue D-6 The target number of cases for Phase 1a is a maximum of 52, and for Phase 1b it is a maximum of 30.

[0212] Queue D-7 The target number of cases for Phase 1a is a maximum of 52, and for Phase 1b it is a maximum of 30.

[0213] Queue D-8 The target number of cases for Phase 1a is a maximum of 52, and for Phase 1b it is a maximum of 30.

[0214] Diagnostic and primary inclusion criteria: Patients with advanced solid tumors who are 18 years of age or older at the time of obtaining informed consent.

[0215] Dosage and administration method: Phase 1a Application method: The application methods for each queue are as follows.

[0216] Table 3 The experimental treatments conducted in each cohort are as follows: Cohort D-2: On day 1, AB122 was administered via intravenous infusion at a rate of 360 mg / individual over 60 minutes. On day 1, AB122 was administered intravenously at a rate of 80 mg / m². 2 Cisplatin. Administered intravenously at 800 mg / m² from day 1 to day 5. 2 / day of 5-fluorouracil. Fubatinib is administered orally once daily on an empty stomach 1 hour or more before meals, or 2 hours or more after meals.

[0217] Cohort D-3: On day 1, AB122 was administered via intravenous infusion of 360 mg / individual over 60 minutes. On day 1, AB154 was administered via intravenous infusion of 1200 mg / individual over 60 minutes. Fubatinib was administered orally once daily, either 1 hour or more before a meal or 2 hours or more after a meal.

[0218] Cohort D-4: On day 1, AB122 was administered via intravenous infusion at a rate of 360 mg / individual over 60 minutes. On day 1, AB122 was administered intravenously at a rate of 100 mg / m². 2 Carboplatin AUC 5 or cisplatin. Administer 1000 mg / m² intravenously continuously from day 1 to day 4. 2 / day of 5-fluorouracil. Fubatinib is administered orally once daily on an empty stomach 1 hour or more before meals, or 2 hours or more after meals.

[0219] Cohort D-5: On Day 1, AB122 was administered via intravenous infusion of 360 mg / individual over 60 minutes. On Day 1, AB154 was administered via intravenous infusion of 1200 mg / individual over 60 minutes. Fubatinib was administered orally once daily, either 1 hour or more before a meal or 2 hours or more after a meal.

[0220] Cohort D-6: On day 1, AB122 was administered via intravenous infusion at a rate of 360 mg / individual over 60 minutes. On days 1, 8, and 15, AB122 was administered intravenously at a rate of 100 mg / m². 2 Albumin-bound paclitaxel; on day 1, carboplatin was administered intravenously at AUC 6. Fubatinib was administered orally once daily, either 1 hour or more before a meal or 2 hours or more after a meal.

[0221] Cohort D-7: On day 1, AB122 was administered via intravenous infusion at a rate of 360 mg / individual over 60 minutes. On days 1 and 8, AB122 was administered intravenously at a rate of 25 mg / m². 2 Cisplatin and 1000 mg / m 2 Gemcitabine. Fubatinib is administered orally once daily on an empty stomach 1 hour or more before meals, or 2 hours or more after meals.

[0222] Cohort D-8: On days 1 and 15, AB122 was administered via intravenous infusion at a rate of 240 mg / individual over 60 minutes. On days 1, 8, and 15, AB122 was administered intravenously at a rate of 125 mg / m². 2 albumin-bound paclitaxel and 1000 mg / m 2 Gemcitabine. Fubatinib is administered orally once daily on an empty stomach 1 hour or more before meals, or 2 hours or more after meals.

[0223] It should be noted that if toxic reactions occur at the start of a cycle or during a cycle, the dosage can be gradually adjusted according to the table below. The dosages of AB122 and AB154 remain constant during administration.

[0224] Table 4 Phase 1b Dosage levels were determined based on tolerability in each cohort during phase 1a.

[0225] During treatment: Queue D-8: One cycle is defined as 28 days.

[0226] Queues D-2 to D-7: One cycle is defined as 21 days.

[0227] The trial treatment continued until any of the criteria for discontinuing treatment were met.

[0228] Evaluation criteria: Validity Tumors were assessed using RECIST (v1.1, 2009) during the trial. Computed tomography (CT) scans were performed at baseline, every 4 weeks after enrollment, every 6 weeks after week 12, and at the end of the trial.

[0229] Security Standard security monitoring and classification were performed using NCI CTCAE v5.0.

[0230] Statistical procedures: The target population for this study has been defined for each phase and cohort, and DLT-evaluable cases have been defined for each cohort in phase 1a.

[0231] Table 5 Primary endpoint analysis Phase 1a: The incidence of DLT was calculated for each level of DLT evaluable case. All DLTs are listed by patient.

[0232] Phase 1b: ORR analysis was performed on the population obtained by pooling the FAS from phases 1a and 1b using RECIST v1.1. A list of best overall responses based on RECIST v1.1 is presented, and ORR and 95% CI were estimated using the Clopper-Pearson method.

[0233] Clinical trial design summary as follows Figure 1 As shown.

[0234] result For cohorts D-2, D-3, and D-7, the tolerability portion did not induce dose-limiting toxicity at level 1 doses, confirming tolerability.

[0235] The further expansion phase is ongoing, and interim results from cohort D-2 are shown in the table below. In the tolerability phase (N=3, level 1) and the expansion phase (N=38), the objective response rate (ORR) and disease control rate (DCR) were 58.5% and 92.7%, respectively. These ORR and DCR values ​​exceeded those of the combination therapy of pembrolizumab, 5-fluorouracil, and cisplatin (ORR (45.0%), DCR (79.4%)) as the primary treatment for unresectable advanced / recurrent esophageal cancer (Lancet. 2021; 398 (10302): 759-771.).

[0236] Table 6

Claims

1. Any of the following (i) to (iii) antitumor agents (excluding antitumor agents containing pembrolizumab as an active ingredient, and antitumor agents used in combination with pembrolizumab): (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with immune checkpoint inhibitors and at least one or more other antitumor agents for use in cancer patients; (ii) The antitumor agents include immune checkpoint inhibitors as active ingredients, which are used in combination with fobatinib or a pharmaceutically acceptable salt thereof and at least one or more other antitumor agents in cancer patients; and (iii) The antitumor agent includes at least one or more other antitumor agents as active ingredients, which are used in combination with fubatinib or its pharmaceutically acceptable salts and immune checkpoint inhibitors in cancer patients.

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

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

4. The antitumor agent according to claim 2 or 3, wherein the antiPD-1 antibody is selected from at least one of nivolumab, cimiprimab, spartazolizumab, tislelizumab, BI754091, dotalimab, sasanlimab, MGA-012, cilimab, AGEN-2034, cepalimab, camrelizumab, bouglimab, and batitilimab.

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

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

7. The antitumor agent according to claim 6, wherein the chemotherapeutic agent is at least one selected from antimetabolites, alkaloid antitumor agents, platinum preparations, 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 antimetabolites, alkaloid antitumor agents, platinum preparations, and immune checkpoint inhibitors.

9. The antitumor agent according to claim 6, wherein the chemotherapeutic agent is selected from at least one of the following: fludarabine, cladribine, nerabine, 5-fluorouracil, tegafur / gemcimethine / oteracil potassium, tegafur / uracil, trifluorouridine / tipyrimidine hydrochloride, capecitabine, deoxyfluorouridine, 5-fluoro-2'-deoxyuridine, gemcitabine, cytarabine, pemetrexed, methotrexate, paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel, eribulin, irinotecan, notecan (topotecan), etoposide, teniposide, vinorelbine, vincristine, vinblastine, cisplatin, carboplatin, oxaliplatin, nedaplatin, dovanalimab, AB308, vimbrolizumab, osperimab, and tireliumab.

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

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

12. The antitumor agent according to any one of claims 1 to 11, wherein the cancer is selected from at least one 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 or soft tissue tumor, leukemia, malignant lymphoma, multiple myeloma, head and neck cancer, brain tumor, mesothelioma, skin cancer, and cancers of unknown primary origin.

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

14. The antitumor agent according to any one of claims 1 to 13, wherein the cancer patient is a cancer patient who has not previously received treatment for advanced cancer or has previously received first-line chemotherapy.

15. The antitumor agent according to any one of claims 1 to 14, wherein the 21-day or 28-day administration cycle is repeated once, twice, or more.

16. The antitumor agent according to claim 15, wherein fobatinib 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 serpalimab is administered for 1 to 2 days during a 21-day or 28-day administration cycle.

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

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

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

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

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

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

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

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

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

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

28. The antitumor agent according to any one of claims 1 to 27, wherein the antitumor agent is any one of the following (i) to (iv): (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, which is used in combination with cepalimumab, cisplatin and 5-fluorouracil for patients with esophageal cancer; (ii) The antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts, cisplatin and 5-fluorouracil in patients with esophageal cancer; (iii) The antitumor agent comprises cisplatin as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, serpalimumab, and 5-fluorouracil in patients with esophageal cancer; and (iv) The antitumor agent includes 5-fluorouracil as an active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and cisplatin for patients with esophageal cancer.

29. The antitumor agent according to claim 28, wherein the 21-day administration cycle is repeated once, twice, or more, wherein fobatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose is administered once daily, and cepalimab at 360 mg / dose is administered once daily, at 80 mg / m 2 A single dose of cisplatin, 800 mg / m². 2 5-Fluorouracil was administered daily for 5 days.

30. The antitumor agent of claim 28, wherein the 21-day administration cycle is repeated once, twice, or more, wherein fobatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose is administered once daily, and cepalimab at 360 mg / dose is administered once on day 1, at 80 mg / m 2 Cisplatin was administered once on day 1, at a dose of 800 mg / m². 2 5-Fluorouracil was administered daily from day 1 to day 5.

31. The antitumor agent according to any one of claims 28 to 30, wherein the cancer patient is an esophageal cancer patient who has not previously received treatment for advanced cancer.

32. The antitumor agent according to any one of claims 1 to 27, wherein the antitumor agent is an antitumor agent of any one of the following (i) to (iii): (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, which is used in combination with cepallimab and dovanalimab for patients with esophageal cancer; (ii) The antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof and dovanalimab in patients with esophageal cancer; and (iii) The antitumor agents include dovanalimab as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof and cepalimumab in patients with esophageal cancer.

33. The antitumor agent according to claim 32, wherein the 21-day administration cycle is repeated once, twice or more, wherein fobatinib is administered once daily at a dose of 12 mg / dose, 16 mg / dose or 20 mg / dose, cepalimab is administered once daily at a dose of 360 mg / dose, and dovanalimab is administered once daily at a dose of 1200 mg / dose.

34. The antitumor agent according to claim 32, wherein the 21-day administration cycle is repeated once or twice or more, wherein fobatinib at 12 mg / dose, 16 mg / dose or 20 mg / dose is administered once daily, cepalimab at 360 mg / dose is administered once on day 1, and dovanalimab at 1200 mg / dose is administered once on day 1.

35. The antitumor agent according to any one of claims 32 to 34, wherein the cancer patient is an esophageal cancer patient who has not previously received treatment for advanced cancer or has previously received first-line chemotherapy.

36. The antitumor agent according to any one of claims 1 to 27, wherein the antitumor agent is an antitumor agent of any one of the following (i) to (iv): (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, which is used in combination with cepalimumab, 5-fluorouracil and carboplatin or cisplatin for patients with head and neck cancer; (ii) The antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, 5-fluorouracil and carboplatin or cisplatin for patients with head and neck cancer; (iii) The antitumor agent comprises 5-fluorouracil as an active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimab, and carboplatin or cisplatin in patients with head and neck cancer; and (iv) The antitumor agents include carboplatin or cisplatin as active ingredients, which are used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and 5-fluorouracil for patients with head and neck cancer.

37. The antitumor agent of claim 36, wherein the 21-day administration cycle is repeated once, twice, or more, wherein fobatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose is administered once daily, cepalimab at 360 mg / dose is administered once daily, and carboplatin at AUC 5 or 100 mg / mcg is administered once daily. 2 A single dose of cisplatin, 1000 mg / m². 2 5-Fluorouracil was administered daily for 4 days.

38. The antitumor agent of claim 36, wherein the 21-day administration cycle is repeated once, twice, or more, wherein fobatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose is administered once daily, cepalimab at 360 mg / dose is administered once on day 1, and carboplatin with an AUC 5 or 100 mg / mcg is administered. 2 Cisplatin was administered once on day 1, at a dose of 1000 mg / m². 2 5-Fluorouracil was administered daily from day 1 to day 4.

39. The antitumor agent according to any one of claims 36 to 38, wherein the cancer patient is a head and neck cancer patient who has not previously received treatment for advanced cancer.

40. The antitumor agent according to any one of claims 1 to 27, wherein the antitumor agent is an antitumor agent of any one of the following (i) to (iii): (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with cepallimab and dovanalimab for patients with head and neck cancer; (ii) The antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof and dovanalimab in patients with head and neck cancer; and (iii) The antitumor agents include dovanalimab as an active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof and cepalimumab for patients with head and neck cancer.

41. The antitumor agent according to claim 40, wherein the 21-day administration cycle is repeated once or twice or more, wherein fobatinib is administered once daily at a dose of 12 mg / dose, 16 mg / dose or 20 mg / dose, cepalimab is administered once daily at a dose of 360 mg / dose, and dovanalimab is administered once daily at a dose of 1200 mg / dose.

42. The antitumor agent according to claim 40, wherein the 21-day administration cycle is repeated once or twice or more, wherein fobatinib at 12 mg / dose, 16 mg / dose or 20 mg / dose is administered once daily, cepalimab at 360 mg / dose is administered once on day 1, and dovanalimab at 1200 mg / dose is administered once on day 1.

43. The antitumor agent according to any one of claims 40 to 42, wherein the cancer patient is a head and neck cancer patient who has not previously received treatment for advanced cancer.

44. The antitumor agent according to any one of claims 1 to 27, wherein the antitumor agent is any one of the following (i) to (iv): (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, which is used in combination with cepalimumab, albumin-bound paclitaxel and carboplatin for patients with non-small cell lung cancer; (ii) The antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salt, albumin-bound paclitaxel and carboplatin for patients with non-small cell lung cancer; (iii) The antitumor agent includes albumin-bound paclitaxel as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and carboplatin for patients with non-small cell lung cancer; and (iv) The antitumor agents include carboplatin as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and albumin-bound paclitaxel for patients with non-small cell lung cancer.

45. The antitumor agent according to claim 44, wherein the 21-day administration cycle is repeated once, twice, or more, wherein fobatinib is administered once daily at a dose of 12 mg / dose, 16 mg / dose, or 20 mg / dose, and cepalimab is administered once daily at a dose of 360 mg / dose, 100 mg / m 2 The drug is administered three times with albumin-bound paclitaxel and once with carboplatin (AUC 6).

46. ​​The antitumor agent according to claim 44, wherein the 21-day administration cycle is repeated once, twice, or more, wherein fobatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose is administered once daily, and cepalimab at 360 mg / dose is administered once on day 1, at a dose of 100 mg / m². 2 The albumin-bound paclitaxel was administered once each on days 1, 8, and 15, while carboplatin with an AUC of 6 was administered on day 1.

47. The antitumor agent according to any one of claims 44 to 46, wherein the cancer patient is a non-small cell lung cancer patient who has not previously received treatment for advanced cancer.

48. The antitumor agent according to any one of claims 1 to 27, wherein the antitumor agent is any one of the following (i) to (iv): (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as the active ingredient, which is used in combination with cepalimumab, cisplatin and gemcitabine for patients with biliary tract cancer; (ii) The antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salts, cisplatin and gemcitabine for patients with biliary tract cancer; (iii) The antitumor agent includes gemcitabine as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and cisplatin in patients with biliary tract cancer; and (iv) The antitumor agents include cisplatin as an active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and gemcitabine for patients with biliary tract cancer.

49. The antitumor agent according to claim 48, wherein the 21-day administration cycle is repeated once, twice, or more, wherein fobatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose is administered once daily, and cepalimab at 360 mg / dose is administered once daily, along with 25 mg / mcg. 2 Cisplatin was administered twice, 1000 mg / m². 2 Apply gemcitabine twice a day.

50. The antitumor agent according to claim 48, wherein the 21-day administration cycle is repeated once, twice, or more, wherein fobatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose is administered once daily, and cepalimab at 360 mg / dose is administered on day 1, 25 mg / m 2 Cisplatin was administered twice daily, on days 1 and 8, at a dose of 1000 mg / m². 2 Gemcitabine was administered once daily on day 1 and once daily on day 8.

51. The antitumor agent according to any one of claims 48 to 50, wherein the cancer patient is a biliary tract cancer patient who has not previously received treatment for advanced cancer.

52. The antitumor agent according to any one of claims 1 to 27, wherein the antitumor agent is any one of the following (i) to (iv): (i) The antitumor agent includes fubatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with cepalimumab, albumin-bound paclitaxel and gemcitabine for patients with pancreatic cancer; (ii) The antitumor agents include cepalimumab as the active ingredient, which is used in combination with fubatinib or its pharmaceutically acceptable salt, albumin-bound paclitaxel and gemcitabine for patients with pancreatic cancer; (iii) The antitumor agent includes gemcitabine as the active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab, and albumin-bound paclitaxel in patients with pancreatic cancer; and (iv) The antitumor agents include albumin-bound paclitaxel as an active ingredient, which is used in combination with fubatinib or a pharmaceutically acceptable salt thereof, cepalimumab and gemcitabine for patients with pancreatic cancer.

53. The antitumor agent according to claim 52, wherein the 28-day administration cycle is repeated once, twice, or more, wherein fobatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose is administered once daily, cepalimab at 240 mg / dose is administered twice daily, and 125 mg / m 2 The albumin-bound paclitaxel was administered three times at a dose of 1000 mg / m². 2 / dose of gemcitabine was administered three times.

54. The antitumor agent according to claim 52, wherein the 28-day administration cycle is repeated once, twice, or more, wherein fobatinib at 12 mg / dose, 16 mg / dose, or 20 mg / dose is administered once daily, cepalimab at 240 mg / dose is administered on days 1 and 15, and 125 mg / m 2 The albumin-bound paclitaxel was administered once each on days 1, 8, and 15, at a dose of 1000 mg / m². 2 Gemcitabine was administered once each on day 1, day 8, and day 15.

55. The antitumor agent according to any one of claims 52 to 54, wherein the cancer patient is a pancreatic cancer patient who has not previously received treatment for advanced cancer.

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