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

Abstract

To provide a novel combination therapy that shows excellent antitumor effects in cancer patients resistant to immune checkpoint inhibitors, using (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof. [Solution] An antitumor agent comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof as an active ingredient, to be administered in combination with an immune checkpoint inhibitor (excluding pembrolizumab) to cancer patients resistant to immune checkpoint inhibitors.

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 enhancer, and a kit formulation.

Background Art

[0002] Fibroblast growth factor (FGF) is expressed in a wide range of tissues and is one of the growth factors that control cell proliferation and differentiation. The physiological activity of FGF is mediated by fibroblast growth factor receptor (FGFR), a specific cell surface receptor. FGFR belongs to the receptor-type protein tyrosine kinase family and is composed 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). FGFR forms a dimer upon binding of FGF and is activated by phosphorylation. Activation of the receptor induces the recruitment and activation of specific downstream signaling molecules, expressing physiological functions. Abnormalities in FGF / FGFR signaling have been reported in relation to various human tumors. Abnormal activation of the FGF / FGFR signal in human tumors is thought to be caused by overexpression and / or gene amplification of FGFR, gene mutations, chromosomal translocations, insertions, inversions, gene fusions, 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, as one of the new cancer treatment methods, the development of cancer immunotherapy is underway.

[0004] The activation of the adaptive immune response begins with the binding of the antigen peptide-MHC complex to the T cell receptor (TCR). This binding is further regulated by costimulation or coinhibition between the B7 family of costimulatory molecules and their receptors, the CD28 family. In other words, two characteristic signaling events are required for T cells to be activated in an antigen-specific manner. T cells that receive antigen stimulation alone without costimulation from the B7 family become unresponsive (anergy), and immune tolerance is induced.

[0005] Cancer cells utilize this mechanism to suppress the activation of antigen-specific T cells, thereby evading the immune surveillance system and continuing to proliferate. Therefore, inducing an anti-tumor immune response in the body of cancer patients by enhancing costimulation or blocking coinhibition, and controlling the immune evasion of tumors, is considered effective in cancer treatment, and various cancer immunotherapies targeting costimulatory molecules (stimulating co-stimulatory molecules) or coinhibitory molecules (inhibitory co-stimulatory molecules) have been proposed (Non-Patent Literature 5). For example, nivolumab (a human IgG4 monoclonal antibody against human PD-1) is used as an immune checkpoint inhibitor that activates T cells by inhibiting the binding of PD-1 to its ligands (PD-L1 and PD-L2) and is used to treat malignant melanoma and other cancers (Patent Literature 1, Non-Patent Literature 6). In addition, pembrolizumab is an immune checkpoint inhibitor with a different antibody type than nivolumab and is used to treat malignant melanoma and non-small cell lung cancer (Non-Patent Literature 6).

[0006] (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or its salts, which are 3,5-disubstituted benzenealkynyl compounds, are known as FGFR inhibitors, and combinations of FGFR inhibitors with other antitumor agents have been reported (Patent Documents 2 and 3). Regarding the co-administration of FGFR inhibitors and immune checkpoint inhibitors, for example, Patent Document 4 describes a method of co-administering an FGFR inhibitor with an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0007] Many cases have been reported regarding immune checkpoint inhibitors, and it has become clear that drug resistance develops with continued administration, and the mechanisms of this are being studied (Non-Patent Documents 9, 10, 11). Examples of the use of immune checkpoint inhibitors and FGFR inhibitors include, for example, a Phase II trial of Erdafitinib (JNJ-42756493) for urothelial carcinoma (NCT02365597) in which FGFR inhibitors were administered to patients who had received prior PD-1 or PD-L1 treatment. In addition, a combination study of the anti-FGFR3 antibody Vofatamab and pembrolizumab is underway (NCT03123055). Regarding continuous administration, there are reports of combinations of the multi-kinase inhibitors with FGFR inhibitory activity, pazopanib and everolimus, Vofatamab and docetaxel, and continuous administration with 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

Non-Patent Document 14

Summary of the Invention

Problems to be Solved by the Invention

[0010] The present disclosure aims 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 exhibits an excellent antitumor effect against cancer patients resistant to immune checkpoint inhibitors.

Means for Solving the Problems

[0011] In view of such a situation, the present inventors have found that the above problems can be solved by combining a compound having FGFR inhibitory activity, (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") or a salt thereof, with an immune checkpoint inhibitor.

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

[0013] Item 1. An antitumor agent that is co-administered with an immune checkpoint inhibitor (excluding pembrolizumab) to cancer patients resistant to 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.

[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 PD-1 pathway antagonists, ICOS pathway agonists, CTLA-4 pathway antagonists, and CD28 pathway agonists.

[0015] Item 3. An 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 anti-PD-1 antibody, anti-PD-L1 antibody, and anti-PD-L2 antibody.

[0017] Item 5. An antitumor agent as described in 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, semiprimab, spartalizumab, tislerizumab, BI754091, dostarizumab, sasamrimab, MGA-012, cetrelimab, AGEN-2034, zimberekimab, camrelizumab, buzigalimab, or valstilimab, preferably nivolumab.

[0019] Item 7. An antitumor agent as described in 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 described in Item 7, wherein the anti-PD-L1 antibody is atezolizumab, durvalumab, or avelumab.

[0021] Item 9. An antitumor agent as described in Item 2, wherein the CTLA-4 pathway antagonist is an anti-CTLA-4 antibody.

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

[0023] Item 11. An 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 FGFR overexpression, FGFR gene abnormalities, and FGFR signaling abnormalities.

[0025] Item 13. An antitumor agent according to any one of items 1 to 12, wherein treatment with the antitumor agent produces a sustained response in the individual after discontinuation of treatment.

[0026] Item 14. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is an antitumor agent according to any one of items 1 to 13, used before an immune checkpoint inhibitor, concurrently with an immune checkpoint inhibitor, or after an immune checkpoint inhibitor.

[0027] Item 15. An antitumor agent according to any one of items 1 to 14, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is used continuously or intermittently.

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

[0029] Section 17. For tumors resistant to immune checkpoint inhibitors, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered once daily in doses selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg, and 20 mg, and nivolumab is administered in doses 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. An antitumor agent as described in any one of items 1-6 and 11-16.

[0030] Section 18. For tumors resistant to immune checkpoint inhibitors, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or its salt, consisting of a group of 8 mg, 12 mg, 16 mg, and 20 mg. It is administered once daily at a dose selected from the following, and is used to administer nivolumab at a dose selected from groups consisting of 240 mg every two weeks and 240 mg every three weeks. The antitumor agent described in item 17.

[0031] Section 19. For tumors resistant to immune checkpoint inhibitors, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered once daily in doses 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 described in item 17.

[0032] Section 20. For tumors resistant to immune checkpoint inhibitors, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered once daily in doses 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 4 doses, and then nivolumab is administered at 240 mg every 2 weeks starting from the 5th dose. The antitumor agent described in item 17.

[0033] Item 21. A pharmaceutical composition containing an immune checkpoint inhibitor (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof as an active ingredient.

[0034] Item 22. The pharmaceutical composition according to Item 21 for treating cancer resistant to immune checkpoint inhibitors.

[0035] Item 23. Use of immune checkpoint inhibitors (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof for the manufacture of antitumor agents for treating cancer resistant to immune checkpoint inhibitors.

[0036] Item 24. Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-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) in patients resistant to immune checkpoint inhibitors.

[0037] Item 25. Use of immune checkpoint inhibitors (excluding pembrolizumab) for the manufacture of antitumor agents administered in combination with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolizin-1-yl)propa-2-en-1-one or a salt thereof in patients resistant to immune checkpoint inhibitors.

[0038] Item 26. Immune checkpoint inhibitors (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4 -d) Combination with pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof.

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

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

[0041] Item 29. Use of immune checkpoint inhibitors (except pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof for the treatment of cancer resistant to immune checkpoint inhibitors.

[0042] Item 30. Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof for the treatment of cancer resistant to immune checkpoint inhibitors in combination with an immune checkpoint inhibitor (excluding pembrolizumab).

[0043] Item 31. Use of immune checkpoint inhibitors (excluding pembrolizumab) in combination with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof to treat cancer resistant to immune checkpoint inhibitors.

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

[0045] Item 33. An antitumor agent containing (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof as an active ingredient, to be administered in combination with an immune checkpoint inhibitor (excluding pembrolizumab) to cancer patients who have not previously received an immune checkpoint inhibitor.

[0046] Item 34. Never having received an immune checkpoint inhibitor (excluding pembrolizumab) or an immune checkpoint inhibitor containing (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof as an active ingredient. A pharmaceutical composition for treating cancer in cancer patients.

[0047] Item 35. The pharmaceutical composition according to item 34 for treating cancer resistant to immune checkpoint inhibitors.

[0048] Item 36. Use of immune checkpoint inhibitors (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof for the manufacture of an antitumor agent for treating cancer in cancer patients who have not received an immune checkpoint inhibitor.

[0049] Item 37. Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof to manufacture an antitumor agent to be administered in combination with an immune checkpoint inhibitor (excluding pembrolizumab) to cancer patients who have not previously received an immune checkpoint inhibitor.

[0050] Item 38. Use of immune checkpoint inhibitors (excluding pembrolizumab) to manufacture an antitumor agent administered in combination with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof to cancer patients who have not previously received an immune checkpoint inhibitor.

[0051] Item 39. Combinations of immune checkpoint inhibitors (excluding pembrolizumab) with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof for use in the treatment of cancer in cancer patients who have not previously received immune checkpoint inhibitors.

[0052] Item 40. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof for use in combination therapy with immune checkpoint inhibitors (excluding pembrolizumab) in the treatment of cancer in cancer patients who have not previously received immune checkpoint inhibitors.

[0053] Item 41. Immune checkpoint inhibitors (excluding pembrolizumab) for use in combination therapy with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof in the treatment of cancer in cancer patients who have not previously received an immune checkpoint inhibitor.

[0054] Item 42. Use of immune checkpoint inhibitors (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof for the treatment of cancer in cancer patients who have not previously received immune checkpoint inhibitors.

[0055] Item 43. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1 for the treatment of cancer in cancer patients who have not previously received immune checkpoint inhibitors, by combination therapy with immune checkpoint inhibitors (excluding pembrolizumab) Use of H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof.

[0056] Item 44. Use of immune checkpoint inhibitors (excluding pembrolizumab) in combination with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof to treat cancer in cancer patients who have not previously received immune checkpoint inhibitors.

[0057] Item 45. A method for treating cancer in cancer patients who have not previously received an immune checkpoint inhibitor, comprising administering a therapeutically effective dose of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof and a therapeutically effective dose of an immune checkpoint inhibitor (excluding pembrolizumab) to a person in need.

[0058] Section 46. A tumor having an abnormality in the FGFR pathway, a composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof, an immune checkpoint inhibitor, or a method.

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

[0060] Item 48. An antitumor agent containing (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof as an active ingredient, to be administered in combination with an immune checkpoint inhibitor (excluding pembrolizumab) to cancer patients who are resistant to immune checkpoint inhibitors and do not have abnormalities in the FGFR pathway.

[0061] Item 49. A pharmaceutical composition for treating cancer without abnormalities in the FGFR pathway, comprising an immune checkpoint inhibitor (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof as an active ingredient.

[0062] Item 50. A pharmaceutical composition according to item 49 for treating cancer resistant to immune checkpoint inhibitors.

[0063] Item 51. Use of immune checkpoint inhibitors (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof for the manufacture of antitumor agents for the treatment of cancers that do not have abnormalities in the FGFR pathway.

[0064] Item 52. Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof for the manufacture of an antitumor agent administered in combination with an immune checkpoint inhibitor (excluding pembrolizumab) to cancer patients without abnormalities in the FGFR pathway.

[0065] Item 53. Use of immune checkpoint inhibitors (excluding pembrolizumab) to manufacture antitumor agents administered in combination with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof to cancer patients without abnormalities in the FGFR pathway.

[0066] Item 54. Combinations of immune checkpoint inhibitors (excluding pembrolizumab) with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof for use in the treatment of cancer without abnormalities in the FGFR pathway.

[0067] Item 55. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof for use in combination therapy with immune checkpoint inhibitors (excluding pembrolizumab) in the treatment of cancers without abnormalities in the FGFR pathway.

[0068] Item 56. Immune checkpoint inhibitors (excluding pembrolizumab) for use in combination therapy with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof in the treatment of cancer without abnormalities in the FGFR pathway.

[0069] Item 57. Use of immune checkpoint inhibitors (excluding pembrolizumab) and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or salt thereof for the treatment of cancers without abnormalities in the FGFR pathway.

[0070] Item 58. Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof for the treatment of cancer without abnormalities in the FGFR pathway in combination with an immune checkpoint inhibitor (excluding pembrolizumab).

[0071] Item 59. Use of immune checkpoint inhibitors (excluding pembrolizumab) for the treatment of cancer without abnormalities in the FGFR pathway by combination therapy with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof.

[0072] Item 60. A method for treating cancer without abnormalities in the FGFR pathway, comprising a therapeutically effective amount of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof, and a therapeutically effective amount of an immune checkpoint inhibitor (pembroliz A method comprising administering (excluding mab) to a person in need thereof.

[0073] Item 61. A composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof, an immune checkpoint inhibitor, or a method, wherein the immune checkpoint inhibitor is at least one selected from the group consisting of PD-1 pathway antagonists, ICOS pathway agonists, CTLA-4 pathway antagonists, and CD28 pathway agonists.

[0074] Section 62. Compositions, uses, combinations, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof, immune checkpoint inhibitor, or method, 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)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-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 anti-PD-1 antibody, anti-PD-L1 antibody, and anti-PD-L2 antibody.

[0076] Section 64. A composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof, an immune checkpoint inhibitor, or a method, 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)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolizumab-1-yl)propa-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, semiprimab, spartalizumab, tislerizumab, BI754091, dostarizumab, sasamlimab, MGA-012, cetrelimab, AGEN-2034, zimberekimab, camrelizumab, buzigalimab or valstirimab, preferably nivolumab.

[0078] Section 66. A composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof, an immune checkpoint inhibitor, or a method, wherein the PD-1 pathway antagonist is an anti-PD-L1 antibody.

[0079] Section 67. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof, immune checkpoint inhibitor, or method described in Section 64, wherein the anti-PD-L1 antibody is atezolizumab, durvalumab, or avelumab.

[0080] Section 68. The composition, use, and combination described in Section 61, in which the CTLA-4 pathway antagonist is an anti-CTLA-4 antibody, (S)-1-(3-(4-amino-3-((3,5-dimethyl Siphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof, an immune checkpoint inhibitor, or a method thereof.

[0081] Section 69. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof, an immune checkpoint inhibitor, or a method thereof, wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

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

[0083] Item 71. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof, used before, concurrently with, or after an immune checkpoint inhibitor, as described in any one of items 21 to 70, a composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof, an immune checkpoint inhibitor, or a method.

[0084] Item 72. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof, used continuously or intermittently, in any composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof, an immune checkpoint inhibitor, or a method.

[0085] Item 73. A composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof and an immune checkpoint inhibitor, as described in any one of items 21 to 71, in which the latter is administered in the same therapeutic regimen.

[0086] Item 74. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof and nivolumab are used in the manner described below, in the compositions, uses, and combinations of any one of items 21-65 and 70-73, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en- 1-ON or its salts or immune checkpoint inhibitors or methods: Cancer patients resistant to immune checkpoint inhibitors are administered (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof once daily in doses selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg, and 20 mg, and nivolumab is administered in doses 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, and 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. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof and nivolumab are used in the manner described below, as described in any one of items 21-65 and 70-73, as a composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof or an immune checkpoint inhibitor or method: Cancer patients resistant to immune checkpoint inhibitors are administered (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof once daily in doses selected from groups consisting of 8 mg, 12 mg, 16 mg, and 20 mg, along with nivolumab at doses selected from groups consisting of 240 mg every two weeks and 240 mg every three weeks.

[0088] Item 76. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof and nivolumab are used in the manner described below, as described in any one of items 21-65 and 70-73, as (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof or an immune checkpoint inhibitor or method: In cancer patients resistant to immune checkpoint inhibitors, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-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 a dose of 240 mg every two weeks.

[0089] Item 77. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof and nivolumab are used in the manner described below, as described in any one of items 21-65 and 70-73, as (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof or an immune checkpoint inhibitor or method: In cancer patients resistant to immune checkpoint inhibitors, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered once daily in doses selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg, and 20 mg, followed by nivolumab 80 mg every 3 weeks for 4 doses, and then nivolumab 240 mg every 2 weeks starting from the 5th dose. [Effects of the Invention]

[0090] According to this disclosure, it is possible to provide a novel combination therapy that shows excellent antitumor effects in cancer patients who have resistance to immune checkpoint inhibitors, using (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof. [Brief explanation of the drawing]

[0091] [Figure 1] The results of Example 1 (effect of compound 1 on myeloid-derived immunosuppressive cells (MDSCs)) are shown. [Modes for carrying out the invention]

[0092] This disclosure relates to the combination of compounds having FGFR inhibitory activity and immune checkpoint inhibitors (excluding pembrolizumab), specifically, antitumor agents containing compounds having FGFR inhibitory activity that are administered in combination with immune checkpoint inhibitors (excluding pembrolizumab), antitumor effect enhancers containing compounds having FGFR inhibitory activity, combinations of compounds having FGFR inhibitory activity and immune checkpoint inhibitors (excluding pembrolizumab), and the use of compounds having FGFR inhibitory activity in the manufacture of pharmaceuticals for the treatment of tumors in combination with immune checkpoint inhibitors (excluding pembrolizumab).

[0093] In this disclosure, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one, which provides excellent antitumor effects when used in combination with immune checkpoint inhibitors, is a disubstituted benzenealkynyl compound having the following structure. In this specification, the above compound will be referred to as "Compound 1" for convenience. Compound 1 is described as Example Compound 2 in Patent Document 2. Compound 1 or a salt thereof has been reported to have excellent FGFR inhibitory activity, inhibiting the phosphorylation ability of tyrosine in the substrate peptide sequences of the receptor protein tyrosine kinases of FGFR1, FGFR3, and FGFR4, respectively (Patent Document 2).

[0094] [ka]

[0095] Compound 1 or its pharmaceutically acceptable salts in the above disclosure are not particularly limited, but can be synthesized, for example, based on the manufacturing method described in Patent Document 2.

[0096] In this disclosure, compound 1 can be used as is or in the form of a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts of compound 1 include, but are not limited to, addition salts with inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as acetic acid, citric acid, tartaric acid, and maleic acid, salts with alkali metals such as potassium and sodium, salts with alkaline earth metals such as calcium and magnesium, and salts with organic bases such as ammonium salts, ethylamine salts, and arginine salts.

[0097] The immune checkpoint inhibitors described herein act on immune checkpoint molecules to induce an antitumor immune response in the target organism and control the immune evasion of tumors.

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

[0099] In this disclosure, 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] PD-1 pathway antagonists inhibit immunosuppressive signals mediated by PD-1 expressed on T cells and its ligands, PD-L1 or PD-L2. Examples include, but are not limited to, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, PD-1 extracellular domains, PD-L1 extracellular domains, PD-L2 extracellular domains, PD-1-Ig (a fusion protein of the PD-1 extracellular domain and the FC region of Ig), PD-L1-Ig, PD-L2-Ig, PD-1 siRNA, PD-L1 siRNA, and PD-L2 siRNA. Preferably, they are anti-PD-1 antibodies, anti-PD-L1 antibodies, or anti-PD-L2 antibodies, and more preferably, anti-PD-1 antibodies or anti-PD-L1 antibodies. Among these, anti-PD-1 antibodies are particularly preferred.

[0101] Furthermore, CTLA-4 pathway antagonists inhibit immunosuppressive signals mediated by CTLA-4 expressed on T cells and its ligands, B7-1(CD80) and B7-2(CD86). Preferably, these are anti-CTLA-4 antibodies, CTLA-4 extracellular domains, CTLA-4-Ig (a fusion protein of the CTLA-4 extracellular domain and the FC region of Ig), anti-B7-1(CD80) antibodies, or anti-B7-2(CD86) antibodies, and more preferably anti-CTLA-4 antibodies or CTLA-4-Ig. Among these, anti-CTLA-4 antibodies are particularly preferred.

[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, Diabody, etc. (Nat. Rev. Immunol., 6:343-357, 2006), and these include monoclonal antibodies or polyclonal antibodies such as human antibodies, humanized antibodies, chimeric antibodies, mouse antibodies, llama antibodies, and chicken antibodies. In this disclosure, immunoglobulins (preferably IgG, etc.) are preferred. In this disclosure, human antibodies or humanized antibodies are preferred. In this disclosure, monoclonal antibodies are preferred.

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

[0104] Preferred anti-PD-1 antibodies in this disclosure include nivolumab, cemiplimab, spartalizumab, tislerizumab, BI754091, dostarlimab, sasanlimab, MGA-012, cetrelimab, AGEN-2034, zimberelimab, cemrelizumab, budigalimab, and balstilimab.

[0105] Preferred anti-PD-L1 antibodies in this disclosure include atezolizumab, durvalumab, avelumab, lodapolimab, and BGB-A333.

[0106] Preferred anti-CTLA-4 antibodies in this disclosure include ipilimumab and tremelimumab.

[0107] Preferred CTLA-4-Ig in this disclosure include abatacept, among others.

[0108] These agonists or antagonists can be manufactured by commonly known methods.

[0109] Furthermore, anti-PD-1 antibodies are already marketed as nivolumab, anti-PD-L1 antibodies as atezolizumab, durvalumab, or avelumab, anti-CTLA-4 antibodies as ipilimumab or tremelimumab, and CTLA-4-Ig as abatacept, and these can also be used.

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

[0111] In this disclosure, when using two or more immune checkpoint inhibitors, for example, immune checkpoint inhibitors such as anti-PD-1 antibodies and anti-CTLA-4 antibodies can be used in combination, or bispecific antibodies capable of binding to different immune checkpoint molecules can be used. An example of a bispecific antibody capable of binding to both PD-1 and CTLA-4 is XmAb20717 (PD-1 × CTLA-4).

[0112] In this disclosure, "treatment" includes procedures performed with the aim of curing or relieving a disease, or of preventing disease progression or relapse, or alleviating symptoms. Treatment includes the administration of drugs before or after surgical procedures, or the administration of drugs during or before or after radiation therapy.

[0113] The therapeutically effective dose of antibody and compound 1 or a salt thereof that blocks the interaction with immune checkpoint molecules depends on several factors, including, without limitation, the stage and severity of cancer, as well as other factors related to the patient's health. Those skilled in the art will know how to determine the therapeutically effective dose.

[0114] In one embodiment, this disclosure is used for tumors having abnormalities in the FGFR pathway. In one embodiment, FGFR is selected from the group consisting of FGFR1, FGFR2, FGFR3, and FGFR4.

[0115] In some embodiments, tumors to which this disclosure applies are preferred that have abnormalities in the FGFR pathway. Abnormalities in the FGFR pathway include FGFR overexpression, FGFR gene abnormalities, and abnormal FGFR signaling states.

[0116] In some embodiments, this disclosure is administered to subjects regardless of the presence or absence of FGF / FGFR abnormalities, but preferably to subjects with abnormalities in the FGFR pathway. Even in cancers without FGFR gene abnormalities, compound 1 can enhance the antitumor effect of immune checkpoint inhibitors. It is known that the sensitivity of cancer to immune checkpoint inhibitors is also influenced by the tumor microenvironment. The microenvironment includes, but is not limited to, cancer-associated fibroblasts (CAFs) and other cell groups regulated by FGF / FGFR pathway activation, and it is known that these cell groups reduce the sensitivity of cancer to immune checkpoint inhibitors. It is conceivable that administration of compound 1 enhances the effect of immune checkpoint inhibitors on cancer by inducing changes in the microenvironment, including inactivation of CAFs.

[0117] Overexpression of FGFRs includes, for example, high gene expression and high expression of gene product proteins. The presence or absence of FGFR expression can be detected by methods known to those skilled in the art. Detection of high gene expression and gene product protein expression can be performed by known methods, such as antibody-based methods (immunohistochemical staining, enzyme immunosorbent assay (ELISA), flow cytometry, immunoblotting, etc.), nucleic acid-based methods (in situ hybridization, PCR, Northern blotting, etc.), and methods based on principles common to these. Detection devices can be known devices (Genechip, microarrays, etc.).

[0118] This disclosure, in one embodiment, is used for tumors having abnormalities in the FGFR gene. Abnormalities in the FGFR pathway include gene amplification, gene mutation, chromosomal translocations, insertions, inversions, gene fusions, and gene rearrangements. Several FGFR gene abnormalities in tumors have already been reported in literature available to those skilled in the art (Non-Patent Documents 7, 8). Methods known to those skilled in the art include pyrosequencing, DNA sequencing including 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). Detection by H) or color-developing in situ hybridization (CISH), etc. I will.

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

[0120] Activation of the FGFR signaling pathway can be detected by methods known to those skilled in the art. Detection of signal activation can be performed, for example, by detecting FGF, a substrate of FGFR; by detecting the direct phosphorylation state or enzymatic activity of FGFR, a phosphorylating enzyme; by detecting the phosphorylation state or enzymatic activity of intracellular substrates and proteins downstream of the FGFR signaling cascade; or by detecting gene products or gene transcripts.

[0121] In another embodiment, tumors to which this disclosure applies include tumors that do not have abnormalities in the FGFR pathway.

[0122] In this disclosure, preferred daily doses of compound 1 or its salt on administration days include, for example, 4 mg to 160 mg, 4 mg to 24 mg, 12 to 24 mg, 16 to 24 mg, and 20 mg. More specifically, preferred daily doses and frequencies of administration on administration days include, once daily, 4 mg, 8 mg, 12 mg, 16 mg, and 20 mg. In another embodiment, preferred daily doses and frequencies of administration on administration days include 8 mg, 12 mg, 16 mg, and 20 mg. In another embodiment, preferred daily doses and frequencies of administration on administration days include 12 mg, 16 mg, and 20 mg. In yet another embodiment, preferred daily doses and frequencies of administration on administration days include 20 mg.

[0123] In some embodiments, this disclosure includes the fact that in cases of cancer types where a stronger effect is desired (e.g., brain tumors), the dose of compound 1 or a salt thereof may be greater than 20 mg once daily.

[0124] When compound 1 or its salt is administered intermittently, the daily dose is, for example, about 2 to 1000 mg of compound 1 or its pharmaceutically acceptable salt 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] Furthermore, the administration schedule for compound 1 or its salt may include daily administration or intermittent administration.

[0126] In this disclosure, "daily administration" refers to, for example, an administration schedule in which one cycle consists of administration for 21 consecutive days, and a drug-free period may be provided after each cycle is completed.

[0127] In this disclosure, "intermittent administration" is not particularly limited, as long as it is administered at least twice a week and the interval between administrations (the number of days between one administration day and the next administration day) is at least one day. For example, a dosing schedule consisting of one cycle per week, in which compound 1 or a pharmaceutically acceptable salt thereof is administered at intervals of 1 to 3 days (with an interval of 1 to 3 days between administrations) at least twice per cycle, and the cycle is repeated once or more times; A 14-day administration cycle in which compound 1 or a salt thereof is administered 4 to 7 times per cycle, with intervals of 1 to 3 days between administrations (1 to 3 days between administrations), and the cycle is repeated once or more times; A 14-day administration cycle, in which compound 1 or its salt is administered on days 1, 4, 8, and 11 of the 14-day cycle; A 14-day administration cycle, wherein compound 1 or its salt is administered on days 1, 3, 5, 7, 9, 11, and 13 of the 14-day cycle; The administration schedule is one cycle of 14 days, and the 14 days included in one cycle Among these, one example is an administration schedule in which compound 1 or a salt thereof is administered on days 1, 3, 5, 8, 10, and 12.

[0128] In one embodiment of the present disclosure, a dosing schedule is given in which 160 mg of compound 1 or a pharmaceutically acceptable salt thereof is administered once daily 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, and 8 mg.

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

[0130] When administering immune checkpoint inhibitors alone, preferred doses vary depending on the type of drug, but examples include 1-4 mg / kg (body weight) per dose, 2-3 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 1-3 mg / kg (body weight) or 80-240 mg per dose, 2-3 mg / kg (body weight) or 160-240 mg per dose, 2 mg / kg (body weight) per dose, 3 mg / kg (body weight) or 240 mg per dose, etc. In another embodiment, preferred doses of nivolumab when administered alone include 80-480 mg, 80 mg, 240 mg, or 480 mg per dose. When semiprimab is administered alone, a preferred dose is 350 mg per dose.

[0131] Preferred doses of atezolizumab when administered alone include 840-1680 mg, 840, 1200, or 1680 mg per dose.

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

[0133] Preferred daily doses of nivolumab on administration days as described herein include 40-480 mg, 80, 240, or 480 mg per dose. The administration interval for nivolumab is preferably 2-4 weeks, more preferably 2-3 weeks, and even more preferably 2 weeks.

[0134] In another preferred embodiment, the dosage and administration interval of nivolumab is as follows: 80 mg or 240 mg of nivolumab is administered four times at 3-week intervals, and then 240 mg of nivolumab is administered at 2-week intervals starting from the fifth dose. In this disclosure, preferred daily doses of semiprimab on administration days include 175-350 mg and 350 mg. The administration interval for semiprimab is preferably 2-4 weeks, more preferably 2-3 weeks, and even more preferably 2 weeks.

[0135] Preferred daily doses of atezolizumab on administration days as described herein include 420-1680 mg, 840 mg, 1200 mg, and 1680 mg per dose. The administration interval for atezolizumab is preferably 2-4 weeks, more preferably 2-3 weeks, and even more preferably 3 weeks.

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

[0137] The preferred daily dose of duravalumab on the day of administration in this disclosure includes 5.0 to 10 mg / kg (body weight) or 10 mg / kg (body weight) per dose. The administration interval for duravalumab is preferably 2 to 4 weeks, more preferably 2 to 3 weeks, and even more preferably 2 weeks.

[0138] In this disclosure, preferred daily doses of avelumab on administration days include 5.0 to 10 g / kg (body weight) or 10 mg / kg (body weight) per dose. In another embodiment, preferred daily doses of avelumab on administration days include 400 to 800 mg or 800 mg per dose. The administration interval for avelumab is preferably 2 to 4 weeks, more preferably 2 to 3 weeks, and even more preferably 2 weeks.

[0139] Preferred daily doses of Compound 1 or its salt on administration days, as well as preferred daily doses of nivolumab, or combinations of dosage and administration, include the following: Compound 1 or a salt thereof as described herein is administered at a dose of 4 mg to 160 mg and nivolumab at a dose of 1 to 4 mg / kg (body weight) per dose. Compound 1 or a salt thereof as described herein is administered at a dose of 4 mg to 160 mg and nivolumab at a dose of 1 to 3 mg / kg (body weight) per dose. Compound 1 or a salt thereof as described herein 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 daily. Compound 1 or its salt as disclosed herein: 4 mg to 160 mg and nivolumab: 1 mg / dose kg (body weight). Compound 1 or its salt as disclosed herein: 4 mg to 160 mg and nivolumab: 2 mg / dose kg (body weight). Compound 1 or its salt as disclosed herein: 4 mg to 160 mg and nivolumab: 3 mg / dose kg (body weight). Compound 1 or a salt thereof as described in this disclosure is administered in doses of 4 mg to 160 mg, and nivolumab is administered in doses of 80 to 240 mg. Compound 1 or a salt thereof as described in this disclosure is administered in doses of 4 mg to 160 mg, and nivolumab is administered in doses of 80 to 480 mg. Compound 1 or a salt thereof as described in this disclosure is administered in doses of 4 mg to 160 mg, and nivolumab is administered in doses of 160 to 480 mg. Compound 1 or a salt thereof as described herein is administered in doses of 4 mg to 160 mg, and nivolumab is administered in single doses of 80 mg. Compound 1 or a salt thereof as described in this disclosure is administered in doses of 4 mg to 160 mg, and nivolumab is administered in single doses of 240 mg. Compound 1 or a salt thereof as described in this disclosure is administered in doses of 4 mg to 160 mg, and nivolumab is administered in single doses of 480 mg. Compound 1 or its salt in this disclosure is 4 mg to 160 mg, and nivolumab is 1 mg / kg. Every two weeks. Compound 1 or its salt in this disclosure is administered at a dose of 4 mg to 160 mg, and nivolumab is administered at a dose of 2 mg / kg. Every two weeks. Compound 1 or its salt in this disclosure is 4 mg to 160 mg, and nivolumab is 3 mg / kg. Every two weeks. Compound 1 or its salt in this disclosure is 4 mg to 160 mg, and nivolumab is 1 mg / kg. Every three weeks. Compound 1 or its salt in this disclosure is administered at a dose of 4 mg to 160 mg, and nivolumab is administered at a dose of 2 mg / kg. Every three weeks. Compound 1 or its salt in this disclosure is 4 mg to 160 mg, and nivolumab is 3 mg / kg. Every three weeks. Compound 1 or its salt in this disclosure is 4 mg to 160 mg, and nivolumab is 1 mg / kg. Every four weeks. Compound 1 or its salt in this disclosure is administered at a dose of 4 mg to 160 mg, and nivolumab is administered at a dose of 2 mg / kg. Every four weeks. Compound 1 or its salt in this disclosure is 4 mg to 160 mg, and nivolumab is 3 mg / kg. Every four weeks. Compound 1 or a salt thereof as described in this disclosure, administered at a dose of 4 mg to 160 mg, and nivolumab, administered at a dose of 80 mg every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 160 mg, along with nivolumab at a dose of 240 mg every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 160 mg, and nivolumab at a dose of 480 mg every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered at doses of 4 mg to 160 mg and nivolumab at doses of 80 mg every 3 weeks. Compound 1 or a salt thereof as described in this disclosure is administered at doses of 4 mg to 160 mg and nivolumab at doses of 240 mg every 3 weeks. Compound 1 or a salt thereof as described in this disclosure is administered at doses of 4 mg to 160 mg and nivolumab at doses of 480 mg every 3 weeks. Compound 1 or a salt thereof as described in this disclosure, administered at a dose of 4 mg to 160 mg, and nivolumab, administered at a dose of 80 mg every 4 weeks. Compound 1 or a salt thereof as described in this disclosure is administered at doses of 4 mg to 160 mg and nivolumab at doses of 240 mg every 4 weeks. Compound 1 or a salt thereof as described in this disclosure is administered at doses of 4 mg to 160 mg and nivolumab at doses of 480 mg every 4 weeks. Compound 1 or a salt thereof is administered in doses of 4 mg to 160 mg and nivolumab at 80 mg intervals for four doses, followed by 240 mg of nivolumab at 2-week intervals starting from the fifth dose. Compound 1 or a salt thereof is administered in doses of 4 mg to 160 mg and nivolumab at 240 mg intervals for four doses, followed by 240 mg of nivolumab at 2-week intervals starting from the fifth dose. Compound 1 or a salt thereof is administered at a dose of 4 mg to 160 mg and nivolumab at 80 mg intervals for four doses, followed by nivolumab at 480 mg intervals for the fifth dose onward. Compound 1 or a salt thereof is administered at a dose of 4 mg to 160 mg and nivolumab at 240 mg intervals for four doses, followed by nivolumab at 480 mg intervals for four doses starting from the fifth dose. Compound 1 or a salt thereof as disclosed herein is administered in doses of 4 mg to 24 mg and nivolumab at a dose of 1 to 4 mg / kg (body weight) per dose. Compound 1 or a salt thereof as disclosed herein is administered in doses of 4 mg to 24 mg and nivolumab at a dose of 1 to 3 mg / kg (body weight) per dose. Compound 1 or a salt thereof as disclosed herein is administered in doses of 4 mg to 24 mg and nivolumab at a dose of 2 to 3 mg / kg (body weight) per dose. Compound 1 or its salt as described in this disclosure is administered at a dose of 4 mg to 24 mg, and nivolumab is administered at a single dose of 1 mg / kJ. g (weight). Compound 1 or its salt as described in this disclosure is administered at a dose of 4 mg to 24 mg, and nivolumab is administered at a single dose of 2 mg / kJ. g (weight). Compound 1 or its salt as described in this disclosure is administered at a dose of 4 mg to 24 mg, and nivolumab is administered at a single dose of 3 mg / kJ. g (weight). Compound 1 or a salt thereof as described herein is administered in 4 mg to 24 mg doses, along with 80 to 240 mg of nivolumab in a single dose. Compound 1 or a salt thereof as described herein is administered in doses of 4 mg to 24 mg, and nivolumab is administered in doses of 80 to 480 mg. Compound 1 or a salt thereof as described in this disclosure is administered in doses of 4 mg to 24 mg and nivolumab in doses of 160 to 480 mg. Compound 1 or a salt thereof as described in this disclosure, 4 mg to 24 mg, and nivolumab, 80 mg, once daily. Compound 1 or a salt thereof as described in this disclosure, 4 mg to 24 mg, and nivolumab, 240 mg, once daily. Compound 1 or a salt thereof as described herein is administered in 4 mg to 24 mg doses, along with 480 mg of nivolumab. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 24 mg and nivolumab at a dose of 1 mg / kg every two weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 24 mg and nivolumab at a dose of 2 mg / kg every two weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 24 mg and nivolumab at a dose of 3 mg / kg every two weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 24 mg and nivolumab at a dose of 1 mg / kg every 3 weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 24 mg and nivolumab at a dose of 2 mg / kg every 3 weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 24 mg and nivolumab at a dose of 3 mg / kg every 3 weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 24 mg and nivolumab at a dose of 1 mg / kg every 4 weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 24 mg and nivolumab at a dose of 2 mg / kg every 4 weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 24 mg and nivolumab at a dose of 3 mg / kg every 4 weeks. Compound 1 or a salt thereof as described in this disclosure, administered at a dose of 4 mg to 24 mg, and nivolumab at a dose of 80 mg every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 24 mg and nivolumab at a dose of 240 mg every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 24 mg, and nivolumab at a dose of 480 mg every two weeks. Compound 1 or a salt thereof as described in this disclosure, administered at a dose of 4 mg to 24 mg, and nivolumab at a dose of 80 mg every three weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 24 mg and nivolumab at a dose of 240 mg every 3 weeks. Compound 1 or a salt thereof as described in this disclosure is administered at doses of 4 mg to 24 mg and nivolumab at doses of 480 mg every 3 weeks. Compound 1 or a salt thereof as disclosed herein, administered at a dose of 4 mg to 24 mg, and nivolumab, administered at a dose of 80 mg every 4 weeks. Compound 1 or its salt in this disclosure is administered in 4 mg to 24 mg doses, and nivolumab is administered in 240 mg doses. Weekly intervals. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 24 mg and nivolumab at a dose of 480 mg every 4 weeks. Compound 1 or a salt thereof is administered in doses of 4 mg to 24 mg and nivolumab at 80 mg intervals of 3 weeks for 4 doses, followed by nivolumab at 240 mg intervals of 2 weeks starting from the 5th dose. Compound 1 or a salt thereof is administered in doses of 4 mg to 24 mg and nivolumab at 240 mg intervals of 3 weeks for 4 doses, followed by nivolumab at 240 mg intervals of 2 weeks starting from the 5th dose. Compound 1 or a salt thereof is administered at a dose of 4 mg to 24 mg and nivolumab at 80 mg intervals of 3 weeks for 4 doses, followed by nivolumab at 480 mg intervals of 4 weeks starting from the 5th dose. The following regimens are administered: 4 mg to 24 mg of compound 1 or a salt thereof as described herein, and 240 mg of nivolumab at 3-week intervals for 4 doses, followed by 480 mg of nivolumab at 4-week intervals starting from the 5th dose. Compound 1 or a salt thereof in this disclosure, 12-24 mg and nivolumab, 1-4 mg / dose kg (body weight). Compound 1 or its salt in this disclosure, 12-24 mg, and nivolumab, 1-3 mg / dose kg (body weight). Compound 1 or a salt thereof in this disclosure, 12-24 mg and nivolumab, 2-3 mg / dose kg (body weight). Compound 1 or its salt as described in this disclosure is administered at a dose of 12-24 mg and nivolumab at a single dose of 1 mg / kg. (body weight). Compound 1 or its salt as described in this disclosure is administered at a dose of 12-24 mg and nivolumab at a single dose of 2 mg / kg. (body weight). Compound 1 or its salt as described in this disclosure is administered at a dose of 12-24 mg, and nivolumab is administered at a single dose of 3 mg / kg. (body weight). Compound 1 or a salt thereof as described herein is administered in doses of 12-24 mg and nivolumab in doses of 80-240 mg. Compound 1 or a salt thereof as described herein is administered in doses of 12-24 mg and nivolumab in doses of 80-480 mg. Compound 1 or a salt thereof as described herein is administered in doses of 12-24 mg and nivolumab in doses of 160-480 mg. Compound 1 or a salt thereof as described herein is administered in doses of 12-24 mg and nivolumab in a single dose of 80 mg. Compound 1 or a salt thereof as disclosed herein, 12-24 mg, and nivolumab, 240 mg, once daily. Compound 1 or a salt thereof as disclosed herein, 12-24 mg, and nivolumab, 480 mg, once daily. Compound 1 or a salt thereof as disclosed herein, 12-24 mg, and nivolumab, 1 mg / kg, every two weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 12-24 mg and nivolumab at a dose of 2 mg / kg every two weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 12-24 mg and nivolumab at a dose of 3 mg / kg every two weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 12-24 mg and nivolumab at a dose of 1 mg / kg every 3 weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 12-24 mg and nivolumab at a dose of 2 mg / kg every 3 weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 12-24 mg and nivolumab at a dose of 3 mg / kg every 3 weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 12-24 mg and nivolumab at a dose of 1 mg / kg every 4 weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 12-24 mg and nivolumab at a dose of 2 mg / kg every 4 weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 12-24 mg and nivolumab at a dose of 3 mg / kg every 4 weeks. Compound 1 or a salt thereof as described in this disclosure, administered at a dose of 12-24 mg and nivolumab at a dose of 80 mg every two weeks. Compound 1 or a salt thereof as described herein is administered at a dose of 12-24 mg and nivolumab at a dose of 240 mg every two weeks. Compound 1 or a salt thereof as described herein is administered at a dose of 12-24 mg and nivolumab at a dose of 480 mg every two weeks. Compound 1 or a salt thereof as disclosed herein, administered in doses of 12-24 mg and nivolumab, administered in doses of 80 mg every three weeks. Compound 1 or a salt thereof as described in this disclosure, administered at 12-24 mg doses, and nivolumab at 240 mg doses every 3 weeks. Compound 1 or a salt thereof as described in this disclosure, administered at 12-24 mg doses and nivolumab at 480 mg doses every 3 weeks. Compound 1 or a salt thereof as described herein, administered at a dose of 12-24 mg and nivolumab at a dose of 80 mg every four weeks. Compound 1 or a salt thereof as described in this disclosure, administered at 12-24 mg doses and nivolumab at 240 mg doses every 4 weeks. Compound 1 or a salt thereof as described in this disclosure, administered at 12-24 mg doses and nivolumab at 480 mg doses every four weeks. Compound 1 or a salt thereof is administered in doses of 12-24 mg and nivolumab at 80 mg intervals for four doses, followed by 240 mg of nivolumab at 2-week intervals starting from the fifth dose. Compound 1 or a salt thereof is administered in doses of 12-24 mg and nivolumab at 240 mg intervals of 3 weeks for 4 doses, followed by nivolumab at 240 mg intervals of 2 weeks starting from the 5th dose. Compound 1 or a salt thereof is administered at a dose of 12-24 mg and nivolumab at 80 mg every 3 weeks for 4 doses, followed by nivolumab at 480 mg every 4 weeks starting from the 5th dose. The following regimen involves administering 12-24 mg of compound 1 or a salt thereof and 240 mg of nivolumab at 3-week intervals for four doses, followed by 480 mg of nivolumab at 4-week intervals starting from the fifth dose. Compound 1 or a salt thereof in this disclosure, 16-24 mg, and nivolumab, 1-4 mg / dose kg (body weight). Compound 1 or its salt in this disclosure, 16-24 mg, and nivolumab, 1-3 mg / dose kg (body weight). Compound 1 or its salt in this disclosure, 16-24 mg, and nivolumab, 2-3 mg / dose kg (body weight). Compound 1 or its salt as described in this disclosure, 16-24 mg, and nivolumab, 1 mg / kg per dose. (body weight). Compound 1 or its salt as described in this disclosure is administered at a dose of 16-24 mg and nivolumab at a single dose of 2 mg / kg. (body weight). Compound 1 or its salt as described in this disclosure is administered at a dose of 16-24 mg and nivolumab at a single dose of 3 mg / kg. (body weight). Compound 1 or a salt thereof as described herein is administered in doses of 16-24 mg and nivolumab in doses of 80-240 mg. Compound 1 or a salt thereof as described herein is administered in doses of 16-24 mg and nivolumab in doses of 80-480 mg. Compound 1 or a salt thereof as described herein is administered in doses of 16-24 mg and nivolumab in doses of 160-480 mg. Compound 1 or a salt thereof as described herein is administered in doses of 16-24 mg and nivolumab in a single dose of 80 mg. Compound 1 or a salt thereof as disclosed herein, 16-24 mg, and nivolumab, 240 mg, once daily. Compound 1 or a salt thereof as disclosed herein, 16-24 mg, and nivolumab, 480 mg, once daily. Compound 1 or a salt thereof as disclosed herein, 16-24 mg, and nivolumab, 1 mg / kg, every two weeks. Compound 1 or its salt in this disclosure is administered in a dose of 16-24 mg and nivolumab at a dose of 2 mg / kg. Weekly intervals. Compound 1 or a salt thereof in this disclosure is administered at a dose of 16-24 mg and nivolumab at a dose of 3 mg / kg every two weeks. Compound 1 or a salt thereof in this disclosure, administered at a dose of 16-24 mg and nivolumab at a dose of 1 mg / kg every 3 weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 16-24 mg and nivolumab at a dose of 2 mg / kg every 3 weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 16-24 mg and nivolumab at a dose of 3 mg / kg every 3 weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 16-24 mg and nivolumab at a dose of 1 mg / kg every 4 weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 16-24 mg and nivolumab at a dose of 2 mg / kg every 4 weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 16-24 mg and nivolumab at a dose of 3 mg / kg every 4 weeks. Compound 1 or a salt thereof as described in this disclosure, administered at 16-24 mg and nivolumab at 80 mg every two weeks. Compound 1 or a salt thereof as described in this disclosure, administered at a dose of 16-24 mg and nivolumab at a dose of 240 mg every two weeks. Compound 1 or a salt thereof as described in this disclosure, administered at a dose of 16-24 mg and nivolumab at a dose of 480 mg every two weeks. Compound 1 or a salt thereof as disclosed herein, administered at a dose of 16-24 mg and nivolumab at a dose of 80 mg every three weeks. Compound 1 or a salt thereof as described in this disclosure, administered at 16-24 mg doses, and nivolumab at 240 mg doses every 3 weeks. Compound 1 or a salt thereof as described in this disclosure, administered at 16-24 mg and nivolumab at 480 mg every 3 weeks. Compound 1 or a salt thereof as described in this disclosure, administered at a dose of 16-24 mg and nivolumab at a dose of 80 mg every four weeks. Compound 1 or a salt thereof as described in this disclosure, administered at 16-24 mg doses, and nivolumab at 240 mg doses every 4 weeks. Compound 1 or a salt thereof as described in this disclosure, administered at a dose of 16-24 mg and nivolumab at a dose of 480 mg every four weeks. Compound 1 or a salt thereof is administered in doses of 16-24 mg and nivolumab at 80 mg intervals for four doses, followed by 240 mg of nivolumab at 2-week intervals starting from the fifth dose. The following regimens are administered: 16-24 mg of compound 1 or a salt thereof and 240 mg of nivolumab at 3-week intervals for 4 doses, followed by 240 mg of nivolumab at 2-week intervals starting from the 5th dose. Compound 1 or a salt thereof is administered at a dose of 16-24 mg and nivolumab at 80 mg every 3 weeks for 4 doses, followed by nivolumab at 480 mg every 4 weeks starting from the 5th dose. The following regimens are administered: 16-24 mg of compound 1 or a salt thereof as described herein, and 240 mg of nivolumab at 3-week intervals for 4 doses, followed by 480 mg of nivolumab at 4-week intervals starting from the 5th dose.

[0140] Examples of the number of daily doses, dosage, and daily dose of nivolumab, or combinations of dosage and administration, of Compound 1 or its salt on the day of administration in this disclosure include the following: Compound 1 or a salt thereof as described herein is administered once daily at a dose of 4 mg and nivolumab at a dose of 1-4 mg / kg (body weight) once daily. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 4 mg and nivolumab at a dose of 1-3 mg / kg (body weight) once daily. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and nivolumab is administered at a dose of 2-3 mg. / kg (body weight). Compound 1 or its salt as disclosed herein is administered once daily at a dose of 4 mg and nivolumab at a dose of 1 mg / kJ. g (weight). Compound 1 or its salt as disclosed herein is administered once daily at a dose of 4 mg, and nivolumab is administered once daily at a dose of 2 mg / kJ. g (weight). Compound 1 or its salt as disclosed herein is administered once daily at a dose of 4 mg, and nivolumab is administered once daily at a dose of 3 mg / kJ. g (weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and nivolumab is administered at a dose of 80-240 mg. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 4 mg, and nivolumab is administered at a dose of 80-480 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and nivolumab is administered at a dose of 160-480 mg. Compound 1 or a salt thereof as disclosed herein, 4 mg once daily, and nivolumab, 80 mg once daily. Compound 1 or a salt thereof as disclosed herein, 4 mg once daily, and nivolumab, 240 mg once daily. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and nivolumab is administered once daily at a dose of 480 mg. Compound 1 or a salt thereof, once daily at a dose of 4 mg, and nivolumab at a dose of 1 mg / kg every two weeks. Compound 1 or a salt thereof, once daily at a dose of 4 mg, and nivolumab at a dose of 2 mg / kg every two weeks. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 4 mg, and nivolumab is administered at a dose of 3 mg / kg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and nivolumab is administered at a dose of 1 mg / kg every 3 weeks. Compound 1 or a salt thereof, once daily at a dose of 4 mg, and nivolumab at a dose of 2 mg / kg every 3 weeks. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 4 mg and nivolumab at a dose of 3 mg / kg every 3 weeks. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 4 mg, and nivolumab is administered at a dose of 1 mg / kg every 4 weeks. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 4 mg, and nivolumab is administered at a dose of 2 mg / kg every 4 weeks. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 4 mg and nivolumab at a dose of 3 mg / kg every 4 weeks. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 4 mg, and nivolumab is administered at a dose of 80 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and nivolumab is administered at a dose of 240 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and nivolumab is administered at a dose of 480 mg every two weeks. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 4 mg, and nivolumab at a dose of 80 mg every three weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and nivolumab is administered at a dose of 240 mg every 3 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and nivolumab is administered at a dose of 480 mg every 3 weeks. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 4 mg, and nivolumab is administered at a dose of 80 mg every 4 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and nivolumab is administered at a dose of 240 mg every 4 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and nivolumab is administered at a dose of 480 mg every 4 weeks. Compound 1 or a salt thereof is administered once daily at a dose of 4 mg and nivolumab at 80 mg every 3 weeks for 4 doses, followed by nivolumab at 240 mg every 2 weeks starting from the 5th dose. Compound 1 or a salt thereof is administered once daily at a dose of 4 mg and nivolumab at 240 mg intervals of 3 weeks for 4 doses, followed by nivolumab at 240 mg intervals of 2 weeks starting from the 5th dose. Compound 1 or a salt thereof is administered once daily at a dose of 4 mg and nivolumab at 80 mg every 3 weeks for 4 doses, followed by nivolumab at 480 mg every 4 weeks starting from the 5th dose. Compound 1 or a salt thereof is administered once daily at a dose of 4 mg and nivolumab at 240 mg every 3 weeks for 4 doses, followed by nivolumab at 480 mg every 4 weeks starting from the 5th dose. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and nivolumab is administered once daily at a dose of 1-4 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and nivolumab is administered once daily at a dose of 1-3 mg / kg (body weight). Compound 1 or a salt thereof, once daily at a dose of 8 mg and nivolumab at a dose of 2-3 mg / kg (body weight) once daily. Compound 1 or its salt as disclosed herein is administered once daily at a dose of 8 mg, and nivolumab is administered once daily at a dose of 1 mg / kJ. g (weight). Compound 1 or its salt as disclosed herein is administered once daily at a dose of 8 mg, and nivolumab is administered once daily at a dose of 2 mg / kJ. g (weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and nivolumab is administered once daily at a dose of 3 mg / kJ. g (weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and nivolumab is administered at a dose of 80-240 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and nivolumab is administered at a dose of 80-480 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and nivolumab is administered at a dose of 160-480 mg. Compound 1 or a salt thereof as disclosed herein, 8 mg once daily, and nivolumab, 80 mg once daily. Compound 1 or a salt thereof as disclosed herein, 8 mg once daily, and nivolumab, 240 mg once daily. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and nivolumab is administered once daily at a dose of 480 mg. Compound 1 or a salt thereof, once daily at a dose of 8 mg, and nivolumab at a dose of 1 mg / kg every two weeks. Compound 1 or a salt thereof, once daily at a dose of 8 mg, and nivolumab at a dose of 2 mg / kg every two weeks. Compound 1 or a salt thereof, once daily at a dose of 8 mg, and nivolumab at a dose of 3 mg / kg every two weeks. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and nivolumab is administered at a dose of 1 mg / kg every 3 weeks. Compound 1 or a salt thereof, once daily at a dose of 8 mg, and nivolumab at a dose of 2 mg / kg every 3 weeks. Compound 1 or a salt thereof, once daily at a dose of 8 mg, and nivolumab at a dose of 3 mg / kg every 3 weeks. Compound 1 or a salt thereof, once daily at a dose of 8 mg, and nivolumab at a dose of 1 mg / kg every 4 weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 8 mg and nivolumab at a dose of 2 mg / kg. Every four weeks. Compound 1 or a salt thereof, once daily at a dose of 8 mg, and nivolumab at a dose of 3 mg / kg every 4 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and nivolumab is administered at a dose of 80 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and nivolumab is administered at a dose of 240 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and nivolumab is administered at a dose of 480 mg every two weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 8 mg, and nivolumab at a dose of 80 mg every three weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and nivolumab is administered at a dose of 240 mg every three weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and nivolumab is administered at a dose of 480 mg every three weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 8 mg, and nivolumab at a dose of 80 mg every 4 weeks. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and nivolumab is administered at a dose of 240 mg every four weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and nivolumab is administered at a dose of 480 mg every four weeks. Compound 1 or a salt thereof is administered once daily at a dose of 8 mg and nivolumab at 80 mg intervals of 3 weeks for 4 doses, followed by nivolumab at 240 mg intervals of 2 weeks starting from the 5th dose. Compound 1 or a salt thereof is administered once daily at a dose of 8 mg and nivolumab at 240 mg intervals of 3 weeks for 4 doses, followed by nivolumab at 240 mg intervals of 2 weeks starting from the 5th dose. Compound 1 or a salt thereof is administered once daily at a dose of 8 mg and nivolumab at 80 mg every 3 weeks for 4 doses, followed by nivolumab at 480 mg every 4 weeks starting from the 5th dose. Compound 1 or a salt thereof is administered once daily at a dose of 8 mg and nivolumab at 240 mg every 3 weeks for 4 doses, followed by nivolumab at 480 mg every 4 weeks starting from the 5th dose. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and nivolumab is administered once daily at a dose of 1-4 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg and nivolumab at a dose of 1-3 mg / kg (body weight) once daily. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg, and nivolumab is administered once daily at a dose of 2-3 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg and nivolumab at a dose of 1 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg and nivolumab at a dose of 2 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg and nivolumab at a dose of 3 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and nivolumab is administered at a dose of 80-240 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and nivolumab is administered at a dose of 80-480 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and nivolumab is administered at a dose of 160-480 mg. Compound 1 or a salt thereof, once daily at a dose of 12 mg, and nivolumab, once daily at a dose of 80 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg and nivolumab at a dose of 240 mg. g. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and nivolumab is administered once daily at a dose of 480 mg. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 12 mg and nivolumab at a dose of 1 mg / kg. Every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 12 mg and nivolumab at a dose of 2 mg / kg. Every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 12 mg and nivolumab at a dose of 3 mg / kg. Every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 12 mg and nivolumab at a dose of 1 mg / kg. Every three weeks. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 12 mg and nivolumab at a dose of 2 mg / kg. Every three weeks. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 12 mg and nivolumab at a dose of 3 mg / kg. Every three weeks. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 12 mg and nivolumab at a dose of 1 mg / kg. Every four weeks. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 12 mg and nivolumab at a dose of 2 mg / kg. Every four weeks. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 12 mg and nivolumab at a dose of 3 mg / kg. Every four weeks. Compound 1 or a salt thereof, once daily at a dose of 12 mg, and nivolumab at a dose of 80 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and nivolumab is administered at a dose of 240 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and nivolumab is administered at a dose of 480 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and nivolumab at a dose of 80 mg every three weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and nivolumab is administered at a dose of 240 mg every three weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and nivolumab is administered at a dose of 480 mg every three weeks. Compound 1 or a salt thereof, once daily at a dose of 12 mg, and nivolumab at a dose of 80 mg every four weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and nivolumab is administered at a dose of 240 mg every four weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and nivolumab is administered at a dose of 480 mg every four weeks. Compound 1 or a salt thereof is administered once daily at a dose of 12 mg and nivolumab at 80 mg every 3 weeks for 4 doses, followed by nivolumab at 240 mg every 2 weeks starting from the 5th dose. Compound 1 or a salt thereof is administered once daily at a dose of 12 mg and nivolumab at 240 mg intervals of 3 weeks for 4 doses, followed by nivolumab at 240 mg intervals of 2 weeks starting from the 5th dose. Compound 1 or a salt thereof is administered once daily at a dose of 12 mg and nivolumab at 80 mg every 3 weeks for 4 doses, followed by nivolumab at 480 mg every 4 weeks starting from the 5th dose. Compound 1 or a salt thereof is administered once daily at a dose of 12 mg and nivolumab at 240 mg every 3 weeks for 4 doses, followed by nivolumab at 480 mg every 4 weeks starting from the 5th dose. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg, and nivolumab is administered once daily at a dose of 1-4 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and nivolumab is administered once daily at a dose of 1 to 3 mg. g / kg (body weight). Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg, and nivolumab is administered once daily at a dose of 2-3 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg and nivolumab at a dose of 1 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg and nivolumab at a dose of 2 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg and nivolumab at a dose of 3 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and nivolumab is administered at a dose of 80-240 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and nivolumab is administered at a dose of 80-480 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and nivolumab is administered at a dose of 160-480 mg. Compound 1 or a salt thereof, once daily at a dose of 16 mg and nivolumab, once daily at a dose of 80 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and nivolumab is administered once daily at a dose of 240 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and nivolumab is administered once daily at a dose of 480 mg. Compound 1 or its salt as described herein is administered once daily at a dose of 16 mg and nivolumab at a dose of 1 mg / kg. Every two weeks. Compound 1 or its salt as described herein is administered once daily at a dose of 16 mg and nivolumab at a dose of 2 mg / kg. Every two weeks. Compound 1 or its salt as disclosed herein is administered once daily at a dose of 16 mg and nivolumab at a dose of 3 mg / kg. Every two weeks. Compound 1 or its salt as described herein is administered once daily at a dose of 16 mg and nivolumab at a dose of 1 mg / kg. Every three weeks. Compound 1 or its salt as described herein is administered once daily at a dose of 16 mg and nivolumab at a dose of 2 mg / kg. Every three weeks. Compound 1 or its salt as disclosed herein is administered once daily at a dose of 16 mg and nivolumab at a dose of 3 mg / kg. Every three weeks. Compound 1 or its salt as described herein is administered once daily at a dose of 16 mg and nivolumab at a dose of 1 mg / kg. Every four weeks. Compound 1 or its salt as described herein is administered once daily at a dose of 16 mg and nivolumab at a dose of 2 mg / kg. Every four weeks. Compound 1 or its salt as disclosed herein is administered once daily at a dose of 16 mg and nivolumab at a dose of 3 mg / kg. Every four weeks. Compound 1 or a salt thereof, once daily at a dose of 16 mg, and nivolumab at a dose of 80 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and nivolumab is administered at a dose of 240 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and nivolumab is administered at a dose of 480 mg every two weeks. Compound 1 or a salt thereof, once daily at a dose of 16 mg, and nivolumab at a dose of 80 mg every three weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and nivolumab is administered at a dose of 240 mg every three weeks. Compound 1 or a salt thereof, once daily at a dose of 16 mg and nivolumab at a dose of 480 mg. Every three weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and nivolumab is administered at a dose of 80 mg every four weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and nivolumab is administered at a dose of 240 mg every four weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and nivolumab is administered at a dose of 480 mg every four weeks. Compound 1 or a salt thereof is administered once daily at a dose of 16 mg and nivolumab at 80 mg every 3 weeks for 4 doses, followed by nivolumab at 240 mg every 2 weeks starting from the 5th dose. Compound 1 or a salt thereof is administered once daily at a dose of 16 mg and nivolumab at 240 mg intervals of 3 weeks for 4 doses, followed by nivolumab at 240 mg intervals of 2 weeks starting from the 5th dose. Compound 1 or a salt thereof is administered once daily at a dose of 16 mg and nivolumab at 80 mg every 3 weeks for 4 doses, followed by nivolumab at 480 mg every 4 weeks starting from the 5th dose. Compound 1 or a salt thereof is administered once daily at a dose of 16 mg and nivolumab at 240 mg every 3 weeks for 4 doses, followed by nivolumab at 480 mg every 4 weeks starting from the 5th dose. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg and nivolumab at a dose of 1-4 mg / kg (body weight) once daily. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg and nivolumab at a dose of 1-3 mg / kg (body weight) once daily. Compound 1 or a salt thereof, once daily at a dose of 20 mg and nivolumab at a dose of 2-3 mg / kg (body weight) once daily. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg and nivolumab at a dose of 1 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg and nivolumab at a dose of 2 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg and nivolumab at a dose of 3 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and nivolumab is administered at a dose of 80-240 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and nivolumab is administered at a dose of 80-480 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and nivolumab is administered at a dose of 160-480 mg. Compound 1 or a salt thereof, once daily at a dose of 20 mg, and nivolumab, once daily at a dose of 80 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and nivolumab is administered once daily at a dose of 240 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and nivolumab is administered once daily at a dose of 480 mg. Compound 1 or its salt as described herein is administered once daily at a dose of 20 mg and nivolumab at a dose of 1 mg / kg. Every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 20 mg and nivolumab at a dose of 2 mg / kg. Every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 20 mg and nivolumab at a dose of 3 mg / kg. Every two weeks. Compound 1 or its salt as described herein is administered once daily at a dose of 20 mg and nivolumab at a dose of 1 mg / kg. Every three weeks. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 20 mg and nivolumab at a dose of 2 mg / kg. Every three weeks. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 20 mg and nivolumab at a dose of 3 mg / kg. Every three weeks. Compound 1 or its salt as described herein is administered once daily at a dose of 20 mg and nivolumab at a dose of 1 mg / kg. Every four weeks. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 20 mg and nivolumab at a dose of 2 mg / kg. Every four weeks. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 20 mg and nivolumab at a dose of 3 mg / kg. Every four weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 20 mg, and nivolumab at a dose of 80 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and nivolumab is administered at a dose of 240 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and nivolumab is administered at a dose of 480 mg every two weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 20 mg, and nivolumab at a dose of 80 mg every three weeks. The compound 1 in the present disclosure or its salt is administered once a day at 20 mg, and nivolumab is administered at 240 mg every three weeks. The compound 1 in the present disclosure or its salt is administered once a day at 20 mg, and nivolumab is administered at 480 mg every three weeks. The compound 1 in the present disclosure or its salt is administered once a day at 20 mg, and nivolumab is administered at 80 mg every four weeks. The compound 1 in the present disclosure or its salt is administered once a day at 20 mg, and nivolumab is administered at 240 mg every four weeks. The compound 1 in the present disclosure or its salt is administered once a day at 20 mg, and nivolumab is administered at 480 mg every four weeks. The compound 1 in the present disclosure or its salt is administered once a day at 20 mg, and nivolumab is administered at 80 mg every three weeks for 4 administrations, and then from the 5th administration, nivolumab is administered at 240 mg every two weeks. The compound 1 in the present disclosure or its salt is administered once a day at 20 mg, and nivolumab is administered at 240 mg every three weeks for 4 administrations, and then from the 5th administration, nivolumab is administered at 240 mg every two weeks. The compound 1 in the present disclosure or its salt is administered once a day at 20 mg, and nivolumab is administered at 80 mg every three weeks for 4 administrations, and then from the 5th administration, nivolumab is administered at 480 mg every four weeks. The compound 1 in the present disclosure or its salt is administered once a day at 20 mg, and nivolumab is administered at 240 mg every three weeks for 4 administrations, and then from the 5th administration, nivolumab is administered at 480 mg every four weeks.

[0141] The daily dosage of the compound 1 in the present disclosure or its salt on the administration day, as well as the daily dosage of atezolizumab, or the preferred combination of usage and dosage, includes the following: The compound 1 in the present disclosure or its salt is administered at 4 mg to 160 mg, and atezolizumab is administered at 420 to 1680 mg per administration. The compound 1 in the present disclosure or its salt is administered at 4 mg to 160 mg, and atezolizumab is administered at 840 to 1680 mg per administration. The compound 1 in the present disclosure or its salt is administered at 4 mg to 160 mg, and atezolizumab is administered at 840 mg per administration. The compound 1 in the present disclosure or its salt is administered at 4 mg to 160 mg, and atezolizumab is administered at 1200 mg per administration. Compound 1 in the present disclosure or a salt thereof, 4 mg to 160 mg, and atezolizumab, 1680 mg once. Compound 1 in the present disclosure or a salt thereof, 4 mg to 160 mg, and atezolizumab, 840 mg at 2-week intervals. Compound 1 in the present disclosure or a salt thereof, 4 mg to 160 mg, and atezolizumab, 1200 mg at 2-week intervals. Compound 1 in the present disclosure or a salt thereof, 4 mg to 160 mg, and atezolizumab, 1680 mg at 2-week intervals. Compound 1 in the present disclosure or a salt thereof, 4 mg to 160 mg, and atezolizumab, 840 mg at 3-week intervals. Compound 1 in the present disclosure or a salt thereof, 4 mg to 160 mg, and atezolizumab, 1200 mg at 3-week intervals. Compound 1 in the present disclosure or a salt thereof, 4 mg to 160 mg, and atezolizumab, 1680 mg at 3-week intervals. Compound 1 in the present disclosure or a salt thereof, 4 mg to 24 mg, and atezolizumab, 420 to 1680 mg once. Compound 1 in the present disclosure or a salt thereof, 4 mg to 24 mg, and atezolizumab, 840 to 1680 mg once. Compound 1 in the present disclosure or a salt thereof, 4 mg to 24 mg, and atezolizumab, 840 mg once. Compound 1 in the present disclosure or a salt thereof, 4 mg to 24 mg, and atezolizumab, 1200 mg once. Compound 1 in the present disclosure or a salt thereof, 4 mg to 24 mg, and atezolizumab, 1680 mg once. Compound 1 in the present disclosure or a salt thereof, 4 mg to 24 mg, and atezolizumab, 840 mg at 2-week intervals. Compound 1 in the present disclosure or a salt thereof, 4 mg to 24 mg, and atezolizumab, 1200 mg at 2-week intervals. Compound 1 in the present disclosure or a salt thereof, 4 mg to 24 mg, and atezolizumab, 1680 mg at 2-week intervals. Compound 1 in the present disclosure or a salt thereof, 4 mg to 24 mg, and atezolizumab, 840 mg at 3-week intervals. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 24 mg and atezolizumab at a dose of 1200 mg every 3 weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 24 mg and atezolizumab at a dose of 1680 mg every 3 weeks. Compound 1 or a salt thereof as described herein is administered in doses of 12-24 mg and atezolizumab in doses of 420-1680 mg. Compound 1 or a salt thereof as described herein is administered in doses of 12-24 mg and atezolizumab in doses of 840-1680 mg. Compound 1 or a salt thereof as described herein is administered in doses of 12-24 mg and atezolizumab in a single dose of 840 mg. Compound 1 or a salt thereof as described herein is administered in doses of 12-24 mg and atezolizumab in single doses of 1200 mg. Compound 1 or a salt thereof as described herein is administered in doses of 12-24 mg and atezolizumab in a single dose of 1680 mg. Compound 1 or a salt thereof as described in this disclosure, administered at a dose of 12-24 mg and atezolizumab at a dose of 840 mg every two weeks. Compound 1 or a salt thereof in this disclosure, 12-24 mg, and atezolizumab, 1200 mg. Every two weeks. Compound 1 or its salt as described in this disclosure, 12-24 mg, and atezolizumab, 1680 mg. Every two weeks. Compound 1 or a salt thereof as described herein is administered at a dose of 12-24 mg and atezolizumab at a dose of 840 mg every three weeks. Compound 1 or a salt thereof in this disclosure, 12-24 mg, and atezolizumab, 1200 mg. Every three weeks. Compound 1 or its salt as described in this disclosure, 12-24 mg, and atezolizumab, 1680 mg. Every three weeks. Compound 1 or a salt thereof as described in this disclosure is administered in doses of 16-24 mg and atezolizumab in doses of 420-1680 mg. Compound 1 or a salt thereof as described in this disclosure is administered in doses of 16-24 mg and atezolizumab in doses of 840-1680 mg. Compound 1 or a salt thereof as described herein is administered in doses of 16-24 mg and atezolizumab in a single dose of 840 mg. Compound 1 or a salt thereof as described herein is administered in doses of 16-24 mg and atezolizumab in single doses of 1200 mg. Compound 1 or a salt thereof as described herein is administered in doses of 16-24 mg and atezolizumab in a single dose of 1680 mg. Compound 1 or a salt thereof as described herein is administered at a dose of 16-24 mg and atezolizumab at a dose of 840 mg every two weeks. 16-24 mg of Compound 1 or its salt as described in this disclosure and 1200 mg of atezolizumab. Every two weeks. Compound 1 or its salt as described in this disclosure, 16-24 mg, and atezolizumab, 1680 mg. Every two weeks. Compound 1 or a salt thereof as described herein is administered at a dose of 16-24 mg and atezolizumab at a dose of 840 mg every three weeks. 16-24 mg of Compound 1 or its salt as described in this disclosure and 1200 mg of atezolizumab. Every three weeks. Compound 1 or its salt as described in this disclosure, 16-24 mg, and atezolizumab, 1680 mg. Every three weeks.

[0142] Examples of the number of daily doses, dosage, and daily dose of atezolizumab, or combinations of dosage and administration, of Compound 1 or its salt on the day of administration in this disclosure include the following: Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and atezolizumab is administered once daily at a dose of 420 to 1680 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and atezolizumab is administered once daily at a dose of 840-1680 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and atezolizumab is administered once daily at a dose of 840 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and atezolizumab is administered once daily at a dose of 1200 mg. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 4 mg, and atezolizumab is administered once daily at a dose of 1680 mg. Compound 1 or a salt thereof, once daily at 4 mg and atezolizumab at 840 mg. Every two weeks. Compound 1 in the present disclosure or a salt thereof at 4 mg once a day and atezolizumab at 1200 mg at two-week intervals. Compound 1 in the present disclosure or a salt thereof at 4 mg once a day and atezolizumab at 1680 mg at two-week intervals. Compound 1 in the present disclosure or a salt thereof at 4 mg once a day and atezolizumab at 840 mg at three-week intervals. Compound 1 in the present disclosure or a salt thereof at 4 mg once a day and atezolizumab at 1200 mg at three-week intervals. Compound 1 in the present disclosure or a salt thereof at 4 mg once a day and atezolizumab at 1680 m g at three-week intervals. Compound 1 in the present disclosure or a salt thereof at 8 mg once a day and atezolizumab at 420 - 1680 mg once. Compound 1 in the present disclosure or a salt thereof at 8 mg once a day and atezolizumab at 840 - 1680 mg once. Compound 1 in the present disclosure or a salt thereof at 8 mg once a day and atezolizumab at 840 mg once. Compound 1 in the present disclosure or a salt thereof at 8 mg once a day and atezolizumab at 1200 mg once. Compound 1 in the present disclosure or a salt thereof at 8 mg once a day and atezolizumab at 1680 mg once. Compound 1 in the present disclosure or a salt thereof at 8 mg once a day and atezolizumab at 840 mg at two-week intervals. Compound 1 in the present disclosure or a salt thereof at 8 mg once a day and atezolizumab at 1200 mg at two-week intervals. Compound 1 in the present disclosure or a salt thereof at 8 mg once a day and atezolizumab at 1680 mg at two-week intervals. Compound 1 in the present disclosure or a salt thereof at 8 mg once a day and atezolizumab at 840 mg at three-week intervals. Compound 1 in the present disclosure or a salt thereof at 8 mg once a day and atezolizumab at 1200 mg at three-week intervals. Compound 1 in the present disclosure or a salt thereof at 8 mg once a day and atezolizumab at 1680 mg at three-week intervals. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and atezolizumab is administered once daily at a dose of 420 to 1680 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and atezolizumab is administered once daily at a dose of 840-1680 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg, and atezolizumab is administered once daily at a dose of 840 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg and atezolizumab at a dose of 1200 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg, and atezolizumab is administered once daily at a dose of 1680 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and atezolizumab at a dose of 840 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and atezolizumab at a dose of 1200 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and atezolizumab at a dose of 1680 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and atezolizumab at a dose of 840 mg every three weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and atezolizumab at a dose of 1200 mg every three weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and atezolizumab at a dose of 1680 mg every three weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and atezolizumab is administered once daily at a dose of 420 to 1680 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and atezolizumab is administered once daily at a dose of 840-1680 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg and atezolizumab at a dose of 84 mg. 0 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg and atezolizumab at a dose of 1200 mg. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 16 mg, and atezolizumab is administered once daily at a dose of 1680 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and atezolizumab at a dose of 840 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and atezolizumab at a dose of 1200 mg every two weeks. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg, and atezolizumab at a dose of 1680 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and atezolizumab at a dose of 840 mg every three weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and atezolizumab at a dose of 1200 mg every three weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and atezolizumab at a dose of 1680 mg every three weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and atezolizumab is administered once daily at a dose of 420 to 1680 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and atezolizumab is administered once daily at a dose of 840-1680 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and atezolizumab is administered once daily at a dose of 840 mg. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg and atezolizumab at a dose of 1200 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and atezolizumab is administered once daily at a dose of 1680 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and atezolizumab at a dose of 840 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and atezolizumab at a dose of 1200 mg every two weeks. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg, and atezolizumab at a dose of 1680 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and atezolizumab at a dose of 840 mg every three weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and atezolizumab at a dose of 1200 mg every three weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and atezolizumab at a dose of 1680 mg every three weeks.

[0143] Preferred daily doses of Compound 1 or its salt on administration days, as well as preferred daily doses of ipilimumab, or combinations of dosage and administration, include the following: Compound 1 or a salt thereof as disclosed herein is administered in doses of 4 mg to 160 mg and ipilimumab at a dose of 0.5 to 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof as described herein 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 dose. Compound 1 or a salt thereof as described herein is administered at a dose of 4 mg to 160 mg, and ipilimumab is administered at a single dose of 1.0 mg / kg (body weight). Compound 1 or a salt thereof as described in this disclosure is administered in a single dose of 4 mg to 160 mg and ipilimumab in a single dose of 3 mg. mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered at a dose of 4 mg to 160 mg and ipilimumab at a dose of 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 160 mg and ipilimumab at a dose of 1.0 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 160 mg and ipilimumab at a dose of 1.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 160 mg and ipilimumab at a dose of 3.0 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 160 mg and ipilimumab at a dose of 3.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 160 mg and ipilimumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 160 mg and ipilimumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as described in this disclosure, administered in doses of 4 mg to 24 mg and ipilimumab, administered in doses of 0.5 to 10 mg / kg (body weight) at a time. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 24 mg and ipilimumab at a dose of 1.0 to 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof as described herein is administered at a dose of 4 mg to 24 mg, and ipilimumab is administered at a single dose of 1.0 mg / kg (body weight). Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 24 mg and ipilimumab at a dose of 3.0 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered in doses of 4 mg to 24 mg and ipilimumab at a dose of 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 24 mg and ipilimumab at a dose of 1.0 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 24 mg and ipilimumab at a dose of 1.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 24 mg and ipilimumab at a dose of 3.0 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 24 mg and ipilimumab at a dose of 3.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 24 mg and ipilimumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 24 mg and ipilimumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as described herein, administered in doses of 12-24 mg and ipilimumab, administered in doses of 0.5-10 mg / kg (body weight) at a time. Compound 1 or a salt thereof as described herein is administered at a dose of 12-24 mg and ipilimumab at a dose of 1.0-10 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered at a dose of 12-24 mg and ipilimumab at a dose of 1.0 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered at a dose of 12-24 mg and ipilimumab at a dose of 3.0 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered in doses of 12-24 mg and ipilimumab at a dose of 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 12-24 mg and ipilimumab at a dose of 1.0 mg / kg (body weight) every two weeks. Compound 1 or its salt in this disclosure is 12-24 mg and ipilimumab is 1.0 mg / kJ. g (body weight) every 3 weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 12-24 mg and ipilimumab at a dose of 3.0 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 12-24 mg and ipilimumab at a dose of 3.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof in this disclosure, administered at a dose of 12-24 mg and ipilimumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof in this disclosure, administered at a dose of 12-24 mg and ipilimumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as described herein, administered in doses of 16-24 mg and ipilimumab, administered in doses of 0.5-10 mg / kg (body weight) at a time. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 16-24 mg and ipilimumab at a dose of 1.0-10 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered at a dose of 16-24 mg and ipilimumab at a dose of 1.0 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered at a dose of 16-24 mg and ipilimumab at a dose of 3.0 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered in doses of 16-24 mg and ipilimumab at a dose of 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 16-24 mg and ipilimumab at a dose of 1.0 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as described in this disclosure, administered at a dose of 16-24 mg and ipilimumab at a dose of 1.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 16-24 mg and ipilimumab at a dose of 3.0 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 16-24 mg and ipilimumab at a dose of 3.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof in this disclosure, administered at a dose of 16-24 mg and ipilimumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof in this disclosure, administered at a dose of 16-24 mg and ipilimumab at a dose of 10 mg / kg (body weight) every 3 weeks.

[0144] Examples of the number of daily doses, dosage, and daily dose of ipilimumab, or combinations of dosage and administration, of Compound 1 or its salt on the day of administration in this disclosure include the following: Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and ipilimumab is administered once daily at a dose of 0.5-10 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and ipilimumab is administered once daily at a dose of 1.0 to 10 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and ipilimumab is administered once daily at a dose of 1.0 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and ipilimumab is administered once daily at a dose of 3.0 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered once daily at a dose of 4 mg and ipilimumab at a dose of 10 mg / kg (body weight). Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 4 mg and ipilimumab at a dose of 1.0 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and ipilimumab is administered at a dose of 1.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 4 mg and ipilimumab at a dose of 3.0 mg / kg (body weight), every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and ipilimumab is administered at a dose of 3.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 4 mg and ipilimumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 4 mg and ipilimumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and ipilimumab is administered once daily at a dose of 0.5-10 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and ipilimumab is administered once daily at a dose of 1.0 to 10 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and ipilimumab is administered once daily at a dose of 1.0 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and ipilimumab is administered once daily at a dose of 3.0 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg and ipilimumab at a dose of 10 mg / kg (body weight). Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 8 mg, and ipilimumab at a dose of 1.0 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and ipilimumab is administered at a dose of 1.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and ipilimumab is administered at a dose of 3.0 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and ipilimumab is administered at a dose of 3.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 8 mg and ipilimumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 8 mg and ipilimumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and ipilimumab is administered once daily at a dose of 0.5-10 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and ipilimumab is administered once daily at a dose of 1.0 to 10 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and ipilimumab is administered once daily at a dose of 1.0 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and ipilimumab is administered once daily at a dose of 3.0 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg and ipilimumab at a dose of 10 mg / kg (body weight). Compound 1 or a salt thereof is administered once daily at a dose of 12 mg and ipilimumab at a dose of 1.0 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof is administered once daily at a dose of 12 mg and ipilimumab at a dose of 1.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof is administered once daily at a dose of 12 mg and ipilimumab at a dose of 3.0 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and ipilimumab is administered at a dose of 3.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 12 mg, and ipilimumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily 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 as disclosed herein is administered once daily at a dose of 16 mg, and ipilimumab is administered once daily at a dose of 0.5-10 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and ipilimumab is administered once daily at a dose of 1.0 to 10 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and ipilimumab is administered once daily at a dose of 1.0 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and ipilimumab is administered once daily at a dose of 3.0 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg and ipilimumab at a dose of 10 mg / kg (body weight). Compound 1 or a salt thereof is administered once daily at a dose of 16 mg and ipilimumab at a dose of 1.0 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and ipilimumab is administered at a dose of 1.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof is administered once daily at a dose of 16 mg and ipilimumab at a dose of 3.0 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and ipilimumab is administered at a dose of 3.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof, once daily at a dose of 16 mg, and ipilimumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof is administered once daily at a dose of 16 mg and ipilimumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and ipilimumab is administered once daily at a dose of 0.5-10 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg and ipilimumab at a dose of 1.0 to 10 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and ipilimumab is administered once daily at a dose of 1.0 mg / kg (body weight). Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and ipilimumab is administered once daily at a dose of 3.0 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg and ipilimumab at a dose of 10 mg / kg (body weight). Compound 1 or a salt thereof is administered once daily at a dose of 20 mg and ipilimumab at a dose of 1.0 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof is administered once daily at a dose of 20 mg and ipilimumab at a dose of 1.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof is administered once daily at a dose of 20 mg and ipilimumab at a dose of 3.0 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof is administered once daily at a dose of 20 mg and ipilimumab at a dose of 3.0 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof is administered once daily at a dose of 20 mg and ipilimumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 20 mg and ipilimumab at a dose of 10 mg / kg (body weight) every 3 weeks.

[0145] Preferred daily doses of Compound 1 or its salt on administration days, as well as daily doses of duravalumab, or preferred combinations of dosage and administration, are as follows: Compound 1 or its salt as described in this disclosure is administered in 4 mg to 160 mg doses, along with duravalumab in 5 mg doses. 0~10mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered at a dose of 4 mg to 160 mg, and duravalumab at a dose of 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 160 mg and duravalumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 160 mg and duravalumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 24 mg, and duravalumab at a dose of 5.0 to 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof as disclosed herein is administered in doses of 4 mg to 24 mg, and duravalumab is administered at a dose of 10 mg / kg (body weight) once daily. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 24 mg and duravalumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 24 mg and duravalumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as described herein is administered at a dose of 12-24 mg and duravalumab at a dose of 5.0-10 mg / kg (body weight) per dose. Compound 1 or a salt thereof as disclosed herein is administered in doses of 12-24 mg and duravalumab at a dose of 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof in this disclosure, administered at a dose of 12-24 mg and duravalumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as described in this disclosure, administered at a dose of 12-24 mg and duravalumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as described herein is administered at a dose of 16-24 mg and duravalumab at a dose of 5.0-10 mg / kg (body weight) per dose. Compound 1 or a salt thereof as disclosed herein is administered in doses of 16-24 mg and duravalumab at a dose of 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof as described in this disclosure, administered at a dose of 16-24 mg and duravalumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as described in this disclosure, administered at a dose of 16-24 mg and duravalumab at a dose of 10 mg / kg (body weight) every 3 weeks.

[0146] Examples of the number of daily doses, dosage, and daily dose of duravalumab, or combinations of dosage and administration, of Compound 1 or its salt on the day of administration in this disclosure include the following: Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and duravalumab is administered once daily at a dose of 5.0-10 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered once daily at a dose of 4 mg, and duravalumab is administered once daily at a dose of 10 mg / kg (body weight). Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 4 mg, and duravalumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 4 mg, and duravalumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and duravalumab is administered once daily at a dose of 5.0-10 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered once daily at a dose of 8 mg, and duravalumab is administered once daily at a dose of 10 mg / kg (body weight). Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 8 mg, and duravalumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg and duravalumab at a dose of 10 mg / kg (body weight), every 3 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and duravalumab is administered once daily at a dose of 5.0-10 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered once daily at a dose of 12 mg, and duravalumab is administered once daily at a dose of 10 mg / kg (body weight). Compound 1 or a salt thereof, once daily at a dose of 12 mg, and duravalumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof, once daily at a dose of 12 mg, and duravalumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and duravalumab is administered once daily at a dose of 5.0-10 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg, and duravalumab is administered once daily at a dose of 10 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg, and duravalumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 16 mg, and duravalumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and duravalumab is administered once daily at a dose of 5.0-10 mg / kg (body weight). Compound 1 or a salt thereof as described herein is administered once daily at a dose of 20 mg, and duravalumab is administered once daily at a dose of 10 mg / kg (body weight). Compound 1 or a salt thereof is administered once daily at a dose of 20 mg, and duravalumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 20 mg, and duravalumab at a dose of 10 mg / kg (body weight) every 3 weeks.

[0147] Preferred daily doses of Compound 1 or its salt on administration days, as well as preferred daily doses of avelumab, or combinations of dosage and administration, include the following: Compound 1 or its salt as disclosed herein is administered in doses of 4 mg to 160 mg, and avelumab is administered in doses of 5.0 to 10 g / kg (body weight) per dose. Compound 1 or a salt thereof as described in this disclosure, administered in doses of 4 mg to 160 mg and avelumab at a dose of 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof as described in this disclosure is administered in doses of 4 mg to 160 mg, and avelumab in doses of 400 to 800 mg. Compound 1 or a salt thereof as described in this disclosure is administered in doses of 4 mg to 160 mg, and avelumab is administered in doses of 800 mg. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 160 mg, and avelumab at a dose of 800 mg every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered at doses of 4 mg to 160 mg and avelumab at doses of 800 mg every three weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 160 mg and avelumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 160 mg and avelumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or its salt as described herein is administered in doses of 4 mg to 24 mg and avelumab at a dose of 5.0 to 10 g / kg (body weight) per dose. Compound 1 or its salt as disclosed herein, 4 mg to 24 mg, and avelumab, 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof as described in this disclosure is administered in 4 mg to 24 mg doses, and avelumab is administered in 400 mg doses at a time. 00mg. Compound 1 or a salt thereof as described in this disclosure is administered in 4 mg to 24 mg doses, along with 800 mg of avelumab. Compound 1 or a salt thereof as described in this disclosure is administered at doses of 4 mg to 24 mg and avelumab at doses of 800 mg every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered at doses of 4 mg to 24 mg and avelumab at doses of 800 mg every three weeks. Compound 1 or a salt thereof in this disclosure is administered at a dose of 4 mg to 24 mg and avelumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof in this disclosure, administered at a dose of 4 mg to 24 mg and avelumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as described in this disclosure, administered in doses of 12-24 mg and avelumab, administered in doses of 5.0-10 g / kg (body weight) per dose. Compound 1 or a salt thereof in this disclosure, 12-24 mg, and avelumab, 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof as described in this disclosure is administered in doses of 12-24 mg and avelumab in doses of 400-800 mg. Compound 1 or a salt thereof as disclosed herein, 12-24 mg, and avelumab, 800 mg, once daily. Compound 1 or a salt thereof as disclosed herein, 12-24 mg, and avelumab, 800 mg, every two weeks. Compound 1 or a salt thereof as described in this disclosure, administered at 12-24 mg doses and avelumab at 800 mg doses every three weeks. Compound 1 or a salt thereof in this disclosure, administered at a dose of 12-24 mg and avelumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof in this disclosure, administered at a dose of 12-24 mg and avelumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as described herein, administered in doses of 16-24 mg and avelumab, administered in doses of 5.0-10 g / kg (body weight) per dose. Compound 1 or a salt thereof in this disclosure, 16-24 mg, and avelumab, 10 mg / kg (body weight) per dose. Compound 1 or a salt thereof as described in this disclosure is administered in doses of 16-24 mg and avelumab in doses of 400-800 mg. Compound 1 or a salt thereof as disclosed herein, 16-24 mg, and avelumab, 800 mg, once daily. Compound 1 or a salt thereof as disclosed herein, 16-24 mg, and avelumab, 800 mg, every two weeks. Compound 1 or a salt thereof as described in this disclosure, administered at 16-24 mg doses and avelumab at 800 mg doses every 3 weeks. Compound 1 or a salt thereof as described in this disclosure, administered at a dose of 16-24 mg and avelumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof in this disclosure, administered at a dose of 16-24 mg and avelumab at a dose of 10 mg / kg (body weight) every 3 weeks.

[0148] Examples of the number of daily doses, dosage, and daily dose of avelumab, or combinations of dosage and administration, of Compound 1 or its salt on the day of administration in this disclosure include the following: Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg and avelumab at a dose of 5.0-10 g / kg (body weight) once daily. Compound 1 or a salt thereof, once daily at a dose of 4 mg and avelumab at a dose of 10 mg / kg (body weight) Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg and avelumab at a dose of 400-8 mg. 00mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and avelumab is administered once daily at a dose of 800 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and avelumab at a dose of 800 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and avelumab at a dose of 800 mg every three weeks. Compound 1 or a salt thereof, once daily at a dose of 4 mg, and avelumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof, once daily at a dose of 4 mg and avelumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and avelumab is administered once daily at a dose of 5.0-10 g / kg (body weight). Compound 1 or a salt thereof, once daily at a dose of 8 mg and avelumab at a dose of 10 mg / kg (body weight) Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and avelumab is administered at a dose of 400-800 mg. Compound 1 or a salt thereof as described in this disclosure is administered once daily at a dose of 8 mg, and avelumab is administered once daily at a dose of 800 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and avelumab is administered at a dose of 800 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and avelumab at a dose of 800 mg every three weeks. Compound 1 or a salt thereof, once daily at a dose of 8 mg, and avelumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 8 mg and avelumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and avelumab is administered once daily at a dose of 5.0-10 g / kg (body weight). Compound 1 or a salt thereof, once daily at a dose of 12 mg and avelumab at a dose of 10 mg / kg (body weight) once daily. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and avelumab is administered at a dose of 400-800 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and avelumab is administered once daily at a dose of 800 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and avelumab at a dose of 800 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and avelumab at a dose of 800 mg every three weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 12 mg and avelumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof, once daily at a dose of 12 mg, and avelumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and avelumab is administered once daily at a dose of 5.0-10 g / kg (body weight). Compound 1 or a salt thereof, once daily at a dose of 16 mg and avelumab at a dose of 10 mg / kg (body weight) Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and avelumab is administered at a dose of 400-800 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg and avelumab at a dose of 800 mg. g. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and avelumab at a dose of 800 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and avelumab at a dose of 800 mg every three weeks. Compound 1 or a salt thereof, once daily at a dose of 16 mg, and avelumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof, once daily at a dose of 16 mg and avelumab at a dose of 10 mg / kg (body weight) every 3 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg and avelumab at a dose of 5.0-10 g / kg (body weight). Compound 1 or a salt thereof, once daily at 20 mg, and avelumab at 10 mg / kg (body weight) once daily. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and avelumab is administered at a dose of 400-800 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and avelumab is administered once daily at a dose of 800 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and avelumab at a dose of 800 mg every two weeks. Compound 1 or a salt thereof, as disclosed herein, is administered once daily at a dose of 20 mg, and avelumab at a dose of 800 mg every three weeks. Compound 1 or a salt thereof is administered once daily at a dose of 20 mg and avelumab at a dose of 10 mg / kg (body weight) every two weeks. Compound 1 or a salt thereof is administered once daily at a dose of 20 mg and avelumab at a dose of 10 mg / kg (body weight) every 3 weeks.

[0149] Preferred daily doses of Compound 1 or its salt on administration days, as well as preferred daily doses of semiprimab, or combinations of dosage and administration, include the following: Compound 1 or a salt thereof as described herein is administered in doses of 4 mg to 160 mg, and semiprimab in doses of 175 to 350 mg. Compound 1 or a salt thereof as described in this disclosure is administered in doses of 4 mg to 160 mg and semiplimab in single doses of 350 mg. Compound 1 or its salt in this disclosure is administered in doses of 4 mg to 160 mg, and semiprimab is administered in doses of 350 mg. Every two weeks. Compound 1 or its salt in this disclosure is administered in doses of 4 mg to 160 mg, and semiprimab is administered in doses of 350 mg. Every three weeks. Compound 1 or a salt thereof as described herein is administered in 4 mg to 24 mg doses, and semiprimab is administered in 175 to 350 mg doses. Compound 1 or a salt thereof as described in this disclosure is administered in doses of 4 mg to 24 mg and semiplimab in a single dose of 350 mg. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 24 mg and semiprimab at a dose of 350 mg every two weeks. Compound 1 or a salt thereof as described in this disclosure is administered at a dose of 4 mg to 24 mg and semiprimab at a dose of 350 mg every 3 weeks. Compound 1 or a salt thereof as described herein is administered in doses of 12-24 mg and semiprimab in doses of 175-350 mg. Compound 1 or a salt thereof as described herein is administered in doses of 12-24 mg and semiprimab in doses of 350 mg. Compound 1 or its salt in this disclosure is administered in 12-24 mg doses, and semiprimab is administered in 350 mg doses. Weekly intervals. Compound 1 or a salt thereof as described herein is administered at a dose of 12-24 mg and semiprimab at a dose of 350 mg every three weeks. Compound 1 or a salt thereof as described herein is administered in doses of 16-24 mg and semiprimab in doses of 175-350 mg. Compound 1 or a salt thereof as described herein is administered in doses of 16-24 mg and semiplimab in a single dose of 350 mg. Compound 1 or a salt thereof as described in this disclosure, administered at a dose of 16-24 mg and semiprimab at a dose of 350 mg every two weeks. Compound 1 or a salt thereof as described in this disclosure, administered at a dose of 16-24 mg and semiprimab at a dose of 350 mg every three weeks.

[0150] Examples of the number of daily doses, dosage, and daily dose of semiprimab on the day of administration of Compound 1 or its salt in this disclosure include the following: Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and semiplimab is administered at a dose of 175-350 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and semiplimab is administered once daily at a dose of 350 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and semiprimab at a dose of 350 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 4 mg, and semiprimab at a dose of 350 mg every 3 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and semiplimab is administered at a dose of 175-350 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and semiplimab is administered once daily at a dose of 350 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and semiplimab at a dose of 350 mg every two weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 8 mg, and semiplimab at a dose of 350 mg every 3 weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and semiplimab at a dose of 175-350 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 12 mg, and semiplimab is administered once daily at a dose of 350 mg. Compound 1 or a salt thereof, once daily at a dose of 12 mg and semiprimab at a dose of 350 mg. Every two weeks. Compound 1 or a salt thereof, once daily at a dose of 12 mg and semiprimab at a dose of 350 mg. Every three weeks. Compound 1 or a salt thereof as described herein is administered once daily at a dose of 16 mg, and semiplimab at a dose of 175-350 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 16 mg, and semiplimab is administered once daily at a dose of 350 mg. Compound 1 or a salt thereof, once daily at a dose of 16 mg and semiprimab at a dose of 350 mg. Every two weeks. Compound 1 or a salt thereof, once daily at a dose of 16 mg and semiprimab at a dose of 350 mg. Every three weeks. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg, and semiplimab is administered at a dose of 175-350 mg. Compound 1 or a salt thereof as disclosed herein is administered once daily at a dose of 20 mg and semiplimab at a dose of 350 mg. mg. Compound 1 or a salt thereof, once daily at a dose of 20 mg and semiprimab at a dose of 350 mg. Every two weeks. Compound 1 or a salt thereof, once daily at a dose of 20 mg and semiprimab at a dose of 350 mg. Every three weeks.

[0151] The ratio of compound 1 or a salt thereof to the immune checkpoint inhibitor used in this disclosure is not particularly limited, but preferably, the amount of 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 this disclosure, the proportion of compound 1 or its salt in a dosage form containing compound 1 or its salt is not particularly limited, but can be appropriately set in the range of, for example, 100 to 100,000% by mass, preferably 1,000 to 10,000% by mass. In this disclosure, the proportion of an immune checkpoint inhibitor in a dosage form containing an immune checkpoint inhibitor is not particularly limited, but can be appropriately set in the range of, for example, 100 to 100,000% by mass, preferably 1,000 to 10,000% by mass. Here, in embodiments in which an antitumor agent is formulated in multiple dosage forms, the above preferred proportion means the proportion of the active ingredient relative to the mass of the dosage form containing the active ingredient, not the proportion of the active ingredient relative to the total amount of the dosage form containing the active ingredient and the dosage form without the active ingredient. For example, in the case of the proportion of compound 1 or its salt, it means the mass % of compound 1 or its salt relative to the mass of the dosage form containing compound 1 or its salt only.

[0153] In one embodiment of this disclosure, the combination therapy of the present invention is administered to patients who have not previously received treatment with hormone therapy, immunotherapy (such as cancer peptide vaccine therapy), surgery, radiotherapy, or chemotherapeutic agents, i.e., treatment-naïve patients. In another embodiment, the combination therapy is administered to patients who have failed to achieve a sustained response after prior treatment with chemotherapeutic agents.

[0154] In one embodiment of this disclosure, the combination therapy of the present invention is administered to a patient who has no prior experience with immune checkpoint inhibitor treatment. In another embodiment, the combination therapy is administered to a patient who has prior experience with FGFR inhibitor treatment.

[0155] In one embodiment of this disclosure, a sustained response refers to the expansion and maintenance of the immune response against cancer, achieved by targeting immunotherapy such as immune checkpoint inhibitors. The sustained response can be determined, for example, by measuring the binding of immune checkpoint inhibitors to T lymphocytes.

[0156] In this disclosure, "recommended dose" refers to the dosage that provides the greatest therapeutic effect while being safe to use without causing serious side effects, as determined by clinical trials, etc. Specifically, this includes dosages approved, recommended, or suggested by public institutions and organizations such as the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan, the Food and Drug Administration (FDA) of the United States, and the European Medicines Agency (EMA), and which are described in package inserts, interview forms, treatment guidelines, etc., with dosages approved by one of the public institutions, PMDA, FDA, or EMA, being preferred.

[0157] The administration schedule for the antitumor agents described herein may be selected as appropriate depending on the type of cancer, stage of the disease, etc.

[0158] For compound 1 or its salt, daily for 1 to 21 days [for example, 3 weeks (21 days)]. The administration schedule is preferred, but a drug-free period may follow, and more preferably, it is administered daily for 3 weeks (21 days). For immune checkpoint inhibitors, the administration schedule 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 intervals of 2 or 3 weeks) is preferred, and more preferably at intervals of 3 weeks. In the case of atezolizumab, an administration schedule of administration at intervals of 2, 3, or 4 weeks is preferred, and more preferably at intervals of 3 weeks. In this disclosure, administration of drug A at X-day intervals means that the day drug A is administered is day 1, the following day is day 2, and so on. If the following day is designated as day 3, then the next administration of drug A will be on day X+1. Also, when calculating the administration schedule, "1 week," "2 weeks," "3 weeks," and "4 weeks" mean "7 days," "14 days," "21 days," and "28 days," respectively. Therefore, in this disclosure, administration of drug A at 3-week intervals means that if the day drug A is administered is designated as day 1, then the next administration of drug A will be on day 22.

[0159] The number of daily doses of the antitumor agents disclosed herein may be appropriately selected depending on the type and stage of cancer. When administered in combination with nivolumab or atezolizumab, once daily is preferred.

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

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

[0162] In one embodiment of this disclosure, the drug is administered to subjects who express PD-L1 at a rate of 1% or more, regardless of whether PD-L1 is expressed or not, and more preferably to subjects who express PD-L1 at a rate of 50% or more.

[0163] In one embodiment of this disclosure, the procedure is performed on a subject with a tumor that has tested positive for PD-L1 expression. PD-L1 expression can be detected using a diagnostic anti-human PD-L1 antibody or its antigen-binding fragment in an IHC assay on FFPE or frozen tissue sections of tumor samples taken from the patient. Typically, a physician would order a diagnostic test to determine PD-L1 expression using tumor tissue samples taken from the subject before initiating combination therapy with an immune checkpoint inhibitor and an FGFR inhibitor. However, it is assumed that a physician may order a pre- or post-treatment diagnostic test after the start of treatment, for example, at the end of a treatment cycle.

[0164] In this disclosure, “cancer” or “tumor” refers to a physiological condition in mammals characterized by uncontrolled cell proliferation. “Cancer” and “tumor” are synonymous and used interchangeably herein. Cancer includes solid tumors and hematological malignancies. Examples include, but are not limited to, carcinomas, lymphomas, leukemias, blastomas, sarcomas, and borderline malignancies (carcinoids).

[0165] Cancers that are eligible for the combined use method described herein include, for example, head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder and bile duct cancer, etc.), pancreatic cancer, small intestine cancer, colorectal cancer (colon and rectal cancer, colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma (malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, scavenging mesothelioma, etc.)), breast cancer, reproductive cancer (ovarian cancer, uterine cancer (cervical cancer, uterine cancer, endometrial cancer, etc.)), kidney cancer, bladder cancer, urothelial carcinoma, prostate cancer, testicular tumor, skin cancer (malignant melanoma, epidermal carcinoma, etc.), hematological cancer (multiple myeloma, acute myeloid leukemia, etc.), bone and soft tissue tumors, rhabdomyosarcoma, brain tumors, malignant schwannomas, neuroendocrine tumors, thyroid cancer, etc.). In one embodiment, the target cancers are bladder cancer, urothelial carcinoma, gastrointestinal cancers (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder and bile duct cancer, etc.), pancreatic cancer, small intestine cancer, colorectal cancer (colon and rectal cancer, colon cancer, rectal cancer, etc.), ovarian cancer, head and neck cancer, and uterine cancer (cervical cancer, endometrial cancer, etc.). Here, cancer includes not only the primary tumor but also cancers that have metastasized to other organs (such as the liver). Furthermore, the antitumor agent of this disclosure may be used in adjuvant chemotherapy performed after surgical removal of a tumor to prevent recurrence, or in adjuvant chemotherapy performed before surgical removal of a tumor.

[0166] In one embodiment of the present disclosure, the cancers targeted by the combination method include malignant melanoma, non-small cell lung cancer, Hodgxi 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 involves the use of a combination of two or more compounds / drugs (as defined above). In this application, the use of compounds / agents in combination, in combination with, and in combination with, means compounds / agents administered as part of the same overall treatment regimen. It is possible. The dosage of each of two or more compounds / drugs may differ: each may be administered simultaneously or at different times. Therefore, the compounds / drugs in a combination may be administered to the same doctor. It is understood that drug formulations (i.e., together) or different drug formulations (i.e., separately) may be administered consecutively (e.g., before or after) or simultaneously. However, while it exists as a single formulation, it is simultaneously non-integrated with different pharmaceutical formulations.

[0168] In this specification, "regmen" and "treatment regimen" refer to a plan that shows the type, amount, duration, and procedure of drugs in drug therapy in chronological order, indicating the dosage, method of administration, order of administration, and day of administration for each drug. An example of a treatment regimen is to start administering drugs to be used in combination on the first day of a cycle simultaneously or substantially at the same time. Alternatively, for example, if one cycle is 3 weeks, drug A may be administered first, and drug B may be administered one week later, but this is also included in a treatment regimen as they are administered substantially simultaneously as one cycle.

[0169] A therapeutic regimen of compound 1 or a salt thereof and an immune checkpoint inhibitor may also include other agents in addition to compound 1 or a salt thereof and an immune checkpoint inhibitor.

[0170] There are no particular restrictions on the administration form of the antitumor agent disclosed herein, and it can be appropriately selected according to the therapeutic purpose. Specifically, examples include oral preparations (tablets, coated tablets, powders, granules, capsules, liquids, etc.), injections, suppositories, patches, ointments, etc. In the case of compound 1 or its salt, oral preparations are preferred. In the case of anti-PD-1 antibodies, anti-PD-L1 antibodies, or anti-CTLA-4 antibodies, the above-mentioned administration forms are examples, and injections are preferred.

[0171] The antitumor agent of this disclosure may be an immune checkpoint inhibitor and compound 1 or a salt thereof as the active ingredient, or it may be a pharmaceutical composition prepared by a commonly known method using a pharmaceutically acceptable carrier, depending on the form of administration. Examples of such carriers include various types commonly used in conventional drugs, such as excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, isotonic agents, pH adjusters, buffers, stabilizers, colorants, flavoring agents, and odorants.

[0172] The antitumor agents disclosed herein may be formulated by dividing each active ingredient into multiple dosage forms or by combining them into a single dosage form, based on the administration form and administration schedule of each active ingredient. Furthermore, each formulation may be manufactured and sold together in a single package suitable for concomitant administration. The preparations may be manufactured and sold in separate packages. The same applies to embodiments of the pharmaceutical composition. Therefore, "a pharmaceutical composition containing an immune checkpoint inhibitor and compound 1 or a salt thereof as active ingredients" includes formulations in which each active ingredient is divided into multiple dosage forms, as well as formulations in which each active ingredient is combined into a single dosage form. A pharmaceutical composition in which each active ingredient is divided into multiple dosage forms includes formulations in which each preparation is combined into a single package suitable for concomitant administration, as well as formulations in which each preparation is divided into separate packages.

[0173] This disclosure relates to a kit formulation that includes an antitumor agent containing compound 1 or a salt thereof, and instructions for use that describe the co-administration of compound 1 or a salt thereof with an immune checkpoint inhibitor to cancer patients. Here, "instructions for use" refers to any document that describes the above dosage, and does not need to be legally binding, but preferably one that recommends the above dosage. Specifically, examples include package inserts, brochures, etc. Furthermore, a kit formulation that includes instructions for use may be one in which the instructions for use are printed and attached to the package of the kit formulation, or one in which the instructions for use are enclosed together with the antitumor agent in the package of the kit formulation.

[0174] Methods for detecting the mechanism of action of FGFR inhibitors and the development of resistance to immune checkpoint inhibitors include investigating the regulation of the tumor immune microenvironment (Non-Patent Literature 13), but the method is not limited to these.

[0175] The efficacy of immune checkpoint inhibitors depends on the surrounding microenvironment of the tumor, and cancer-associated fibroblasts (CAFs) are known to play a crucial role in this microenvironment. FGF is a factor that regulates the proliferation of fibroblast cells, and its receptor, FGFR, is a molecule that receives signals from FGF in cells and promotes cell proliferation. Myeoloid-derived suppressor cells (MDSCs) are immature myeloid cells that increase in tumor tissue, lymph nodes, and peripheral blood under pathological conditions, and are known to possess potent immunosuppressive activity.

[0176] MDSCs have been reported to be an indicator that can serve as a predictive marker for the effectiveness of immune checkpoint inhibitors and may contribute to patient resistance to immune checkpoint inhibitors (Non-Patent Literature 14).

[0177] In this specification, resistance to immune checkpoint inhibitors (also called resistance or refractory) refers to a condition in which, after administration of an immune checkpoint inhibitor, the therapeutic effect is no longer expected and disease progression is confirmed in at least one clinical evaluation; intolerance to immune checkpoint inhibitors; relapse after administration of immune checkpoint inhibitors; or a condition in which there is no prior experience with immune checkpoint inhibitor treatment but the therapeutic effect of immune checkpoint inhibitors is not expected. In some embodiments, this also includes the failure to show an effective effect on immune checkpoint inhibitors in pharmacological studies, for example, the response of cell lines that are considered ineffective. Resistance includes spontaneous resistance, in which the anticancer drug is ineffective from the beginning of treatment, and acquired resistance, in which the anticancer drug, which was initially effective, becomes ineffective as treatment continues, leading to cancer progression. In this specification, resistance encompasses both spontaneous resistance and acquired resistance.

[0178] In this specification, refractory to immune checkpoint inhibitors refers to a situation where, after administration of an immune checkpoint inhibitor, the inhibitor ceases to be effective and fails to exert its effects. One possible cause of refractory drug refractory is resistance.

[0179] The antitumor agents disclosed herein can be used in the treatment of cancer. When referring to cancer patients receiving treatment with the combination therapies or other treatment regimens described herein, “antitumor effect” means, for example, This refers to at least one evaluation such as PFS (progression-free survival), DCR (disease control rate), DOR (duration of response), OS (overall survival), ORR (objective response rate), DCR (disease control rate), TTR (time to first response), PROs (patient-reported outcomes). In one embodiment, when targeting solid tumors, the tumor evaluation to the combination therapy described herein is evaluated according to the RECIST 1.1 criteria (criteria for evaluating the effectiveness of solid tumors), and the antitumor effect is indicated as SD (stable), PR (partial response), CR (complete response), or PD (progression). In the case of brain tumors, tumor evaluation can also be performed by Gd-MRI (standard brain tumor MRI including pre- and post-enhancement using gadolium (Gd) chelate contrast agent). [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 in any way by these examples, and many modifications are possible within the technical concept of the present disclosure by those who are ordinary skill in the art.

[0181] (Example) Clinical trial of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof in combination with pembrolizumab in patients with cancer immunotherapy-resistant cancer (e.g., non-small cell lung cancer, esophageal cancer, urothelial carcinoma). This study evaluates the efficacy and safety of combination therapy with 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, patients will be administered compound 1 or its salt orally in various doses (e.g., 20 mg) for 21 days over a predetermined period (e.g., 24 weeks), and pembrolizumab (e.g., 200 mg once) will be administered intravenously every 3 weeks (every 21 days). One cycle will consist of 21 days, and this will be repeated. 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. Furthermore, compound 1 or its salt may be administered in combination with pembrolizumab to patients with prior pembrolizumab treatment experience.

[0182] The combination of compound 1 or a salt thereof with pembrolizumab may produce therapeutic effects that cannot be expected from these monotherapies alone. For example, in certain embodiments of this disclosure, the combination may be found to be more effective than at least one of the measured results of either monotherapy. Also, for example, in certain embodiments of this disclosure, a synergistic effect may be obtained by combining compound 1 or a salt thereof with pembrolizumab.

[0183] According to at least one of the following measurement results, the combination of compound 1 or a salt thereof and pembrolizumab may be more effective than either one alone: ​​a reduction in the number of cancer cells, a reduction in tumor size, a decrease in the rate of cancer cell invasion into peripheral organs, a decrease in the rate of tumor metastasis or tumor growth, an overall response rate, or an extension of progression-free survival or overall survival.

[0184] (Example 1) Effects on tumor immunity in a mouse mammary cancer cell 4T1 subcutaneous transplant model. Mouse mammary cancer cell line 4T1 was transplanted subcutaneously into 6-week-old male BALB / cAJcl mice. The day of cell transplantation was designated as Day 0, and from the following day (Day 1), compound 1 was administered at a dose of 15 mg / kg / day for 14 weeks. The drug was administered orally daily for several days. On the day following the final administration (Day 15), lymphocyte cell fractions were isolated from the tumor, spleen, and peripheral blood, and myeloid-derived immunosuppressive cells (MDSCs) (CD11b) were sorted using a cell sorter. + / Gr-1 + We measured the number of T cells, CD4-positive T cells, and CD8-positive T cells. In addition, mouse mammary cancer cells were prepared in the same manner as above, except that the dose of compound 1 was set to 30 mg / kg / day. A 4T1 subcutaneous graft model was created, drug administration was performed, and measurements of each cell were taken. For the control group, the same procedure was followed except that compound 1 was not administered. The results are shown in Figure 1.

[0185] Administration of compound 1 significantly reduced MDSCs in the spleen lymphocyte fraction compared to the control group (Student t-test, P<0.01) at all doses. MDSCs in the peripheral blood lymphocyte fraction showed a dose-dependent decrease compared to the control group. CD4-positive T cells and spleen lymphocytes in the peripheral blood lymphocyte fraction... Regarding CD8-positive T cells in the lymphocyte cell fraction and peripheral blood lymphocyte cell fraction, Cont It showed a dose-dependent increasing trend compared to rol.

[0186] These results suggest that compound 1 has an inhibitory effect on MDSCs in an in vivo model. The confirmation of this suggests that compound 1 may exhibit antitumor effects via an immunosuppressive mechanism. Furthermore, an increase in CD4-positive T cells and CD8-positive T cells was observed after administration of compound 1, confirming the activation of immune activity in tumor-bearing mice by compound 1. Therefore, it is suggested that combining compound 1 or its salt with an immune checkpoint inhibitor enhances the antitumor effect.

[0187] The 4T1 cells used in Example 1 were breast cancer cells without FGFR gene abnormalities. However, administration of compound 1 confirmed an inhibitory effect on MDSCs, and an increase in CD4-positive T cells and CD8-positive T cells was observed, demonstrating that compound 1 exhibits an antitumor effect via an immunosuppressive mechanism. Furthermore, by administering the anti-FGFR3 antibody Vofatamab to patients with urothelial carcinoma, the cancer changed from a "cold" state (low sensitivity to immune checkpoint inhibitors) to a "hot" state (high sensitivity), resulting in a response with pembrolizumab combination therapy even in patients without FGFR gene abnormalities (W. Choi et al., Presented at AACR Bladder cancer: Transforming the Field Special Conference, May 18-21, 2019). Denver, USA.

[0188] (Example 2) Phase I clinical trial in patients with solid tumors using (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof in combination with nivolumab. This study evaluates the efficacy and safety of compound 1 or its salt in combination with nivolumab in patients with solid tumors. The patient is administered compound 1 or its salt orally in various doses (8 mg, 12 mg, 16 mg, 20 mg) for 21 days over a specified period (e.g., 24 weeks), and nivolumab (240 mg once) is administered by intravenous infusion every two weeks (every 14 days). Alternatively, the patient may be administered compound 1 or its salt orally in various doses (8 mg, 12 mg, 16 mg, 20 mg) for 21 days over a specified period (e.g., 24 weeks), followed by nivolumab (80 mg) administered by intravenous infusion every 3 weeks (every 21 days) for 4 doses, and then nivolumab (240 mg) administered by intravenous infusion every 2 weeks (every 14 days) from the 5th dose onward. Alternatively, the patient may be administered compound 1 or its salt orally in various doses (8 mg, 12 mg, 16 mg, 20 mg) for 21 days over a specified period (e.g., 24 weeks), followed by nivolumab (240 mg) administered by intravenous infusion every 3 weeks (every 21 days) for 4 doses, and then nivolumab (240 mg) administered by intravenous infusion every 2 weeks (every 14 days) from the 5th dose onward. Compound 1 is administered repeatedly for 21 days. In some cases, compound 1 or a salt thereof and / or nivolumab may be administered additionally to further patients. Furthermore, compound 1 or a salt thereof may be administered in combination with nivolumab to patients with prior nivolumab treatment experience.

[0189] The combination of compound 1 or a salt thereof with nivolumab may produce therapeutic effects that cannot be expected from these monotherapies alone. For example, in one embodiment of this disclosure, the combination is either It may be found that the effect is higher compared to at least one of the measurement results of treatment alone. Furthermore, in one embodiment of this disclosure, for example, a synergistic effect may be obtained by using compound 1 or a salt thereof in combination with nivolumab.

[0190] According to at least one of the following measurement results, the combination of compound 1 or a salt thereof and nivolumab may be more effective than either one alone: ​​a reduction in the number of cancer cells, a reduction in tumor size, a decrease in the rate of cancer cell invasion into peripheral organs, a decrease in the rate of tumor metastasis or tumor growth, an increase in overall response rate, or an extension of progression-free survival or overall survival.

Claims

1. An antitumor agent containing (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof as an active ingredient, to be administered in combination with an immune checkpoint inhibitor (excluding pembrolizumab) to cancer patients resistant to immune checkpoint inhibitors.

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

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, semiprimab, spartalizumab, tislerizumab, BI754091, dostarizumab, sasamrimab, MGA-012, cetrelimab, AGEN-2034, zimberekimab, camrelizumab, buzigalimab, or valstilimab.

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. An 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 FGFR overexpression, FGFR gene abnormality, and FGFR signaling abnormality.

14. The antitumor agent according to any one of claims 1 to 13, wherein treatment with the antitumor agent produces a sustained response in the individual after discontinuation of treatment.

15. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is used before an immune checkpoint inhibitor, simultaneously with an immune checkpoint inhibitor, or after an immune checkpoint inhibitor, according to any one of claims 1 to 14.

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]pyrimidine-1-yl)pyrrolidine-1-yl)propa-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)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof and an immune checkpoint inhibitor are administered in the same treatment regimen.

18. For tumors resistant to immune checkpoint inhibitors, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered once daily in doses selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg, and 20 mg, and nivolumab is administered in doses 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. For tumors resistant to immune checkpoint inhibitors, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered once daily in doses selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg, and nivolumab is administered in doses 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. For tumors resistant to immune checkpoint inhibitors, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered once daily in doses 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. For tumors resistant to immune checkpoint inhibitors, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-en-1-one or a salt thereof is administered once daily in doses selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg, and 20 mg, and nivolumab is administered 80 mg at 3-week intervals for 4 doses, and then 240 mg of nivolumab is administered at 2-week intervals starting from the 5th dose. The antitumor agent according to claim 18.

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