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

Abstract

To provide a novel combination therapy using (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, the combination therapy exhibiting an excellent antitumor effect on cancer patients with resistance to immune checkpoint inhibitors.SOLUTION: The present disclosure provides an antitumor agent comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient, the antitumor agent being administered in combination with an immune checkpoint inhibitor, excluding pembrolizumab, to a cancer patient with resistance to immune checkpoint inhibitors.SELECTED DRAWING: None

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims priority based on Japanese Patent Application No. 2019-035603, filed on February 28, 2019, and Japanese Patent Application No. 2019-112619, filed on June 18, 2019, the entire disclosures of which are incorporated herein by reference. The present disclosure relates to an antitumor agent, an antitumor effect enhancing agent, and a kit preparation. [Background technology]

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

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

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

[0005] Cancer cells utilize this mechanism to suppress the activation of antigen-specific T cells, thereby escaping from the immune surveillance mechanism and continuing to grow. Therefore, it is believed that inducing an antitumor immune response in the body of a cancer patient by strengthening costimulation or blocking coinhibition and controlling the immune escape of tumors is effective in cancer treatment, and various cancer immunotherapies targeting costimulatory molecules (stimulatory costimulatory molecules) or coinhibitory molecules (inhibitory costimulatory molecules) have been proposed (Non-Patent Document 5). For example, nivolumab (human IgG4 monoclonal antibody against human PD-1) is used in the treatment of malignant melanoma and the like as an immune checkpoint inhibitor that activates T cells by inhibiting the binding of PD-1 and its ligands (PD-L1 and PD-L2) (Patent Document 1, Non-Patent Document 6). In addition, pembrolizumab is an immune checkpoint inhibitor with a different type of antibody from nivolumab, and is used in the treatment of malignant melanoma, non-small cell lung cancer, and the like (Non-Patent Document 6).

[0006] The 3,5-disubstituted benzenealkynyl compound, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, is known as an FGFR inhibitor, and combinations of FGFR inhibitors with other antitumor agents have been reported (Patent Documents 2 and 3). Concomitant administration of an FGFR inhibitor with an immune checkpoint inhibitor, for example, Patent Document 4 describes a method of combining an FGFR inhibitor with an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0007] Many cases of immune checkpoint inhibitors have been reported, and it has become clear that continued administration leads to resistance to the drug, and the mechanism is being studied (Non-Patent Documents 9, 10, 11). As an example of the use of immune checkpoint inhibitors and FGFR inhibitors, for example, a Phase II study (NCT02365597) of Erdafitinib (JNJ-42756493) targeting urothelial carcinoma has been reported in which an FGFR inhibitor was administered to subjects with previous PD-1 or PD-L1 treatment. In addition, a combination study of the anti-FGFR3 antibody Vofatamab and pembrolizumab is underway (NCT03123055). As for sequential administration, there are reports of the combination of pazopanib, a multikinase inhibitor with FGFR inhibitory activity, and everolimus, the combination of Vofatamab and docetaxel, and the sequential administration of atezolizumab (Non-Patent Document 12). [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2004 / 004771 [Patent Document 2] International Publication No. 2013 / 108809 [Patent Document 3] International Publication No. 2017 / 150725 [Patent Document 4] International Publication No. 2016 / 161239

Non-licensed literature

[0009]

Non-licensed literature 1

Non-licensed Document 2

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

[0010] An objective of the present disclosure is to provide a new combination therapy that uses (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, and that shows excellent antitumor effects in cancer patients who are resistant to immune checkpoint inhibitors. [Means for solving the problem]

[0011] In view of the current situation, the present inventors have discovered that the above problems can be solved by using (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (hereinafter also referred to as "Compound 1"), a compound having FGFR inhibitory activity, or a salt thereof in combination with an immune checkpoint inhibitor.

[0012] Accordingly, the present disclosure provides the following items 1 to 77.

[0013] Item 1. An antitumor agent which contains (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient and is administered in combination with an immune checkpoint inhibitor (excluding pembrolizumab) to a cancer patient who has resistance to the immune checkpoint inhibitor.

[0014] Item 2. The antitumor agent according to Item 1, wherein the immune checkpoint inhibitor is at least one selected from the group consisting of a PD-1 pathway antagonist, an ICOS pathway agonist, a CTLA-4 pathway antagonist, and a CD28 pathway agonist.

[0015] Item 3. The antitumor agent according to Item 1 or 2, wherein the immune checkpoint inhibitor is a PD-1 pathway antagonist.

[0016] Item 4. The antitumor agent according to Item 2 or 3, wherein the PD-1 pathway antagonist is at least one selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-PD-L2 antibody.

[0017] Item 5. The antitumor agent according to any one of Items 2 to 4, wherein the PD-1 pathway antagonist is an anti-PD-1 antibody.

[0018] Item 6. The antitumor agent according to Item 4 or 5, wherein the anti-PD-1 antibody is nivolumab, cemiplimab, spartalizumab, tislelizumab, BI754091, dostalizumab, sasanlimab, MGA-012, cetrelimab, AGEN-2034, zimverekimab, camrelizumab, budigalimab or balstilimab, preferably nivolumab.

[0019] Item 7. The antitumor agent according to any one of Items 2 to 4, wherein the PD-1 pathway antagonist is an anti-PD-L1 antibody.

[0020] Item 8. The antitumor agent according to Item 7, wherein the anti-PD-L1 antibody is atezolizumab, durvalumab or avelumab.

[0021] Item 9. The antitumor agent according to Item 2, wherein the CTLA-4 pathway antagonist is an anti-CTLA-4 antibody.

[0022] Item 10. The antitumor agent according to Item 9, wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

[0023] Item 11. The antitumor agent according to any one of Items 1 to 10, wherein the tumor has an abnormality in the FGFR pathway.

[0024] Item 12. The antitumor agent according to Item 11, wherein the abnormality in the FGFR pathway is at least one selected from the group consisting of overexpression of FGFR, an abnormality in the FGFR gene, and an abnormal state of FGFR signaling.

[0025] Item 13. The antitumor agent according to any one of Items 1 to 12, wherein treatment with the antitumor agent results in a sustained response in an individual after cessation of treatment.

[0026] Item 14. The antitumor agent according to any one of Items 1 to 13, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is used before an immune checkpoint inhibitor, used simultaneously with an immune checkpoint inhibitor, or used after an immune checkpoint inhibitor.

[0027] Item 15. The antitumor agent according to any one of Items 1 to 14, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is used continuously or intermittently.

[0028] Item 16. The antitumor agent according to any one of items 1 to 15, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and an immune checkpoint inhibitor are administered in the same therapeutic regimen.

[0029] Item 17. Targeting tumors resistant to immune checkpoint inhibitors used to administer (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg, and 20 mg once daily, and administer nivolumab at a dose selected from the group consisting of 1 mg / kg every 3 weeks, 2 mg / kg every 3 weeks, 3 mg / kg every 3 weeks, 80 mg every 3 weeks, 240 mg every 3 weeks, 1 mg / kg every 2 weeks, 2 mg / kg every 2 weeks, 3 mg / kg every 2 weeks, 80 mg, every 2 weeks, and 240 mg every 2 weeks; The antitumor agent according to any one of items 1 to 6 and items 11 to 16.

[0030] Item 18. Targeting tumors resistant to immune checkpoint inhibitors A group consisting of 8 mg, 12 mg, 16 mg, and 20 mg of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and nivolumab at a dose selected from the group consisting of 240 mg once daily every 2 weeks and 240 mg once every 3 weeks. Item 18. An antitumor agent according to item 17.

[0031] Item 19. Targeting tumors resistant to immune checkpoint inhibitors (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg, and nivolumab is administered at 240 mg every two weeks. Item 18. An antitumor agent according to item 17.

[0032] Item 20. Targeting tumors resistant to immune checkpoint inhibitors (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg, and 20 mg, and nivolumab is administered at 80 mg every 3 weeks for four doses, and then nivolumab is administered at 240 mg every 2 weeks from the fifth dose. Item 18. An antitumor agent according to item 17.

[0033] Item 21. A pharmaceutical composition comprising an immune checkpoint inhibitor (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as active ingredients.

[0034] Item 22. The pharmaceutical composition according to Item 21, for treating a cancer resistant to an immune checkpoint inhibitor.

[0035] Item 23. Use of an immune checkpoint inhibitor (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for the manufacture of an antitumor agent for treating a cancer having resistance to an immune checkpoint inhibitor.

[0036] Item 24. Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for the manufacture of an antitumor agent to be administered in combination with an immune checkpoint inhibitor (excluding pembrolizumab) to a patient having resistance to the immune checkpoint inhibitor.

[0037] Item 25. Use of an immune checkpoint inhibitor (excluding pembrolizumab) for the manufacture of an antitumor agent to be administered in combination with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof to a patient having resistance to an immune checkpoint inhibitor.

[0038] Item 26. An immune checkpoint inhibitor (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4 -d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof.

[0039] Item 27. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for use in combination therapy with an immune checkpoint inhibitor (excluding pembrolizumab) in the treatment of cancer resistant to the immune checkpoint inhibitor.

[0040] Item 28. An immune checkpoint inhibitor (excluding pembrolizumab) for use in combination therapy with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof in the treatment of cancer resistant to immune checkpoint inhibitors.

[0041] Item 29. Use of an immune checkpoint inhibitor (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof to treat a cancer resistant to the immune checkpoint inhibitor.

[0042] Item 30. Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for treating a cancer resistant to an immune checkpoint inhibitor by combination therapy with an immune checkpoint inhibitor (excluding pembrolizumab).

[0043] Item 31. Use of an immune checkpoint inhibitor (excluding pembrolizumab) for treating a cancer resistant to an immune checkpoint inhibitor by combination therapy with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof.

[0044] Item 32. A method for treating a cancer resistant to an immune checkpoint inhibitor, comprising administering a therapeutically effective amount of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and a therapeutically effective amount of an immune checkpoint inhibitor (excluding pembrolizumab) to a human in need thereof.

[0045] Item 33. An antitumor agent administered in combination with an immune checkpoint inhibitor (excluding pembrolizumab) to a cancer patient who has not been administered an immune checkpoint inhibitor, comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient.

[0046] Item 34. No previous administration of immune checkpoint inhibitors (excluding pembrolizumab) or immune checkpoint inhibitors containing (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient. A pharmaceutical composition for treating cancer in a cancer patient.

[0047] Item 35. The pharmaceutical composition according to Item 34, for treating a cancer resistant to an immune checkpoint inhibitor.

[0048] Item 36. Use of an immune checkpoint inhibitor (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for the manufacture of an antitumor agent for treating cancer in a cancer patient who has not been administered an immune checkpoint inhibitor.

[0049] Item 37. Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for the manufacture of an antitumor agent to be administered in combination with an immune checkpoint inhibitor (excluding pembrolizumab) to a cancer patient who has not been administered an immune checkpoint inhibitor.

[0050] Item 38. Use of an immune checkpoint inhibitor (excluding pembrolizumab) for the manufacture of an antitumor agent to be administered in combination with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof to a cancer patient who has not been administered an immune checkpoint inhibitor.

[0051] Item 39. A combination of an immune checkpoint inhibitor (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for use in the treatment of cancer in cancer patients who have not been administered an immune checkpoint inhibitor.

[0052] Item 40. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for use in combination therapy with an immune checkpoint inhibitor (excluding pembrolizumab) in the treatment of cancer in cancer patients who have not been administered an immune checkpoint inhibitor.

[0053] Item 41. An immune checkpoint inhibitor (excluding pembrolizumab) for use in combination therapy with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof in the treatment of cancer in cancer patients who have not been administered an immune checkpoint inhibitor.

[0054] Item 42. Use of an immune checkpoint inhibitor (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof to treat cancer in a cancer patient who has not been administered an immune checkpoint inhibitor.

[0055] Item 43. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1-methyl-1,2-dioxanediol for the treatment of cancer in a cancer patient who has not been administered an immune checkpoint inhibitor, in combination with an immune checkpoint inhibitor (excluding pembrolizumab). Use of H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof.

[0056] Item 44. Use of an immune checkpoint inhibitor (excluding pembrolizumab) in combination with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof to treat cancer in a cancer patient who has not been administered an immune checkpoint inhibitor.

[0057] Item 45. A method for treating cancer in a cancer patient who has not been administered an immune checkpoint inhibitor, comprising administering a therapeutically effective amount of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and a therapeutically effective amount of an immune checkpoint inhibitor (excluding pembrolizumab) to a human in need thereof. The method comprises administering the therapeutically effective amount of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and a therapeutically effective amount of an immune checkpoint inhibitor (excluding pembrolizumab).

[0058] Item 46. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, immune checkpoint inhibitor, or method according to any one of items 21 to 45, wherein the tumor has an abnormality in the FGFR pathway.

[0059] Item 47. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, immune checkpoint inhibitor, or method described in Item 46, wherein the abnormality in the FGFR pathway is at least one selected from the group consisting of overexpression of FGFR, genetic abnormalities in FGFR, and abnormal states of FGFR signaling.

[0060] Item 48. An antitumor agent containing (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient, which is administered in combination with an immune checkpoint inhibitor (excluding pembrolizumab) to a cancer patient who has resistance to immune checkpoint inhibitors and has no abnormality in the FGFR pathway.

[0061] Item 49. A pharmaceutical composition for treating a cancer not having an abnormality in the FGFR pathway, comprising an immune checkpoint inhibitor (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient.

[0062] Item 50. The pharmaceutical composition according to Item 49, for treating a cancer resistant to an immune checkpoint inhibitor.

[0063] Item 51. Use of an immune checkpoint inhibitor (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for the manufacture of an antitumor agent for treating cancers that do not have an abnormality in the FGFR pathway.

[0064] Item 52. Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for the manufacture of an antitumor agent to be administered in combination with an immune checkpoint inhibitor (excluding pembrolizumab) to a cancer patient without an abnormality in the FGFR pathway.

[0065] Item 53. Use of an immune checkpoint inhibitor (excluding pembrolizumab) for the manufacture of an antitumor agent to be administered in combination with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof to a cancer patient without an abnormality in the FGFR pathway.

[0066] Item 54. A combination of an immune checkpoint inhibitor (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for use in treating cancers that do not have an abnormality in the FGFR pathway.

[0067] Item 55. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for use in combination therapy with an immune checkpoint inhibitor (excluding pembrolizumab) in the treatment of cancer not having an abnormality in the FGFR pathway.

[0068] Item 56. An immune checkpoint inhibitor (excluding pembrolizumab) for use in combination therapy with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof in the treatment of cancer not having an abnormality in the FGFR pathway.

[0069] Item 57. Use of an immune checkpoint inhibitor (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for treating cancers without abnormalities in the FGFR pathway.

[0070] Item 58. Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for treating cancers not having abnormalities in the FGFR pathway by combination therapy with immune checkpoint inhibitors (excluding pembrolizumab).

[0071] Item 59. Use of an immune checkpoint inhibitor (excluding pembrolizumab) for treating cancers not having abnormalities in the FGFR pathway by combination therapy with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof.

[0072] Item 60. A method for treating a cancer that does not have an abnormality in the FGFR pathway, comprising administering a therapeutically effective amount of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and a therapeutically effective amount of an immune checkpoint inhibitor (pembrolizumab). and a mab) to a human in need thereof.

[0073] Item 61. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, immune checkpoint inhibitor, or method according to any one of items 18 to 29, wherein the immune checkpoint inhibitor is at least one selected from the group consisting of a PD-1 pathway antagonist, an ICOS pathway agonist, a CTLA-4 pathway antagonist, and a CD28 pathway agonist.

[0074] Item 62. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, immune checkpoint inhibitor, or method according to any one of items 21 to 61, wherein the immune checkpoint inhibitor is a PD-1 pathway antagonist.

[0075] Item 63. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, immune checkpoint inhibitor, or method according to item 61 or 62, wherein the PD-1 pathway antagonist is at least one selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-PD-L2 antibody.

[0076] Item 64. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, immune checkpoint inhibitor, or method according to any one of items 61 to 63, wherein the PD-1 pathway antagonist is an anti-PD-1 antibody.

[0077] Item 65. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, immune checkpoint inhibitor, or method according to item 63 or 64, wherein the anti-PD-1 antibody is nivolumab, cemiplimab, spartalizumab, tislelizumab, BI754091, dostalizumab, sasanlimab, MGA-012, cetrelimab, AGEN-2034, zimverekimab, camrelizumab, budigalimab, or balstilimab, preferably nivolumab.

[0078] Clause 66. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, immune checkpoint inhibitor, or method according to any one of clauses 61 to 63, wherein the PD-1 pathway antagonist is an anti-PD-L1 antibody.

[0079] Clause 67. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, immune checkpoint inhibitor, or method according to clause 64, wherein the anti-PD-L1 antibody is atezolizumab, durvalumab, or avelumab.

[0080] Item 68. The composition, use, combination, and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)-2 ... (phenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, an immune checkpoint inhibitor, or a method.

[0081] Item 69. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, immune checkpoint inhibitor, or method according to Item 68, wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

[0082] Item 70. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, immune checkpoint inhibitor, or method according to any one of items 21 to 69, wherein treatment with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and an immune checkpoint inhibitor results in a sustained response in the individual after cessation of treatment.

[0083] Item 71. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, immune checkpoint inhibitor, or method according to any one of items 21 to 70, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is used before an immune checkpoint inhibitor, used simultaneously with an immune checkpoint inhibitor, or used after an immune checkpoint inhibitor.

[0084] Item 72. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, immune checkpoint inhibitor, or method according to any one of items 21 to 71, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is used continuously or intermittently.

[0085] Item 73. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, immune checkpoint inhibitor or method according to any one of items 21 to 71, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, immune checkpoint inhibitor or method are administered in the same therapeutic regimen.

[0086] Item 74. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and nivolumab are used by the following method according to any one of items 21 to 65 and 70 to 73. 1-one or a salt thereof or an immune checkpoint inhibitor or method: A cancer patient having resistance to an immune checkpoint inhibitor is administered (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg, and 20 mg once daily, and nivolumab at a dose selected from the group consisting of 1 mg / kg every 3 weeks, 2 mg / kg every 3 weeks, 3 mg / kg every 3 weeks, 80 mg every 3 weeks, 240 mg every 3 weeks, 1 mg / kg every 2 weeks, 2 mg / kg every 2 weeks, 1 mg / kg, 3 mg / kg every 2 weeks, 80 mg every 2 weeks, and 240 mg every 2 weeks.

[0087] Item 75. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof or an immune checkpoint inhibitor or method according to any one of items 21 to 65 and 70 to 73, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and nivolumab are used by the following method: A cancer patient having resistance to an immune checkpoint inhibitor is administered (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg once daily, and nivolumab at a dose selected from the group consisting of 240 mg every two weeks and 240 mg every three weeks.

[0088] Item 76. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof or an immune checkpoint inhibitor or method according to any one of items 21 to 65 and 70 to 73, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and nivolumab are used by the following method: A cancer patient having resistance to an immune checkpoint inhibitor is administered (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg once daily, and nivolumab at 240 mg every 2 weeks.

[0089] Item 77. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof or an immune checkpoint inhibitor or method according to any one of items 21 to 65 and 70 to 73, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and nivolumab are used by the following method: A cancer patient having resistance to an immune checkpoint inhibitor is administered (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg, and 20 mg once a day, and nivolumab at 80 mg administered at 3-week intervals for four doses, after which nivolumab at 240 mg is administered at 2-week intervals from the fifth dose. Effect of the Invention

[0090] According to the present disclosure, it is possible to provide a new combination therapy that uses (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, which exhibits excellent antitumor effects for cancer patients who are resistant to immune checkpoint inhibitors. [Brief description of the drawings]

[0091] [Figure 1] 1 shows the results of Example 1 (the effect of Compound 1 on bone marrow-derived immunosuppressive cells (MDSC)). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0092] The present disclosure relates to the provision of a combination of a compound having FGFR inhibitory activity and an immune checkpoint inhibitor (excluding pembrolizumab), i.e., an antitumor agent containing a compound having FGFR inhibitory activity, which is administered in combination with an immune checkpoint inhibitor (excluding pembrolizumab), an antitumor effect enhancing agent containing a compound having FGFR inhibitory activity, a combination of a compound having FGFR inhibitory activity and an immune checkpoint inhibitor (excluding pembrolizumab), use of a compound having FGFR inhibitory activity in the manufacture of a medicament for the treatment of a tumor, which is administered in combination with an immune checkpoint inhibitor (excluding pembrolizumab), etc.

[0093] In the present disclosure, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one, which provides an excellent antitumor effect when used in combination with an immune checkpoint inhibitor, is a disubstituted benzenealkynyl compound having the following structure. In this specification, the above compound is referred to as "compound 1" for convenience. Compound 1 is described as Example compound 2 in the above Patent Document 2. Compound 1 or a salt thereof has an excellent FGFR inhibitory effect and has been reported to inhibit the phosphorylation ability of the receptor protein tyrosine kinases FGFR1, FGFR3, and FGFR4 to tyrosine in the substrate peptide sequence (Patent Document 2).

[0094] [ka]

[0095] The above-mentioned compound 1 or a pharma- ceutically acceptable salt thereof in the present disclosure can be synthesized, for example, based on the production method described in Patent Document 2, without being particularly limited thereto.

[0096] In the present disclosure, Compound 1 can be used as it is or in the form of a pharma- ceutically acceptable salt. The pharma- ceutically acceptable salt of Compound 1 includes, but is not limited to, addition salts with inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as acetic acid, citric acid, tartaric acid, and maleic acid, salts with alkali metals such as potassium and sodium, salts with alkaline earth metals such as calcium and magnesium, and salts with organic bases such as ammonium salts, ethylamine salts, and arginine salts.

[0097] The immune checkpoint inhibitor disclosed herein acts on immune checkpoint molecules, induces an anti-tumor immune response in the subject's body, and has the effect of controlling immune escape by tumors.

[0098] Examples of such substances include substances that promote the function of costimulatory molecules (stimulatory co-stimulatory molecules) and substances that suppress the function of coinhibitory molecules (inhibitory co-stimulatory molecules). Examples of immune checkpoint molecules include the B7 family (B7-1, B7-2, PD-L1, PD-L2, etc.), the CD28 family (CTLA-4, PD-1, etc.), the TNF superfamily (4-1B BL, OX40L), TNF receptor superfamily (4-1BB , OX40) molecules, and the immune checkpoint inhibitors can be substances that target immune checkpoint molecules, such as PD-1 pathway antagonists, ICOS pathway agonists, CTLA-4 pathway antagonists, CD28 pathway agonists, BTLA pathway antagonists, and 4-1BB pathway agonists.

[0099] In the present disclosure, the antagonist is preferably at least one selected from a PD-1 pathway antagonist, an ICOS pathway agonist, a CTLA-4 pathway antagonist, and a CD28 pathway agonist, more preferably at least one selected from a PD-1 pathway antagonist and a CTLA-4 pathway antagonist, and even more preferably a PD-1 pathway antagonist.

[0100] The PD-1 pathway antagonist inhibits the immunosuppressive signal by PD-1 expressed on T cells or its ligand PD-L1 or PD-L2, and examples thereof include, but are not limited to, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, 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. Preferred are anti-PD-1 antibody, anti-PD-L1 antibody, or anti-PD-L2 antibody, more preferably anti-PD-1 antibody or anti-PD-L1 antibody. Of these, particularly preferred is anti-PD-1 antibody.

[0101] The CTLA-4 pathway antagonist inhibits immunosuppressive signals by CTLA-4 expressed on T cells and its ligands B7-1 (CD80) and B7-2 (CD86), and is preferably an anti-CTLA-4 antibody, a CTLA-4 extracellular domain, a CTLA-4-Ig (a fusion protein of a CTLA-4 extracellular domain and an Ig Fc region), an anti-B7-1 (CD80) antibody, or an anti-B7-2 (CD86) antibody, more preferably an anti-CTLA-4 antibody or a CTLA-4-Ig. Of these, an anti-CTLA-4 antibody is particularly preferred.

[0102] These antibodies include immunoglobulins (IgA, IgD, IgE, IgG, IgM, IgY, etc.), Fab fragments, F(ab')2 fragments, single-chain antibody fragments (scFv), single domain antibodies, diabodies, etc. (Nat. Rev. Immunol., 6:343-357, 2006), including monoclonal or polyclonal antibodies such as human antibodies, humanized antibodies, chimeric antibodies, mouse antibodies, llama antibodies, and chicken antibodies. In the present disclosure, immunoglobulins (preferably IgG, etc.) are preferred. In the present disclosure, human antibodies or humanized antibodies are preferred. In the present disclosure, monoclonal antibodies are preferred.

[0103] Preferably, the antibody is a humanized IgG monoclonal antibody or a human IgG monoclonal antibody.

[0104] Preferred anti-PD-1 antibodies in the present disclosure include Nivolumab, Cemiplimab, Spartalizumab, Tislelizumab, BI754091, Dostarlimab, Sasanlimab, MGA-012, Cetrelimab, AGEN-2034, Zimberelimab, Camrelizumab, Budigalimab, Balstilimab, and the like.

[0105] Preferred anti-PD-L1 antibodies in the present disclosure include Atezolizumab, Durvalumab, Avelumab, Lodapolimab, BGB-A333, and the like.

[0106] Preferred anti-CTLA-4 antibodies in the present disclosure include Ipilimumab, Tremelimumab, and the like.

[0107] Preferred CTLA-4-Ig of the present disclosure include abatacept, and the like.

[0108] These agonists and antagonists can be produced by generally known production methods.

[0109] In addition, the anti-PD-1 antibody, nivolumab; the anti-PD-L1 antibody, atezolizumab, durvalumab, or avelumab; the anti-CTLA-4 antibody, ipilimumab or tremelimumab; and the CTLA-4-Ig, abatacept, are already on the market or are scheduled to be marketed, and these can also be used.

[0110] In the present disclosure, immune checkpoint inhibitors may be used alone or in combination of two or more.

[0111] In the present disclosure, 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 capable of binding to different immune checkpoint molecules can be used. An example of a bispecific antibody capable of binding to both PD-1 and CTLA-4 is XmAb20717 (PD-1×CTLA-4).

[0112] In the present disclosure, treatment includes procedures performed with the intent of curing or ameliorating a disease, or inhibiting the progression or recurrence of a disease, or alleviating symptoms. Treatment includes administration of a drug before or after a surgical procedure, or administration of a drug before, during, or after radiation therapy.

[0113] The therapeutically effective amount of an antibody that blocks the interaction between an immune checkpoint molecule and Compound 1 or a salt thereof will depend on several factors, including, but not limited to, the stage and severity of the cancer, as well as other factors related to the health of the patient. Those skilled in the art will know how to determine a therapeutically effective amount.

[0114] In some embodiments, the present disclosure is used for tumors having abnormalities in the FGFR pathway, hi some embodiments, the FGFR is selected from the group consisting of FGFR1, FGFR2, FGFR3 and FGFR4.

[0115] In one embodiment, the tumors to which the present disclosure is applicable are preferably tumors having an abnormality in the FGFR pathway. The abnormality in the FGFR pathway includes overexpression of FGFR, an abnormality in the FGFR gene, and an abnormal state of FGFR signaling.

[0116] In one embodiment, the present disclosure is administered to a subject with or without abnormality in FGF / FGFR, preferably to a subject with abnormality in the FGFR pathway. Even in carcinomas without FGFR gene abnormality, compound 1 can promote the antitumor effect of immune checkpoint inhibitors. It is known that the sensitivity of cancer to immune checkpoint inhibitors is also affected by the cancer microenvironment. The microenvironment includes, but is not limited to, cell groups controlled by FGF / FGFR pathway activation, such as cancer associated fibroblasts (CAFs), and it is known that these cell groups attenuate the sensitivity of cancer to immune checkpoint inhibitors. It is considered that administration of compound 1 promotes the effect of immune checkpoint inhibitors on cancer by causing changes in the microenvironment, including inactivation of CAFs.

[0117] Overexpression of FGFR includes, for example, gene expression and high expression of gene product protein. The presence or absence of FGFR expression can be detected by a method known to those skilled in the art. Detection of gene expression and high expression of gene product protein can be performed by a known method, for example, a method using an antibody (immunohistochemical staining, enzyme-linked immunosorbent assay (ELISA), flow cytometry, immunoblotting, etc.), a method using a nucleic acid (in situ hybridization, PCR, Northern blotting, etc.), and a method based on a principle common to these. The detection device can be a known device (Genechip, microarray, etc.).

[0118] In one embodiment, the present disclosure is used for tumors having FGFR gene abnormalities. Gene abnormalities in the FGFR pathway include gene amplification, gene mutation, chromosomal translocation / insertion / inversion, gene fusion, gene rearrangement, and the like. Some FGFR gene abnormalities in tumors have already been reported in literature available to those skilled in the art (Non-Patent Documents 7 and 8). FGFR gene abnormalities can be detected by methods known to those skilled in the art, such as DNA sequencing including pyrosequencing and NGS (next-generation sequencing), PCR-based methods including allele-specific PCR chain reaction, microarray-based comparative genomic hybridization (aCGH), and fluorescence in situ hybridization (FIS). H) or colorimetric in situ hybridization (CISH) It is possible.

[0119] In addition, in one embodiment, the present disclosure is used for tumors in which FGFR signaling is activated. FGFR forms a dimer upon binding to FGF and is activated by phosphorylation, thereby inducing the recruitment and activation of specific downstream signaling molecules, thereby exerting physiological functions.

[0120] Activation of FGFR signaling can be detected by a method known to those skilled in the art. Detection of signaling activation can be performed, for example, by detecting FGF, which is a substrate of FGFR, by detecting the direct phosphorylation state or biological activity, including enzymatic activity, of FGFR, which is a phosphorylation enzyme, by detecting the phosphorylation state or biological activity, including enzymatic activity, of intracellular substrates and intracellular proteins present downstream of the FGFR signaling cascade, or by detecting gene products or gene transcription products.

[0121] In another embodiment, the tumor to which the present disclosure is applicable also includes a tumor that does not have an abnormality in the FGFR pathway.

[0122] In the present disclosure, preferred dosages of compound 1 or a salt thereof per day on the day of administration include, for example, 4 mg to 160 mg, 4 mg to 24 mg, 12 to 24 mg, 16 to 24 mg, 20 mg, etc. More specifically, preferred dosages and times of administration per day on the day of administration include once a day, 4 mg, 8 mg, 12 mg, 16 mg, 20 mg, etc. In another embodiment, preferred dosages and times of administration per day on the day of administration include 8 mg, 12 mg, 16 mg, 20 mg, etc. In another embodiment, preferred dosages and times of administration per day on the day of administration include 12 mg, 16 mg, 20 mg, etc. In another embodiment, preferred dosages and times of administration per day on the day of administration include 20 mg, etc.

[0123] The disclosure includes, in some embodiments, for cancer types where stronger efficacy is desired (eg, brain tumors), the dosage of Compound 1 or a salt thereof is greater than 20 mg once daily.

[0124] When the daily dose of compound 1 or a salt thereof is administered intermittently, the dose is, for example, about 2 to 1000 mg of compound 1 or a pharma- ceutically acceptable salt thereof per day, preferably 10 to 500 mg per day, more preferably 20 to 200 mg per day, and even more preferably 50 to 160 mg per day.

[0125] The administration schedule of Compound 1 or a salt thereof may be daily administration or intermittent administration.

[0126] In the present disclosure, "daily administration" refers to, for example, an administration schedule in which administration is performed for 21 consecutive days as one cycle, and a drug holiday may be provided after each cycle.

[0127] In the present disclosure, "intermittent administration" is not particularly limited as long as it satisfies the conditions of two or more times a week with an administration interval (the number of days between one administration day and the next administration day) of one day or more. For example, an administration schedule in which one cycle is administered per week, in which Compound 1 or a pharma- ceutically acceptable salt thereof is administered at intervals of 1 to 3 days (the interval between one administration day and the next administration day is 1 to 3 days) two or more times per cycle, and the cycle is repeated one or more times; an administration schedule in which one cycle is performed over 14 days, in which compound 1 or a salt thereof is administered 4 to 7 times every 1 to 3 days (the interval between one administration day and the next administration day is 1 to 3 days) per cycle, and the cycle is repeated once or twice or more; an administration schedule in which one cycle is administered over 14 days, in which compound 1 or a salt thereof is administered on days 1, 4, 8, and 11 of the 14 days in one cycle; an administration schedule in which one cycle is administered over 14 days, in which compound 1 or a salt thereof is administered on days 1, 3, 5, 7, 9, 11, and 13 of the 14 days in one cycle; A dosing schedule of 14 days per cycle, Among these, an administration schedule in which Compound 1 or a salt thereof is administered on the 1st, 3rd, 5th, 8th, 10th and 12th days is exemplified.

[0128] In one embodiment of the present disclosure, the administration schedule includes administering 160 mg of compound 1 or a pharma- ceutically acceptable salt thereof once a day on days 1, 3, 5, 8, 10, and 12. The dose of compound 1 or a salt thereof can be reduced to 120 mg, 80 mg, 56 mg, 36 mg, 24 mg, 16 mg, or 8 mg.

[0129] In the present disclosure, the daily dose on the day of administration of the immune checkpoint inhibitor, from the viewpoint of the enhancing effect of the antitumor effect of the immune checkpoint inhibitor by compound 1 or a salt thereof, is preferably 30 to 100% of the recommended dose when the immune checkpoint inhibitor is administered alone, more preferably 50 to 100%, more preferably 70 to 100%, more preferably 80 to 100%, more preferably 90 to 100%, and even more preferably 100%.

[0130] A preferred dose when an immune checkpoint inhibitor is administered alone varies depending on the type of drug, etc., but examples include 1 to 4 mg / kg (body weight) per dose, 2 to 3 mg / kg (body weight) per dose, 2 mg / kg (body weight) per dose, and 3 mg / kg (body weight) per dose. Specifically, preferred doses of nivolumab when administered alone include 1 to 3 mg / kg (body weight) or 80 to 240 mg, 2 to 3 mg / kg (body weight) or 160 to 240 mg, 2 mg / kg (body weight), 3 mg / kg (body weight), or 240 mg, etc. In another embodiment, preferred doses when nivolumab is administered alone include 80 to 480 mg, 80 mg, 240 mg, or 480 mg. A preferred dose of cemiplimab when administered alone is 350 mg or the like.

[0131] When atezolizumab is administered alone, a preferred dose is 840 to 1680 mg, such as 840, 1200, or 1680 mg.

[0132] A preferred dose of ipilimumab when administered alone is 1.0 to 10 mg / kg (body weight) per administration, such as 1.0, 3.0, or 10 mg / kg (body weight) per administration. When duravalumab is administered alone, a preferred dose is 5.0 to 10 mg / kg (body weight) per administration, 10 mg / kg (body weight) per administration, etc. Preferred doses of avelumab when administered alone include 10 mg / kg (body weight) or 800 mg.

[0133] In the present disclosure, the preferred daily dose of nivolumab on the day of administration is 40 to 480 mg, 80, 240, or 480 mg, etc. The administration interval of nivolumab is preferably every 2 to 4 weeks, more preferably every 2 to 3 weeks, and even more preferably every 2 weeks.

[0134] In addition, in a preferred embodiment, the dosage and administration interval of nivolumab are 80 mg or 240 mg of nivolumab administered four times at three-week intervals, and then from the fifth administration, 240 mg of nivolumab is administered every two weeks. In the present disclosure, the preferred daily dose on the day of administration of cemiplimab is 175 to 350 mg, 350 mg, etc. The administration interval of cemiplimab is preferably every 2 to 4 weeks, more preferably every 2 to 3 weeks, and even more preferably every 2 weeks.

[0135] In the present disclosure, preferred daily doses of atezolizumab on the day of administration include 420 to 1680 mg, 840, 1200, 1680 mg, etc. The administration interval of atezolizumab is preferably every 2 to 4 weeks, more preferably every 2 to 3 weeks, and even more preferably every 3 weeks.

[0136] In the present disclosure, the preferred daily dose of ipilimumab on the day of administration is 0.5 to 10 mg / kg (body weight), 1.0, 3.0, or 10 mg / kg (body weight), etc. The administration interval of ipilimumab is preferably every 2 to 4 weeks, more preferably every 2 to 3 weeks, and even more preferably every 3 weeks.

[0137] In the present disclosure, the preferred daily dose on the day of administration of duravalumab is 5.0 to 10 mg / kg (body weight), 10 mg / kg (body weight), etc. The administration interval of duravalumab is preferably every 2 to 4 weeks, more preferably every 2 to 3 weeks, and even more preferably every 2 weeks.

[0138] In the present disclosure, the preferred daily dose of avelumab on the day of administration is 5.0 to 10 g / kg (body weight), 10 mg / kg (body weight), etc. In another embodiment, the preferred daily dose of avelumab on the day of administration is 400 to 800 mg, 800 mg, etc. The administration interval of avelumab is preferably 2 to 4 weeks, more preferably 2 to 3 weeks, and even more preferably 2 weeks.

[0139] Preferred combinations of the daily dose of Compound 1 or a salt thereof on the day of administration and the daily dose of Nivolumab in the present disclosure, or the method and dose thereof, include the following: Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and nivolumab is administered at a dose of 1 to 4 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and nivolumab is administered at a dose of 1 to 3 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and nivolumab is administered at a dose of 2 to 3 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg and nivolumab is administered at a dose of 1 mg / kg(weight). Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg and nivolumab is administered at a dose of 2 mg / kg(weight). Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg and nivolumab is administered at a dose of 3 mg / kg(weight). Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and nivolumab is administered at a dose of 80 mg to 240 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and nivolumab is administered at a dose of 80 mg to 480 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and nivolumab is administered at a dose of 160 to 480 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and nivolumab is administered at a dose of 80 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and nivolumab is administered at a dose of 240 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and nivolumab is administered at a dose of 480 mg. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg and nivolumab is administered at 1 mg / kg. Two week intervals. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg and nivolumab is administered at 2 mg / kg. Two week intervals. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg and nivolumab is administered at 3 mg / kg. Two week intervals. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg and nivolumab is administered at 1 mg / kg. Every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg and nivolumab is administered at 2 mg / kg. Every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg and nivolumab is administered at 3 mg / kg. Every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg and nivolumab is administered at 1 mg / kg. Every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg and nivolumab is administered at 2 mg / kg. Every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg and nivolumab is administered at 3 mg / kg. Every 4 weeks. Compound 1 of the present disclosure or a salt thereof at 4 mg to 160 mg and nivolumab at 80 mg every 2 weeks. Compound 1 of the present disclosure or a salt thereof at 4 mg to 160 mg and nivolumab at 240 mg every 2 weeks. Compound 1 of the present disclosure or a salt thereof at 4 mg to 160 mg and nivolumab at 480 mg every 2 weeks. Compound 1 of the present disclosure or a salt thereof at 4 mg to 160 mg and nivolumab at 80 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and nivolumab at 240 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and nivolumab at 480 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 4 mg to 160 mg, and nivolumab, 80 mg, every 4 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and nivolumab at 240 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and nivolumab at 480 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg and nivolumab at 80 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg and nivolumab at 240 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg and nivolumab at 80 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 480 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg and nivolumab at 240 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 480 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and nivolumab at 1 to 4 mg / kg (body weight) per dose. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and nivolumab is administered at a dose of 1 to 3 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and nivolumab is administered at a dose of 2 to 3 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 24 mg and nivolumab is administered at 1 mg / kg once. g (weight). Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 24 mg and nivolumab is administered at 2 mg / kg once. g (weight). Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 24 mg and nivolumab is administered at 3 mg / kg once. g (weight). Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and nivolumab is administered at a dose of 80 mg to 240 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and nivolumab is administered at a dose of 80 mg to 480 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and nivolumab is administered at a dose of 160 mg to 480 mg. Compound 1 or a salt thereof according to the present disclosure, 4 mg to 24 mg, and nivolumab, 80 mg each time. Compound 1 or a salt thereof according to the present disclosure, 4 mg to 24 mg, and nivolumab, 240 mg each time. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and nivolumab is administered at a dose of 480 mg. Compound 1 of the present disclosure or a salt thereof at 4 mg to 24 mg and nivolumab at 1 mg / kg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and nivolumab at 2 mg / kg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and nivolumab at 3 mg / kg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and nivolumab at 1 mg / kg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and nivolumab at 2 mg / kg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and nivolumab at 3 mg / kg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and nivolumab at 1 mg / kg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and nivolumab at 2 mg / kg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and nivolumab at 3 mg / kg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and nivolumab at 80 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and nivolumab at 240 mg every 2 weeks. Compound 1 of the present disclosure or a salt thereof at 4 mg to 24 mg and nivolumab at 480 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and nivolumab at 80 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and nivolumab at 240 mg every 3 weeks. Compound 1 of the present disclosure or a salt thereof at 4 mg to 24 mg and nivolumab at 480 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and nivolumab at 80 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is 4 mg to 24 mg, and nivolumab is 240 mg. Weekly interval. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and nivolumab at 480 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 24 mg and nivolumab at 80 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 24 mg and nivolumab at 240 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 24 mg and nivolumab at 80 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 480 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 24 mg and nivolumab at 240 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 480 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 12 to 24 mg and nivolumab is administered in an amount of 1 to 4 mg / dose. kg(weight). Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 12 to 24 mg and nivolumab is administered in an amount of 1 to 3 mg / dose. kg(weight). Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 12 to 24 mg and nivolumab is administered in an amount of 2 to 3 mg / dose. kg(weight). Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 12 to 24 mg and nivolumab is administered in an amount of 1 mg / kg per dose. (body weight). Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 12 to 24 mg and nivolumab is administered in a single dose of 2 mg / kg. (body weight). Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 12 to 24 mg and nivolumab is administered in a single dose of 3 mg / kg. (body weight). Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 12 to 24 mg, and nivolumab is administered in an amount of 80 to 240 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 12 to 24 mg, and nivolumab is administered at a dose of 80 to 480 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 12 to 24 mg, and nivolumab is administered at a dose of 160 to 480 mg. Compound 1 or a salt thereof according to the present disclosure, 12 to 24 mg, and nivolumab, 80 mg per dose. 12 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 240 mg of nivolumab once. 12 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 480 mg of nivolumab once. 12 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 1 mg / kg of nivolumab every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and nivolumab at 2 mg / kg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and nivolumab at 3 mg / kg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and nivolumab at 1 mg / kg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and nivolumab at 2 mg / kg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and nivolumab at 3 mg / kg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and nivolumab at 1 mg / kg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and nivolumab at 2 mg / kg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and nivolumab at 3 mg / kg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and nivolumab at 80 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and nivolumab at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and nivolumab at 480 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and nivolumab at 80 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and nivolumab at 240 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and nivolumab at 480 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and nivolumab at 80 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and nivolumab at 240 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and nivolumab at 480 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 12 to 24 mg and nivolumab at 80 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 12 to 24 mg and nivolumab at 240 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 12 to 24 mg and nivolumab at 80 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 480 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 12 to 24 mg and nivolumab at 240 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 480 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 16 to 24 mg and nivolumab is administered in an amount of 1 to 4 mg / dose. kg(weight). Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 16 to 24 mg and nivolumab is administered in an amount of 1 to 3 mg / dose. kg(weight). Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 16 to 24 mg and nivolumab is administered in an amount of 2 to 3 mg / dose. kg(weight). Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 16 to 24 mg and nivolumab is administered in an amount of 1 mg / kg per dose. (body weight). Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 16 to 24 mg and nivolumab is administered in a single dose of 2 mg / kg. (body weight). Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 16 to 24 mg and nivolumab is administered in a single dose of 3 mg / kg. (body weight). Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 16 to 24 mg, and nivolumab is administered in an amount of 80 to 240 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 16 to 24 mg, and nivolumab is administered in an amount of 80 to 480 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 16 to 24 mg, and nivolumab is administered in an amount of 160 to 480 mg per dose. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and nivolumab, 80 mg per dose. 16 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 240 mg of nivolumab once. 16 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 480 mg of nivolumab once. 16 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 1 mg / kg of nivolumab every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and nivolumab at 2 mg / kg 2 Weekly interval. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and nivolumab at 3 mg / kg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and nivolumab at 1 mg / kg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and nivolumab at 2 mg / kg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and nivolumab at 3 mg / kg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and nivolumab at 1 mg / kg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and nivolumab at 2 mg / kg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and nivolumab at 3 mg / kg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and nivolumab, 80 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and nivolumab, 240 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and nivolumab, 480 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and nivolumab, 80 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and nivolumab, 240 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and nivolumab, 480 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and nivolumab, 80 mg, every 4 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and nivolumab, 240 mg, every 4 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and nivolumab, 480 mg, every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 16 to 24 mg and nivolumab at 80 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 16 to 24 mg and nivolumab at 240 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 16 to 24 mg and nivolumab at 80 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 480 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 16 to 24 mg and nivolumab at 240 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 480 mg every 4 weeks.

[0140] The number of administrations per day, the dosage amount, and the daily dose of nivolumab on the administration day of compound 1 or a salt thereof in the present disclosure, or the combination of administration method and dosage amount, may be as follows: Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day, and nivolumab is administered at 1 to 4 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day, and nivolumab is administered at 1 to 3 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure is administered once a day at 4 mg, and nivolumab is administered once a day at 2 to 3 mg. / kg (body weight). Compound 1 or a salt thereof of the present disclosure is administered once a day at 4 mg, and nivolumab is administered once a day at 1 mg / kg. g (weight). Compound 1 or a salt thereof of the present disclosure is administered once a day at 4 mg, and nivolumab is administered once a day at 2 mg / kg. g (weight). Compound 1 or a salt thereof of the present disclosure is administered once a day at 4 mg, and nivolumab is administered once a day at 3 mg / kg. g (weight). Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day, and nivolumab is administered at 80 to 240 mg once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day, and nivolumab is administered at 80 to 480 mg once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day, and nivolumab is administered at 160 to 480 mg once a day. Compound 1 or a salt thereof according to the present disclosure, 4 mg once a day, and nivolumab, 80 mg once a day. Compound 1 or a salt thereof according to the present disclosure, 4 mg once a day, and nivolumab, 240 mg once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day, and nivolumab is administered at 480 mg once a day. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and nivolumab at 1 mg / kg every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and nivolumab at 2 mg / kg every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and nivolumab at 3 mg / kg every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and nivolumab at 1 mg / kg every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and nivolumab at 2 mg / kg every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and nivolumab at 3 mg / kg every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and nivolumab at 1 mg / kg every 4 weeks. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and nivolumab at 2 mg / kg every 4 weeks. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and nivolumab at 3 mg / kg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure, 4 mg, once daily and nivolumab, 80 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 4 mg once a day and nivolumab, 240 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 4 mg once daily and nivolumab, 480 mg, every 2 weeks. Compound 1 or a salt thereof of the present disclosure, 4 mg once daily and nivolumab, 80 mg, every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and nivolumab at 240 mg every 3 weeks. Compound 1 or a salt thereof of the present disclosure, 4 mg once daily and nivolumab, 480 mg, every 3 weeks. Compound 1 or a salt thereof of the present disclosure, 4 mg once a day and nivolumab, 80 mg, every 4 weeks. Compound 1 or a salt thereof of the present disclosure, 4 mg once daily and nivolumab, 240 mg, every 4 weeks. Compound 1 or a salt thereof of the present disclosure, 4 mg once daily and nivolumab, 480 mg, every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day and nivolumab at 80 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day and nivolumab at 240 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day and nivolumab at 80 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 480 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day and nivolumab at 240 mg every 3 weeks for 4 doses, and then nivolumab at 480 mg every 4 weeks from the 5th dose. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and nivolumab, 1 to 4 mg / kg (body weight), once a day. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and nivolumab, 1 to 3 mg / kg (body weight), once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 8 mg once a day, and nivolumab is administered at 2 to 3 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 8 mg once a day, and nivolumab is administered at 1 mg / kg once a day. g (weight). Compound 1 or a salt thereof of the present disclosure is administered once a day at 8 mg, and nivolumab is administered once a day at 2 mg / kg. g (weight). Compound 1 or a salt thereof of the present disclosure is administered once a day at 8 mg, and nivolumab is administered once a day at 3 mg / kg. g (weight). Compound 1 or a salt thereof according to the present disclosure, 8 mg, and nivolumab, 80 to 240 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and nivolumab, 80 to 480 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and nivolumab, 160 to 480 mg, per day. Compound 1 or a salt thereof in the present disclosure, 8 mg, once a day and nivolumab, 80 mg. Compound 1 or a salt thereof in the present disclosure, 8 mg, once a day and nivolumab, 240 mg. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and nivolumab, 480 mg, once a day. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and nivolumab at 1 mg / kg every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and nivolumab at 2 mg / kg every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and nivolumab at 3 mg / kg every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and nivolumab at 1 mg / kg every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and nivolumab at 2 mg / kg every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and nivolumab at 3 mg / kg every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and nivolumab at 1 mg / kg every 4 weeks. Compound 1 or a salt thereof of the present disclosure is administered once daily at 8 mg and nivolumab is administered at 2 mg / kg. Every 4 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and nivolumab at 3 mg / kg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure, 8 mg, once a day and nivolumab, 80 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 8 mg once daily and nivolumab at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 8 mg once daily and nivolumab at 480 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 8 mg, once daily and nivolumab, 80 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 8 mg once daily and nivolumab at 240 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 8 mg once daily and nivolumab at 480 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 8 mg, once daily and nivolumab, 80 mg, every 4 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and nivolumab at 240 mg every 4 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and nivolumab at 480 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 8 mg once a day and nivolumab at 80 mg every 3 weeks for 4 doses, and then nivolumab is administered at 240 mg every 2 weeks from the 5th dose. Compound 1 or a salt thereof according to the present disclosure is administered at 8 mg once a day and nivolumab at 240 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 8 mg once a day and nivolumab at 80 mg every 3 weeks for 4 doses, and then nivolumab at 480 mg every 4 weeks from the 5th dose. Compound 1 or a salt thereof according to the present disclosure is administered at 8 mg once a day and nivolumab at 240 mg every 3 weeks for 4 doses, and then nivolumab at 480 mg every 4 weeks from the 5th dose. Compound 1 or a salt thereof according to the present disclosure, 12 mg, and nivolumab, 1 to 4 mg / kg (body weight), once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg, and nivolumab, 1 to 3 mg / kg (body weight), once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 12 mg once a day, and nivolumab is administered at 2 to 3 mg / kg (body weight) once a day. Compound 1 or a salt thereof of the present disclosure is administered once a day at 12 mg, and nivolumab is administered once a day at 1 mg / kg. kg(weight). Compound 1 or a salt thereof of the present disclosure is administered once a day at 12 mg / day, and nivolumab is administered once a day at 2 mg / day. kg(weight). Compound 1 or a salt thereof of the present disclosure is administered once a day at 12 mg / day, and nivolumab is administered once a day at 3 mg / day. kg(weight). Compound 1 or a salt thereof according to the present disclosure, 12 mg, and nivolumab, 80 to 240 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg, and nivolumab, 80 to 480 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg, and nivolumab, 160 to 480 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg, and nivolumab, 80 mg, once a day. Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 12 mg, and nivolumab is administered once a day at a dose of 240 mg. g. Compound 1 or a salt thereof according to the present disclosure, 12 mg, and nivolumab, 480 mg, once a day. Compound 1 or a salt thereof of the present disclosure is administered once daily at a dose of 12 mg and nivolumab at a dose of 1 mg / kg. Two week intervals. Compound 1 or a salt thereof of the present disclosure is administered once daily at 12 mg and nivolumab is administered at 2 mg / kg. Two week intervals. Compound 1 or a salt thereof of the present disclosure is administered once daily at 12 mg and nivolumab at 3 mg / kg Two week intervals. Compound 1 or a salt thereof of the present disclosure is administered once daily at a dose of 12 mg and nivolumab at a dose of 1 mg / kg. Every 3 weeks. Compound 1 or a salt thereof of the present disclosure is administered once daily at 12 mg and nivolumab is administered at 2 mg / kg. Every 3 weeks. Compound 1 or a salt thereof of the present disclosure is administered once daily at 12 mg and nivolumab at 3 mg / kg Every 3 weeks. Compound 1 or a salt thereof of the present disclosure is administered once daily at a dose of 12 mg and nivolumab at a dose of 1 mg / kg. Every 4 weeks. Compound 1 or a salt thereof of the present disclosure is administered once daily at 12 mg and nivolumab is administered at 2 mg / kg. Every 4 weeks. Compound 1 or a salt thereof of the present disclosure is administered once daily at 12 mg and nivolumab at 3 mg / kg Every 4 weeks. Compound 1 or a salt thereof of the present disclosure, 12 mg once daily and nivolumab, 80 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 12 mg once daily and nivolumab, 240 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 12 mg once daily and nivolumab, 480 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 12 mg once daily and nivolumab, 80 mg, every 3 weeks. Compound 1 or a salt thereof of the present disclosure, 12 mg once daily and nivolumab, 240 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 12 mg once daily and nivolumab, 480 mg, every 3 weeks. Compound 1 or a salt thereof of the present disclosure, 12 mg once daily and nivolumab, 80 mg, every 4 weeks. Compound 1 or a salt thereof of the present disclosure, 12 mg once daily and nivolumab, 240 mg, every 4 weeks. Compound 1 or a salt thereof according to the present disclosure, 12 mg once daily and nivolumab, 480 mg, every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered once a day at 12 mg, and nivolumab is administered at 80 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered once a day at 12 mg, and nivolumab is administered at 240 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered once a day at 12 mg, and nivolumab is administered at 80 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 480 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered once a day at 12 mg, and nivolumab is administered at 240 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 480 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 mg, and nivolumab, 1 to 4 mg / kg (body weight), once a day. Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 16 mg, and nivolumab is administered once a day at a dose of 1 to 3 mg. g / kg (body weight). Compound 1 or a salt thereof according to the present disclosure is administered at 16 mg once a day, and nivolumab is administered at 2 to 3 mg / kg (body weight) once a day. Compound 1 or a salt thereof of the present disclosure is administered once a day at 16 mg, and nivolumab is administered once a day at 1 mg / kg. kg(weight). Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 16 mg, and nivolumab is administered once a day at a dose of 2 mg / kg. kg(weight). Compound 1 or a salt thereof of the present disclosure is administered once a day at 16 mg / day, and nivolumab is administered once a day at 3 mg / day. kg(weight). Compound 1 or a salt thereof according to the present disclosure, 16 mg, and nivolumab, 80 to 240 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 16 mg, and nivolumab, 80 to 480 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 16 mg, and nivolumab, 160 to 480 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 16 mg, and nivolumab, 80 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 16 mg, and nivolumab, 240 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 16 mg, and nivolumab, 480 mg, once a day. Compound 1 or a salt thereof of the present disclosure is administered once daily at a dose of 16 mg and nivolumab at a dose of 1 mg / kg. Two week intervals. Compound 1 or a salt thereof of the present disclosure is administered once daily at a dose of 16 mg and nivolumab at a dose of 2 mg / kg. Two week intervals. Compound 1 or a salt thereof of the present disclosure is administered once daily at a dose of 16 mg and nivolumab at a dose of 3 mg / kg. Two week intervals. Compound 1 or a salt thereof of the present disclosure is administered once daily at a dose of 16 mg and nivolumab at a dose of 1 mg / kg. Every 3 weeks. Compound 1 or a salt thereof of the present disclosure is administered once daily at a dose of 16 mg and nivolumab at a dose of 2 mg / kg. Every 3 weeks. Compound 1 or a salt thereof of the present disclosure is administered once daily at a dose of 16 mg and nivolumab at a dose of 3 mg / kg. Every 3 weeks. Compound 1 or a salt thereof of the present disclosure is administered once daily at a dose of 16 mg and nivolumab at a dose of 1 mg / kg. Every 4 weeks. Compound 1 or a salt thereof of the present disclosure is administered once daily at a dose of 16 mg and nivolumab at a dose of 2 mg / kg. Every 4 weeks. Compound 1 or a salt thereof of the present disclosure is administered once daily at a dose of 16 mg and nivolumab at a dose of 3 mg / kg. Every 4 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 mg once daily and nivolumab, 80 mg, every 2 weeks. Compound 1 or a salt thereof of the present disclosure, 16 mg once daily and nivolumab, 240 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 mg once daily and nivolumab, 480 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 mg once daily and nivolumab, 80 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 mg once daily and nivolumab, 240 mg, every 3 weeks. Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 16 mg and nivolumab at a dose of 480 mg. Every 3 weeks. Compound 1 or a salt thereof of the present disclosure, 16 mg once daily and nivolumab, 80 mg, every 4 weeks. Compound 1 or a salt thereof of the present disclosure, 16 mg once daily and nivolumab, 240 mg, every 4 weeks. Compound 1 or a salt thereof of the present disclosure, 16 mg once daily and nivolumab, 480 mg, every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered once a day at 16 mg, and nivolumab is administered at 80 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered once a day at 16 mg, and nivolumab is administered at 240 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered once a day at 16 mg, and nivolumab is administered at 80 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 480 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered once a day at 16 mg, and nivolumab is administered at 240 mg every 3 weeks for 4 doses, followed by nivolumab at 480 mg every 4 weeks from the 5th dose. Compound 1 or a salt thereof according to the present disclosure, 20 mg, and nivolumab, 1 to 4 mg / kg (body weight), once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg, and nivolumab, 1 to 3 mg / kg (body weight), once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg, and nivolumab, 2 to 3 mg / kg (body weight), once a day. Compound 1 or a salt thereof of the present disclosure is administered once a day at 20 mg, and nivolumab is administered once a day at 1 mg / kg. kg(weight). Compound 1 or a salt thereof of the present disclosure is administered once a day at 20 mg, and nivolumab is administered once a day at 2 mg / kg. kg(weight). Compound 1 or a salt thereof of the present disclosure is administered once a day at 20 mg, and nivolumab is administered once a day at 3 mg / kg. kg(weight). Compound 1 or a salt thereof according to the present disclosure, 20 mg, and nivolumab, 80 to 240 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg, and nivolumab, 80 to 480 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg, and nivolumab, 160 to 480 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg, and nivolumab, 80 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg, and nivolumab, 240 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg, and nivolumab, 480 mg, once a day. Compound 1 or a salt thereof of the present disclosure is administered once daily at 20 mg and nivolumab at 1 mg / kg Two week intervals. Compound 1 or a salt thereof of the present disclosure is administered once daily at 20 mg and nivolumab is administered at 2 mg / kg. Two week intervals. Compound 1 or a salt thereof of the present disclosure is administered once daily at 20 mg and nivolumab at 3 mg / kg. Two week intervals. Compound 1 or a salt thereof of the present disclosure is administered once daily at 20 mg and nivolumab at 1 mg / kg Every 3 weeks. Compound 1 or a salt thereof of the present disclosure is administered once daily at 20 mg and nivolumab is administered at 2 mg / kg. Every 3 weeks. Compound 1 or a salt thereof of the present disclosure is administered once daily at 20 mg and nivolumab at 3 mg / kg. Every 3 weeks. Compound 1 or a salt thereof of the present disclosure is administered once daily at 20 mg and nivolumab at 1 mg / kg Every 4 weeks. Compound 1 or a salt thereof of the present disclosure is administered once daily at 20 mg and nivolumab is administered at 2 mg / kg. Every 4 weeks. Compound 1 or a salt thereof of the present disclosure is administered once daily at 20 mg and nivolumab at 3 mg / kg. Every 4 weeks. Compound 1 or a salt thereof according to the present disclosure, 20 mg once a day and nivolumab, 80 mg, every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 20 mg once daily and nivolumab at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 20 mg once daily and nivolumab, 480 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 20 mg once a day and nivolumab, 80 mg, every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 20 mg once daily and nivolumab at 240 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 20 mg once daily and nivolumab at 480 mg every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 20 mg once daily and nivolumab at 80 mg every 4 weeks. Compound 1 or a salt thereof of the present disclosure at 20 mg once daily and nivolumab at 240 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure, 20 mg once daily and nivolumab, 480 mg, every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 20 mg once a day and nivolumab at 80 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 20 mg once a day and nivolumab at 240 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 240 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 20 mg once a day and nivolumab at 80 mg every 3 weeks for 4 doses, and then from the 5th dose onwards, nivolumab is administered at 480 mg every 4 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 20 mg once a day and nivolumab at 240 mg every 3 weeks for 4 doses, and then nivolumab at 480 mg every 4 weeks from the 5th dose.

[0141] Preferred combinations of the daily dose of Compound 1 or a salt thereof on the day of administration and the daily dose of atezolizumab, or the method of administration and the dose, in the present disclosure, include the following: Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and atezolizumab is administered at a dose of 420 to 1680 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a rate of 4 mg to 160 mg, and atezolizumab is administered at a rate of 840 mg to 1680 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and atezolizumab is administered at a dose of 840 mg. Compound 1 of the present disclosure or a salt thereof is administered at a dose of 4 mg to 160 mg, and atezolizumab is administered at a dose of 1200 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and atezolizumab is administered at a dose of 1680 mg. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and atezolizumab at 840 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is added in an amount of 4 mg to 160 mg, and atezolizumab is added in an amount of 1200 mg to 160 mg. mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and atezolizumab at 1680 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and atezolizumab at 840 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and atezolizumab at 1200 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and atezolizumab at 1680 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and atezolizumab is administered at a dose of 420 to 1680 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and atezolizumab is administered at a dose of 840 to 1680 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and atezolizumab is administered at a dose of 840 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and atezolizumab is administered at a dose of 1200 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and atezolizumab is administered at a dose of 1680 mg. Compound 1 or a salt thereof according to the present disclosure is 4 mg to 24 mg, and atezolizumab is 840 mg. Two week intervals. Compound 1 of the present disclosure or a salt thereof at 4 mg to 24 mg and atezolizumab at 1200 mg every 2 weeks. Compound 1 of the present disclosure or a salt thereof at 4 mg to 24 mg and atezolizumab at 1680 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is 4 mg to 24 mg, and atezolizumab is 840 mg. Every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and atezolizumab at 1200 mg every 3 weeks. Compound 1 of the present disclosure or a salt thereof at 4 mg to 24 mg and atezolizumab at 1680 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 12 to 24 mg, and atezolizumab is administered in an amount of 420 to 1680 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 12 to 24 mg, and atezolizumab is administered in an amount of 840 to 1680 mg per dose. Compound 1 or a salt thereof according to the present disclosure, 12 to 24 mg, and atezolizumab, 840 mg per dose. Compound 1 or a salt thereof according to the present disclosure, 12 to 24 mg, and atezolizumab, 1200 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 12 to 24 mg, and atezolizumab is administered at a dose of 1680 mg. Compound 1 or a salt thereof according to the present disclosure, 12 to 24 mg, and atezolizumab, 840 mg, every 2 weeks. 12 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 1200 mg of atezolizumab Two week intervals. 12 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 1680 mg of atezolizumab Two week intervals. Compound 1 or a salt thereof according to the present disclosure, 12 to 24 mg, and atezolizumab, 840 mg, every 3 weeks. 12 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 1200 mg of atezolizumab Every 3 weeks. 12 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 1680 mg of atezolizumab Every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 16 to 24 mg, and atezolizumab is administered in an amount of 420 to 1680 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 16 to 24 mg, and atezolizumab is administered in an amount of 840 to 1680 mg per dose. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and atezolizumab, 840 mg per dose. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and atezolizumab, 1200 mg per dose. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and atezolizumab, 1680 mg per dose. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and atezolizumab, 840 mg, every 2 weeks. 16 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 1200 mg of atezolizumab Two week intervals. Compound 1 or a salt thereof according to the present disclosure is 16 to 24 mg, and atezolizumab is 1680 mg. Two week intervals. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and atezolizumab, 840 mg, every 3 weeks. 16 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 1200 mg of atezolizumab Every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is 16 to 24 mg, and atezolizumab is 1680 mg. Every 3 weeks.

[0142] The number of administrations per day, the dosage amount, and the daily dose of atezolizumab on the administration day of compound 1 or a salt thereof in the present disclosure, or the combination of administration method and dosage amount, may be as follows: Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day, and atezolizumab is administered at 420 to 1680 mg once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day, and atezolizumab is administered at 840 to 1680 mg once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day, and atezolizumab is administered at 840 mg once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day, and atezolizumab is administered at 1200 mg once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day, and atezolizumab is administered at 1680 mg once a day. Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 4 mg and atezolizumab at a dose of 840 mg. Two week intervals. Compound 1 or a salt thereof according to the present disclosure, 4 mg, once a day and atezolizumab, 1200 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 4 mg once daily and atezolizumab, 1680 mg, every 2 weeks. Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 4 mg and atezolizumab at a dose of 840 mg. Every 3 weeks. Compound 1 or a salt thereof of the present disclosure, 4 mg once a day and atezolizumab, 1200 mg, every 3 weeks. Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 4 mg and atezolizumab at a dose of 1680 mg. g 3 weeks apart. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and atezolizumab, 420 to 1680 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and atezolizumab, 840 to 1680 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and atezolizumab, 840 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and atezolizumab, 1200 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and atezolizumab, 1680 mg, once a day. Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 8 mg and atezolizumab at a dose of 840 mg. Two week intervals. Compound 1 or a salt thereof according to the present disclosure at 8 mg once a day and atezolizumab at 1200 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 8 mg once a day and atezolizumab at 1680 mg every 2 weeks. Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 8 mg and atezolizumab at a dose of 840 mg. Every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 8 mg once a day and atezolizumab at 1200 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 8 mg once a day and atezolizumab at 1680 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 12 mg, and atezolizumab, 420 to 1680 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg, and atezolizumab, 840 to 1680 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg, and atezolizumab, 840 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg, and atezolizumab, 1200 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg, and atezolizumab, 1680 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg once daily and atezolizumab, 840 mg, every 2 weeks. Compound 1 or a salt thereof of the present disclosure, 12 mg once a day and atezolizumab, 1200 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 12 mg once daily and atezolizumab, 1680 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 12 mg once daily and atezolizumab, 840 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 12 mg once a day and atezolizumab, 1200 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 12 mg once daily and atezolizumab, 1680 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 mg, and atezolizumab, 420 to 1680 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 16 mg, and atezolizumab, 840 to 1680 mg, once a day. Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 16 mg and atezolizumab is administered once a day at a dose of 84 mg. 0mg. Compound 1 or a salt thereof according to the present disclosure, 16 mg, and atezolizumab, 1200 mg, once a day. Compound 1 or a salt thereof of the present disclosure, 16 mg, and atezolizumab, 1680 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 16 mg once daily and atezolizumab, 840 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 mg once a day and atezolizumab, 1200 mg, every 2 weeks. Compound 1 or a salt thereof of the present disclosure, 16 mg once a day and atezolizumab, 1680 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 mg once daily and atezolizumab, 840 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 mg once a day and atezolizumab, 1200 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 mg once daily and atezolizumab, 1680 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 20 mg, and atezolizumab, 420 to 1680 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg once a day, and atezolizumab, 840 to 1680 mg once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg, and atezolizumab, 840 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg once a day, and atezolizumab, 1200 mg once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg, and atezolizumab, 1680 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg once daily and atezolizumab, 840 mg, every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 20 mg once a day and atezolizumab at 1200 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 20 mg once a day and atezolizumab, 1680 mg, every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 20 mg once daily and atezolizumab at 840 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 20 mg once a day and atezolizumab, 1200 mg, every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 20 mg once daily and atezolizumab at 1680 mg every 3 weeks.

[0143] Preferred combinations of the daily dose of Compound 1 or a salt thereof on the day of administration and the daily dose of ipilimumab, or the method and dose, of the present disclosure include the following: Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg, and ipilimumab is administered at 0.5 to 10 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and ipilimumab is administered at a dose of 1.0 to 10 mg / kg (body weight) per administration. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg, and ipilimumab is administered at 1.0 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg and ipilimumab at a dose of 3.0 mg per dose. mg / kg (body weight). Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg, and ipilimumab is administered at 10 mg / kg (body weight) once. Compound 1 of the present disclosure or a salt thereof at 4 mg to 160 mg and ipilimumab at 1.0 mg / kg (body weight) every 2 weeks. Compound 1 of the present disclosure or a salt thereof at 4 mg to 160 mg and ipilimumab at 1.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and ipilimumab at 3.0 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and ipilimumab at 3.0 mg / kg (body weight) every 3 weeks. Compound 1 of the present disclosure or a salt thereof at 4 mg to 160 mg and ipilimumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and ipilimumab at 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and ipilimumab is administered at a dose of 0.5 to 10 mg / kg (body weight) Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and ipilimumab is administered at a dose of 1.0 to 10 mg / kg (body weight) per administration. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 24 mg, and ipilimumab is administered at 1.0 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and ipilimumab at 3.0 mg / kg (body weight) per dose. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 24 mg, and ipilimumab is administered at 10 mg / kg (body weight) once. Compound 1 of the present disclosure or a salt thereof at 4 mg to 24 mg and ipilimumab at 1.0 mg / kg (body weight) every 2 weeks. Compound 1 of the present disclosure or a salt thereof at 4 mg to 24 mg and ipilimumab at 1.0 mg / kg (body weight) every 3 weeks. Compound 1 of the present disclosure or a salt thereof at 4 mg to 24 mg and ipilimumab at 3.0 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and ipilimumab at 3.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and ipilimumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and ipilimumab at 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 12 to 24 mg and ipilimumab is administered in an amount of 0.5 to 10 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 12 to 24 mg, and ipilimumab is administered at a dose of 1.0 to 10 mg / kg (body weight) per administration. Compound 1 or a salt thereof according to the present disclosure, 12 to 24 mg, and ipilimumab, 1.0 mg / kg (body weight) per dose. Compound 1 or a salt thereof according to the present disclosure, 12 to 24 mg, and ipilimumab, 3.0 mg / kg (body weight) per dose. Compound 1 or a salt thereof according to the present disclosure, 12 to 24 mg, and ipilimumab, 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and ipilimumab at 1.0 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 12 to 24 mg and ipilimumab is administered in an amount of 1.0 mg / kg. g (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and ipilimumab at 3.0 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and ipilimumab at 3.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and ipilimumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and ipilimumab at 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 16 to 24 mg and ipilimumab is administered in an amount of 0.5 to 10 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 16 to 24 mg, and ipilimumab is administered at a dose of 1.0 to 10 mg / kg (body weight) per administration. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and ipilimumab, 1.0 mg / kg (body weight) per dose. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and ipilimumab, 3.0 mg / kg (body weight) per dose. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and ipilimumab, 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and ipilimumab at 1.0 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and ipilimumab at 1.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and ipilimumab at 3.0 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and ipilimumab at 3.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and ipilimumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and ipilimumab at 10 mg / kg (body weight) every 3 weeks.

[0144] The number of administrations per day, the dosage amount, and the daily dose of ipilimumab on the administration day of Compound 1 or a salt thereof in the present disclosure, or the combination of administration method and dosage amount, may be as follows: Compound 1 or a salt thereof according to the present disclosure is administered once a day at 4 mg, and ipilimumab is administered once a day at 0.5 to 10 mg / kg (body weight). Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day, and ipilimumab is administered at 1.0 to 10 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure, 4 mg, and ipilimumab, 1.0 mg / kg (body weight), once a day. Compound 1 or a salt thereof according to the present disclosure, 4 mg, and ipilimumab, 3.0 mg / kg (body weight), once a day. Compound 1 or a salt thereof according to the present disclosure, 4 mg, and ipilimumab, 10 mg / kg (body weight), once a day. Compound 1 or a salt thereof of the present disclosure at 4 mg once a day and ipilimumab at 1.0 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and ipilimumab at 1.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 4 mg and ipilimumab at a dose of 3.0 mg / kg. kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and ipilimumab at 3.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 4 mg once a day and ipilimumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 4 mg once a day and ipilimumab at 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered once a day at 8 mg, and ipilimumab is administered once a day at 0.5 to 10 mg / kg (body weight). Compound 1 or a salt thereof according to the present disclosure is administered at 8 mg once a day, and ipilimumab is administered at 1.0 to 10 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and ipilimumab, 1.0 mg / kg (body weight), once a day. Compound 1 or a salt thereof according to the present disclosure at 8 mg once a day and ipilimumab at 3.0 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure at 8 mg once a day and ipilimumab at 10 mg / kg (body weight) once a day. Compound 1 or a salt thereof of the present disclosure at 8 mg once a day and ipilimumab at 1.0 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and ipilimumab at 1.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once a day and ipilimumab at 3.0 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and ipilimumab at 3.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once a day and ipilimumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once a day and ipilimumab at 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered once a day at 12 mg, and ipilimumab is administered once a day at 0.5 to 10 mg / kg (body weight). Compound 1 or a salt thereof according to the present disclosure is administered at 12 mg once a day, and ipilimumab is administered at 1.0 to 10 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg, once a day, and ipilimumab, 1.0 mg / kg (body weight), once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg, once a day, and ipilimumab, 3.0 mg / kg (body weight), once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg, once a day, and ipilimumab, 10 mg / kg (body weight), once a day. Compound 1 or a salt thereof of the present disclosure, 12 mg once daily and ipilimumab, 1.0 mg / kg (body weight), every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 12 mg once daily and ipilimumab at 1.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 12 mg once daily and ipilimumab at 3.0 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 12 mg once daily and ipilimumab at 3.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 12 mg once a day and ipilimumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 12 mg and ipilimumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered once a day at a dose of 16 mg, and ipilimumab is administered once a day at a dose of 0.5 to 10 mg / kg (body weight). Compound 1 or a salt thereof according to the present disclosure is administered at 16 mg once a day, and ipilimumab is administered at 1.0 to 10 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure, 16 mg, once a day, and ipilimumab, 1.0 mg / kg (body weight), once a day. Compound 1 or a salt thereof according to the present disclosure, 16 mg, and ipilimumab, 3.0 mg / kg (body weight), once a day. Compound 1 or a salt thereof according to the present disclosure, 16 mg, once a day, and ipilimumab, 10 mg / kg (body weight), once a day. Compound 1 or a salt thereof of the present disclosure, 16 mg once daily and ipilimumab, 1.0 mg / kg (body weight), every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 16 mg once daily and ipilimumab at 1.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 16 mg once daily and ipilimumab at 3.0 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 16 mg once daily and ipilimumab at 3.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof of the present disclosure, 16 mg once a day and ipilimumab, 10 mg / kg (body weight), every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 16 mg once a day and ipilimumab at 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered once a day at 20 mg, and ipilimumab is administered once a day at 0.5 to 10 mg / kg (body weight). Compound 1 or a salt thereof according to the present disclosure is administered at 20 mg once a day, and ipilimumab is administered at 1.0 to 10 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg once a day, and ipilimumab, 1.0 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg once a day, and ipilimumab, 3.0 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg once a day, and ipilimumab, 10 mg / kg (body weight) once a day. Compound 1 or a salt thereof of the present disclosure at 20 mg once daily and ipilimumab at 1.0 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 20 mg once daily and ipilimumab at 1.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 20 mg once a day and ipilimumab at 3.0 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 20 mg once daily and ipilimumab at 3.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 20 mg once a day and ipilimumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 20 mg once a day and ipilimumab at 10 mg / kg (body weight) every 3 weeks.

[0145] Preferred combinations of the daily dose of Compound 1 or a salt thereof on the day of administration and the daily dose of duravalumab, or the method and dosage thereof, according to the present disclosure include the following: Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg and duravalumab is administered at a dose of 5. 0~10mg / kg (body weight). Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and duravalumab is administered at a dose of 10 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and duravalumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and duravalumab at 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and duravalumab is administered at a dose of 5.0 to 10 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and duravalumab is administered at a dose of 10 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and duravalumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and duravalumab at 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 12 to 24 mg, and duravalumab is administered at a dose of 5.0 to 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof according to the present disclosure, 12 to 24 mg, and duravalumab, 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and duravalumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and duravalumab at 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 16 to 24 mg, and duravalumab is administered at a dose of 5.0 to 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and duravalumab, 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and duravalumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and duravalumab at 10 mg / kg (body weight) every 3 weeks.

[0146] The number of administrations per day, the dosage amount, and the daily dose of duravalumab on the administration day of compound 1 or a salt thereof in the present disclosure, or the combination of administration method and dosage amount, include the following: Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day, and duravalumab is administered at 5.0 to 10 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure, 4 mg, and duravalumab, 10 mg / kg (body weight), once a day. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and duravalumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and duravalumab at 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 8 mg once a day, and duravalumab is administered at 5.0 to 10 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and duravalumab, 10 mg / kg (body weight), once a day. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and duravalumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure is administered once a day at 8 mg and duravalumab is administered once a day at 10 mg / kg. kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 12 mg once a day, and duravalumab is administered at 5.0 to 10 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg, once a day, and duravalumab, 10 mg / kg (body weight), once a day. Compound 1 or a salt thereof of the present disclosure, 12 mg once daily and duravalumab, 10 mg / kg (body weight), every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 12 mg once daily and duravalumab at 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at 16 mg once a day, and duravalumab is administered at 5.0 to 10 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure, 16 mg, once a day, and duravalumab, 10 mg / kg (body weight), once a day. Compound 1 or a salt thereof of the present disclosure, 16 mg once daily and duravalumab, 10 mg / kg (body weight), every 2 weeks. Compound 1 or a salt thereof of the present disclosure, 16 mg once daily and duravalumab, 10 mg / kg (body weight), every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 20 mg, and duravalumab, 5.0 to 10 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg once a day, and duravalumab, 10 mg / kg (body weight) once a day. Compound 1 or a salt thereof of the present disclosure at 20 mg once daily and duravalumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 20 mg once daily and duravalumab at 10 mg / kg (body weight) every 3 weeks.

[0147] Preferred combinations of the daily dose of compound 1 or a salt thereof on the day of administration and the daily dose of avelumab, or the method and dosage thereof, according to the present disclosure include the following: Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and avelumab is administered at a dose of 5.0 to 10 g / kg (body weight) Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg, and avelumab is administered at 10 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and avelumab is administered at a dose of 400 mg to 800 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and avelumab is administered at a dose of 800 mg. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and avelumab at 800 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and avelumab at 800 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and avelumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and avelumab at 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and avelumab is administered at a dose of 5.0 to 10 g / kg (body weight) Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 24 mg, and avelumab is administered at 10 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 4 mg to 24 mg and avelumab is administered in an amount of 400 to 800 mg. 00mg. 4 mg to 24 mg of compound 1 or a salt thereof according to the present disclosure and 800 mg of avelumab per dose. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and avelumab at 800 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and avelumab at 800 mg every 3 weeks. Compound 1 of the present disclosure or a salt thereof at 4 mg to 24 mg and avelumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and avelumab at 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 12 to 24 mg, and avelumab is administered in an amount of 5.0 to 10 g / kg (body weight) per dose. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 12 to 24 mg, and avelumab is administered at a dose of 10 mg / kg (body weight) 12 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 400 to 800 mg of avelumab per dose. 12 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 800 mg of avelumab once. 12 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 800 mg of avelumab every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 12 to 24 mg, and avelumab, 800 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and avelumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 12 to 24 mg and avelumab at 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 16 to 24 mg, and avelumab is administered in an amount of 5.0 to 10 g / kg (body weight) per dose. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 16 to 24 mg and avelumab is administered in an amount of 10 mg / kg (body weight) once. 16 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 400 to 800 mg of avelumab per dose. 16 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 800 mg of avelumab once. 16 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 800 mg of avelumab every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and avelumab, 800 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and avelumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 16 to 24 mg and avelumab at 10 mg / kg (body weight) every 3 weeks.

[0148] The number of administrations per day, the dosage amount, and the daily dose of avelumab on the administration day of compound 1 or a salt thereof in the present disclosure, or the combination of administration method and dosage amount, may be as follows: Compound 1 or a salt thereof of the present disclosure is administered once a day at 4 mg, and avelumab is administered once a day at 5.0 to 10 g / kg (body weight). Compound 1 or a salt thereof of the present disclosure is administered once a day at 4 mg, and avelumab is administered once a day at 10 mg / kg (body weight). Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 4 mg, and avelumab is administered once a day at a dose of 400 to 800 mg. 00mg. Compound 1 or a salt thereof of the present disclosure is administered at 4 mg once a day, and avelumab is administered at 800 mg once a day. Compound 1 or a salt thereof of the present disclosure, 4 mg once daily and avelumab, 800 mg, every 2 weeks. Compound 1 or a salt thereof of the present disclosure, 4 mg once daily and avelumab, 800 mg, every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and avelumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and avelumab at 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof of the present disclosure is administered once a day at 8 mg, and avelumab is administered once a day at 5.0 to 10 g / kg (body weight). Compound 1 or a salt thereof of the present disclosure is administered once a day at 8 mg, and avelumab is administered once a day at 10 mg / kg (body weight). Compound 1 or a salt thereof according to the present disclosure, 8 mg, and avelumab, 400 to 800 mg, once a day. Compound 1 or a salt thereof of the present disclosure, 8 mg, and avelumab, 800 mg, once a day. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and avelumab at 800 mg every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and avelumab at 800 mg every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and avelumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and avelumab at 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof of the present disclosure is administered once a day at 12 mg, and avelumab is administered once a day at 5.0 to 10 g / kg (body weight). Compound 1 or a salt thereof of the present disclosure is administered once a day at 12 mg, and avelumab is administered once a day at 10 mg / kg (body weight). Compound 1 or a salt thereof according to the present disclosure, 12 mg, and avelumab, 400 to 800 mg, once a day. Compound 1 or a salt thereof of the present disclosure, 12 mg, and avelumab, 800 mg, once a day. Compound 1 or a salt thereof of the present disclosure, 12 mg once daily and avelumab, 800 mg, every 2 weeks. Compound 1 or a salt thereof of the present disclosure, 12 mg once daily and avelumab, 800 mg, every 3 weeks. Compound 1 or a salt thereof of the present disclosure, 12 mg once daily and avelumab, 10 mg / kg (body weight), every 2 weeks. Compound 1 or a salt thereof of the present disclosure, 12 mg once daily and avelumab, 10 mg / kg (body weight), every 3 weeks. Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 16 mg, and avelumab is administered once a day at a dose of 5.0 to 10 g / kg (body weight). Compound 1 or a salt thereof of the present disclosure is administered once a day at 16 mg, and avelumab is administered once a day at 10 mg / kg (body weight). Compound 1 or a salt thereof according to the present disclosure, 16 mg, and avelumab, 400 to 800 mg, once a day. Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 16 mg, and avelumab is administered once a day at a dose of 800 mg. g. Compound 1 or a salt thereof of the present disclosure, 16 mg once daily and avelumab, 800 mg, every 2 weeks. Compound 1 or a salt thereof of the present disclosure, 16 mg once daily and avelumab, 800 mg, every 3 weeks. Compound 1 or a salt thereof of the present disclosure, 16 mg once daily and avelumab, 10 mg / kg (body weight), every 2 weeks. Compound 1 or a salt thereof of the present disclosure, 16 mg once daily and avelumab, 10 mg / kg (body weight), every 3 weeks. Compound 1 or a salt thereof of the present disclosure is administered once a day at 20 mg, and avelumab is administered once a day at 5.0 to 10 g / kg (body weight). Compound 1 or a salt thereof of the present disclosure is administered once a day at 20 mg, and avelumab is administered once a day at 10 mg / kg (body weight). Compound 1 or a salt thereof according to the present disclosure, 20 mg, and avelumab, 400 to 800 mg, once a day. Compound 1 or a salt thereof of the present disclosure, 20 mg once a day, and avelumab, 800 mg once a day. Compound 1 or a salt thereof of the present disclosure at 20 mg once daily and avelumab at 800 mg every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 20 mg once daily and avelumab at 800 mg every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 20 mg once daily and avelumab at 10 mg / kg (body weight) every 2 weeks. Compound 1 or a salt thereof of the present disclosure at 20 mg once daily and avelumab at 10 mg / kg (body weight) every 3 weeks.

[0149] Preferred combinations of the daily dose of Compound 1 or a salt thereof on the day of administration and the daily dose of cemiplimab in the present disclosure, or the method and dose thereof, include the following: Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and cemiplimab is administered at a dose of 175 mg to 350 mg. Compound 1 of the present disclosure or a salt thereof is administered at a dose of 4 mg to 160 mg, and cemiplimab is administered at a dose of 350 mg. Compound 1 or a salt thereof according to the present disclosure is 4 mg to 160 mg, and cemiplimab is 350 mg. Two week intervals. Compound 1 or a salt thereof according to the present disclosure is 4 mg to 160 mg, and cemiplimab is 350 mg. Every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and cemiplimab is administered at a dose of 175 mg to 350 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and cemiplimab is administered at a dose of 350 mg. Compound 1 of the present disclosure or a salt thereof at 4 mg to 24 mg and cemiplimab at 350 mg every 2 weeks. Compound 1 of the present disclosure or a salt thereof at 4 mg to 24 mg and cemiplimab at 350 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 12 to 24 mg, and cemiplimab is administered in an amount of 175 to 350 mg per dose. Compound 1 or a salt thereof according to the present disclosure, 12 to 24 mg, and cemiplimab, 350 mg per dose. 12 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 350 mg of cemiplimab Weekly interval. Compound 1 of the present disclosure or a salt thereof, 12 to 24 mg, and cemiplimab, 350 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 16 to 24 mg, and cemiplimab is administered in an amount of 175 to 350 mg per dose. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and cemiplimab, 350 mg per dose. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and cemiplimab, 350 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and cemiplimab, 350 mg, every 3 weeks.

[0150] The number of administrations per day, the dosage amount, and the daily dose of cemiplimab on the administration day of compound 1 or a salt thereof in the present disclosure, or the combination of administration method and dosage amount, may be as follows: Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day, and cemiplimab is administered at 175 to 350 mg once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day, and cemiplimab is administered at 350 mg once a day. Compound 1 or a salt thereof according to the present disclosure, 4 mg once a day and cemiplimab, 350 mg, every 2 weeks. Compound 1 or a salt thereof according to the present disclosure, 4 mg once a day and cemiplimab, 350 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and cemiplimab, 175 to 350 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and cemiplimab, 350 mg, once a day. Compound 1 or a salt thereof according to the present disclosure at 8 mg once a day and cemiplimab at 350 mg every 2 weeks. Compound 1 or a salt thereof according to the present disclosure at 8 mg once a day and cemiplimab at 350 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 12 mg, and cemiplimab, 175 to 350 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg, and cemiplimab, 350 mg, once a day. Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 12 mg and cemiplimab at a dose of 350 mg. Two week intervals. Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 12 mg and cemiplimab at a dose of 350 mg. Every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 mg, and cemiplimab, 175 to 350 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 16 mg, and cemiplimab, 350 mg, once a day. Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 16 mg and cemiplimab at a dose of 350 mg. Two week intervals. Compound 1 or a salt thereof of the present disclosure is administered once a day at a dose of 16 mg and cemiplimab at a dose of 350 mg. Every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 20 mg, and cemiplimab, 175 to 350 mg, once a day. Compound 1 or a salt thereof of the present disclosure is administered once a day at 20 mg, and cemiplimab is administered once a day at 350 mg. mg. Compound 1 or a salt thereof of the present disclosure is administered once a day at 20 mg and cemiplimab at 350 mg. Two week intervals. Compound 1 or a salt thereof of the present disclosure is administered once a day at 20 mg and cemiplimab at 350 mg. Every 3 weeks.

[0151] The ratio of compound 1 or a salt thereof to the immune checkpoint inhibitor used in the present disclosure is not particularly limited, but preferably, the immune checkpoint inhibitor can be set in the range of 10 to 10,000 parts by mass, more preferably 100 to 1,000 parts by mass, per 100 parts by mass of compound 1 or a salt thereof.

[0152] In the present disclosure, the blending ratio of compound 1 or a salt thereof in a dosage form containing compound 1 or a salt thereof is not particularly limited, but can be appropriately set, for example, in the range of 100 to 100000 mass%, preferably 1000 to 10000 mass%. In the present disclosure, the blending ratio of the immune checkpoint inhibitor in a dosage form containing an immune checkpoint inhibitor is not particularly limited, but can be appropriately set, for example, in the range of 100 to 100000 mass%, preferably 1000 to 10000 mass%. Here, in an embodiment in which an antitumor agent is formulated by dividing it into a plurality of dosage forms, the above-mentioned preferred blending ratio does not mean the blending ratio of the active ingredient to the total amount of a dosage form containing an active ingredient and a dosage form not containing an active ingredient, but means the blending ratio of the active ingredient to the mass of a dosage form containing an active ingredient. For example, in the case of the blending ratio of compound 1 or a salt thereof, it means the mass% of compound 1 or a salt thereof to the mass of only the dosage form containing compound 1 or a salt thereof.

[0153] In one embodiment of the present disclosure, the combination therapy of the present invention is administered to patients who have not been previously treated with hormone therapy, immunotherapy (such as cancer peptide vaccine therapy), surgery, radiation therapy, or chemotherapy, i.e., treatment-naive patients. In another embodiment, the combination therapy is administered to patients who have failed to achieve a sustained response after previous treatment with a chemotherapy agent.

[0154] In one embodiment of the disclosure, the combination therapy of the present invention is administered to a patient who has not previously been treated with an immune checkpoint inhibitor, while in another embodiment, the combination therapy is administered to a patient who has previously been treated with an FGFR inhibitor.

[0155] In one embodiment of the present disclosure, a sustained response refers to the expansion and maintenance of an immune response against a cancer by targeted immunotherapy, such as an immune checkpoint inhibitor, which may be measured, for example, by the binding of immune checkpoint inhibitors to T lymphocytes.

[0156] In this disclosure, the term "recommended dose" refers to a dosage that provides the greatest therapeutic effect within the range that can be used safely without causing serious side effects, as determined by clinical trials or the like. Specifically, this refers to dosages approved, recommended or advised by public institutions or organizations such as the Pharmaceuticals and Medical Devices Agency (PMDA), the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), etc., and that are described in package inserts, interview forms, treatment guidelines, etc., with a dosage approved by any of the public institutions, PMDA, FDA or EMA, being preferred.

[0157] The administration schedule of the antitumor agent of the present disclosure can be appropriately selected depending on the type of cancer, stage of the disease, etc.

[0158] In the case of Compound 1 or a salt thereof, every day from the first day to 21 days [for example, 3 weeks (21 days)] An administration schedule of 2 to 4 weeks is preferred, but there may be a drug holiday thereafter, and more preferably daily administration for 3 weeks (21 days). The administration schedule of immune checkpoint inhibitors is preferably, for example, at intervals of 2 to 4 weeks. In the case of nivolumab, an administration schedule of administration at intervals of 2 to 4 weeks (for example, at 2 or 3 week intervals) is preferred, more preferably at 3 week intervals. In the case of atezolizumab, an administration schedule of administration at intervals of 2, 3, or 4 weeks is preferred, more preferably at 3 week intervals. In the present disclosure, administration of drug A at X day intervals means that the day on which drug A is administered is designated as day 1, the following day as day 2, and so on. This means that if the day after is designated as day 3..., then the next administration of drug A will be on day X+1. Furthermore, when calculating an administration schedule, "1 week", "2 weeks", "3 weeks", and "4 weeks" respectively mean "7 days", "14 days", "21 days", and "28 days". Therefore, in the present disclosure, administration of drug A at 3-week intervals means that if the day on which drug A was administered is designated as day 1, then the next administration of drug A will be on day 22.

[0159] The number of times the antitumor agent of the present disclosure is administered per day may be appropriately selected depending on the type of cancer, stage of disease, etc. When administered in combination with nivolumab or atezolizumab, it is preferably administered once a day.

[0160] The order of administration of compound 1 or a salt thereof and the immune checkpoint inhibitor can be appropriately selected depending on the type of cancer, stage of disease, etc., but in one treatment regimen, either one may be administered first, or they may be administered simultaneously.

[0161] In one embodiment, Compound 1 or a salt thereof enhances the effect of an immune checkpoint inhibitor, and in another embodiment, the immune checkpoint inhibitor enhances the effect of Compound 1 or a salt thereof.

[0162] In one embodiment of the present disclosure, the tumor necrosis factor is administered to subjects expressing PD-L1 in 1% or more of subjects, and more preferably in 50% or more of subjects, regardless of whether or not PD-L1 is expressed.

[0163] In one embodiment of the present disclosure, the method is performed on subjects with tumors that test positive for PD-L1 expression. PD-L1 expression can be detected using a diagnostic anti-human PD-L1 antibody, or an antigen-binding fragment thereof, in an IHC assay on FFPE or frozen tissue sections of tumor samples taken from the patient. Typically, a physician will order a diagnostic test to determine PD-L1 expression using a tumor tissue sample taken from the subject prior to initiating the combined immune checkpoint inhibitor and FGFR inhibitor, although it is contemplated that a physician may order a pre-treatment or post-treatment diagnostic test after treatment has commenced, e.g., at the end of a treatment cycle.

[0164] In this disclosure, "cancer" or "tumor" refers to a physiological condition in mammals characterized by unregulated cell growth. "Cancer" and "tumor" are synonymous and used interchangeably herein. Cancer includes solid and hematological cancers. Examples include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma, sarcoma, and borderline malignant tumors (carcinoid).

[0165] Examples of cancers that can be treated with the combination method of the present disclosure include head and neck cancer, digestive cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder and bile duct cancer, etc.), pancreatic cancer, small intestine cancer, large intestine cancer (colorectal cancer, colon cancer, rectal cancer, etc.)), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma (malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, scavenging mesothelioma, etc.), breast cancer, reproductive cancer (ovarian cancer, uterine cancer (cervical cancer, uterine body cancer, endometrial cancer, etc.)), kidney cancer, bladder cancer, urothelial cancer, prostate cancer, testicular tumor, skin cancer (malignant melanoma, epidermal cancer, etc.), blood cancer (multiple myeloma, acute myeloid leukemia, etc.), bone and soft tissue tumors, rhabdomyosarcoma, brain tumor, malignant sheath tumor, neuroendocrine tumor, thyroid cancer, etc. In certain embodiments, the target cancers are bladder cancer, urothelial cancer, digestive cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder / bile duct cancer, etc.), pancreatic cancer, small intestine cancer, large intestine cancer (colorectal cancer, colon cancer, rectal cancer, etc.), ovarian cancer, head and neck cancer, and uterine cancer (cervical cancer, uterine body cancer, etc.). Note that the cancer herein includes not only primary lesions but also cancer that has metastasized to other organs (liver, etc.). The antitumor agent of the present disclosure may be used in postoperative adjuvant chemotherapy carried out to prevent recurrence after surgical removal of a tumor, or may be used in preoperative adjuvant chemotherapy carried out before surgical removal of a tumor.

[0166] In one embodiment of the present disclosure, the cancers targeted by the combination method include malignant melanoma, non-small cell lung cancer, Hodgkin's lymphoma, gastric cancer, renal cell carcinoma, head and neck cancer, malignant pleural mesothelioma, esophageal cancer, and urothelial carcinoma.

[0167] As used herein, the term "combination therapy" is intended to define a therapy that includes the use of a combination of two or more compounds / agents (as defined above). Thus, the use of "combination," "combination," and "in combination" compounds / agents in this application refers to compounds / agents that are administered as part of the same overall treatment regimen. The respective posologies of the two or more compounds / agents may vary: each may be administered at the same time or at different times. Thus, the compounds / agents of a combination may be administered in the same manner as in the case of a single compound / agent. It will be understood that the two agents may be administered sequentially (e.g., before or after) or simultaneously, either in a pharmaceutical formulation (i.e., together) or in different pharmaceutical formulations (i.e., separately). At the same time, as a single formulation, but at the same time, in different pharmaceutical formulations, non-integral.

[0168] In this specification, the term "regimen" or "therapeutic regimen" refers to a plan showing the type, amount, duration, procedure, etc. of drugs in drug treatment in a chronological order, and indicates the dosage, administration method, administration order, and administration date of each drug. An example of treatment with one therapeutic regimen is a method in which the administration of concomitant drugs is started simultaneously or substantially at the same time on the first day of one cycle. In addition, for example, one cycle is three weeks, and administration of drug A is started first, and administration of drug B is started one week later, but a form in which the drugs are administered substantially simultaneously as one cycle is also included in treatment with one therapeutic regimen.

[0169] The treatment regimen of the present disclosure comprising Compound 1 or a salt thereof and an immune checkpoint inhibitor may further comprise other drugs in addition to Compound 1 or a salt thereof and an immune checkpoint inhibitor.

[0170] The administration form of the antitumor agent of the present disclosure is not particularly limited and can be appropriately selected depending on the purpose of treatment. Specific examples include oral agents (tablets, coated tablets, powders, granules, capsules, liquids, etc.), injections, suppositories, patches, ointments, etc. In the case of Compound 1 or a salt thereof, oral agents are preferred. In the case of anti-PD-1 antibodies, anti-PD-L1 antibodies, or anti-CTLA-4 antibodies, the administration forms include those mentioned above, with injections being preferred.

[0171] The antitumor agent of the present disclosure may be an immune checkpoint inhibitor and Compound 1 or a salt thereof, which are active ingredients, themselves used as an antitumor agent, or may be a pharmaceutical composition prepared by a commonly known method using a pharma- ceutical acceptable carrier depending on the form of administration. Examples of such carriers include various types commonly used in conventional medicines, such as excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, isotonicity agents, pH adjusters, buffers, stabilizers, colorants, flavorings, and odorants.

[0172] The antitumor agent of the present disclosure may be formulated by dividing each active ingredient into multiple dosage forms based on the administration form and administration schedule of each active ingredient, or may be formulated together into a single dosage form. In addition, each formulation may be manufactured and sold together in a single package suitable for combined administration, or each formulation may be sold separately. The pharmaceutical composition may be manufactured and sold in separate packages. The same applies to the pharmaceutical composition embodiment. Therefore, the "pharmaceutical composition containing an immune checkpoint inhibitor and Compound 1 or a salt thereof as active ingredients" includes both formulations in which each active ingredient is divided into multiple dosage forms and formulations in which each active ingredient is combined into one dosage form. The pharmaceutical composition in which each active ingredient is divided into multiple dosage forms includes both formulations in which each formulation is combined into one package suitable for combined administration and formulations in which each formulation is divided into separate packages.

[0173] The present disclosure relates to a kit formulation including an antitumor agent containing Compound 1 or a salt thereof, and an instruction manual describing the co-administration of Compound 1 or a salt thereof and an immune checkpoint inhibitor to a cancer patient. Here, the "instructions" may be any instruction manual that describes the dosage amount, and may be legally binding or not, but preferably recommends the dosage amount. Specific examples include package inserts and pamphlets. In addition, the kit formulation including the instructions may be one in which the instructions are printed and attached to the package of the kit formulation, or one in which the instructions are enclosed in the package of the kit formulation together with the antitumor agent.

[0174] Methods for detecting the mechanism of action of FGFR inhibitors and the onset of resistance to immune checkpoint inhibitors include, but are not limited to, a method for examining the regulation of the tumor immune microenvironment (Non-Patent Document 13).

[0175] The efficacy of immune checkpoint inhibitors is influenced by the microenvironment surrounding the cancer, and CAFs (Cancer Associated fibroblasts) are known to play an important role in this regard. FGF is a factor that controls the proliferation of fibroblast cells, and its receptor, FGFR, is a molecule that receives FGF signals and promotes cell proliferation. Myeloid-derived positive cells (MDSCs (Myeoloid-derived suppressor cells)) are immature bone marrow cells that increase in tumor tissues, lymph nodes, and peripheral blood under pathological conditions, and are known to have strong immunosuppressive activity.

[0176] It has been reported that MDSCs may be a potential marker for predicting the efficacy of immune checkpoint inhibitors and may contribute to patient resistance to immune checkpoint inhibitors (Non-Patent Document 14).

[0177] As used herein, resistance to immune checkpoint inhibitors (also referred to as resistance or refractory) includes the state of a subject in which the therapeutic effect is no longer expected after administration of an immune checkpoint inhibitor and the progression of the disease has been confirmed in at least one clinical evaluation, intolerance to an immune checkpoint inhibitor, recurrence after administration of an immune checkpoint inhibitor, or the state of a subject in which the therapeutic effect of an immune checkpoint inhibitor is not expected, although there has been no experience of treatment with an immune checkpoint inhibitor. In some embodiments, it also includes the absence of an effective effect against an immune checkpoint inhibitor in a pharmacological test, for example, the reaction of a cell line that is considered to be ineffective. Resistance includes natural resistance, in which an anticancer drug is not effective from the beginning of treatment, and acquired resistance, in which an anticancer drug that was initially effective becomes ineffective as treatment continues, leading to the exacerbation of the cancer. As used herein, resistance encompasses both natural resistance and acquired resistance.

[0178] As used herein, refractory to an immune checkpoint inhibitor refers to a state in which the immune checkpoint inhibitor becomes ineffective after administration of the immune checkpoint inhibitor, and fails to exert its effect. One of the causes of refractory disease is thought to be resistance.

[0179] The antitumor agents of the present disclosure can be used to treat cancer. An "antitumor effect" when referring to a cancer patient treated with a treatment regimen, such as a combination therapy, described herein, can be, for example, , PFS (progression-free survival), DCR (disease control rate), DOR (duration of response), OS (overall survival), ORR (objective response rate), DCR (disease control rate), TTR (time to first response), PROs (Patient-Reported Outcomes), etc. In one embodiment, in the case of solid tumors, tumor evaluation for the combination therapy described herein is evaluated by the RECIST 1.1 criteria (response criteria for solid tumors), and the antitumor effect is indicated by SD (stable disease), PR (partial response), CR (complete response), and PD (progression). In the case of tumor evaluation of brain tumors, Gd-MRI (standard brain tumor MRI including pre-enhancement and post-enhancement using gadolinium (Gd) chelate contrast agent) can also be performed. EXAMPLES

[0180] The present disclosure will now be described in more detail with reference to examples and reference examples, but the present disclosure is not limited to these examples in any way, and many modifications can be made by those having ordinary skill in the art within the technical spirit of the present disclosure.

[0181] (Reference Example) Clinical trial of patients with cancer immunotherapy-resistant cancers (e.g., non-small cell lung cancer, esophageal cancer, urothelial cancer) using (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof in combination with pembrolizumab This study evaluates the efficacy and safety of the combination of compound 1 or its salt and pembrolizumab in patients with FGFR-overexpressing cancer (e.g., non-small cell lung cancer, esophageal cancer) based on a clinical trial registered with the Japan Pharmaceutical Information Center as JapicCTI-195063. Specifically, the patient is administered various doses (e.g., 20 mg) of compound 1 or its salt orally for 21 days for a specified period (e.g., 24 weeks), and pembrolizumab (e.g., 200 mg once) is administered by intravenous infusion every 3 weeks (every 21 days). This cycle is repeated for 21 days. In some cases, a placebo may be used as a control, and compound 1 or its salt and / or pembrolizumab may be administered to additional patients. Compound 1 or its salt may also be administered in combination with pembrolizumab to patients who have been treated with pembrolizumab.

[0182] The combination of Compound 1 or a salt thereof with pembrolizumab may provide therapeutic effects that would not be expected from these monotherapies. For example, in some embodiments of the present disclosure, the combination may be found to be more effective than at least one of the measurements of either treatment alone. Also, for example, in some embodiments of the present disclosure, the combination of Compound 1 or a salt thereof with pembrolizumab may provide a synergistic effect.

[0183] The combination of Compound 1 or a salt thereof and pembrolizumab may be more effective than either alone according to at least one of the following measurements: reduction in cancer cell count, reduction in tumor size, reduction in the rate of cancer cell infiltration into peripheral organs, reduction in the rate of tumor metastasis or tumor growth, overall response rate, or prolongation of progression-free survival or overall survival.

[0184] Example 1: Effect on tumor immunity in a mouse breast cancer cell 4T1 subcutaneous transplantation model Mouse breast cancer line 4T1 was transplanted subcutaneously into 6-week-old male BALB / cAJcl mice. The day of cell transplantation was set as Day 0, and from the next day (Day 1), Compound 1 was administered at a dose of 15 mg / kg / day for 14 days. On the day following the final administration (Day 15), lymphocyte fractions were isolated from the tumor, spleen, and peripheral blood, and bone marrow-derived immunosuppressive cells (MDSCs) (CD11b + / Gr-1 + The CD4 positive T cells and CD8 positive T cells were measured. In addition, mouse breast cancer cells were cultured in the same manner as above, except that the dose of Compound 1 was 30 mg / kg / day. A 4T1 subcutaneous tumor model was prepared, drugs were administered, and each cell was measured. As a control, the same procedure as above was carried out except that Compound 1 was not administered. The results are shown in FIG. 1.

[0185] Administration of Compound 1 at any dose significantly (Student t-test, P<0.01) reduced MDSC in the splenic lymphocyte cell fraction compared to the drug-free control. MDSC in the peripheral blood lymphocyte cell fraction showed a dose-dependent decrease compared to the control. CD4 positive T cells in the peripheral blood lymphocyte cell fraction and splenic Cont A dose-dependent increase was observed compared with rol.

[0186] These results suggest that compound 1 has an inhibitory effect on MDSCs in an in vivo model. This confirmed the possibility that compound 1 may have an antitumor effect via an immunosuppressive mechanism. Furthermore, the administration of compound 1 increased CD4 positive T cells and CD8 positive T cells, confirming that compound 1 activates immune activity in tumor-bearing mice. These findings suggest that the combined use of compound 1 or its salt with an immune checkpoint inhibitor enhances the antitumor effect.

[0187] The 4T1 used in Example 1 is a breast cancer cell that does not have FGFR gene abnormalities, but the administration of compound 1 was confirmed to have an inhibitory effect on MDSCs, and an increase in CD4 positive T cells and CD8 positive T cells was observed, indicating that compound 1 exhibits an antitumor effect via an immunosuppressive mechanism. In addition, by administering the anti-FGFR3 antibody Vofatamab to urothelial cancer patients, the cancer changes from a "cold" state, which is less sensitive to immune checkpoint inhibitors, to a "hot" state, which is highly sensitive, and even patients without FGFR gene abnormalities have been shown to respond to the combination of pembrolizumab (W. Choi et al., Presented at AACR Bladder cancer: Transforming the Field Special Conference, May 18-21, 2019, Denver, USA).

[0188] (Example 2) A Phase I clinical study of patients with solid tumors using (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof in combination with nivolumab This study evaluates the efficacy and safety of the combination of Compound 1 or its salt and nivolumab in patients with solid tumors. Patients are administered various doses (8 mg, 12 mg, 16 mg, 20 mg) of compound 1 or a salt thereof orally for 21 days for a specified period (e.g., 24 weeks) and nivolumab (240 mg at a time) by intravenous infusion every 2 weeks (every 14 days). Alternatively, the patient is administered various doses (8 mg, 12 mg, 16 mg, 20 mg) of compound 1 or a salt thereof orally for 21 days for a specified period (e.g., 24 weeks), nivolumab (80 mg per dose) is administered by intravenous infusion every 3 weeks (every 21 days) for 4 doses, and then nivolumab (240 mg per dose) is administered by intravenous infusion every 2 weeks (every 14 days) from the 5th dose onwards. Alternatively, the patient is administered various doses (8 mg, 12 mg, 16 mg, 20 mg) of compound 1 or a salt thereof orally for 21 days for a specified period (e.g., 24 weeks), nivolumab (240 mg at a time) by intravenous infusion every 3 weeks (every 21 days) for 4 doses, and then nivolumab (240 mg at a time) is administered by intravenous infusion every 2 weeks (every 14 days) from the 5th dose onwards. Compound 1 was administered repeatedly for 21 days. In some cases, compound 1 or a salt thereof and / or nivolumab may be additionally administered to additional patients. Compound 1 or a salt thereof may also be administered in combination with nivolumab to patients who have previously been treated with nivolumab.

[0189] The combination of Compound 1 or a salt thereof with nivolumab may provide therapeutic benefits that would not be expected from these monotherapies. For example, in certain embodiments of the present disclosure, the combination is It may be found that the efficacy is higher than at least one of the measurements of the treatment alone. Also, for example, in some embodiments of the present disclosure, the combination of compound 1 or a salt thereof with nivolumab may provide a synergistic effect.

[0190] The combination of Compound 1 or a salt thereof and nivolumab may be more effective than either alone according to at least one of the following measurements: reduction in cancer cell count, reduction in tumor size, reduction in the rate of cancer cell infiltration into peripheral organs, reduction in the rate of tumor metastasis or tumor growth, overall response rate, or prolongation of progression-free or overall survival.

Claims

1. An antitumor agent which is administered in combination with an immune checkpoint inhibitor (excluding pembrolizumab) to a cancer patient having resistance to an immune checkpoint inhibitor, comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient.

2. The antitumor agent according to claim 1, wherein the immune checkpoint inhibitor is at least one selected from the group consisting of a PD-1 pathway antagonist, an ICOS pathway agonist, a CTLA-4 pathway antagonist, and a CD28 pathway agonist.

3. The antitumor agent according to claim 1 or 2, wherein the immune checkpoint inhibitor is a PD-1 pathway antagonist.

4. The antitumor agent according to claim 2 or 3, wherein the PD-1 pathway antagonist is at least one selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-PD-L2 antibody.

5. The antitumor agent according to any one of claims 2 to 4, wherein the PD-1 pathway antagonist is an anti-PD-1 antibody.

6. The antitumor agent according to claim 4 or 5, wherein the anti-PD-1 antibody is nivolumab, cemiplimab, spartalizumab, tislelizumab, BI754091, dostalizumab, sasanlimab, MGA-012, cetrelimab, AGEN-2034, zimverekimab, camrelizumab, budigalimab or balstilimab.

7. The antitumor agent according to claim 6, wherein the anti-PD-1 antibody is nivolumab.

8. The antitumor agent according to any one of claims 2 to 7, wherein the PD-1 pathway antagonist is an anti-PD-L1 antibody.

9. The antitumor agent according to claim 8, wherein the anti-PD-L1 antibody is atezolizumab, durvalumab or avelumab.

10. The antitumor agent according to claim 2, wherein the CTLA-4 pathway antagonist is an anti-CTLA-4 antibody.

11. The antitumor agent according to claim 10, wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

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

13. The antitumor agent according to claim 12, wherein the abnormality in the FGFR pathway is at least one selected from the group consisting of overexpression of FGFR, an abnormality in the FGFR gene, and an abnormal state of FGFR signaling.

14. The antitumor agent according to any one of claims 1 to 13, wherein treatment with said antitumor agent results in a sustained response in an individual after cessation of treatment.

15. The antitumor agent according to any one of claims 1 to 14, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is used prior to an immune checkpoint inhibitor, simultaneously with an immune checkpoint inhibitor, or after an immune checkpoint inhibitor.

16. The antitumor agent according to any one of claims 1 to 15, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is used continuously or intermittently.

17. The antitumor agent according to any one of claims 1 to 16, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and an immune checkpoint inhibitor are administered in the same therapeutic regimen treatment.

18. Targeting tumors resistant to immune checkpoint inhibitors (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg, and 20 mg, and nivolumab is administered at a dose selected from the group consisting of 1 mg / kg every 3 weeks, 2 mg / kg every 3 weeks, 3 mg / kg every 3 weeks, 80 mg every 3 weeks, 240 mg every 3 weeks, 1 mg / kg every 2 weeks, 2 mg / kg every 2 weeks, 3 mg / kg every 2 weeks, 80 mg every 2 weeks, and 240 mg every 2 weeks. The antitumor agent according to any one of claims 1 to 7 and 12 to 17.

19. Targeting tumors resistant to immune checkpoint inhibitors The compound is used for administering (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof once daily at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg, and for administering nivolumab at a dose selected from the group consisting of 240 mg every two weeks and 240 mg every three weeks. The antitumor agent according to claim 18.

20. Targeting tumors resistant to immune checkpoint inhibitors (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg, and nivolumab is administered at 240 mg every two weeks. The antitumor agent according to claim 18.

21. Targeting tumors resistant to immune checkpoint inhibitors (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once a day at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg, and 20 mg, and nivolumab is administered at 80 mg every 3 weeks for four doses, and then nivolumab is administered at 240 mg every 2 weeks from the fifth dose. The antitumor agent according to claim 18.

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