Cancer therapy using 3,5-disubstituted benzene alkynyl compound and pembrolizumab

Abstract

To provide a novel combination therapy that uses (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidine-1-yl)propa-2-ene-1-one or salt thereof, and shows excellent anti-tumor effect to a cancer patient having tolerance against an immune checkpoint inhibitor.SOLUTION: Provided is an anti-tumor agent that contains (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d] pyrimidine-1-yl)pyrrolidine-1-yl)propane-2-ene-1-one or salt thereof as an active ingredient, and is administered to a cancer patient having tolerance against an immune checkpoint inhibitor in combination with pembrolizumab.SELECTED DRAWING: None

Description

[Technical field]

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

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

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

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

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

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

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

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

Non-licensed literature

[0009] [Non-licensed document 1] Nat.Rev.Cancer 10:116-129(2010) [Non-licensed document 2] J. Clin. Oncol. 24, 3664-3671 (2006) [Non-licensed document 3] Mol. Cancer Res. 3, 655-667 (2005)

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

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

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

[0012] Therefore, the present disclosure provides the following items 1 to 55.

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

[0014] Item 2. The antitumor agent according to Item 1, wherein the tumor has an abnormality in the FGFR pathway.

[0015] Item 3. The antitumor agent according to Item 2, wherein the abnormality in the FGFR pathway is at least one selected from the group consisting of overexpression of FGFR, an abnormality in the FGFR gene, and an abnormal state of FGFR signaling.

[0016] Item 4. The antitumor agent according to any one of Items 1 to 3, wherein treatment with the antitumor agent results in a sustained response in an individual after cessation of treatment.

[0017] Item 5. The antitumor agent according to any one of items 1 to 4, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is used before pembrolizumab, used simultaneously with pembrolizumab, or used after immuno-pembrolizumab.

[0018] Item 6. The antitumor agent according to any one of Items 1 to 5, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is used continuously or intermittently.

[0019] Item 7. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethyl) The antitumor agent according to any one of items 1 to 6, wherein)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and pembrolizumab are administered in the same therapeutic regimen.

[0020] Item 8. Targeting tumors resistant to immune checkpoint inhibitors used to administer (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg, and 20 mg once daily, and administer nivolumab at a dose selected from the group consisting of 1 mg / kg every 3 weeks, 2 mg / kg every 3 weeks, 3 mg / kg every 3 weeks, 80 mg every 3 weeks, 240 mg every 3 weeks, 1 mg / kg every 2 weeks, 2 mg / kg every 2 weeks, 3 mg / kg every 2 weeks, 80 mg, every 2 weeks, and 240 mg every 2 weeks; Item 8. The antitumor agent according to any one of Items 1 to 7.

[0021] Item 9. Targeting tumors resistant to immune checkpoint inhibitors (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg, and pembrolizumab is administered at a dose consisting of 200 mg every 3 weeks. Item 9. The antitumor agent according to any one of Items 1 to 8.

[0022] Item 10. The antitumor agent according to any one of Items 1 to 9, wherein the tumor having resistance to an immune checkpoint inhibitor is esophageal cancer or non-small cell lung cancer.

[0023] Item 11. A pharmaceutical composition comprising pembrolizumab and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as active ingredients.

[0024] Item 12. The pharmaceutical composition according to Item 11, for treating a cancer resistant to an immune checkpoint inhibitor.

[0025] Item 13. Use of pembrolizumab and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for the manufacture of an antitumor agent for treating a cancer resistant to an immune checkpoint inhibitor.

[0026] Item 14. Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for the manufacture of an antitumor agent to be administered in combination with pembrolizumab to patients having resistance to immune checkpoint inhibitors.

[0027] Item 15. Use of pembrolizumab for the manufacture of an antitumor agent to be administered in combination with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof to a patient having resistance to an immune checkpoint inhibitor.

[0028] Item 16. A combination of pembrolizumab and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for use in treating cancer resistant to immune checkpoint inhibitors.

[0029] Item 17. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for use in combination therapy with pembrolizumab in the treatment of cancer resistant to immune checkpoint inhibitors.

[0030] Item 18. Pembrolizumab for use in combination therapy with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof in the treatment of cancer resistant to immune checkpoint inhibitors.

[0031] Item 19. Use of pembrolizumab and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for treating cancer resistant to immune checkpoint inhibitors.

[0032] Item 20. Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for treating cancer resistant to immune checkpoint inhibitors in combination with pembrolizumab.

[0033] Item 21. Use of pembrolizumab in combination with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof to treat a cancer resistant to an immune checkpoint inhibitor.

[0034] Item 22. A method for treating a cancer resistant to an immune checkpoint inhibitor, comprising administering a therapeutically effective amount of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and a therapeutically effective amount of pembrolizumab to a human in need thereof.

[0035] Item 23. An antitumor agent administered in combination with pembrolizumab to a cancer patient who has not been administered an immune checkpoint inhibitor, comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient.

[0036] Item 24. A pharmaceutical composition for treating cancer in a cancer patient who has not been administered an immune checkpoint inhibitor, comprising pembrolizumab and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient.

[0037] Item 25. Item 24 for treating cancer resistant to immune checkpoint inhibitors The pharmaceutical composition described in

[0038] Item 26. Use of pembrolizumab and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for the manufacture of an antitumor agent for treating cancer in a cancer patient who has not been administered an immune checkpoint inhibitor.

[0039] Item 27. Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for the manufacture of an antitumor agent to be administered in combination with pembrolizumab to cancer patients who have not been administered an immune checkpoint inhibitor.

[0040] Item 28. Use of pembrolizumab for the manufacture of an antitumor agent to be administered in combination with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof to a cancer patient who has not been administered an immune checkpoint inhibitor.

[0041] Item 29. A combination of pembrolizumab and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for use in treating cancer in cancer patients who have not been administered an immune checkpoint inhibitor.

[0042] Item 30. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for use in combination therapy with pembrolizumab in the treatment of cancer in cancer patients who have not been administered an immune checkpoint inhibitor.

[0043] Item 31. Pembrolizumab for use in combination therapy with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof in the treatment of cancer in cancer patients who have not been administered an immune checkpoint inhibitor.

[0044] Item 32. Use of pembrolizumab and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof to treat cancer in a cancer patient who has not been administered an immune checkpoint inhibitor.

[0045] Item 33. Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for treating cancer in a cancer patient who has not been administered an immune checkpoint inhibitor by combination therapy with pembrolizumab.

[0046] Item 34. Cancer in cancer patients who have not been administered an immune checkpoint inhibitor is treated with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)propan-2-yl 2. Use of pembrolizumab for the treatment of rheumatoid arthritis in combination with a cefotaxime or a salt thereof.

[0047] Item 35. A method for treating cancer in a cancer patient who has not been administered an immune checkpoint inhibitor, comprising administering a therapeutically effective amount of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and a therapeutically effective amount of pembrolizumab to a human in need thereof.

[0048] Item 36. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, pembrolizumab, or method according to any one of items 11 to 22, wherein the tumor has an abnormality in the FGFR pathway.

[0049] Item 37. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, pembrolizumab, or method according to Item 36, wherein the abnormality in the FGFR pathway is at least one selected from the group consisting of overexpression of FGFR, genetic abnormalities in FGFR, and abnormal states of FGFR signaling.

[0050] Item 38. An antitumor agent which contains (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient and is administered in combination with pembrolizumab to a cancer patient who has resistance to immune checkpoint inhibitors and has no abnormality in the FGFR pathway.

[0051] Item 39. A pharmaceutical composition for treating a cancer having no abnormality in the FGFR pathway, comprising pembrolizumab and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient.

[0052] Item 40. The pharmaceutical composition according to Item 24, for treating a cancer resistant to an immune checkpoint inhibitor.

[0053] Item 41. Use of pembrolizumab and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for the manufacture of an antitumor agent for treating cancers that do not have an abnormality in the FGFR pathway.

[0054] Item 42. Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for the manufacture of an antitumor agent to be administered in combination with pembrolizumab to cancer patients without abnormalities in the FGFR pathway.

[0055] Item 43. Use of pembrolizumab for the manufacture of an antitumor agent to be administered in combination with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof to a cancer patient without abnormalities in the FGFR pathway.

[0056] Item 44. A combination of pembrolizumab and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for use in treating cancers that do not have abnormalities in the FGFR pathway.

[0057] Item 45. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for use in combination therapy with pembrolizumab in the treatment of cancer not having an abnormality in the FGFR pathway.

[0058] Item 46. Pembrolizumab for use in combination with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof in the treatment of cancers not having an abnormality in the FGFR pathway.

[0059] Item 47. Use of pembrolizumab and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for treating cancers without abnormalities in the FGFR pathway.

[0060] Item 48. Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for treating cancers not having abnormalities in the FGFR pathway by combination therapy with pembrolizumab.

[0061] Item 49. Use of pembrolizumab to treat cancers not having abnormalities in the FGFR pathway in combination with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof.

[0062] Item 50. A method for treating a cancer that does not have an abnormality in the FGFR pathway, comprising administering a therapeutically effective amount of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and a therapeutically effective amount of pembrolizumab to a human in need thereof.

[0063] Item 51. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, pembrolizumab, or method according to any one of items 11 to 50, wherein treatment with compound 1 or a salt thereof and pembrolizumab results in a sustained response in the individual after cessation of treatment.

[0064] Item 52. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, pembrolizumab, or method according to any one of items 11 to 51, wherein compound 1 or a salt thereof is used before pembrolizumab, used simultaneously with pembrolizumab, or used after pembrolizumab.

[0065] Item 53. Compound 1 or a salt thereof is used continuously or intermittently, according to items 11 to 52. 2. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, pembrolizumab, or method according to any one of claims 1 to 11.

[0066] Item 54. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, pembrolizumab, or method according to any one of items 11 to 53, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, pembrolizumab, or method is administered in the same therapeutic regimen.

[0067] Item 55. The composition, use, combination, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof or pembrolizumab or method according to any one of items 11 to 54, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof or pembrolizumab is used by the following method: (a) administering (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg, and 20 mg once daily to a cancer patient having resistance to an immune checkpoint inhibitor, and administering pembrolizumab at a dose selected from the group consisting of 1 mg / kg every 3 weeks, 2 mg / kg every 3 weeks, and 200 mg every 3 weeks. Effect of the Invention

[0068] According to the present disclosure, it is possible to provide a new combination therapy that uses (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, which exhibits excellent antitumor effects for cancer patients who are resistant to immune checkpoint inhibitors. [Brief description of the drawings]

[0069] [Figure 1] 1 shows the results of Example 2 (the effect of Compound 1 on bone marrow-derived immunosuppressive cells (MDSC)). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0070] The present disclosure relates to the provision of combinations of compounds having FGFR inhibitory activity with immune checkpoint inhibitors, i.e., antitumor agents containing compounds having FGFR inhibitory activity that are administered in combination with immune checkpoint inhibitors, antitumor effect enhancers containing compounds having FGFR inhibitory activity, combinations of compounds having FGFR inhibitory activity with immune checkpoint inhibitors, and use of compounds having FGFR inhibitory activity in the manufacture of medicaments for the treatment of tumors in combination with immune checkpoint inhibitors.

[0071] In the present disclosure, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one, which provides an excellent antitumor effect when used in combination with an immune checkpoint inhibitor, is a disubstituted benzenealkynyl compound having the following structure: In this specification, the above compound is referred to as "Compound 1" for the sake of simplicity. Compound 1 is described as Example Compound 2 in the above Patent Document 2. Compound 1 or a salt thereof has an excellent FGFR inhibitory effect, and has been reported to inhibit the phosphorylation ability of the receptor protein tyrosine kinases of FGFR1, FGFR3, and FGFR4 to tyrosine in the substrate peptide sequence (Patent Document 2).

[0072] [ka]

[0073] The above-mentioned compound 1 or a pharma- ceutically acceptable salt thereof in the present disclosure can be synthesized, for example, based on the production method described in Patent Document 2, without being particularly limited thereto.

[0074] In the present disclosure, Compound 1 can be used as it is or in the form of a pharma- ceutically acceptable salt. The pharma- ceutically acceptable salt of Compound 1 includes, but is not limited to, addition salts with inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as acetic acid, citric acid, tartaric acid, and maleic acid, salts with alkali metals such as potassium and sodium, salts with alkaline earth metals such as calcium and magnesium, and salts with organic bases such as ammonium salts, ethylamine salts, and arginine salts.

[0075] The immune checkpoint inhibitor disclosed herein acts on immune checkpoint molecules, induces an anti-tumor immune response in the subject's body, and has the effect of controlling immune escape by tumors.

[0076] Examples of such substances include substances that promote the function of costimulatory molecules (stimulatory co-stimulatory molecules) and substances that suppress the function of coinhibitory molecules (inhibitory co-stimulatory molecules). Examples of immune checkpoint molecules include the B7 family (B7-1, B7-2, PD-L1, PD-L2, etc.), the CD28 family (CTLA-4, PD-1, etc.), the TNF superfamily (4-1B BL, OX40L), TNF receptor superfamily (4-1BB , OX40) molecules, and immune checkpoint inhibitors can be substances that target immune checkpoint molecules. For example, PD-1 pathway antagonists, ICO These include S pathway agonists, CTLA-4 pathway antagonists, CD28 pathway agonists, BTLA pathway antagonists, and 4-1BB pathway agonists.

[0077] PD-1 pathway antagonists inhibit the immunosuppressive signals produced by PD-1 expressed on T cells or its ligands PD-L1 or PD-L2, and examples of such antagonists include anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, PD-1 extracellular domain, PD-L1 extracellular domain, PD-L2 extracellular domain, PD-1-Ig (a fusion protein of the PD-1 extracellular domain and the FC region of Ig), PD-L1-Ig, PD-L2-Ig, PD-1 siRNA, PD-L1 siRNA, and PD-L2 siRNA.

[0078] These antibodies include immunoglobulins (IgA, IgD, IgE, IgG, IgM, IgY, etc.), Fab fragments, F(ab')2 fragments, single-chain antibody fragments (scFv), single domain antibodies, diabodies, etc. (Nat. Rev. Immunol., 6:343-357, 2006), including monoclonal or polyclonal antibodies such as human antibodies, humanized antibodies, chimeric antibodies, mouse antibodies, llama antibodies, and chicken antibodies. Preferably, the antibody is a humanized IgG monoclonal antibody or a human IgG monoclonal antibody.

[0079] These agonists and antagonists can be produced by generally known production methods.

[0080] In addition, an anti-PD-1 antibody, pembrolizumab, is already on the market and can also be used.

[0081] In the present disclosure, immune checkpoint inhibitors may be used alone or in combination of two or more.

[0082] In the present disclosure, when two or more immune checkpoint inhibitors are used, for example, immune checkpoint inhibitors such as anti-PD-1 antibody and anti-CTLA-4 antibody can be used in combination, or bispecific antibodies capable of binding to different immune checkpoint molecules can be used. An example of a bispecific antibody capable of binding to both PD-1 and CTLA-4 is XmAb20717 (PD-1×CTLA-4).

[0083] In the present disclosure, treatment includes procedures performed with the intent of curing or ameliorating a disease, or inhibiting the progression or recurrence of a disease, or alleviating symptoms. Treatment includes administration of a drug before or after a surgical procedure, or administration of a drug before, during, or after radiation therapy.

[0084] The therapeutically effective amount of an antibody that blocks the interaction between an immune checkpoint molecule and Compound 1 or a salt thereof will depend on several factors, including, but not limited to, the stage and severity of the cancer, as well as other factors related to the health of the patient. Those skilled in the art will know how to determine a therapeutically effective amount.

[0085] In some embodiments, the present disclosure is used for tumors having abnormalities in the FGFR pathway, hi some embodiments, the FGFR is selected from the group consisting of FGFR1, FGFR2, FGFR3 and FGFR4.

[0086] In one embodiment, the tumors to which the present disclosure is applicable are preferably tumors having an abnormality in the FGFR pathway. The abnormality in the FGFR pathway includes overexpression of FGFR, FGF These include R gene abnormalities and abnormal FGFR signaling states.

[0087] In one embodiment, the present disclosure is administered to a subject with or without abnormality in FGF / FGFR, preferably to a subject with abnormality in the FGFR pathway. Even in carcinomas without FGFR gene abnormality, compound 1 can promote the antitumor effect of immune checkpoint inhibitors. It is known that the sensitivity of cancer to immune checkpoint inhibitors is also affected by the cancer microenvironment. The microenvironment includes, but is not limited to, cell groups controlled by FGF / FGFR pathway activation, such as cancer associated fibroblasts (CAFs), and it is known that these cell groups attenuate the sensitivity of cancer to immune checkpoint inhibitors. It is considered that administration of compound 1 promotes the effect of immune checkpoint inhibitors on cancer by causing changes in the microenvironment, including inactivation of CAFs.

[0088] Overexpression of FGFR includes, for example, gene expression and high expression of gene product protein. The presence or absence of FGFR expression can be detected by a method known to those skilled in the art. Detection of gene expression and high expression of gene product protein can be performed by a known method, for example, a method using an antibody (immunohistochemical staining, enzyme-linked immunosorbent assay (ELISA), flow cytometry, immunoblotting, etc.), a method using a nucleic acid (in situ hybridization, PCR, Northern blotting, etc.), and a method based on a principle common to these. The detection device can be a known device (Genechip, microarray, etc.).

[0089] In one embodiment, the present disclosure is used for tumors having FGFR gene abnormalities. Gene abnormalities in the FGFR pathway include gene amplification, gene mutation, chromosomal translocation / insertion / inversion, gene fusion, gene rearrangement, and the like. Some FGFR gene abnormalities in tumors have already been reported in literature available to those skilled in the art (Non-Patent Documents 7 and 8). FGFR gene abnormalities can be detected by methods known to those skilled in the art, such as DNA sequencing including pyrosequencing and NGS (next-generation sequencing), PCR-based methods including allele-specific PCR chain reaction, microarray-based comparative genomic hybridization (aCGH), and fluorescence in situ hybridization (FIS). H) or colorimetric in situ hybridization (CISH), etc.

[0090] In addition, in one embodiment, the present disclosure is used for tumors in which FGFR signaling is activated. FGFR forms a dimer upon binding to FGF and is activated by phosphorylation, thereby inducing the recruitment and activation of specific downstream signaling molecules, thereby exerting physiological functions.

[0091] Activation of FGFR signaling can be detected by a method known to those skilled in the art. Detection of signaling activation can be performed, for example, by detecting FGF, which is a substrate of FGFR, by detecting the direct phosphorylation state or biological activity, including enzymatic activity, of FGFR, which is a phosphorylation enzyme, by detecting the phosphorylation state or biological activity, including enzymatic activity, of intracellular substrates and intracellular proteins present downstream of the FGFR signaling cascade, or by detecting gene products or gene transcription products.

[0092] In another embodiment, the tumor to which the present disclosure is applicable also includes a tumor that does not have an abnormality in the FGFR pathway.

[0093] In the present disclosure, preferred doses of Compound 1 or a salt thereof per day on the day of administration include, for example, 4 mg to 160 mg, 4 mg to 24 mg, 12 to 24 mg, 16 to 24 mg, 20 mg, etc. More specifically, the number of doses per day on the day of administration In another aspect, the preferred number of times of administration and the preferred dosage per day on the day of administration are 8 mg, 12 mg, 16 mg, 20 mg, etc. In another aspect, the preferred number of times of administration and the preferred dosage per day on the day of administration are 12 mg, 16 mg, 20 mg, etc. In another aspect, the preferred number of times of administration and the preferred dosage per day on the day of administration are 20 mg, etc.

[0094] The disclosure includes, in some embodiments, for cancer types where stronger efficacy is desired (eg, brain tumors), the dosage of Compound 1 or a salt thereof is greater than 20 mg once daily.

[0095] When the daily dose of Compound 1 or a salt thereof is administered intermittently, the dose is, for example, about 2 to 1000 mg of Compound 1 or a salt thereof per day, preferably 10 to 500 mg per day, more preferably 20 to 200 mg per day, and even more preferably 50 to 160 mg per day.

[0096] The administration schedule of Compound 1 or a salt thereof may be daily administration or intermittent administration.

[0097] In the present disclosure, "daily administration" refers to, for example, an administration schedule in which administration is performed for 21 consecutive days as one cycle, and a drug holiday may be provided after each cycle.

[0098] In the present disclosure, "intermittent administration" is not particularly limited as long as it satisfies the conditions of two or more times a week with an administration interval (the number of days between one administration day and the next administration day) of one day or more.

[0099] For example, an administration schedule in which one cycle is administered per week, in which Compound 1 or a salt thereof is administered twice or more every 1 to 3 days (the interval between one administration day and the next administration day is 1 to 3 days) per cycle, and the cycle is repeated once or twice or more; an administration schedule in which one cycle is performed over 14 days, in which compound 1 or a salt thereof is administered 4 to 7 times every 1 to 3 days (the interval between one administration day and the next administration day is 1 to 3 days) per cycle, and the cycle is repeated once or twice or more; an administration schedule in which one cycle is administered over 14 days, in which compound 1 or a salt thereof is administered on days 1, 4, 8, and 11 of the 14 days in one cycle; an administration schedule in which one cycle is administered over 14 days, in which compound 1 or a salt thereof is administered on days 1, 3, 5, 7, 9, 11, and 13 of the 14 days in one cycle; An example of such an administration schedule is one cycle of 14 days, in which compound 1 or a salt thereof is administered on the 1st, 3rd, 5th, 8th, 10th, and 12th days of the 14 days included in one cycle.

[0100] In one embodiment of the present disclosure, the administration schedule includes administering 160 mg of compound 1 or a salt thereof once a day on days 1, 3, 5, 8, 10, and 12. The dose of compound 1 or a salt thereof can be reduced to 120 mg, 80 mg, 56 mg, 36 mg, 24 mg, 16 mg, or 8 mg.

[0101] In the present disclosure, the daily dose of pembrolizumab on the day of administration is preferably 30 to 100%, more preferably 50 to 100%, more preferably 70 to 100%, and more preferably 8 to 100% of the recommended dose when pembrolizumab is administered alone, from the viewpoint of the enhancing effect of the antitumor effect of pembrolizumab by compound 1 or a salt thereof. It is 0 to 100%, more preferably 90 to 100%, and further preferably 100%.

[0102] Preferred doses of pembrolizumab when administered alone include 100 to 200 mg, 200, or 400 mg, etc. In another embodiment, preferred doses of pembrolizumab when administered alone include 1.0 to 2.0 mg / kg (body weight) or 2.0 mg / kg (body weight) per administration.

[0103] In the present disclosure, the preferred daily dose of pembrolizumab on the day of administration is 100 to 400 mg, 200, or 400 mg, etc. In another embodiment, the preferred daily dose of pembrolizumab on the day of administration is 1.0 to 2.0 mg / kg (body weight), 2.0 mg / kg (body weight), etc. The administration interval of pembrolizumab is preferably 3 to 4 weeks, more preferably 3 weeks.

[0104] Preferred combinations of the daily dose of Compound 1 or a salt thereof on the day of administration and the daily dose of pembrolizumab in the present disclosure, or the method and dose thereof, include the following: Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and pembrolizumab is administered at a dose of 100 to 400 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and pembrolizumab is administered at a dose of 100 to 200 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and pembrolizumab is administered at a dose of 200 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 160 mg, and pembrolizumab is administered at a dose of 400 mg. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg to 160 mg, and pembrolizumab is administered at 1.0 to 2.0 mg / kg (body weight) per dose. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and pembrolizumab at 2.0 mg / kg (body weight) per dose. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and pembrolizumab at 200 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 160 mg and pembrolizumab at 400 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and pembrolizumab is administered at a dose of 100 to 400 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and pembrolizumab is administered at a dose of 100 to 200 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and pembrolizumab is administered at a dose of 200 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and pembrolizumab is administered at a dose of 400 mg. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 4 mg to 24 mg, and pembrolizumab is administered at a dose of 1.0 to 2.0 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and pembrolizumab at 2.0 mg / kg (body weight) per dose. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and pembrolizumab at 200 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure at 4 mg to 24 mg and pembrolizumab at 400 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 12 to 24 mg, and pembrolizumab is administered in an amount of 100 to 400 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered in an amount of 12 to 24 mg, and pembrolizumab is administered in an amount of 100 to 200 mg per dose. Compound 1 or a salt thereof according to the present disclosure, 12 to 24 mg, and pembrolizumab, 200 mg per dose. Compound 1 or a salt thereof according to the present disclosure, 12 to 24 mg, and pembrolizumab, 400 mg per dose. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 12 to 24 mg, and pembrolizumab is administered at a dose of 1.0 to 2.0 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure, 12 to 24 mg, and pembrolizumab, 2.0 mg / kg (body weight) per dose. 12 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 200 mg of pembrolizumab Every 3 weeks. 12 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 400 mg of pembrolizumab Every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and pembrolizumab, 100 to 400 mg per dose. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and pembrolizumab, 100 to 200 mg per dose. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and pembrolizumab, 200 mg per dose. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and pembrolizumab, 400 mg, administered once. Compound 1 or a salt thereof according to the present disclosure is administered at a dose of 16 to 24 mg, and pembrolizumab is administered at a dose of 1.0 to 2.0 mg / kg (body weight) once. Compound 1 or a salt thereof according to the present disclosure, 16 to 24 mg, and pembrolizumab, 2.0 mg / kg (body weight) per dose. 16 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 200 mg of pembrolizumab Every 3 weeks. 16 to 24 mg of compound 1 or a salt thereof according to the present disclosure and 400 mg of pembrolizumab Every 3 weeks.

[0105] The number of administrations per day, the dosage amount, and the daily dose of pembrolizumab on the day of administration of Compound 1 or a salt thereof in the present disclosure, or the combination of administration method and dosage amount, may be as follows: Compound 1 or a salt thereof according to the present disclosure, 4 mg, and pembrolizumab, 100 to 400 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 4 mg, and pembrolizumab, 100 to 200 mg, once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day, and pembrolizumab is administered at 200 mg once a day. Compound 1 or a salt thereof according to the present disclosure, 4 mg, and pembrolizumab, 400 mg, once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 4 mg once a day, and pembrolizumab is administered at 1.0 to 2.0 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure, 4 mg, and pembrolizumab, 2.0 mg / kg (body weight), once a day. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and pembrolizumab at 200 mg every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 4 mg once daily and pembrolizumab at 400 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and pembrolizumab, 100 to 400 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and pembrolizumab, 100 to 200 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and pembrolizumab, 200 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 8 mg, and pembrolizumab, 400 mg, once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 8 mg once a day, and pembrolizumab is administered at 1.0 to 2.0 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure at 8 mg once a day and pembrolizumab at 2.0 mg / kg (body weight) once a day. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and pembrolizumab at 200 mg every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 8 mg once daily and pembrolizumab at 400 mg every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 12 mg, and pembrolizumab, 100 to 400 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg, and pembrolizumab, 100 to 200 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg, and pembrolizumab, 200 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg, and pembrolizumab, 400 mg, once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 12 mg once a day, and pembrolizumab is administered at 1.0 to 2.0 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure, 12 mg once a day, and pembrolizumab, 2.0 mg / kg (body weight) once a day. Compound 1 or a salt thereof of the present disclosure, 12 mg once daily and pembrolizumab, 200 mg, every 3 weeks. Compound 1 or a salt thereof of the present disclosure, 12 mg once daily and pembrolizumab, 400 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 16 mg, and pembrolizumab, 100 to 400 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 16 mg, and pembrolizumab, 100 to 200 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 16 mg, and pembrolizumab, 200 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 16 mg, and pembrolizumab, 400 mg, once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 16 mg once a day, and pembrolizumab is administered at 1.0 to 2.0 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure, 16 mg, once a day, and pembrolizumab, 2.0 mg / kg (body weight), once a day. Compound 1 or a salt thereof of the present disclosure, 16 mg once daily and pembrolizumab, 200 mg, every 3 weeks. Compound 1 or a salt thereof of the present disclosure, 16 mg once daily and pembrolizumab, 400 mg, every 3 weeks. Compound 1 or a salt thereof according to the present disclosure, 20 mg, and pembrolizumab, 100 to 400 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg, and pembrolizumab, 100 to 200 mg, once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg once a day, and pembrolizumab, 200 mg once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg once a day, and pembrolizumab, 400 mg once a day. Compound 1 or a salt thereof according to the present disclosure is administered at 20 mg once a day, and pembrolizumab is administered at 1.0 to 2.0 mg / kg (body weight) once a day. Compound 1 or a salt thereof according to the present disclosure, 20 mg once a day, and pembrolizumab, 2.0 mg / kg (body weight) once a day. Compound 1 or a salt thereof of the present disclosure at 20 mg once daily and pembrolizumab at 200 mg every 3 weeks. Compound 1 or a salt thereof of the present disclosure at 20 mg once daily and pembrolizumab at 400 mg every 3 weeks.

[0106] The ratio of compound 1 or a salt thereof to pembrolizumab used in the present disclosure is not particularly limited, but can be set preferably in the range of 10 to 10,000 parts by mass, more preferably 100 to 1,000 parts by mass, of pembrolizumab per 100 parts by mass of compound 1 or a salt thereof.

[0107] In the present disclosure, the blending ratio of compound 1 or a salt thereof in a dosage form containing compound 1 or a salt thereof is not particularly limited, but can be appropriately set, for example, in the range of 100 to 100000 mass%, preferably 1000 to 10000 mass%. In the present disclosure, the blending ratio of the immune checkpoint inhibitor in a dosage form containing an immune checkpoint inhibitor is not particularly limited, but can be appropriately set, for example, in the range of 100 to 100000 mass%, preferably 1000 to 10000 mass%. Here, in an embodiment in which an antitumor agent is formulated by dividing it into a plurality of dosage forms, the above-mentioned preferred blending ratio does not mean the blending ratio of the active ingredient to the total amount of a dosage form containing an active ingredient and a dosage form not containing an active ingredient, but means the blending ratio of the active ingredient to the mass of a dosage form containing an active ingredient. For example, in the case of the blending ratio of compound 1 or a salt thereof, it means the mass% of compound 1 or a salt thereof to the mass of only the dosage form containing compound 1 or a salt thereof.

[0108] In one embodiment of the present disclosure, the combination therapy of the present invention is administered to patients who have not been previously treated with hormone therapy, immunotherapy (such as cancer peptide vaccine therapy), surgery, radiation therapy, or chemotherapy, i.e., treatment-naive patients. In another embodiment, the combination therapy is administered to patients who have failed to achieve a sustained response after previous treatment with a chemotherapy agent.

[0109] In one embodiment of the disclosure, the combination therapy of the present invention is administered to a patient who has not previously been treated with an immune checkpoint inhibitor, while in another embodiment, the combination therapy is administered to a patient who has previously been treated with an FGFR inhibitor.

[0110] In one embodiment of the present disclosure, a sustained response refers to the expansion and maintenance of an immune response against a cancer by targeted immunotherapy, such as an immune checkpoint inhibitor, which may be measured, for example, by the binding of immune checkpoint inhibitors to T lymphocytes.

[0111] In this disclosure, the term "recommended dose" refers to the dosage that provides the maximum therapeutic effect within the range that can be safely used without causing serious side effects, as determined by clinical trials, etc., and is specifically the dosage recommended by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan. Examples of dosages include dosages approved, recommended or advised by public institutions or organizations such as the Pharmaceuticals and Medical Devices Agency, the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), etc., and are described in package inserts, interview forms, treatment guidelines, etc., and dosages approved by any of the public institutions, such as the PMDA, FDA or EMA, are preferred.

[0112] The administration schedule of the antitumor agent of the present disclosure can be appropriately selected depending on the type of cancer, stage of the disease, etc.

[0113] In the case of Compound 1 or a salt thereof, every day from the first day to 21 days [for example, 3 weeks (21 days)] A dosing schedule of 2-week intervals is preferred, but may be followed by a drug holiday, and more preferably is daily administration for 3 weeks (21 days). The dosing schedule of immune checkpoint inhibitors is preferably, for example, every 2 to 4 weeks. In the case of pembrolizumab, a dosing schedule of 2-week, 3-week, or 4-week intervals is preferred, more preferably every 3 weeks. In the present disclosure, administration of drug A at X-day intervals means that the day on which drug A is administered is designated as day 1, and This means that if the day after that is day 2, and the day after that is day 3, etc., then the next administration of drug A will be on day X+1. Furthermore, when calculating an administration schedule, "1 week", "2 weeks", "3 weeks", and "4 weeks" mean "7 days", "14 days", "21 days", and "28 days", respectively. Therefore, in the present disclosure, administration of drug A at 3-week intervals means that if the day drug A was administered is day 1, then the next administration of drug A will be on day 22.

[0114] The number of times the antitumor agent of the present disclosure is administered per day may be appropriately selected depending on the type of cancer, stage of disease, etc. When administered in combination with pembrolizumab, once a day is preferred.

[0115] The order of administration of Compound 1 or a salt thereof and pembrolizumab can be appropriately selected depending on the type of cancer, stage of disease, etc., but in one treatment regimen, either one may be administered first, or they may be administered simultaneously.

[0116] In one embodiment of the present disclosure, compound 1 or a salt thereof enhances the effect of pembrolizumab, and in another embodiment, pembrolizumab enhances the effect of compound 1 or a salt thereof.

[0117] In one embodiment of the present disclosure, the tumor necrosis factor is administered to subjects expressing PD-L1 in 1% or more of subjects, and more preferably in 50% or more of subjects, regardless of whether or not PD-L1 is expressed.

[0118] In one embodiment of the present disclosure, the method is performed on subjects with tumors that test positive for PD-L1 expression. PD-L1 expression can be detected using a diagnostic anti-human PD-L1 antibody, or an antigen-binding fragment thereof, in an IHC assay on FFPE or frozen tissue sections of tumor samples taken from the patient. Typically, a physician will order a diagnostic test to determine PD-L1 expression using a tumor tissue sample taken from the subject prior to initiating the combined immune checkpoint inhibitor and FGFR inhibitor, although it is contemplated that a physician may order a pre-treatment or post-treatment diagnostic test after treatment has commenced, e.g., at the end of a treatment cycle.

[0119] In this disclosure, "cancer" or "tumor" refers to a physiological condition in mammals characterized by unregulated cell growth. "Cancer" and "tumor" are synonymous and used interchangeably herein. Cancer includes solid and hematological cancers. Examples include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma, sarcoma, and borderline malignant tumors (carcinoid).

[0120] Examples of cancers that can be treated with the combination method of the present disclosure include head and neck cancer, digestive cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder and bile duct cancer, etc.), pancreatic cancer, urothelial cancer, small intestine cancer, large intestine cancer (colorectal cancer, colon cancer, rectal cancer, etc.)), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma (malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, etc.)), breast cancer, reproductive cancer (ovarian cancer, uterine cancer (cervical cancer, uterine cancer, endometrial cancer, etc.)), kidney cancer, bladder cancer, prostate cancer, testicular tumor, skin cancer (malignant melanoma, epidermal cancer, etc.), blood cancer (multiple myeloma, acute myeloid leukemia, etc.), bone and soft tissue tumor, rhabdomyosarcoma, brain tumor, malignant neurilemmoma, neuroendocrine tumor, thyroid cancer, etc. In certain embodiments, the cancers targeted are bladder cancer, urothelial cancer, digestive cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder / bile duct cancer, etc.), pancreatic cancer, small intestine cancer, large intestine cancer (colorectal cancer, colon cancer, rectal cancer, etc.), ovarian cancer, head and neck cancer, and uterine cancer (cervical cancer, uterine body cancer, etc.). Urothelial cancer, esophageal cancer, and non-small cell lung cancer are preferred, and esophageal cancer and non-small cell lung cancer are more preferred. Note that cancer here includes not only primary lesions but also cancer that has metastasized to other organs (liver, etc.). The antitumor agent of the present disclosure may be used in postoperative adjuvant chemotherapy performed to prevent recurrence after surgical removal of a tumor, or may be used in preoperative adjuvant chemotherapy performed in advance of surgical removal of a tumor.

[0121] In one embodiment of the present disclosure, the cancers targeted by the combination method include malignant melanoma, non-small cell lung cancer, Hodgkin's lymphoma, urothelial carcinoma, solid tumors with high microsatellite instability (MSI-High), renal cell carcinoma, head and neck cancer, esophageal cancer, and gastric cancer.

[0122] As used herein, the term "combination therapy" is intended to define a therapy that includes the use of a combination of two or more compounds / agents (as defined above). Thus, the use of "combination," "combination," and "in combination" compounds / agents in this application refers to compounds / agents that are administered as part of the same overall treatment regimen. The respective posologies of the two or more compounds / agents may vary: each may be administered at the same time or at different times. Thus, the compounds / agents of a combination may be administered in the same manner as in the case of a single compound / agent. It will be understood that the two agents may be administered sequentially (e.g., before or after) or simultaneously, either in a pharmaceutical formulation (i.e., together) or in different pharmaceutical formulations (i.e., separately). At the same time, as a single formulation, but at the same time, in different pharmaceutical formulations, non-integral.

[0123] In this specification, the term "regimen" or "therapeutic regimen" refers to a plan showing the type, amount, duration, procedure, etc. of drugs in drug treatment in a chronological order, and indicates the dosage, administration method, administration order, and administration date of each drug. An example of treatment with one therapeutic regimen is a method in which the administration of concomitant drugs is started simultaneously or substantially at the same time on the first day of one cycle. In addition, for example, one cycle is three weeks, and administration of drug A is started first, and administration of drug B is started one week later, but a form in which the drugs are administered substantially simultaneously as one cycle is also included in treatment with one therapeutic regimen.

[0124] The treatment regimen of compound 1 or a salt thereof and pembrolizumab disclosed herein may further include other drugs in addition to compound 1 or a salt thereof and pembrolizumab.

[0125] The administration form of the antitumor agent of the present disclosure is not particularly limited and can be appropriately selected according to the purpose of treatment. Specific examples include oral agents (tablets, coated tablets, powders, granules, capsules, liquids, etc.), injections, suppositories, patches, ointments, etc. In the case of compound 1 or a salt thereof, oral agents are preferred. In the case of pembrolizumab, the administration forms include the above, and injections are preferred.

[0126] The antitumor agent of the present disclosure may be the active ingredient pembrolizumab and Compound 1 or a salt thereof, which are used as such, or may be a pharmaceutical composition prepared by a commonly known method using a pharma- ceutical acceptable carrier depending on the administration form. Examples of suitable agents include various agents commonly used in ordinary pharmaceuticals, such as excipients, binders, disintegrants, lubricants, diluents, solubilizing agents, suspending agents, isotonicity agents, pH adjusters, buffers, stabilizers, colorants, flavorings, and odorants.

[0127] The antitumor agent of the present disclosure may be formulated by dividing each active ingredient into multiple dosage forms, or may be formulated together in one dosage form, based on the dosage form and administration schedule of each active ingredient. In addition, each formulation may be manufactured and sold together in one package suitable for combined administration, or each formulation may be manufactured and sold separately in separate packages. The same applies to the embodiment of the pharmaceutical composition. Therefore, the "pharmaceutical composition containing pembrolizumab and compound 1 or a salt thereof as active ingredients" includes those in which each active ingredient is formulated into multiple dosage forms, and those in which each active ingredient is formulated together in one dosage form. The pharmaceutical composition in which each active ingredient is formulated into multiple dosage forms includes those in which each formulation is combined into one package suitable for combined administration, and those in which each formulation is divided into separate packages.

[0128] The present disclosure relates to a kit formulation including an antitumor agent containing Compound 1 or a salt thereof, and an instruction manual describing the co-administration of Compound 1 or a salt thereof and pembrolizumab to a cancer patient. Here, the "instructions" may be any instruction manual that describes the above-mentioned dosage, and may be legally binding or not, but preferably recommends the above-mentioned dosage. Specific examples include package inserts and pamphlets. In addition, the kit formulation including the instructions may be one in which the instructions are printed and attached to the package of the kit formulation, or one in which the instructions are enclosed in the package of the kit formulation together with the antitumor agent.

[0129] Methods for detecting the mechanism of action of FGFR inhibitors and the onset of resistance to immune checkpoint inhibitors include, but are not limited to, a method for examining the regulation of the tumor immune microenvironment (Non-Patent Document 13).

[0130] The efficacy of immune checkpoint inhibitors is influenced by the microenvironment surrounding the cancer, and CAFs (Cancer Associated fibroblasts) are known to play an important role in this regard. FGF is a factor that controls the proliferation of fibroblast cells, and its receptor, FGFR, is a molecule that receives FGF signals and promotes cell proliferation. Myeloid-derived positive cells (MDSCs (Myeoloid-derived suppressor cells)) are immature bone marrow cells that increase in tumor tissues, lymph nodes, and peripheral blood under pathological conditions, and are known to have strong immunosuppressive activity.

[0131] It has been reported that MDSCs may be a potential marker for predicting the efficacy of immune checkpoint inhibitors and may contribute to patient resistance to immune checkpoint inhibitors (Non-Patent Document 14).

[0132] As used herein, resistance to immune checkpoint inhibitors (also referred to as resistance or refractory) includes the state of a subject in which the therapeutic effect is no longer expected after administration of an immune checkpoint inhibitor and the progression of the disease has been confirmed in at least one clinical evaluation, intolerance to an immune checkpoint inhibitor, relapse after administration of an immune checkpoint inhibitor, or the state of a subject in which the therapeutic effect of an immune checkpoint inhibitor is not expected, although there has been no experience of treatment with an immune checkpoint inhibitor. In some embodiments, it also includes the absence of an effective effect against an immune checkpoint inhibitor in a pharmacological test, for example, the reaction of a cell line that is considered to be ineffective. Resistance includes natural resistance, in which an anticancer drug is not effective from the beginning of treatment, and acquired resistance, in which an anticancer drug that was initially effective becomes ineffective as treatment continues, leading to the exacerbation of the cancer. In this specification, resistance includes both natural resistance and acquired resistance.

[0133] As used herein, refractory to an immune checkpoint inhibitor refers to a state in which the immune checkpoint inhibitor becomes ineffective after administration of the immune checkpoint inhibitor, and fails to exert its effect. One of the causes of refractory disease is thought to be resistance.

[0134] The antitumor agent of the present disclosure can be used to treat cancer. When referring to a cancer patient receiving treatment with a treatment regimen such as the combination therapy described herein, "antitumor effect" refers to at least one evaluation, such as, for example, PFS (progression-free survival), DCR (disease control rate), DOR (duration of response), OS (overall survival), ORR (objective response rate), DCR (disease control rate), TTR (time to first response), PROs (Patient-Reported Outcomes), etc. In one embodiment, when a solid tumor is targeted, tumor evaluation for the combination therapy described herein is evaluated by the RECIST 1.1 criteria (response criteria for solid tumors), and the antitumor effect is indicated by SD (stable disease), PR (partial response), CR (complete response), and PD (progression). In the case of tumor evaluation of a brain tumor, Gd-MRI (standard brain tumor MRI including pre-enhancement and post-enhancement using a gadolinium (Gd) chelate contrast agent) can also be performed. EXAMPLES

[0135] The present disclosure will now be described in more detail with reference to examples and reference examples, but the present disclosure is not limited to these examples in any way, and many modifications can be made by those skilled in the art within the technical spirit of the present disclosure.

[0136] (Example 1) Clinical trial of patients with cancer immunotherapy-resistant cancer (e.g., non-small cell lung cancer, esophageal cancer, urothelial cancer) using (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof in combination with pembrolizumab This study is based on a clinical trial registered with the Japan Pharmaceutical Information Center as JapicCTI-195063, and evaluates the efficacy and safety of the combination of compound 1 or its salt and pembrolizumab in patients with FGFR-overexpressing cancer (e.g., non-small cell lung cancer, esophageal cancer, urothelial cancer). Specifically, the patient is administered various doses (e.g., 20 mg) of compound 1 or its salt orally for 21 days for a specified period (e.g., 24 weeks), and pembrolizumab (e.g., 200 mg once) is administered by intravenous infusion every 3 weeks (every 21 days). This cycle is repeated for 21 days. In some cases, a placebo may be used as a control, and compound 1 or its salt and / or pembrolizumab may be administered to additional patients. Compound 1 or its salt may also be administered in combination with pembrolizumab to patients who have experience of treatment with pembrolizumab.

[0137] The combination of Compound 1 or a salt thereof with pembrolizumab may provide therapeutic effects that would not be expected from these monotherapies. For example, in some embodiments of the present disclosure, the combination may be found to be more effective than at least one of the measurements of either treatment alone. Also, for example, in some embodiments of the present disclosure, the combination of Compound 1 or a salt thereof with pembrolizumab may provide a synergistic effect.

[0138] The combination of Compound 1 or a salt thereof and pembrolizumab may be more effective than either alone according to at least one of the following measurements: reduction in cancer cell count, reduction in tumor size, reduction in the rate of cancer cell infiltration into peripheral organs, reduction in the rate of tumor metastasis or tumor growth, overall response rate, or prolongation of progression-free survival or overall survival.

[0139] (Example 2) Effect on tumor immunity in a mouse subcutaneously xenografted 4T1 breast cancer cell model The mouse breast cancer line 4T1 was subcutaneously implanted into 6-week-old male BALB / cAJcl mice. The day of transplantation was Day 0, and from the next day (Day 1), Compound 1 was administered at a dose of 15 mg / kg / day. The drug was orally administered every day for 4 days. On the day after the final administration (Day 15), lymphocyte cell fractions were isolated from the tumor, spleen, and peripheral blood, and bone marrow-derived immunosuppressive cells (MDSCs) (CD11b + / Gr-1 + cells), CD4 positive T cells, and CD8 positive T cells were measured. In addition, mouse breast cancer cells were cultured in the same manner as above, except that the dose of compound 1 was 30 mg / kg / day. A subcutaneous 4T1 tumor model was prepared, drug administration was performed, and each cell was measured. As a control, the same procedure as above was performed except that Compound 1 was not administered. The results are shown in FIG. 1.

[0140] Administration of Compound 1 at any dose showed a significant ( The number of MDSCs in the splenic lymphocyte fraction was decreased in a dose-dependent manner compared to the control group (Student t-test, P<0.01). The number of MDSCs in the peripheral blood lymphocyte fraction was decreased in a dose-dependent manner compared to the control group. The lymphocyte fraction and CD8 positive T cells in the peripheral blood lymphocyte fraction showed a dose-dependent increase compared to the control.

[0141] These results suggest that compound 1 has an inhibitory effect on MDSCs in an in vivo model. This confirmed the possibility that compound 1 may have an antitumor effect via an immunosuppressive mechanism. Furthermore, the administration of compound 1 increased CD4 positive T cells and CD8 positive T cells, confirming that compound 1 activates immune activity in tumor-bearing mice. These findings suggest that the combined use of compound 1 or its salt with an immune checkpoint inhibitor enhances the antitumor effect.

[0142] The mouse breast cancer line 4T1 used in Example 2 is a breast cancer cell line that does not have an FGFR gene abnormality, but the administration of compound 1 was confirmed to have an inhibitory effect on MDSC, and an increase in CD4 positive T cells and CD8 positive T cells was observed, indicating that compound 1 exhibits an antitumor effect via an immunosuppressive mechanism. In addition, by administering the anti-FGFR3 antibody Vofatamab to urothelial cancer patients, the cancer changes from a "cold" state, which is less sensitive to immune checkpoint inhibitors, to a "hot" state, which is highly sensitive, and even patients without FGFR gene abnormalities have been shown to respond to the combination of pembrolizumab (W. Choi et al., Presented at AACR Bladder cancer: Transforming the Field Special Conference, May 18-21, 2019, Denver, USA).

Claims

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

2. The anti-tumor agent of claim 1 , wherein treatment with the anti-tumor agent results in a sustained response in the individual after treatment is discontinued.

3. The antitumor agent according to claim 1, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is used before pembrolizumab, used simultaneously with pembrolizumab, or used after pembrolizumab.

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

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

6. The antitumor agent according to claim 1, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once a day at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg, and 20 mg, and pembrolizumab is administered to a cancer patient at a dose selected from the group consisting of 1 mg / kg every 3 weeks, 2 mg / kg every 3 weeks, and 200 mg every 3 weeks.

7. The antitumor agent according to claim 1, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once a day at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg, and 20 mg, and pembrolizumab is administered at a dose of 200 mg every 3 weeks to a cancer patient.

8. The antitumor agent according to claim 1, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered at a dose of 20 mg once a day, and pembrolizumab is administered at a dose of 200 mg every 3 weeks to a cancer patient.

9. The antitumor agent according to any one of claims 1 to 8, wherein the tumor is esophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer, or urothelial cancer.

10. The antitumor agent according to claim 9, wherein the tumor is esophageal cancer.

11. The antitumor agent according to any one of claims 1 to 8, wherein the cancer patient has never been administered an immune checkpoint inhibitor.

12. The antitumor agent according to any one of claims 1 to 8, wherein the cancer patient is a cancer patient having resistance to an immune checkpoint inhibitor.

13. The antitumor agent according to claim 11, wherein the tumor is esophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer or urothelial cancer.

14. The antitumor agent according to claim 11, wherein the tumor is esophageal cancer.

15. The antitumor agent according to claim 12, wherein the tumor is esophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer or urothelial cancer.

16. The antitumor agent according to claim 12, wherein the tumor is esophageal cancer.

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