RU2843836C2 - Anticancer therapy using 3,5-disubstituted benzalkynyl compounds and immune check point inhibitor - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: disclosed are applications 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 in combination with an anti-PD-1 antibody, with the exception of pembrolizumab, which demonstrate an excellent anticancer effect on cancer patients with resistance to immune checkpoint inhibitors or without aberrations in the FGFR path, enhancing effect of immune check point inhibitor on cancer. Cancer is oesophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer or urothelial cancer.

EFFECT: disclosed is anti-cancer therapy using compounds of 3,5-disubstituted benzalkynyl and immune check point inhibitor.

25 cl, 1 dwg, 2 ex

Description

Field of technology

[0001]

Cross-reference to related applications

This application claims priority from 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 contents of which are incorporated herein by reference. The present disclosure relates to an antitumor agent, an antitumor effect enhancer, and a kit of preparation.

State of the art

[0002]

Fibroblast growth factors (FGFs) are expressed in various tissues and are among the growth factors that regulate cell proliferation and differentiation. The physiological activities of FGFs are mediated by fibroblast growth factor receptors (FGFRs), which are specific cell surface receptors. FGFRs belong to the receptor protein tyrosine kinase family and include an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain. Four types of FGFRs (FGFR1, FGFR2, FGFR3, and FGFR4) have been identified so far. FGFRs bind to FGFs to form dimers and are activated by phosphorylation. Activation of the receptors causes the mobilization and activation of specific downstream signal transduction molecules, thereby promoting physiological functions. Some reports have been made on the relationship between aberrant FGF/FGFR signaling and various human tumors. It is believed that aberrant activation of FGF/FGFR signaling in human tumors may be due to FGFR overexpression and/or gene amplification, gene mutation, chromosomal translocation, insertion and inversion, gene fusion, or an autocrine or paracrine mechanism through overproduction of FGF (ligands) (NPL 1, 2, 3, and 4).

[0003]

On the other hand, the development of anti-cancer immunotherapy is developing into a qualitatively new method of cancer treatment.

[0004]

Activation of the adaptive immune response is initiated by binding of antigen peptide-MHC complexes to T cell receptors (TCRs). This binding is further mediated by costimulation or coinhibition through binding between a B7 family costimulatory molecule and its CD28 family receptor. That is, for T cells to specifically activate an antigen, two characteristic signaling events are required, and T cells that have received only antigen stimulation without costimulation from the B7 family enter a state of anergy and immune tolerance is induced.

[0005]

By taking advantage of this mechanism to suppress the activation of antigen-specific T cells, cancer cells escape the immune surveillance system and continue to grow. Therefore, it is considered effective for cancer treatment to induce anti-tumor immune responses in cancer patients by enhancing costimulation and blocking coinhibition, and to prevent tumor from escaping the immune system. Various proposals have been made for anti-cancer immunotherapy targeting costimulatory molecules (stimulating costimulatory molecules) or coinhibitory molecules (inhibitory costimulatory molecules) (NPL 5). For example, nivolumab (human IgG4 monoclonal antibody against human PD-1) is used for the treatment of malignant melanoma etc. as an immune checkpoint inhibitor that activates T cells through inhibiting the binding of PD-1 to its ligands (PD-L1 and PD-L2) (PTL 1 and NPL 6). In addition, pembrolizumab is used as an immune checkpoint inhibitor, which differs from nivolumab in the type of antibodies, for the treatment of malignant melanoma, non-small cell lung cancer, etc. (NPL 6).

[0006]

(S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one, which is a 3,5-disubstituted benzenealkynyl compound, or a salt thereof, is known as an FGFR inhibitor. Combinations of FGFR inhibitors and other antitumor agents have been described so far (PTL 2 and PTL 3). Regarding the combined administration of an FGFR inhibitor and an immune checkpoint inhibitor, for example, PTL 4 describes a method using an FGFR inhibitor and an anti-PD-1 antibody or an anti-PD-L1 antibody in combination.

[0007]

Many cases involving immune checkpoint inhibitor have been reported, and it has been found that long-term administration leads to drug resistance, and the mechanism has been studied (NPL 9, NPL 10, and NPL 11). As an example of the use of immune checkpoint inhibitor and FGFR inhibitor, for example, a phase II trial (NCT02365597) of erdafitinib (JNJ-42756493) for the treatment of urothelial cancer has been reported, in which the FGFR inhibitor was administered to subjects who were previously treated with PD-1 or PD-L1. In addition, a combination trial of vofatamab, which is an anti-FGFR3 antibody, and pembrolizumab (NCT03123055) is still ongoing. Regarding long-term administration, there have been reports on the combined use of everolimus and pazopanib, which is a multikinase inhibitor that has an FGFR inhibition effect, on the combined use of vofatamab and docetaxel, and on the long-term administration of atezolizumab (NPL 12).

References

Patent literature

[0008]

PTL 1: WO2004/004771

PTL 2: WO2013/108809

PTL 3: WO2017/150725

PTL 4: WO2016/161239

Non-patent literature

[0009]

NPL 1: Nat. Rev. Cancer, 10, 116-129 (2010)

NPL 2: J. Clin. Oncol., 24, 3664-3671 (2006)

NPL 3: Mol. Cancer Res., 3, 655-667 (2005)

NPL 4: Cancer Res., 70, 2085-2094 (2010)

NPL 5: Nat. Rev. Cancer, 12, 252-264 (2012)

NPL 6: N. Engl. J. Med., 366, 2443-2454 (2012)

NPL 7: The Breast, 37, 126-133 (2018)

NPL 8: Oncotarget, 8, 16052-16074 (2017)

NPL 9: Cell, 168, 707-723 (2017)

NPL 10: N. Engl. J. Med., 375, 819-829 (2016)

NPL 11: Sci. Transl. Med. 9, eaal 3604 (2017)

NPL 12: JCO Precision Oncology (DOI: 10.1200/P0.18.00117), July 24, 2018

NPL 13: Cellular Physiology and Biochemistry, 33, pp. 633-645 (2014)

NPL 14: Frontiers in Immunology, 9, 2018, Article 1310.doi:10.3389/fimmu.2018.01310

The essence of the invention

Technical problem

[0010]

The object of the present description is to obtain a new combination therapy that has an excellent antitumor effect for cancer patients who are resistant to immune checkpoint inhibitors, 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.

Solution to the problem

[0011]

In view of the above circumstances, the inventors of the present invention found that the above problems can be solved by the combined 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 (hereinafter also referred to as “compound 1”), which is a compound having an FGFR inhibiting activity, or a salt thereof, with an immune checkpoint inhibitor.

[0012]

Therefore, the following items 1-77 are provided in the present description.

[0013]

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

[0014]

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

[0015]

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

[0016]

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

[0017]

Item 5. An anti-tumor agent according to any one of items 2-4, wherein the PD-1 pathway antagonist is an anti-PD-1 antibody.

[0018]

Item 6. The anti-tumor agent of item 4 or 5, wherein the anti-PD-1 antibody is nivolumab, cemiplimab, spartalizumab, tislelizumab, BI754091, dostarlimab, sasanlimab, MGA-012, cetrelimab, AGEN-2034, zimberelimab, camrelizumab, budigalimab or balstilimab; and, preferably, nivolumab.

[0019]

Item 7. An anti-tumor agent according to any one of items 2-4, wherein the PD-1 pathway antagonist is an anti-PD-L1 antibody.

[0020]

Item 8. The anti-tumor agent of item 7, wherein the anti-PD-L1 antibody is atezolizumab, durvalumab or avelumab.

[0021]

Item 9. The antitumor agent of item 2, wherein the CTLA-4 pathway antagonist is an anti-CTLA-4 antibody.

[0022]

Item 10. The anti-tumor agent of item 9, wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

[0023]

Item 11. An anti-tumor agent according to any one of items 1-10, wherein the tumor has an aberration in the FGFR pathway.

[0024]

Item 12. The anti-tumor agent of item 11, wherein the aberration in the FGFR pathway is at least one member selected from the group consisting of FGFR overexpression, FGFR genetic aberration, and aberrant FGFR signaling.

[0025]

Item 13. An anti-tumor agent according to any one of items 1-12, wherein treatment with the anti-tumor agent produces a long-term response in the individual after cessation of treatment.

[0026]

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

[0027]

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

[0028]

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

[0029]

Item 17. An antitumor agent according to any one of items 1-6 and 11-16, where for a tumor with resistance to immune checkpoint inhibitors, the antitumor agent is used for administering (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof once a day at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg and 20 mg and for administering nivolumab at a dose selected from the group consisting of 1 mg/kg at 3-week intervals, 2 mg/kg at 3-week intervals, 3 mg/kg at 3-week intervals, 80 mg at 3-week intervals, 240 mg at 3-week intervals, 1 mg/kg at 2-week intervals, 2 mg/kg at 2-week intervals, 3 mg/kg at 2-week intervals, 80 mg at 2-week intervals, and 240 mg at 2-week intervals.

[0030]

Item 18. The antitumor agent of item 17, wherein for a tumor with resistance to immune checkpoint inhibitors, the antitumor agent is 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 once a day at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg and 20 mg and to administer nivolumab at a dose selected from the group consisting of 240 mg at 2-week intervals and 240 mg at 3-week intervals.

[0031]

Item 19. The antitumor agent of item 17, wherein for a tumor with resistance to immune checkpoint inhibitors, the antitumor agent is used for administering (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof once a day at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg and 20 mg and for administering nivolumab at a dose of 240 mg at 2-week intervals.

[0032]

Item 20. The antitumor agent of item 17, wherein for a tumor with resistance to immune checkpoint inhibitors, the antitumor agent is 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 once a day at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg and 20 mg, and to administer nivolumab at a dose of 80 mg four times at 3-week intervals and then from the fifth time 240 mg at 2-week intervals.

[0033]

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

[0034]

Item 22. The pharmaceutical composition according to item 21, for the treatment of cancer with resistance to immune checkpoint inhibitors.

[0035]

Item 23. Use of an immune checkpoint inhibitor, except 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 antineoplastic agent for the treatment of cancer with resistance to immune checkpoint inhibitors.

[0036]

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

[0037]

Item 25. Use of an immune checkpoint inhibitor, except pembrolizumab, for the manufacture of an antineoplastic agent for administration 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 with resistance to immune checkpoint inhibitors.

[0038]

Item 26. A combination of an immune checkpoint inhibitor, except pembrolizumab, and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for use in the treatment of cancer resistant to immune checkpoint inhibitors.

[0039]

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

[0040]

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

[0041]

Item 29. Use of an immune checkpoint inhibitor, except 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 treatment of cancer resistant to immune checkpoint inhibitors.

[0042]

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

[0043]

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

[0044]

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

[0045]

Item 33. An antitumor agent comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient, wherein the antitumor agent is administered in combination with an immune checkpoint inhibitor, except pembrolizumab, to an oncology patient who has been administered immune checkpoint inhibitors.

[0046]

Item 34. A pharmaceutical composition comprising an immune checkpoint inhibitor, except 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, for the treatment of cancer in a cancer patient who has not been administered immune checkpoint inhibitors.

[0047]

Item 35. The pharmaceutical composition according to item 34, for the treatment of cancer with resistance to immune checkpoint inhibitors.

[0048]

Item 36. Use of an immune checkpoint inhibitor, except 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 antineoplastic agent for the treatment of cancer in a cancer patient who has not been administered immune checkpoint inhibitors.

[0049]

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

[0050]

Item 38. Use of an immune checkpoint inhibitor, except pembrolizumab, for the manufacture of an antineoplastic agent for administration 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 immune checkpoint inhibitors.

[0051]

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

[0052]

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

[0053]

Item 41. An immune checkpoint inhibitor, other than 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 a cancer patient who has not been treated with immune checkpoint inhibitors.

[0054]

Item 42. Use of an immune checkpoint inhibitor, except 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 treatment of cancer in a cancer patient who has not been treated with immune checkpoint inhibitors.

[0055]

Item 43. 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 treatment of cancer in a cancer patient who has not been treated with immune checkpoint inhibitors, with combination therapy with an immune checkpoint inhibitor, except pembrolizumab.

[0056]

Item 44. Use of an immune checkpoint inhibitor, other than pembrolizumab, for the treatment of cancer in a cancer patient who has not been treated with immune checkpoint inhibitors, with 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.

[0057]

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

[0058]

Item 46. A 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, an immune checkpoint inhibitor or the method according to any of items 21-45, wherein the tumor has an aberration in the FGFR pathway.

[0059]

Item 47. A 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, an immune checkpoint inhibitor or the method of item 46, wherein the aberration in the FGFR pathway is at least one member selected from the group consisting of FGFR overexpression, FGFR genetic aberration and aberrant FGFR signaling.

[0060]

Item 48. An antineoplastic agent comprising (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof as an active ingredient, wherein the antineoplastic agent is administered in combination with an immune checkpoint inhibitor, except pembrolizumab, to an oncology patient with resistance to immune checkpoint inhibitors and without aberrations in the FGFR pathway.

[0061]

Item 49. A pharmaceutical composition comprising an immune checkpoint inhibitor, except 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, for the treatment of cancer without aberrations in the FGFR pathway.

[0062]

Item 50. The pharmaceutical composition according to item 49, for the treatment of cancer with resistance to immune checkpoint inhibitors.

[0063]

Item 51. Use of an immune checkpoint inhibitor, except 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 antineoplastic agent for the treatment of cancer without aberrations in the FGFR pathway.

[0064]

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

[0065]

Item 53. Use of an immune checkpoint inhibitor, other than pembrolizumab, for the manufacture of an antineoplastic agent for administration 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 aberrations in the FGFR pathway.

[0066]

Item 54. Combination of an immune checkpoint inhibitor, except pembrolizumab, and (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for use in the treatment of cancer without aberrations in the FGFR pathway.

[0067]

Item 55. (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for use in combination therapy with an immune checkpoint inhibitor, except pembrolizumab, in the treatment of cancer without aberrations in the FGFR pathway.

[0068]

Item 56. An immune checkpoint inhibitor, other than 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 without aberrations in the FGFR pathway.

[0069]

Item 57. Use of an immune checkpoint inhibitor other than 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 treatment of cancer without aberrations in the FGFR pathway.

[0070]

Item 58. Use of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof for the treatment of cancer without aberrations in the FGFR pathway by combination therapy with an immune checkpoint inhibitor, except for pembrolizumab.

[0071]

Item 59. Use of an immune checkpoint inhibitor, other than pembrolizumab, for the treatment of cancer without aberrations in the FGFR pathway 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.

[0072]

Item 60. A method for treating cancer without aberrations in the FGFR pathway, wherein the method comprises a therapeutically effective amount of (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and a therapeutically effective amount of an immune checkpoint inhibitor, except pembrolizumab, to a human in need thereof.

[0073]

Item 61. A 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, an immune checkpoint inhibitor or the method according to any one of items 18-29, wherein the immune checkpoint inhibitor is at least one member selected from the group consisting of a PD-1 pathway antagonist, an ICOS pathway agonist, a CTLA-4 pathway antagonist and a CD28 pathway agonist.

[0074]

Item 62. A 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, an immune checkpoint inhibitor or the method according to any of items 21-61, wherein the immune checkpoint inhibitor is a PD-1 pathway antagonist.

[0075]

Item 63. A 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, an immune checkpoint inhibitor or the method according to item 61 or 62, wherein the PD-1 pathway antagonist is at least one member selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody and an anti-PD-L2 antibody.

[0076]

Item 64. A 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, an immune checkpoint inhibitor or a method according to any of items 61-63, wherein the PD-1 pathway antagonist is an anti-PD-1 antibody.

[0077]

Item 65. A 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, an immune checkpoint inhibitor or the method according to item 63 or 64, wherein the anti-PD-1 antibody is nivolumab, cemiplimab, spartalizumab, tislelizumab, BI754091, dostarlimab, sasanlimab, MGA-012, cetrelimab, AGEN-2034, zimberelimab, camrelizumab, budigalimab or balstilimab; and preferably nivolumab.

[0078]

Item 66. A 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, an immune checkpoint inhibitor or a method according to any one of items 61-63, wherein the PD-1 pathway antagonist is an anti-PD-L1 antibody.

[0079]

Item 67. A 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, an immune checkpoint inhibitor or the method of item 64, wherein the anti-PD-L1 antibody is atezolizumab, durvalumab or avelumab.

[0080]

Item 68. A 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, an immune checkpoint inhibitor, or the method of item 61, wherein the CTLA-4 pathway antagonist is an anti-CTLA-4 antibody.

[0081]

Item 69. A 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, an immune checkpoint inhibitor, or the method of item 68, 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]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof, an immune checkpoint inhibitor, or the method according to any one of items 21-69, wherein treatment with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and an immune checkpoint inhibitor produces a sustained response in the individual after completion of the treatment.

[0083]

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

[0084]

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

[0085]

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

[0086]

Item 74. A 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, an immune checkpoint inhibitor, or a method according to any one of items 21-65 and 70-73, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and nivolumab are used as follows: to an oncology patient with resistance to immune checkpoint inhibitors, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg and 20 mg; and nivolumab is administered at a dose selected from the group consisting of 1 mg/kg at 3-week intervals, 2 mg/kg at 3-week intervals, 3 mg/kg at 3-week intervals, 80 mg at 3-week intervals, 240 mg at 3-week intervals, 1 mg/kg at 2-week intervals, 2 mg/kg at 2-week intervals, 3 mg/kg at 2-week intervals, 80 mg at 2-week intervals, and 240 mg at 2-week intervals.

[0087]

Item 75. A 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, an immune checkpoint inhibitor, or a method according to any one of items 21-65 and 70-73, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and nivolumab are used as follows: to an oncology patient with resistance to immune checkpoint inhibitors, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg and 20 mg; and nivolumab is administered at a dose selected from the group consisting of 240 mg at 2-week intervals and 240 mg at 3-week intervals.

[0088]

Item 76. A 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, an immune checkpoint inhibitor, or a method according to any one of items 21-65 and 70-73, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and nivolumab are used as follows: to an oncology patient with resistance to immune checkpoint inhibitors, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 8 mg, 12 mg, 16 mg and 20 mg; and nivolumab is administered at a dose of 240 mg at 2-week intervals.

[0089]

Item 77. A 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, an immune checkpoint inhibitor, or a method according to any one of items 21-65 and 70-73, wherein (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof and nivolumab are used as follows: to an oncology patient with resistance to immune checkpoint inhibitors, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered once daily at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg and 20 mg; and nivolumab is administered at a dose of 80 mg four times at 3-week intervals and then, starting with the fifth dose, 240 mg at 2-week intervals.

Advantages of the invention

[0090]

The present disclosure can provide a novel combination therapy that has excellent antitumor effects on cancer patients who are resistant to immune checkpoint inhibitors 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.

Brief description of the drawings

[0091]

Fig. 1 shows the results of Example 1 (effect of compound 1 on myeloid-derived suppressor cells (MDSC)).

Description of embodiments

[0092]

The present disclosure relates to the provision of, for example, a combined use of a compound having FGFR inhibitory activity and an immune checkpoint inhibitor other than pembrolizumab, i.e., an antitumor agent comprising a compound having FGFR inhibitory activity administered in combination with an immune checkpoint inhibitor other than pembrolizumab, an antitumor enhancer comprising a compound having FGFR inhibitory activity, a combination of a compound having FGFR inhibitory activity and an immune checkpoint inhibitor other than pembrolizumab, and the use of a compound having FGFR inhibitory activity in the manufacture of a medicament for treating tumors, administered in combination with an immune checkpoint inhibitor other than pembrolizumab.

[0093]

In the present specification, (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 has an excellent antitumor effect when used in combination with an immune checkpoint inhibitor, is a disubstituted benzenealkynyl compound having the following structure. In the present specification, this compound is simply referred to as "compound 1". Compound 1 is described in Example Compound 2 in PTL 2 described above. Compound 1 or a salt thereof has been reported to have an excellent FGFR inhibitory effect and inhibit the ability of receptor protein tyrosine kinases (FGFR1, FGFR3 and FGFR4) to phosphorylate tyrosine in a substrate peptide sequence (PTL 2).

[0094]

[0095]

Compound 1 or a pharmaceutically acceptable salt thereof in the present specification can be synthesized by any method; for example, it can be synthesized according to the production method described in PTL 2.

[0096]

In the present specification, compound 1 can be used as is or in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salt of compound 1 is not particularly limited, and examples include addition salts with inorganic acids such as hydrochloric acid and sulfuric acid, or with organic acids such as acetic acid, citric acid, tartaric acid and maleic acid; salts with alkali metals such as potassium and sodium; salts of alkaline earth metals such as calcium and magnesium; salts with organic bases such as ammonium salts, ethylamine salts and arginine salts; and the like.

[0097]

In the present description, immune checkpoint inhibitors act on immune checkpoint molecules and have the effect of inducing antitumor immune responses in the bodies of subjects and preventing tumor evasion from the immune response.

Examples of such immune checkpoint inhibitors include substances that improve the function of costimulatory molecules (stimulatory costimulatory molecules) and substances that inhibit the function of coinhibitory molecules (inhibitory costimulatory molecules). Examples of immune checkpoint molecules include molecules of the B7 family (B7-1, B7-2, PD-L1, PD-L2, etc.), the CD28 family (CTLA-4, PD-1, etc.), the TNF superfamily (4-1BBL, OX40L), and the TNF receptor superfamily (4-1BB, OX40). Substances that target immune checkpoint molecules can be used as immune checkpoint inhibitors. Examples include PD-1 pathway antagonists, ICOS pathway agonists, CTLA-4 pathway antagonists, CD28 pathway agonists, BTLA pathway antagonists, 4-1BB pathway agonists, and the like.

[0099]

In the present description, at least one or more members selected from the group consisting of PD-1 pathway antagonists, ICOS pathway agonists, CTLA-4 pathway antagonists and CD28 pathway agonists are preferred; at least one or more members selected from the group consisting of PD-1 pathway antagonists and CTLA-4 pathway antagonists are more preferred; and PD-1 pathway antagonists are even more preferred.

[0100]

PD-1 pathway antagonists inhibit the immunosuppressive signals of 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 PD-1 extracellular domain and the FC region of Ig), PD-L1-Ig, PD-L2-Ig, PD-1 siRNA, PD-L1 siRNA, PD-L2 siRNA and the like. Preferred are anti-PD-1 antibodies, anti-PD-L1 antibodies or anti-PD-L2 antibodies; and more preferred are anti-PD-1 antibodies or anti-PD-L1 antibodies. Particularly preferred among them are anti-PD-1 antibodies.

[0101]

In addition, CTLA-4 pathway antagonists inhibit the immunosuppressive signals of CTLA-4 expressed on T cells and their ligands B7-1 (CD80) and B7-2 (CD86). Preferred examples include anti-CTLA-4 antibodies, CTLA-4 extracellular domains, CTLA-4-Ig (a fusion protein of CTLA-4 extracellular domain and the FC region of Ig), anti-B7-1 (CD80) antibodies or anti-B7-2 (CD86) antibodies; and more preferred are anti-CTLA-4 antibodies or CTLA-4-Ig. Particularly preferred among these are anti-CTLA-4 antibodies.

[0102]

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

[0103]

A humanized IgG monoclonal antibody or a human IgG monoclonal antibody is preferred.

[0104]

In the present description, preferred anti-PD-1 antibodies include nivolumab, cemiplimab, spartalizumab, tislelizumab, BI754091, dostarlimab, sasanlimab, MGA-012, cetrelimab, AGEN-2034, zimberelimab, camrelizumab, budigalimab, balstilimab and the like.

[0105]

In the present description, preferred anti-PD-L1 antibodies include atezolizumab, durvalumab, avelumab, lodapolimab, BGB-A333 and the like.

[0106]

In the present description, preferred anti-CTLA-4 antibodies include ipilimumab, tremelimumab and the like.

[0107]

In the present description, preferred CTLA-4-Igs include abatacept and the like.

[0108]

These agonists or antagonists can be obtained by a generally known method of preparation.

[0109]

In addition, anti-PD-1 antibodies are already marketed or will be 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. These may also be used.

[0110]

In the present description, immune checkpoint inhibitors may be used alone or in combination of two or more.

[0111]

In the present description, when using two or more immune checkpoint inhibitors, for example, anti-PD-1 antibody, anti-CTLA-4 antibody and similar immune checkpoint inhibitors can be used in combination, or bispecific antibodies that can bind to different immune checkpoint molecules can also be used. Examples of bispecific antibodies include XmAb20717 (PD-1 x CTLA-4), which can bind to both PD-1 and CTLA-4.

[0112]

Treatment as used herein includes procedures performed for the purpose of treating or alleviating diseases or for the purpose of inhibiting the progression or recurrence of a disease or alleviating symptoms. Treatment includes the administration of drugs before or after a surgical procedure or the administration of drugs during, before, or after radiation therapy.

[0113]

Therapeutically effective amounts of antibodies and compound 1 or a salt thereof that block interaction with immune checkpoint molecules are not limited and depend on several factors, including the stage and severity of cancer, as well as other factors related to the patient's health. Those skilled in the art know how to determine therapeutically effective amounts.

[0114]

Embodiments of the present disclosure apply to tumors having aberrations of the FGFR pathway. In an embodiment, the FGFR is selected from the group consisting of FGFR1, FGFR2, FGFR3, and FGFR4.

[0115]

In an embodiment, the tumors to which the present invention is applied are preferably tumors having aberrations in the FGFR pathway. Aberrations in the FGFR pathway include FGFR overexpression, FGFR genetic aberration, and aberrant FGFR signaling.

[0116]

In an embodiment of the present disclosure, the presence of FGF/FGFR aberrations is not important; however, the subject of administration is advantageously one who has aberrations in the FGFR pathway. Compound 1 can enhance the antitumor effect of an immune checkpoint inhibitor even in cancer types without a genetic aberration of FGFR. It is known that the susceptibility of cancer to an immune checkpoint inhibitor is also influenced by the tumor microenvironment. The microenvironment includes, but is not limited to, cell groups controlled by activation of the FGF/FGFR pathway, such as tumor-associated fibroblasts (CAF). These cell groups are known to reduce the susceptibility of cancer to an immune checkpoint inhibitor. It is believed that administration of Compound 1 causes changes in the microenvironment, including inactivation of CAF, thereby enhancing the effect of the immune checkpoint inhibitor on cancer.

[0117]

Examples of FGFR overexpression include gene expression and high expression of gene product proteins. FGFR expression can be determined by methods known to those skilled in the art. Gene expression and high expression of gene product proteins can be determined by known methods such as antibody methods (immunohistochemistry, enzyme immunoassay (ELISA), flow cytometry, immunoblotting, etc.), nucleic acid methods ( in situ hybridization, PCR, Northern blotting, etc.) and methods based on the general principles of these methods. The detection device can be any known device (GeneChip, microarray, etc.).

[0118]

An embodiment of the present disclosure is used for tumors having genetic aberrations of FGFR. Genetic aberrations in the FGFR pathway include gene amplification, gene mutation, chromosomal translocation, insertion and inversion, gene fusion, genetic rearrangement, etc.). Some genetic aberrations in tumors have already been described in documents available to those skilled in the art (NPL 7 and NPL 8). Genetic aberration of FGFR can be detected by methods known to those skilled in the art, such as pyrosequencing, DNA sequencing including next generation sequencing (NGS), PCR-based methods including allele-specific PCR chain reactions, array-based comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH), and chromogenic in situ hybridization (CISH).

[0119]

In addition, an embodiment of the present disclosure applies to tumors with activated FGFR signaling. FGFRs bind to FGF to form dimers and are activated after phosphorylation, which induces the mobilization and activation of certain downstream signal transduction molecules, thereby developing physiological functions.

[0120]

Activation of FGFR signaling can be determined by methods known to those skilled in the art. Activation of signaling can be determined, for example, by determining FGFs that are substrates for FGFRs; by determining the direct phosphorylation state of FGFRs that are phosphorylated enzymes, or biological activity, including enzymatic activity; by determining the phosphorylation state of intracellular substrates and intracellular proteins that exist in the downstream signaling cascade of FGFRs or biological activity, including enzymatic activity; or by determining gene products or gene transcripts.

[0121]

In another embodiment, tumors to which the present disclosure applies also include tumors that do not have an aberration in the FGFR pathway.

[0122]

In the present specification, preferred examples of the daily dose of compound 1 or a salt thereof on the administration day include 4 mg to 160 mg, 4 mg to 24 mg, 12 to 24 mg, 16 to 24 mg, 20 mg and the like. More specifically, preferred examples of the plurality of doses and the daily dose on the administration day include once a day, 4 mg, 8 mg, 12 mg, 16 mg, 20 mg and the like. In another embodiment, preferred examples of the plurality of doses and the daily dose on the administration day include 8 mg, 12 mg, 16 mg, 20 mg and the like. In another embodiment, preferred examples of the plurality of doses and the daily dose on the administration day include 12 mg, 16 mg, 20 mg and the like. In another embodiment, preferred examples of the plurality of doses and the daily dose on the administration day include 20 mg and the like.

[0123]

In an embodiment of the present disclosure, in the case of a cancer type for which a stronger effect is desired (e.g., brain tumor), the dose of compound 1 or a salt thereof comprises a dose exceeding 20 mg once a day.

[0124]

If the daily dose of compound 1 or a salt thereof is administered intermittently, the daily dose of compound 1 or a pharmaceutically acceptable salt thereof is, for example, about 2 to 1000 mg, preferably 10 to 500 mg, more preferably 20 to 200 mg, and even more preferably 50 to 160 mg.

[0125]

Regarding the administration schedule, compound 1 or its salt may be administered every day or periodically.

[0126]

As used herein, “every day administration” may be a cycle-based administration regimen in which dosing is administered for 21 days every day (one cycle), and a drug rest period may be provided at the end of each cycle.

[0127]

In the present description, “periodic administration” is not particularly limited as long as the conditions of administration at least twice a week and an administration interval of at least one day between dosing (the number of days between a certain administration day and the next administration day) are satisfied.

Examples include a 1-week cycle-based administration regimen in which compound 1 or a pharmaceutically acceptable salt thereof is administered at least twice every one to three days in a cycle (with an interval of 1-3 days between a given administration day and the next administration day) and the cycle is administered once or repeated two or more times;

a 14-day cycle-based administration regimen in which compound 1 or its salt is administered 4-7 times every 1-3 days per cycle (with an interval between a certain administration day and the next administration day of 1-3 days) and this cycle is performed once or repeated two or more times;

a 14-day cycle-based administration regimen in which, over the course of 14 days comprising one cycle, compound 1 or its salt is administered on days 1, 4, 8, and 11;

a 14-day cycle dosing regimen in which, over the 14 days comprising one cycle, compound 1 or a salt thereof is administered on days 1, 3, 5, 7, 9, 11, and 13; and

a 14-day cycle-based dosing regimen in which, over the 14 days that comprise one cycle, compound 1 or its salt is administered on days 1, 3, 5, 8, 10, and 12.

[0128]

In an embodiment of the present disclosure, an exemplary administration regimen is one 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 may be reduced to 120 mg, 80 mg, 56 mg, 36 mg, 24 mg, 16 mg, or 8 mg.

[0129]

In the present description, in order to improve the antitumor activity of the immune checkpoint inhibitor by compound 1 or a salt thereof, the daily dose of the immune checkpoint inhibitor on the day of administration is preferably 30-100%, more preferably 50-100%, even more preferably 70-100%, even more preferably 80-100%, further still more preferably 90-100%, and further still more preferably 100%, of the recommended dose in the case of administering only the immune checkpoint inhibitor.

[0130]

The preferred dose of the immune checkpoint inhibitor when administered alone varies depending on the type of the drug, etc. 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, 3 mg/kg (body weight) per dose, and the like.

More specifically, the preferred dose of nivolumab when administered alone is, for example, 1-3 mg/kg (body weight) per dose or 80-240 mg per dose, 2-3 mg/kg (body weight) per dose or 160-240 mg per dose, 2 mg/kg (body weight) per dose, 3 mg/kg (body weight) per dose or 240 mg per dose.

In another embodiment, a preferred dose of nivolumab when administered alone is, for example, 80-480 mg per dose, 80 mg per dose, 240 mg per dose, or 480 mg per dose.

The preferred dose of cemiplimab when administered alone is, for example, 350 mg per dose.

[0131]

The preferred dose of atezolizumab when administered alone is, for example, 840-1680 mg per dose, or 840, 1200, or 1680 mg per dose.

[0132]

The preferred dose of ipilimumab when administered alone is, for example, 1.0-10 mg/kg (body weight) per dose, or 1.0, 3.0, or 10 mg/kg (body weight) per dose.

The preferred dose of durvalumab when administered alone is, for example, 5.0-10 mg/kg (body weight) per dose or 10 mg/kg (body weight) per dose.

The preferred dose of avelumab when administered alone is, for example, 10 mg/kg (body weight) per dose or 800 mg per dose.

[0133]

In the present description, the preferred dose of nivolumab per day on the day of administration is, for example, 40-480 mg per dose, or 80, 240 or 480 mg per dose. In addition, the administration interval of nivolumab is preferably 2-4 weeks, more preferably 2-3 weeks, and even more preferably 2 weeks.

[0134]

Furthermore, in a preferred embodiment, the dose and administration interval of nivolumab are such that 80 mg or 240 mg of nivolumab is administered four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab is administered at two-week intervals.

In the present description, the preferred dose of cemiplimab per day on the day of administration is, for example, 175-350 mg per dose or 350 mg per dose. The administration interval of cemiplimab is preferably 2-4 weeks, more preferably 2-3 weeks, and even more preferably 2 weeks.

[0135]

In the present description, the preferred dose of atezolizumab per day on the day of administration is, for example, 420-1680 mg per dose or 840, 1200 or 1680 mg. The administration interval of atezolizumab is preferably 2-4 weeks, more preferably 2-3 weeks, and even more preferably 3 weeks.

[0136]

In the present description, the preferred dose of ipilimumab per day on the day of administration is, for example, 0.5 to 10 mg/kg (body weight) per dose or 1.0, 3.0 or 10 mg/kg (body weight) per dose. The administration interval of ipilimumab is preferably 2-4 weeks, more preferably 2-3 weeks, and even more preferably 3 weeks.

[0137]

In the present description, the preferred dose of durvalumab per day on the day of administration is, for example, 5.0-10 mg/kg (body weight) per dose or 10 mg/kg (body weight) per dose. The interval of administration of durvalumab is preferably 2-4 weeks, more preferably 2-3 weeks, and even more preferably 2 weeks.

[0138]

In the present description, the preferred dose of avelumab per day on the day of administration is, for example, 5.0-10 g/kg (body weight) per dose or 10 mg/kg (body weight) per dose. In addition, in another embodiment, the preferred dose of avelumab per day on the day of administration is, for example, 400-800 mg per dose or 800 mg per dose. The administration interval of avelumab is preferably 2-4 weeks, more preferably 2-3 weeks, and even more preferably 2 weeks.

[0139]

Examples of the dose of compound 1 or a salt thereof according to the present description per day on the day of administration and the dose of nivolumab per day or a preferred combination of administration and dosing include the following:

4 mg - 160 mg of compound 1 or its salt as described herein and 1-4 mg/kg (body weight) per dose of nivolumab.

4 mg - 160 mg of compound 1 or its salt as described herein and 1-3 mg/kg (body weight) per dose of nivolumab.

4 mg - 160 mg of compound 1 or its salt as described herein and 2-3 mg/kg (body weight) per dose of nivolumab.

4 mg - 160 mg of compound 1 or its salt as described herein and 1 mg/kg (body weight) per dose of nivolumab.

4 mg - 160 mg of compound 1 or its salt as described herein and 2 mg/kg (body weight) per dose of nivolumab.

4 mg - 160 mg of compound 1 or its salt as described herein and 3 mg/kg (body weight) per dose of nivolumab.

4 mg - 160 mg of compound 1 or a salt thereof as described herein and 80-240 mg of nivolumab per dose.

4 mg - 160 mg of compound 1 or a salt thereof as described herein and 80-480 mg of nivolumab per dose.

4 mg - 160 mg of compound 1 or a salt thereof as described herein and 160-480 mg of nivolumab per dose.

4 mg - 160 mg of compound 1 or a salt thereof as described herein and 80 mg of nivolumab per dose.

4 mg - 160 mg of compound 1 or a salt thereof as described herein and 240 mg of nivolumab per dose.

4 mg - 160 mg of compound 1 or a salt thereof as described herein and 480 mg of nivolumab per dose.

4 mg - 160 mg of compound 1 or its salt as described herein and 1 mg/kg nivolumab at 2-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 2 mg/kg nivolumab at 2-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 3 mg/kg nivolumab at 2-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 1 mg/kg nivolumab at 3-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 2 mg/kg nivolumab at 3-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 3 mg/kg nivolumab at 3-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 1 mg/kg nivolumab at 4-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 2 mg/kg nivolumab at 4-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 3 mg/kg nivolumab at 4-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 80 mg of nivolumab at 2-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 240 mg of nivolumab at 2-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 480 mg of nivolumab at 2-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 80 mg of nivolumab at 3-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 240 mg of nivolumab at 3-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 480 mg of nivolumab at 3-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 80 mg of nivolumab at 4-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 240 mg of nivolumab at 4-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 480 mg of nivolumab at 4-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

4 mg - 160 mg of compound 1 or a salt thereof as described herein and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 1-4 mg/kg (body weight) per dose of nivolumab.

4 mg - 24 mg of compound 1 or its salt as described herein and 1-3 mg/kg (body weight) per dose of nivolumab.

4 mg - 24 mg of compound 1 or its salt as described herein and 2-3 mg/kg (body weight) per dose of nivolumab.

4 mg - 24 mg of compound 1 or its salt as described herein and 1 mg/kg (body weight) per dose of nivolumab.

4 mg - 24 mg of compound 1 or its salt as described herein and 2 mg/kg (body weight) per dose of nivolumab.

4 mg - 24 mg of compound 1 or its salt as described herein and 3 mg/kg (body weight) per dose of nivolumab.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 80-240 mg of nivolumab per dose.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 80-480 mg of nivolumab per dose.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 160-480 mg of nivolumab per dose.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 80 mg of nivolumab per dose.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 240 mg of nivolumab per dose.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 480 mg of nivolumab per dose.

4 mg - 24 mg of compound 1 or its salt as described herein and 1 mg/kg nivolumab at 2-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 2 mg/kg nivolumab at 2-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 3 mg/kg nivolumab at 2-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 1 mg/kg nivolumab at 3-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 2 mg/kg nivolumab at 3-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 3 mg/kg nivolumab at 3-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 1 mg/kg nivolumab at 4-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 2 mg/kg nivolumab at 4-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 3 mg/kg nivolumab at 4-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 80 mg of nivolumab at 2-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 240 mg of nivolumab at 2-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 480 mg of nivolumab at 2-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 80 mg of nivolumab at 3-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 240 mg of nivolumab at 3-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 480 mg of nivolumab at 3-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 80 mg of nivolumab at 4-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 240 mg of nivolumab at 4-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 480 mg of nivolumab at 4-week intervals.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

12-24 mg of compound 1 or its salt as described herein and 1-4 mg/kg (body weight) per dose of nivolumab.

12-24 mg of compound 1 or its salt as described herein and 1-3 mg/kg (body weight) per dose of nivolumab.

12-24 mg of compound 1 or its salt as described herein and 2-3 mg/kg (body weight) per dose of nivolumab.

12-24 mg of compound 1 or its salt as described herein and 1 mg/kg (body weight) per dose of nivolumab.

12-24 mg of compound 1 or its salt as described herein and 2 mg/kg (body weight) per dose of nivolumab.

12-24 mg of compound 1 or its salt as described herein and 3 mg/kg (body weight) per dose of nivolumab.

12-24 mg of compound 1 or a salt thereof as described herein and 80-240 mg of nivolumab per dose.

12-24 mg of compound 1 or a salt thereof as described herein and 80-480 mg of nivolumab per dose.

12-24 mg of compound 1 or a salt thereof as described herein and 160-480 mg of nivolumab per dose.

12-24 mg of compound 1 or a salt thereof as described herein and 80 mg of nivolumab per dose.

12-24 mg of compound 1 or a salt thereof as described herein and 240 mg of nivolumab per dose.

12-24 mg of compound 1 or a salt thereof as described herein and 480 mg of nivolumab per dose.

12-24 mg of compound 1 or its salt as described herein and 1 mg/kg nivolumab at 2-week intervals.

12-24 mg of compound 1 or its salt as described herein and 2 mg/kg nivolumab at 2-week intervals.

12-24 mg of compound 1 or its salt as described herein and 3 mg/kg nivolumab at 2-week intervals.

12-24 mg of compound 1 or its salt as described herein and 1 mg/kg nivolumab at 3-week intervals.

12-24 mg of compound 1 or its salt as described herein and 2 mg/kg nivolumab at 3-week intervals.

12-24 mg of compound 1 or its salt as described herein and 3 mg/kg nivolumab at 3-week intervals.

12-24 mg of compound 1 or its salt as described herein and 1 mg/kg nivolumab at 4-week intervals.

12-24 mg of compound 1 or its salt as described herein and 2 mg/kg nivolumab at 4-week intervals.

12-24 mg of compound 1 or its salt as described herein and 3 mg/kg nivolumab at 4-week intervals.

12-24 mg of compound 1 or its salt as described herein and 80 mg of nivolumab at 2-week intervals.

12-24 mg of compound 1 or its salt as described herein and 240 mg of nivolumab at 2-week intervals.

12-24 mg of compound 1 or its salt as described herein and 480 mg of nivolumab at 2-week intervals.

12-24 mg of compound 1 or its salt as described herein and 80 mg of nivolumab at 3-week intervals.

12-24 mg of compound 1 or its salt as described herein and 240 mg of nivolumab at 3-week intervals.

12-24 mg of compound 1 or its salt as described herein and 480 mg of nivolumab at 3-week intervals.

12-24 mg of compound 1 or its salt as described herein and 80 mg of nivolumab at 4-week intervals.

12-24 mg of compound 1 or its salt as described herein and 240 mg of nivolumab at 4-week intervals.

12-24 mg of compound 1 or its salt as described herein and 480 mg of nivolumab at 4-week intervals.

12-24 mg of compound 1 or a salt thereof as described herein and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

12-24 mg of compound 1 or a salt thereof as described herein and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

12-24 mg of compound 1 or a salt thereof as described herein and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

12-24 mg of compound 1 or a salt thereof as described herein and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

16-24 mg of compound 1 or its salt as described herein and 1-4 mg/kg (body weight) per dose of nivolumab.

16-24 mg of compound 1 or its salt as described herein and 1-3 mg/kg (body weight) per dose of nivolumab.

16-24 mg of compound 1 or its salt as described herein and 2-3 mg/kg (body weight) per dose of nivolumab.

16-24 mg of compound 1 or its salt as described herein and 1 mg/kg (body weight) per dose of nivolumab.

16-24 mg of compound 1 or its salt as described herein and 2 mg/kg (body weight) per dose of nivolumab.

16-24 mg of compound 1 or its salt as described herein and 3 mg/kg (body weight) per dose of nivolumab.

16-24 mg of compound 1 or a salt thereof as described herein and 80-240 mg of nivolumab per dose.

16-24 mg of compound 1 or a salt thereof as described herein and 80-480 mg of nivolumab per dose.

16-24 mg of compound 1 or a salt thereof as described herein and 160-480 mg of nivolumab per dose.

16-24 mg of compound 1 or a salt thereof as described herein and 80 mg of nivolumab per dose.

16-24 mg of compound 1 or a salt thereof as described herein and 240 mg of nivolumab per dose.

16-24 mg of compound 1 or a salt thereof as described herein and 480 mg of nivolumab per dose.

16-24 mg of compound 1 or its salt as described herein and 1 mg/kg nivolumab at 2-week intervals.

16-24 mg of compound 1 or its salt as described herein and 2 mg/kg nivolumab at 2-week intervals.

16-24 mg of compound 1 or its salt as described herein and 3 mg/kg nivolumab at 2-week intervals.

16-24 mg of compound 1 or its salt as described herein and 1 mg/kg nivolumab at 3-week intervals.

16-24 mg of compound 1 or its salt as described herein and 2 mg/kg nivolumab at 3-week intervals.

16-24 mg of compound 1 or its salt as described herein and 3 mg/kg nivolumab at 3-week intervals.

16-24 mg of compound 1 or its salt as described herein and 1 mg/kg nivolumab at 4-week intervals.

16-24 mg of compound 1 or its salt as described herein and 2 mg/kg nivolumab at 4-week intervals.

16-24 mg of compound 1 or its salt as described herein and 3 mg/kg nivolumab at 4-week intervals.

16-24 mg of compound 1 or its salt as described herein and 80 mg of nivolumab at 2-week intervals.

16-24 mg of compound 1 or its salt as described herein and 240 mg of nivolumab at 2-week intervals.

16-24 mg of compound 1 or its salt as described herein and 480 mg of nivolumab at 2-week intervals.

16-24 mg of compound 1 or its salt as described herein and 80 mg of nivolumab at 3-week intervals.

16-24 mg of compound 1 or its salt as described herein and 240 mg of nivolumab at 3-week intervals.

16-24 mg of compound 1 or its salt as described herein and 480 mg of nivolumab at 3-week intervals.

16-24 mg of compound 1 or its salt as described herein and 80 mg of nivolumab at 4-week intervals.

16-24 mg of compound 1 or its salt as described herein and 240 mg of nivolumab at 4-week intervals.

16-24 mg of compound 1 or its salt as described herein and 480 mg of nivolumab at 4-week intervals.

16-24 mg of compound 1 or a salt thereof as described herein and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

16-24 mg of compound 1 or a salt thereof as described herein and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

16-24 mg of compound 1 or a salt thereof as described herein and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

16-24 mg of compound 1 or a salt thereof as described herein and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

[0140]

Examples of a plurality of doses and a dose of compound 1 or a salt thereof according to the present description per day on the day of administration and a dose of nivolumab per day or a combination for use and dosing include the following:

4 mg of compound 1 or its salt as described herein once daily and 1-4 mg/kg (body weight) per dose of nivolumab.

4 mg of compound 1 or its salt as described herein once daily and 1-3 mg/kg (body weight) per dose of nivolumab.

4 mg of compound 1 or its salt as described herein once daily and 2-3 mg/kg (body weight) per dose of nivolumab.

4 mg of compound 1 or its salt as described herein once daily and 1 mg/kg (body weight) per dose of nivolumab.

4 mg of compound 1 or its salt as described herein once daily and 2 mg/kg (body weight) per dose of nivolumab.

4 mg of compound 1 or its salt as described herein once daily and 3 mg/kg (body weight) per dose of nivolumab.

4 mg of compound 1 or a salt thereof as described herein once daily and 80-240 mg of nivolumab per dose.

4 mg of compound 1 or a salt thereof as described herein once daily and 80-480 mg of nivolumab per dose.

4 mg of compound 1 or a salt thereof as described herein once daily and 160-480 mg of nivolumab per dose.

4 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab per dose.

4 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab per dose.

4 mg of compound 1 or a salt thereof as described herein once daily and 480 mg of nivolumab per dose.

4 mg of compound 1 or its salt as described herein once daily and 1 mg/kg nivolumab at 2-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 2 mg/kg nivolumab at 2-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 3 mg/kg nivolumab at 2-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 1 mg/kg nivolumab at 3-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 2 mg/kg nivolumab at 3-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 3 mg/kg nivolumab at 3-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 1 mg/kg nivolumab at 4-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 2 mg/kg nivolumab at 4-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 3 mg/kg nivolumab at 4-week intervals.

4 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab at 2-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 240 mg of nivolumab at 2-week intervals.

4 mg of compound 1 or a salt thereof as described herein once daily and 480 mg of nivolumab at 2-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 80 mg of nivolumab at 3-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 240 mg of nivolumab at 3-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 480 mg of nivolumab at 3-week intervals.

4 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab at 4-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 240 mg of nivolumab at 4-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 480 mg of nivolumab at 4-week intervals.

4 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

4 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

4 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

4 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 1-4 mg/kg (body weight) per dose of nivolumab.

8 mg of compound 1 or its salt as described herein once daily and 1-3 mg/kg (body weight) per dose of nivolumab.

8 mg of compound 1 or its salt as described herein once daily and 2-3 mg/kg (body weight) per dose of nivolumab.

8 mg of compound 1 or its salt as described herein once daily and 1 mg/kg (body weight) per dose of nivolumab.

8 mg of compound 1 or its salt as described herein once daily and 2 mg/kg (body weight) per dose of nivolumab.

8 mg of compound 1 or its salt as described herein once daily and 3 mg/kg (body weight) per dose of nivolumab.

8 mg of compound 1 or a salt thereof as described herein once daily and 80-240 mg of nivolumab per dose.

8 mg of compound 1 or a salt thereof as described herein once daily and 80-480 mg of nivolumab per dose.

8 mg of compound 1 or a salt thereof as described herein once daily and 160-480 mg of nivolumab per dose.

8 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab per dose.

8 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab per dose.

8 mg of compound 1 or a salt thereof as described herein once daily and 480 mg of nivolumab per dose.

8 mg of compound 1 or its salt as described herein once daily and 1 mg/kg nivolumab at 2-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 2 mg/kg nivolumab at 2-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 3 mg/kg nivolumab at 2-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 1 mg/kg nivolumab at 3-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 2 mg/kg nivolumab at 3-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 3 mg/kg nivolumab at 3-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 1 mg/kg nivolumab at 4-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 2 mg/kg nivolumab at 4-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 3 mg/kg nivolumab at 4-week intervals.

8 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab at 2-week intervals.

8 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab at 2-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 480 mg of nivolumab at 2-week intervals.

8 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab at 3-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 240 mg of nivolumab at 3-week intervals.

8 mg of compound 1 or a salt thereof as described herein once daily and 480 mg of nivolumab at 3-week intervals.

8 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab at 4-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 240 mg of nivolumab at 4-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 480 mg of nivolumab at 4-week intervals.

8 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

8 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

8 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

8 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 1-4 mg/kg (body weight) per dose of nivolumab.

12 mg of compound 1 or its salt as described herein once daily and 1-3 mg/kg (body weight) per dose of nivolumab.

12 mg of compound 1 or its salt as described herein once daily and 2-3 mg/kg (body weight) per dose of nivolumab.

12 mg of compound 1 or its salt as described herein once daily and 1 mg/kg (body weight) per dose of nivolumab.

12 mg of compound 1 or its salt as described herein once daily and 2 mg/kg (body weight) per dose of nivolumab.

12 mg of compound 1 or its salt as described herein once daily and 3 mg/kg (body weight) per dose of nivolumab.

12 mg of compound 1 or a salt thereof as described herein once daily and 80-240 mg of nivolumab per dose.

12 mg of compound 1 or a salt thereof as described herein once daily and 80-480 mg of nivolumab per dose.

12 mg of compound 1 or a salt thereof as described herein once daily and 160-480 mg of nivolumab per dose.

12 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab per dose.

12 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab per dose.

12 mg of compound 1 or a salt thereof as described herein once daily and 480 mg of nivolumab per dose.

12 mg of compound 1 or its salt as described herein once daily and 1 mg/kg nivolumab at 2-week intervals.

12 mg of compound 1 or a salt thereof as described herein once daily and 2 mg/kg nivolumab at 2-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 3 mg/kg nivolumab at 2-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 1 mg/kg nivolumab at 3-week intervals.

12 mg of compound 1 or a salt thereof as described herein once daily and 2 mg/kg nivolumab at 3-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 3 mg/kg nivolumab at 3-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 1 mg/kg nivolumab at 4-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 2 mg/kg nivolumab at 4-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 3 mg/kg nivolumab at 4-week intervals.

12 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab at 2-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 240 mg of nivolumab at 2-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 480 mg of nivolumab at 2-week intervals.

12 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab at 3-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 240 mg of nivolumab at 3-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 480 mg of nivolumab at 3-week intervals.

12 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab at 4-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 240 mg of nivolumab at 4-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 480 mg of nivolumab at 4-week intervals.

12 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

12 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

12 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

12 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 1-4 mg/kg (body weight) per dose of nivolumab.

16 mg of compound 1 or its salt as described herein once daily and 1-3 mg/kg (body weight) per dose of nivolumab.

16 mg of compound 1 or its salt as described herein once daily and 2-3 mg/kg (body weight) per dose of nivolumab.

16 mg of compound 1 or its salt as described herein once daily and 1 mg/kg (body weight) per dose of nivolumab.

16 mg of compound 1 or its salt as described herein once daily and 2 mg/kg (body weight) per dose of nivolumab.

16 mg of compound 1 or its salt as described herein once daily and 3 mg/kg (body weight) per dose of nivolumab.

16 mg of compound 1 or a salt thereof as described herein once daily and 80-240 mg of nivolumab per dose.

16 mg of compound 1 or a salt thereof as described herein once daily and 80-480 mg of nivolumab per dose.

16 mg of compound 1 or a salt thereof as described herein once daily and 160-480 mg of nivolumab per dose.

16 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab per dose.

16 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab per dose.

16 mg of compound 1 or a salt thereof as described herein once daily and 480 mg of nivolumab per dose.

16 mg of compound 1 or its salt as described herein once daily and 1 mg/kg nivolumab at 2-week intervals.

16 mg of compound 1 or a salt thereof as described herein once daily and 2 mg/kg nivolumab at 2-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 3 mg/kg nivolumab at 2-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 1 mg/kg nivolumab at 3-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 2 mg/kg nivolumab at 3-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 3 mg/kg nivolumab at 3-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 1 mg/kg nivolumab at 4-week intervals.

16 mg of compound 1 or a salt thereof as described herein once daily and 2 mg/kg nivolumab at 4-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 3 mg/kg nivolumab at 4-week intervals.

16 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab at 2-week intervals.

16 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab at 2-week intervals.

16 mg of compound 1 or a salt thereof as described herein once daily and 480 mg of nivolumab at 2-week intervals.

16 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab at 3-week intervals.

16 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab at 3-week intervals.

16 mg of compound 1 or a salt thereof as described herein once daily and 480 mg of nivolumab at 3-week intervals.

16 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab at 4-week intervals.

16 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab at 4-week intervals.

16 mg of compound 1 or a salt thereof as described herein once daily and 480 mg of nivolumab at 4-week intervals.

16 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

16 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

16 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

16 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 1-4 mg/kg (body weight) per dose of nivolumab.

20 mg of compound 1 or its salt as described herein once daily and 1-3 mg/kg (body weight) per dose of nivolumab.

20 mg of compound 1 or its salt as described herein once daily and 2-3 mg/kg (body weight) per dose of nivolumab.

20 mg of compound 1 or its salt as described herein once daily and 1 mg/kg (body weight) per dose of nivolumab.

20 mg of compound 1 or its salt as described herein once daily and 2 mg/kg (body weight) per dose of nivolumab.

20 mg of compound 1 or its salt as described herein once daily and 3 mg/kg (body weight) per dose of nivolumab.

20 mg of compound 1 or a salt thereof as described herein once daily and 80-240 mg of nivolumab per dose.

20 mg of compound 1 or a salt thereof as described herein once daily and 80-480 mg of nivolumab per dose.

20 mg of compound 1 or a salt thereof as described herein once daily and 160-480 mg of nivolumab per dose.

20 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab per dose.

20 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab per dose.

20 mg of compound 1 or a salt thereof as described herein once daily and 480 mg of nivolumab per dose.

20 mg of compound 1 or its salt as described herein once daily and 1 mg/kg nivolumab at 2-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 2 mg/kg nivolumab at 2-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 3 mg/kg nivolumab at 2-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 1 mg/kg nivolumab at 3-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 2 mg/kg nivolumab at 3-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 3 mg/kg nivolumab at 3-week intervals.

20 mg of compound 1 or a salt thereof as described herein once daily and 1 mg/kg nivolumab at 4-week intervals.

20 mg of compound 1 or a salt thereof as described herein once daily and 2 mg/kg nivolumab at 4-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 3 mg/kg nivolumab at 4-week intervals.

20 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab at 2-week intervals.

20 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab at 2-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 480 mg of nivolumab at 2-week intervals.

20 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab at 3-week intervals.

20 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab at 3-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 480 mg of nivolumab at 3-week intervals.

20 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab at 4-week intervals.

20 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab at 4-week intervals.

20 mg of compound 1 or a salt thereof as described herein once daily and 480 mg of nivolumab at 4-week intervals.

20 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

20 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 240 mg of nivolumab at 2-week intervals.

20 mg of compound 1 or a salt thereof as described herein once daily and 80 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

20 mg of compound 1 or a salt thereof as described herein once daily and 240 mg of nivolumab four times at 3-week intervals and then, from the fifth time, 480 mg of nivolumab at 4-week intervals.

[0141]

Examples of the dose of compound 1 or its salt of the present disclosure per day on the day of administration and the dose of atezolizumab per day or the preferred combination of administration and dosing include the following:

4 mg - 160 mg of compound 1 or a salt thereof as described herein and 420-1680 mg of atezolizumab per dose.

4 mg - 160 mg of compound 1 or a salt thereof as described herein and 840-1680 mg of atezolizumab per dose.

4 mg - 160 mg of compound 1 or a salt thereof as described herein and 840 mg of atezolizumab per dose.

4 mg - 160 mg of compound 1 or a salt thereof as described herein and 1200 mg of atezolizumab per dose.

4 mg - 160 mg of compound 1 or a salt thereof as described herein and 1680 mg of atezolizumab per dose.

4 mg - 160 mg of compound 1 or its salt as described herein and 840 mg of atezolizumab at 2-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 1200 mg of atezolizumab at 2-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 1680 mg of atezolizumab at 2-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 840 mg of atezolizumab at 3-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 1200 mg of atezolizumab at 3-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 1680 mg of atezolizumab at 3-week intervals.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 420-1680 mg of atezolizumab per dose.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 840-1680 mg of atezolizumab per dose.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 840 mg of atezolizumab per dose.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 1200 mg of atezolizumab per dose.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 1680 mg of atezolizumab per dose.

4 mg - 24 mg of compound 1 or its salt as described herein and 840 mg of atezolizumab at 2-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 1200 mg of atezolizumab at 2-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 1680 mg of atezolizumab at 2-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 840 mg of atezolizumab at 3-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 1200 mg of atezolizumab at 3-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 1680 mg of atezolizumab at 3-week intervals.

12-24 mg of compound 1 or a salt thereof as described herein and 420-1680 mg of atezolizumab per dose.

12-24 mg of compound 1 or a salt thereof as described herein and 840-1680 mg of atezolizumab per dose.

12-24 mg of compound 1 or a salt thereof as described herein and 840 mg of atezolizumab per dose.

12-24 mg of compound 1 or a salt thereof as described herein and 1200 mg of atezolizumab per dose.

12-24 mg of compound 1 or a salt thereof as described herein and 1680 mg of atezolizumab per dose.

12-24 mg of compound 1 or its salt as described herein and 840 mg of atezolizumab at 2-week intervals.

12-24 mg of compound 1 or its salt as described herein and 1200 mg of atezolizumab at 2-week intervals.

12-24 mg of compound 1 or its salt as described herein and 1680 mg of atezolizumab at 2-week intervals.

12-24 mg of compound 1 or its salt as described herein and 840 mg of atezolizumab at 3-week intervals.

12-24 mg of compound 1 or its salt as described herein and 1200 mg of atezolizumab at 3-week intervals.

12-24 mg of compound 1 or its salt as described herein and 1680 mg of atezolizumab at 3-week intervals.

16-24 mg of compound 1 or a salt thereof as described herein and 420-1680 mg of atezolizumab per dose.

16-24 mg of compound 1 or a salt thereof as described herein and 840-1680 mg of atezolizumab per dose.

16-24 mg of compound 1 or a salt thereof as described herein and 840 mg of atezolizumab per dose.

16-24 mg of compound 1 or a salt thereof as described herein and 1200 mg of atezolizumab per dose.

16-24 mg of compound 1 or a salt thereof as described herein and 1680 mg of atezolizumab per dose.

16-24 mg of compound 1 or its salt as described herein and 840 mg of atezolizumab at 2-week intervals.

16-24 mg of compound 1 or its salt as described herein and 1200 mg of atezolizumab at 2-week intervals.

16-24 mg of compound 1 or its salt as described herein and 1680 mg of atezolizumab at 2-week intervals.

16-24 mg of compound 1 or its salt as described herein and 840 mg of atezolizumab at 3-week intervals.

16-24 mg of compound 1 or its salt as described herein and 1200 mg of atezolizumab at 3-week intervals.

16-24 mg of compound 1 or its salt as described herein and 1680 mg of atezolizumab at 3-week intervals.

[0142]

Examples of a plurality of doses and a dose of compound 1 or a salt thereof according to the present description per day on the day of administration and a dose of atezolizumab per day or a combination of administration and dosing include the following:

4 mg of compound 1 or a salt thereof as described herein once daily and 420-1680 mg of atezolizumab per dose.

4 mg of compound 1 or a salt thereof as described herein once daily and 840-1680 mg of atezolizumab per dose.

4 mg of compound 1 or a salt thereof as described herein once daily and 840 mg of atezolizumab per dose.

4 mg of compound 1 or a salt thereof as described herein once daily and 1200 mg of atezolizumab per dose.

4 mg of compound 1 or a salt thereof as described herein once daily and 1680 mg of atezolizumab per dose.

4 mg of compound 1 or its salt as described herein once daily and 840 mg of atezolizumab at 2-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 1200 mg of atezolizumab at 2-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 1680 mg of atezolizumab at 2-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 840 mg of atezolizumab at 3-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 1200 mg of atezolizumab at 3-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 1680 mg of atezolizumab at 3-week intervals.

8 mg of compound 1 or a salt thereof as described herein once daily and 420-1680 mg of atezolizumab per dose.

8 mg of compound 1 or a salt thereof as described herein once daily and 840-1680 mg of atezolizumab per dose.

8 mg of compound 1 or a salt thereof as described herein once daily and 840 mg of atezolizumab per dose.

8 mg of compound 1 or a salt thereof as described herein once daily and 1200 mg of atezolizumab per dose.

8 mg of compound 1 or a salt thereof as described herein once daily and 1680 mg of atezolizumab per dose.

8 mg of compound 1 or its salt as described herein once daily and 840 mg of atezolizumab at 2-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 1200 mg of atezolizumab at 2-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 1680 mg of atezolizumab at 2-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 840 mg of atezolizumab at 3-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 1200 mg of atezolizumab at 3-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 1680 mg of atezolizumab at 3-week intervals.

12 mg of compound 1 or a salt thereof as described herein once daily and 420-1680 mg of atezolizumab per dose.

12 mg of compound 1 or a salt thereof as described herein once daily and 840-1680 mg of atezolizumab per dose.

12 mg of compound 1 or a salt thereof as described herein once daily and 840 mg of atezolizumab per dose.

12 mg of compound 1 or a salt thereof as described herein once daily and 1200 mg of atezolizumab per dose.

12 mg of compound 1 or a salt thereof as described herein once daily and 1680 mg of atezolizumab per dose.

12 mg of compound 1 or its salt as described herein once daily and 840 mg of atezolizumab at 2-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 1200 mg of atezolizumab at 2-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 1680 mg of atezolizumab at 2-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 840 mg of atezolizumab at 3-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 1200 mg of atezolizumab at 3-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 1680 mg of atezolizumab at 3-week intervals.

16 mg of compound 1 or a salt thereof as described herein once daily and 420-1680 mg of atezolizumab per dose.

16 mg of compound 1 or a salt thereof as described herein once daily and 840-1680 mg of atezolizumab per dose.

16 mg of compound 1 or a salt thereof as described herein once daily and 840 mg of atezolizumab per dose.

16 mg of compound 1 or a salt thereof as described herein once daily and 1200 mg of atezolizumab per dose.

16 mg of compound 1 or a salt thereof as described herein once daily and 1680 mg of atezolizumab per dose.

16 mg of compound 1 or its salt as described herein once daily and 840 mg of atezolizumab at 2-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 1200 mg of atezolizumab at 2-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 1680 mg of atezolizumab at 2-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 840 mg of atezolizumab at 3-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 1200 mg of atezolizumab at 3-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 1680 mg of atezolizumab at 3-week intervals.

20 mg of compound 1 or a salt thereof as described herein once daily and 420-1680 mg of atezolizumab per dose.

20 mg of compound 1 or a salt thereof as described herein once daily and 840-1680 mg of atezolizumab per dose.

20 mg of compound 1 or a salt thereof as described herein once daily and 840 mg of atezolizumab per dose.

20 mg of compound 1 or a salt thereof as described herein once daily and 1200 mg of atezolizumab per dose.

20 mg of compound 1 or a salt thereof as described herein once daily and 1680 mg of atezolizumab per dose.

20 mg of compound 1 or its salt as described herein once daily and 840 mg of atezolizumab at 2-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 1200 mg of atezolizumab at 2-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 1680 mg of atezolizumab at 2-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 840 mg of atezolizumab at 3-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 1200 mg of atezolizumab at 3-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 1680 mg of atezolizumab at 3-week intervals.

[0143]

Examples of the dose of compound 1 or its salt of the present disclosure per day on the day of administration and the dose of ipilimumab per day or the preferred combination of administration and dosing include the following:

4 mg - 160 mg of compound 1 or its salt as described herein and 0.5-10 mg/kg (body weight) per dose of ipilimumab

4 mg - 160 mg of compound 1 or its salt as described herein and 1.0-10 mg/kg (body weight) per dose of ipilimumab.

4 mg - 160 mg of compound 1 or its salt as described herein and 1.0 mg/kg (body weight) per dose of ipilimumab.

4 mg - 160 mg of compound 1 or its salt as described herein and 3.0 mg/kg (body weight) per dose of ipilimumab.

4 mg - 160 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) per dose of ipilimumab.

4 mg - 160 mg of compound 1 or its salt as described herein and 1.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 1.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 3.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 3.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of ipilimumab at 2-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of ipilimumab at 3-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 0.5-10 mg/kg (body weight) per dose of ipilimumab

4 mg - 24 mg of compound 1 or its salt as described herein and 1.0-10 mg/kg (body weight) per dose of ipilimumab.

4 mg - 24 mg of compound 1 or its salt as described herein and 1.0 mg/kg (body weight) per dose of ipilimumab.

4 mg - 24 mg of compound 1 or its salt as described herein and 3.0 mg/kg (body weight) per dose of ipilimumab.

4 mg - 24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) per dose of ipilimumab.

4 mg - 24 mg of compound 1 or its salt as described herein and 1.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 1.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 3.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 3.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of ipilimumab at 2-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of ipilimumab at 3-week intervals.

12-24 mg of compound 1 or its salt as described herein and 0.5-10 mg/kg (body weight) per dose of ipilimumab

12-24 mg of compound 1 or its salt as described herein and 1.0-10 mg/kg (body weight) per dose of ipilimumab.

12-24 mg of compound 1 or its salt as described herein and 1.0 mg/kg (body weight) per dose of ipilimumab.

12-24 mg of compound 1 or its salt as described herein and 3.0 mg/kg (body weight) per dose of ipilimumab.

12-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) per dose of ipilimumab.

12-24 mg of compound 1 or its salt as described herein and 1.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

12-24 mg of compound 1 or its salt as described herein and 1.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

12-24 mg of compound 1 or its salt as described herein and 3.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

12-24 mg of compound 1 or its salt as described herein and 3.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

12-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of ipilimumab at 2-week intervals.

12-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of ipilimumab at 3-week intervals.

16-24 mg of compound 1 or its salt as described herein and 0.5-10 mg/kg (body weight) per dose of ipilimumab

16-24 mg of compound 1 or its salt as described herein and 1.0-10 mg/kg (body weight) per dose of ipilimumab.

16-24 mg of compound 1 or its salt as described herein and 1.0 mg/kg (body weight) per dose of ipilimumab.

16-24 mg of compound 1 or its salt as described herein and 3.0 mg/kg (body weight) per dose of ipilimumab.

16-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) per dose of ipilimumab.

16-24 mg of compound 1 or its salt as described herein and 1.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

16-24 mg of compound 1 or its salt as described herein and 1.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

16-24 mg of compound 1 or its salt as described herein and 3.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

16-24 mg of compound 1 or its salt as described herein and 3.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

16-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of ipilimumab at 2-week intervals.

16-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of ipilimumab at 3-week intervals.

[0144]

Examples of a plurality of doses and a dose of compound 1 or a salt thereof according to the present description per day on the day of administration and a dose of ipilimumab per day or a combination of administration and dosing include the following:

4 mg of compound 1 or its salt as described herein once daily and 0.5-10 mg/kg (body weight) per dose of ipilimumab

4 mg of compound 1 or its salt as described herein once daily and 1.0-10 mg/kg (body weight) per dose of ipilimumab.

4 mg of compound 1 or its salt as described herein once daily and 1.0 mg/kg (body weight) per dose of ipilimumab.

4 mg of compound 1 or its salt as described herein once daily and 3.0 mg/kg (body weight) per dose of ipilimumab.

4 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) per dose of ipilimumab.

4 mg of compound 1 or its salt as described herein once daily and 1.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 1.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 3.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 3.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of ipilimumab at 2-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of ipilimumab at 3-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 0.5-10 mg/kg (body weight) per dose of ipilimumab

8 mg of compound 1 or its salt as described herein once daily and 1.0-10 mg/kg (body weight) per dose of ipilimumab.

8 mg of compound 1 or its salt as described herein once daily and 1.0 mg/kg (body weight) per dose of ipilimumab.

8 mg of compound 1 or its salt as described herein once daily and 3.0 mg/kg (body weight) per dose of ipilimumab.

8 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) per dose of ipilimumab.

8 mg of compound 1 or its salt as described herein once daily and 1.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 1.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 3.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 3.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of ipilimumab at 2-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of ipilimumab at 3-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 0.5-10 mg/kg (body weight) per dose of ipilimumab

12 mg of compound 1 or its salt as described herein once daily and 1.0-10 mg/kg (body weight) per dose of ipilimumab.

12 mg of compound 1 or its salt as described herein once daily and 1.0 mg/kg (body weight) per dose of ipilimumab.

12 mg of compound 1 or its salt as described herein once daily and 3.0 mg/kg (body weight) per dose of ipilimumab.

12 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) per dose of ipilimumab.

12 mg of compound 1 or its salt as described herein once daily and 1.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 1.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 3.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 3.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of ipilimumab at 2-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of ipilimumab at 3-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 0.5-10 mg/kg (body weight) per dose of ipilimumab

16 mg of compound 1 or its salt as described herein once daily and 1.0-10 mg/kg (body weight) per dose of ipilimumab.

16 mg of compound 1 or its salt as described herein once daily and 1.0 mg/kg (body weight) per dose of ipilimumab.

16 mg of compound 1 or its salt as described herein once daily and 3.0 mg/kg (body weight) per dose of ipilimumab.

16 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) per dose of ipilimumab.

16 mg of compound 1 or its salt as described herein once daily and 1.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 1.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 3.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 3.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of ipilimumab at 2-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of ipilimumab at 3-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 0.5-10 mg/kg (body weight) per dose of ipilimumab

20 mg of compound 1 or its salt as described herein once daily and 1.0-10 mg/kg (body weight) per dose of ipilimumab.

20 mg of compound 1 or its salt as described herein once daily and 1.0 mg/kg (body weight) per dose of ipilimumab.

20 mg of compound 1 or its salt as described herein once daily and 3.0 mg/kg (body weight) per dose of ipilimumab.

20 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) per dose of ipilimumab.

20 mg of compound 1 or its salt as described herein once daily and 1.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 1.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 3.0 mg/kg (body weight) of ipilimumab at 2-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 3.0 mg/kg (body weight) of ipilimumab at 3-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of ipilimumab at 2-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of ipilimumab at 3-week intervals.

[0145]

Examples of the dose of compound 1 or its salt of the present disclosure per day on the day of administration and the dose of durvalumab per day or a preferred combination of administration and dosing include the following:

4 mg - 160 mg of compound 1 or its salt as described herein and 5.0-10 mg/kg (body weight) per dose of durvalumab.

4 mg - 160 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) per dose of durvalumab.

4 mg - 160 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of durvalumab at 2-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of durvalumab at 3-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 5.0-10 mg/kg (body weight) per dose of durvalumab.

4 mg - 24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) per dose of durvalumab.

4 mg - 24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of durvalumab at 2-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of durvalumab at 3-week intervals.

12-24 mg of compound 1 or its salt as described herein and 5.0-10 mg/kg (body weight) per dose of durvalumab.

12-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) per dose of durvalumab.

12-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of durvalumab at 2-week intervals.

12-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of durvalumab at 3-week intervals.

16-24 mg of compound 1 or its salt as described herein and 5.0-10 mg/kg (body weight) per dose of durvalumab.

16-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) per dose of durvalumab.

16-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of durvalumab at 2-week intervals.

16-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of durvalumab at 3-week intervals.

[0146]

Examples of a plurality of doses and a dose of compound 1 or a salt thereof according to the present description per day on the day of administration and a dose of durvalumab per day or a combination of administration and dosing include the following:

4 mg of compound 1 or its salt as described herein once daily and 5.0-10 mg/kg (body weight) per dose of durvalumab.

4 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) per dose of durvalumab.

4 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of durvalumab at 2-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of durvalumab at 3-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 5.0-10 mg/kg (body weight) per dose of durvalumab.

8 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) per dose of durvalumab.

8 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of durvalumab at 2-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of durvalumab at 3-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 5.0-10 mg/kg (body weight) per dose of durvalumab.

12 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) per dose of durvalumab.

12 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of durvalumab at 2-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of durvalumab at 3-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 5.0-10 mg/kg (body weight) per dose of durvalumab.

16 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) per dose of durvalumab.

16 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of durvalumab at 2-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of durvalumab at 3-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 5.0-10 mg/kg (body weight) per dose of durvalumab.

20 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) per dose of durvalumab.

20 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of durvalumab at 2-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of durvalumab at 3-week intervals.

[0147]

Examples of the dose of compound 1 or its salt of the present disclosure per day on the day of administration and the dose of avelumab per day or the preferred combination of administration and dosing include the following:

4 mg - 160 mg of compound 1 or its salt as described herein and 5.0-10 g/kg (body weight) per dose of avelumab

4 mg - 160 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) per dose of avelumab

4 mg - 160 mg of compound 1 or a salt thereof as described herein and 400-800 mg of avelumab per dose.

4 mg - 160 mg of compound 1 or a salt thereof as described herein and 800 mg of avelumab per dose.

4 mg - 160 mg of compound 1 or its salt as described herein and 800 mg of avelumab at 2-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 800 mg of avelumab at 3-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of avelumab at 2-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of avelumab at 3-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 5.0-10 g/kg (body weight) per dose of avelumab

4 mg - 24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) per dose of avelumab

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 400-800 mg of avelumab per dose.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 800 mg of avelumab per dose.

4 mg - 24 mg of compound 1 or its salt as described herein and 800 mg of avelumab at 2-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 800 mg of avelumab at 3-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of avelumab at 2-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of avelumab at 3-week intervals.

12-24 mg of compound 1 or its salt as described herein and 5.0-10 g/kg (body weight) per dose of avelumab

12-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) per dose of avelumab

12-24 mg of compound 1 or a salt thereof as described herein and 400-800 mg of avelumab per dose.

12-24 mg of compound 1 or a salt thereof as described herein and 800 mg of avelumab per dose.

12-24 mg of compound 1 or its salt as described herein and 800 mg of avelumab at 2-week intervals.

12-24 mg of compound 1 or its salt as described herein and 800 mg of avelumab at 3-week intervals.

12-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of avelumab at 2-week intervals.

12-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of avelumab at 3-week intervals.

16-24 mg of compound 1 or its salt as described herein and 5.0-10 g/kg (body weight) per dose of avelumab

16-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) per dose of avelumab

16-24 mg of compound 1 or a salt thereof as described herein and 400-800 mg of avelumab per dose.

16-24 mg of compound 1 or a salt thereof as described herein and 800 mg of avelumab per dose.

16-24 mg of compound 1 or its salt as described herein and 800 mg of avelumab at 2-week intervals.

16-24 mg of compound 1 or its salt as described herein and 800 mg of avelumab at 3-week intervals.

16-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of avelumab at 2-week intervals.

16-24 mg of compound 1 or its salt as described herein and 10 mg/kg (body weight) of avelumab at 3-week intervals.

[0148]

Examples of a plurality of doses and a dose of compound 1 or a salt thereof according to the present description per day on the day of administration and a dose of avelumab per day or a combination of administration and dosing include the following:

4 mg of compound 1 or its salt as described herein once daily and 5.0-10 g/kg (body weight) per dose of avelumab

4 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) per dose of avelumab

4 mg of compound 1 or a salt thereof as described herein once daily and 400-800 mg of avelumab per dose.

4 mg of compound 1 or a salt thereof as described herein once daily and 800 mg of avelumab per dose.

4 mg of compound 1 or its salt as described herein once daily and 800 mg of avelumab at 2-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 800 mg of avelumab at 3-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of avelumab at 2-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of avelumab at 3-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 5.0-10 g/kg (body weight) per dose of avelumab

8 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) per dose of avelumab

8 mg of compound 1 or a salt thereof as described herein once daily and 400-800 mg of avelumab per dose.

8 mg of compound 1 or a salt thereof as described herein once daily and 800 mg of avelumab per dose.

8 mg of compound 1 or its salt as described herein once daily and 800 mg of avelumab at 2-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 800 mg of avelumab at 3-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of avelumab at 2-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of avelumab at 3-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 5.0-10 g/kg (body weight) per dose of avelumab

12 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) per dose of avelumab

12 mg of compound 1 or a salt thereof as described herein once daily and 400-800 mg of avelumab per dose.

12 mg of compound 1 or a salt thereof as described herein once daily and 800 mg of avelumab per dose.

12 mg of compound 1 or its salt as described herein once daily and 800 mg of avelumab at 2-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 800 mg of avelumab at 3-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of avelumab at 2-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of avelumab at 3-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 5.0-10 g/kg (body weight) per dose of avelumab

16 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) per dose of avelumab

16 mg of compound 1 or a salt thereof as described herein once daily and 400-800 mg of avelumab per dose.

16 mg of compound 1 or a salt thereof as described herein once daily and 800 mg of avelumab per dose.

16 mg of compound 1 or its salt as described herein once daily and 800 mg of avelumab at 2-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 800 mg of avelumab at 3-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of avelumab at 2-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of avelumab at 3-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 5.0-10 g/kg (body weight) per dose of avelumab

20 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) per dose of avelumab

20 mg of compound 1 or a salt thereof as described herein once daily and 400-800 mg of avelumab per dose.

20 mg of compound 1 or a salt thereof as described herein once daily and 800 mg of avelumab per dose.

20 mg of compound 1 or its salt as described herein once daily and 800 mg of avelumab at 2-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 800 mg of avelumab at 3-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of avelumab at 2-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 10 mg/kg (body weight) of avelumab at 3-week intervals.

[0149]

Examples of the dose of compound 1 or its salt of the present disclosure per day on the day of administration and the dose of cemiplimab per day or the preferred combination of administration and dosing include the following:

4 mg - 160 mg of compound 1 or a salt thereof as described herein and 175-350 mg of cemiplimab per dose.

4 mg - 160 mg of compound 1 or a salt thereof as described herein and 350 mg of cemiplimab per dose.

4 mg - 160 mg of compound 1 or its salt as described herein and 350 mg of cemiplimab at 2-week intervals.

4 mg - 160 mg of compound 1 or its salt as described herein and 350 mg of cemiplimab at 3-week intervals.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 175-350 mg of cemiplimab per dose.

4 mg - 24 mg of compound 1 or a salt thereof as described herein and 350 mg of cemiplimab per dose.

4 mg - 24 mg of compound 1 or its salt as described herein and 350 mg of cemiplimab at 2-week intervals.

4 mg - 24 mg of compound 1 or its salt as described herein and 350 mg of cemiplimab at 3-week intervals.

12-24 mg of compound 1 or a salt thereof as described herein and 175-350 mg of cemiplimab per dose.

12-24 mg of compound 1 or a salt thereof as described herein and 350 mg of cemiplimab per dose.

12-24 mg of compound 1 or its salt as described herein and 350 mg of cemiplimab at 2-week intervals.

12-24 mg of compound 1 or its salt as described herein and 350 mg of cemiplimab at 3-week intervals.

16-24 mg of compound 1 or a salt thereof as described herein and 175-350 mg of cemiplimab per dose.

16-24 mg of compound 1 or a salt thereof as described herein and 350 mg of cemiplimab per dose.

16-24 mg of compound 1 or its salt as described herein and 350 mg of cemiplimab at 2-week intervals.

16-24 mg of compound 1 or its salt as described herein and 350 mg of cemiplimab at 3-week intervals.

[0150]

Examples of a plurality of doses and a dose of compound 1 or a salt thereof according to the present description per day on the day of administration and a dose of cemiplimab per day or a combination of administration and dosing include the following:

4 mg of compound 1 or a salt thereof as described herein once daily and 175-350 mg of cemiplimab per dose.

4 mg of compound 1 or a salt thereof as described herein once daily and 350 mg of cemiplimab per dose.

4 mg of compound 1 or its salt as described herein once daily and 350 mg of cemiplimab at 2-week intervals.

4 mg of compound 1 or its salt as described herein once daily and 350 mg of cemiplimab at 3-week intervals.

8 mg of compound 1 or a salt thereof as described herein once daily and 175-350 mg of cemiplimab per dose.

8 mg of compound 1 or a salt thereof as described herein once daily and 350 mg of cemiplimab per dose.

8 mg of compound 1 or its salt as described herein once daily and 350 mg of cemiplimab at 2-week intervals.

8 mg of compound 1 or its salt as described herein once daily and 350 mg of cemiplimab at 3-week intervals.

12 mg of compound 1 or a salt thereof as described herein once daily and 175-350 mg of cemiplimab per dose.

12 mg of compound 1 or a salt thereof as described herein once daily and 350 mg of cemiplimab per dose.

12 mg of compound 1 or its salt as described herein once daily and 350 mg of cemiplimab at 2-week intervals.

12 mg of compound 1 or its salt as described herein once daily and 350 mg of cemiplimab at 3-week intervals.

16 mg of compound 1 or a salt thereof as described herein once daily and 175-350 mg of cemiplimab per dose.

16 mg of compound 1 or a salt thereof as described herein once daily and 350 mg of cemiplimab per dose.

16 mg of compound 1 or its salt as described herein once daily and 350 mg of cemiplimab at 2-week intervals.

16 mg of compound 1 or its salt as described herein once daily and 350 mg of cemiplimab at 3-week intervals.

20 mg of compound 1 or a salt thereof as described herein once daily and 175-350 mg of cemiplimab per dose.

20 mg of compound 1 or a salt thereof as described herein once daily and 350 mg of cemiplimab per dose.

20 mg of compound 1 or its salt as described herein once daily and 350 mg of cemiplimab at 2-week intervals.

20 mg of compound 1 or its salt as described herein once daily and 350 mg of cemiplimab at 3-week intervals.

[0151]

The ratio of compound 1 or a salt thereof to the immune checkpoint inhibitor used in the present specification is not particularly limited, but can be set such that the amount of the immune checkpoint inhibitor is preferably in the range of 10-10,000 parts by weight, and more preferably 100-1,000 parts by weight, relative to 100 parts by weight of compound 1 or a salt thereof.

[0152]

In the present specification, the mixing ratio of the compound 1 or a salt thereof in the dosage form containing the compound 1 or a salt thereof is not particularly limited, but can be suitably set in the range of, for example, 100-100000% by weight, and preferably 1000-10000% by weight. In the present specification, the mixing ratio of the immune checkpoint inhibitor in the dosage form containing the immune checkpoint inhibitor is not particularly limited, but can be suitably set in the range of, for example, 100-100000% by weight, and preferably 1000-10000% by weight. In the embodiment in which the antitumor agent is formulated in a plurality of dosage forms, the above-mentioned preferred mixing ratios mean the mixing ratio of the active ingredient to the total weight of the dosage form containing the active ingredient, rather than the ratio of the active ingredient to the total amount of the dosage form containing the active ingredient and the dosage form not containing the active ingredient. For example, the mixing ratio of compound 1 or its salt means the mass % of compound 1 or its salt relative to only the dosage form containing compound 1 or its salt.

[0153]

In one embodiment of the present description, the combination therapy of the present invention is administered to patients who have not been treated with hormonal therapy, immunotherapy (anti-cancer peptide, vaccine therapy, etc.), surgery, or chemotherapeutic agents, i.e., previously untreated patients. In another embodiment, the combination therapy is administered to patients who have not achieved a stable response after previous treatment with chemotherapeutic agents.

[0154]

In one embodiment of the present disclosure, the combination therapy of the present invention is administered to patients who are inexperienced with immune checkpoint inhibitors. In another embodiment, the combination therapy is administered to patients who are experienced with FGFR inhibitor treatment.

[0155]

In one embodiment of the present disclosure, "sustainable responses" means that sustained responses to cancer are expanded and maintained when immunotherapy is administered using an immune checkpoint inhibitor, etc. to a subject. Sustained responses can be determined, for example, by measuring the binding of T lymphocytes to an immune checkpoint inhibitor.

[0156]

In the present description, the "recommended dose" is the dose that produces the maximum therapeutic effect in the range that can be safely administered without developing serious similar effects as determined by clinical trials, etc. Specific examples include doses that are described in package inserts, discussions, treatment instructions, etc., and that have been approved or recommended by public institutions or organizations such as the Japan Pharmaceuticals and Medical Devices Agency (PMDA), the U.S. Food and Drug Administration (FDA), and the European Medicines Agency (EMA). Doses that have been approved by any of the public agencies PMDA, FDA, and EMA are preferred.

[0157]

The administration regimen of the antitumor agent according to the present description can be appropriately selected according to the type of cancer, stage of cancer and the like.

[0158]

In the case of compound 1 or a salt thereof, a daily administration schedule for 1 to 21 days (e.g., 3 weeks (21 days)) is preferable; however, there may be a break in the administration of the drug after this schedule, and daily administration for 3 weeks (21 days) is more preferable. The administration schedule of the immune checkpoint inhibitor preferably includes 2-week to 4-week intervals, for example. The administration schedule of nivolumab preferably includes 2-week to 4-week (e.g., 2-week or 3-week) intervals, and more preferably 3-week intervals. The administration schedule of atezolizumab preferably includes 2-week, 3-week or 4-week intervals, and more preferably 3-week intervals. In the present description, administration of drug A at intervals of X days means that if the day on which drug A is administered is day 1, the next day is day 2 and the day after it is day 3 . . . , the drug is administered next time on day X+1. In addition, if the administration schedule is calculated, “1 week”, “2 weeks”, “3 weeks” and “4 weeks” mean “7 days”, “14 days”, “21 days” and “28 days”, respectively. Therefore, in the present description, administering the drug at intervals of 3 weeks means that if the day on which drug A is administered is day 1, drug A will be administered next time on day 22.

[0159]

The daily dose number of the antitumor agent of the present disclosure can be appropriately selected according to the cancer type, cancer stage, etc. In the case of combined administration with nivolumab or atezolizumab, the dose number is preferably once a day.

[0160]

The order of administration of compound 1 or a salt thereof and the immune checkpoint inhibitor can be properly selected according to the type of cancer, stage of cancer and the like; however, in one therapeutic regimen, either of them may be administered first or both of them may be administered simultaneously.

[0161]

In one embodiment, compound 1 or a salt thereof improves the effect of an immune checkpoint inhibitor. In another embodiment, an immune checkpoint inhibitor improves the effect of compound 1 or a salt thereof.

[0162]

In one embodiment of the present disclosure, although PD-L1 may or may not be expressed, the subject of administration is preferably one that expresses 1% or more, and more preferably 50% or more, of PD-L1.

[0163]

In one embodiment of the present disclosure, the subject is one that has a tumor that is positive for PD-L1 expression. PD-L1 expression can be determined using an anti-human PD-L1 antibody for diagnostic purposes or an antigen-binding fragment thereof in an IHC assay on FFPE or frozen tissue sections of tumor samples taken from the patient. In general, it is contemplated that the physician will order diagnostic tests to determine PD-L1 expression using tumor tissue samples from the patient before starting combined administration of an immune checkpoint inhibitor and an FGFR inhibitor; however, it is contemplated that the physician may order diagnostic tests before or after the start of treatment, after the start of treatment, for example, at the end of a treatment cycle.

[0164]

As used herein, "cancer" or "tumor" refers to physiological conditions in a mammal characterized by unregulated cell growth. "Cancer" or "tumor" have the same meaning in this specification and are used interchangeably. Cancers include solid and hematological cancers. Examples include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma, sarcoma, and borderline malignancies (carcinoids).

[0165]

Examples of cancers targeted by the combination method of the present disclosure include head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (eg, gallbladder and cholangiocarcinoma), pancreatic cancer, small intestine cancer, colon cancer). bowel cancer (such as colorectal cancer, colon cancer, and rectal cancer), etc.), lung cancer (such as non-small cell lung cancer and small cell lung cancer), mesothelioma (such as malignant pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, and testicular mesothelioma), breast cancer, genital cancer (ovarian cancer, uterine cancer (such as cervical cancer, uterine cancer, and endometrial cancer), etc.), kidney cancer, bladder cancer, urothelial cancer, prostate cancer, testicular cancer, skin cancer (such as malignant melanoma and epidermal cancer), blood cancer (such as multiple myeloma and acute myeloid leukemia), bone and soft tissue tumor, rhabdomyosarcoma, brain tumor, malignant schwannoma, neuroendocrine tumor, thyroid cancer, and the like. In one embodiment, the targets are bladder cancer, urothelial cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (eg, gallbladder and cholangiocarcinoma), pancreatic cancer, small intestine cancer, colon cancer (eg, colorectal cancer, colon cancer and rectal cancer), etc.), ovarian cancer, head and neck cancer and uterine cancer (eg, cervical cancer and endometrial cancer). The cancers mentioned herein include not only the primary lesion, but also cancer metastasizing to other organs (eg, liver). The antitumor agent of the present disclosure can also be used in postoperative adjuvant chemotherapy performed to prevent recurrence after surgical removal of a tumor, or can be used in preoperative adjuvant chemotherapy performed for surgical removal of a tumor.

[0166]

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

[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). Thus, "combination (therapy)", "combination" and the use of compounds/drugs "in combination" in the present application may mean compounds/drugs administered as part of the same overall therapeutic regimen. The dose of each of the two or more compounds/drugs may be different: each of them may be administered simultaneously or at different times. Therefore, it is understood that the compounds/drugs of the combination may be administered sequentially (e.g. before or after) or simultaneously, either in the same pharmaceutical formulation (i.e. together) or in different pharmaceutical formulations (i.e. separately). The same formulation at the same time is a single formulation. On the other hand, different pharmaceutical formulations are not integral.

[0168]

As used herein, the terms "schedule" and "therapeutic regimen" refer to a plan that shows in chronological order the type and amount of drugs, duration, procedure, etc., in treatment with a drug, and that shows the dose, route of administration, order of administration, and day of administration of each drug. Treatment according to a single therapeutic regimen includes, for example, the manner in which the administration of the combined drugs is started, simultaneously or substantially simultaneously on the first day of the cycle. Treatment according to a single therapeutic regimen also includes, for example, one cycle of three weeks in which the administration of drug A is started first, and the administration of drug B is started a week later; however, both drugs are administered substantially simultaneously in one cycle.

[0169]

The therapeutic regimen of compound 1 or a salt thereof and an immune checkpoint inhibitor of the present disclosure may include not only compound 1 or a salt thereof and an immune checkpoint inhibitor but also other drugs.

[0170]

The administration form of the antitumor agent of the present disclosure is not limited and can be appropriately selected depending on the therapeutic purpose. Specific examples thereof include oral preparations (tablets, coated tablets, powders, granules, capsules, solutions, etc.), injections, suppositories, patches, ointments and the like. For compound 1 or a salt thereof, oral preparations are preferable. For anti-PD-1 antibody, anti-PD-L1 antibody or anti-CTLA-4 antibody, the above-mentioned administration forms can be used, and injections are preferable.

[0171]

According to the antitumor agent of the present disclosure, the immune checkpoint inhibitor and compound 1 or a salt thereof, which are active ingredients, can be used directly as an antitumor agent. Depending on the administration form, a pharmaceutically acceptable carrier can be used to prepare a composition in a generally known manner. Examples of such carriers include various carriers commonly used in conventional drugs, such as excipients, binders, disintegrants, lubricants, diluents, solubilizing agents, suspending agents, isotonizing agents, pH adjusters, buffers, stabilizers, colorants, flavors and the like.

[0172]

The antitumor agent of the present description may be formulated as a plurality of dosage forms or may be formulated as a single dosage form based on the administration form and administration schedule of each active ingredient. In addition, the formulations may be manufactured and sold in a single package suitable for combined administration, or the formulations may be manufactured and sold in separate packages. The same applies to embodiments of the pharmaceutical composition. Accordingly, "a pharmaceutical composition containing an immune checkpoint inhibitor and compound 1 or a salt thereof as active ingredients" includes a pharmaceutical composition obtained by separately formulating the active ingredients in a plurality of dosage forms, and a pharmaceutical composition obtained by formulating the active ingredients in a single dosage form. A pharmaceutical composition obtained by separately formulating the active ingredients in a plurality of dosage forms includes a pharmaceutical composition obtained by formulating the formulations in a single package suitable for combined administration, and a pharmaceutical composition obtained by formulating the formulations in separate packages.

[0173]

The present description relates to a preparation kit containing an antitumor agent comprising compound 1 or a salt thereof, and instructions for use, which indicate that compound 1 or a salt thereof is administered to cancer patients in combination with an immune checkpoint inhibitor. The "instructions for use" used herein may specify the above-mentioned dose. Regardless of whether it is legally binding, an instruction that recommends the above-mentioned doses is preferred. Specific examples include package inserts, leaflets, and the like. A preparation kit containing a instructions for use may be one in which the instructions for use are printed or attached to the preparation package of the preparation kit, or may be one in which the instructions for use are inserted together with the antitumor agent into the preparation package of the preparation kit.

[0174]

Examples of methods for determining the mechanism of action of an FGFR inhibitor and demonstrating resistance to immune checkpoint inhibitors include, but are not limited to, a method for studying modulation of the tumor immune microenvironment (NPL 13).

[0175]

The cancer microenvironment is important for the efficacy of immune checkpoint inhibitors, and tumor-associated fibroblasts (CAFs) are known to play an important role. FGFs are factors that regulate fibroblast cell growth, and their receptors, FGFRs, are molecules that receive signals from FGFs in cells and promote cell growth. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are enriched in tumor tissues, lymph nodes, and peripheral blood in pathological conditions and are known to have potent immunosuppressive activity.

[0176]

It has been described that MDSC can be used as a prognostic marker for the efficacy of immune checkpoint inhibitors and may play a role in patient resistance to immune checkpoint inhibitors (NPL 14).

[0177]

As used herein, resistance (also referred to as tolerance or insurmountability) to immune checkpoint inhibitors includes conditions in subjects in which a therapeutic effect is not expected after administration of an immune checkpoint inhibitor and in which disease progression is confirmed by at least one clinical assessment; and conditions in subjects in which a therapeutic effect of immune checkpoint inhibitors cannot be expected, although the subject has no intolerance to the immune checkpoint inhibitor, relapse after administration of immune checkpoint inhibitors, or experience with immune checkpoint inhibitors. In one embodiment, it is also contemplated that pharmacological tests do not demonstrate effective actions of immune checkpoint inhibitors, such as responses of cell lines that are not considered to exhibit an effect. Resistance includes natural resistance, in which an antitumor agent is ineffective at the start of treatment, and acquired resistance, in which an antitumor agent that was initially effective becomes ineffective as treatment continues and leads to worsening of the cancer. As used herein, resistance includes both natural and acquired resistance.

[0178]

In the present description, immune checkpoint inhibitor refractoriness means that the immune checkpoint inhibitor becomes ineffective and does not show an effect after the immune checkpoint inhibitor is administered. It is believed that one of the reasons for refractoriness is resistance.

The antitumor agent of the present disclosure may be used to treat cancer. "Antitumor effect" with respect to a cancer patient who is receiving treatment with a therapeutic regimen, such as a combination therapy described herein, means at least one of, 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 response), PRO (patient-assessed treatment outcome), and the like. In one embodiment, the tumor assessment for the combination therapy described herein for solid tumors is based on the RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors) and the antitumor effect is described as SD (stable disease), PR (partial response), CR (complete response), and PD (progressive disease). Tumor evaluation for brain tumors can be performed by standard brain tumor MRI, including pre- and post-enhancement MRI, using Gd-MRI (gadolinium (Gd)) chelated contrast agent.

Examples

[0180]

The present disclosure is explained in more detail below with reference to Examples and a Reference Example; however, the present description is not limited to these Examples, and many modifications can be made by a person skilled in the art within the technical idea of the present description.

[0181]

Reference example: A clinical trial in patients with cancer resistant to cancer immunotherapy (e.g. non-small cell lung cancer, oesophageal cancer and urothelial cancer) using the combination 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 its salt and pembrolizumab.

This study evaluates the efficacy and safety of the combined use of compound 1 or its salt and pembrolizumab in FGFR-overexpressing cancer patients (e.g., non-small cell lung cancer or esophageal cancer), based on a clinical trial registered as JapicCTI-195063 by Japan Pharmaceutical Information Center. Specifically, the administration is carried out for a predetermined period of time (e.g., 24 weeks). Compound 1 or its salt is orally administered to the patient at different doses (e.g., 20 mg) for 21 days, and pembrolizumab (e.g., 200 mg per administration) is administered by intravenous drip infusion every three weeks (every 21 days). One cycle is 21 days and is repeated. In some cases, placebo may be used as a control, and compound 1 or its salt and/or pembrolizumab may be additionally administered to other patients. Moreover, the combined administration of compound 1 or its salt can be performed in patients who have experience with pembrolizumab treatment.

[0182]

The combined use of compound 1 or a salt thereof and pembrolizumab may provide therapeutic effects that would not be expected from monotherapies using each of them separately. For example, in an embodiment of the present disclosure, this combined use may be found to have a higher degree of effect than at least one of the results measured by treatment with either of them. Moreover, for example, in an embodiment of the present disclosure, a synergistic effect may be obtained by the combined use of compound 1 or a salt thereof and pembrolizumab.

[0183]

The combined use of compound 1 or a salt thereof and pembrolizumab may be more effective than either alone, according to at least one of the following outcome measures: reduced cancer cell count, regression in tumor size, reduced rate of cancer cell infiltration into peripheral organs, reduced rate of tumor metastasis or tumor growth, objective response rate, and increased progression-free or overall survival.

[0184]

Example 1: Effect of tumor immunity in a subcutaneously implanted mouse model of 4T1 breast cancer cells

The 4T1 mouse breast cancer cell line was subcutaneously implanted into 6-week-old male BALB/cAJcl mice. The day of cell implantation was set as day 0, and compound 1 was orally administered daily starting from the next day (day 1) for 14 days at a dose of 15 mg/kg/day. On the day after the last administration (day 15), lymphocyte fractions were isolated from the tumor, spleen and peripheral blood, and myeloid-derived suppressor cells (MDSC) (CD11b ⁺ /Gr-1 ⁺ cells), CD4-positive T cells and CD8-positive T cells were measured using a cell sorter. Moreover, preparation of the subcutaneously implanted 4T1 mouse breast cancer cell model, drug administration and measurement of each cell were carried out according to the same procedure as described above, except for changing the dose of compound 1 to 30 mg/kg/day. As a control, the same operation was carried out as described above, except that compound 1 was not introduced. Fig. 1 shows the results.

[0185]

Administration of compound 1 at any dose resulted in a significant reduction in MDSC in spleen lymphocyte fractions (Student's t-test, P<0.01) compared to the control without drug administration. MDSC in peripheral blood lymphocyte fractions tended to decrease in a dose-dependent manner compared to the control. CD4-positive T cells in peripheral blood lymphocyte fractions and CD8-positive T cells in spleen lymphocyte fractions and peripheral blood lymphocyte fractions tended to increase in a dose-dependent manner compared to the control.

[0186]

These results confirmed the inhibitory effect of compound 1 on MDSC in in vivo models and thus suggested the possibility that compound 1 exerts its antitumor effect through an immunosuppressive mechanism. In addition, since the number of CD4-positive T cells and CD8-positive T cells was increased by the administration of compound 1, the activation of immune activity by compound 1 in cancer-bearing mice was confirmed. The above results suggest that the combined use of compound 1 or its salt with an immune checkpoint inhibitor enhances the antitumor effect.

[0187]

Although 4T1 used in Example 1 are breast cancer cells that do not have the genetic aberration of FGFR, administration of Compound 1 confirmed the inhibitory effect on MDSCs as well as increased CD4-positive T cells and CD8-positive T cells, indicating that Compound 1 has an antitumor effect through an immunosuppressive mechanism. Moreover, administration of vofatamab, which is an anti-FGFR3 antibody, to patients with urothelial cancer caused the cancer to change from a “cold” state (low sensitivity to immune checkpoint inhibitors) to a “hot” state (high sensitivity to immune checkpoint inhibitors); thus, the response to combined use with pembrolizumab is observed even in patients without FGFR genetic aberration (W. Choi et al., presentation at AACR Special Conference on Bladder Cancer: Transforming Field, May 18-21, 2019, Denver, USA).

[0188]

Example 2: Phase I clinical trial in patients with solid cancer using combination therapy 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 its salt and nivolumab

This study evaluates the efficacy and safety of the combined use of compound 1 or its salt and nivolumab in patients with solid cancer.

The administration is carried out for a certain period of time (eg, 24 weeks). Compound 1 or its salt is orally administered to patients at different doses (8 mg, 12 mg, 16 mg, and 20 mg) for 21 days, and nivolumab (240 mg per administration) is administered by intravenous drip infusion every two weeks (every 14 days). Alternatively, the administration is carried out for a predetermined period of time (eg, 24 weeks). Compound 1 or its salt is orally administered to patients at different doses (8 mg, 12 mg, 16 mg, and 20 mg) for 21 days, nivolumab (80 mg per administration) is administered by intravenous drip infusion every three weeks (every 21 days) four times, and then nivolumab (240 mg per administration) is administered by intravenous drip infusion every two weeks (every 14 days), starting from the fifth time. Alternatively, the administration is carried out for a predetermined period of time (e.g., 24 weeks). Compound 1 or its salt is orally administered to patients at different doses (8 mg, 12 mg, 16 mg, and 20 mg) for 21 days, nivolumab (240 mg per administration) is administered by intravenous drip infusion every three weeks (every 21 days) four times and then, from the fifth time, every two weeks (every 14 days), and the 21-day administration of compound 1 is repeated. In some cases, compound 1 or its salt and/or nivolumab may be additionally administered to other patients. Moreover, combined administration with compound 1 or its salt may be carried out in patients who are experienced in treatment with nivolumab.

[0189]

The combined use of compound 1 or a salt thereof and nivolumab may provide a therapeutic effect that would not be expected from monotherapies using each of them separately. For example, in an embodiment of the present disclosure, such a combined use may be found to have a higher degree of efficacy than at least one of the results of measuring treatment with either of them. In addition, for example, in an embodiment of the present disclosure, a synergistic effect may be obtained from the combined use of compound 1 or a salt thereof and nivolumab.

[0190]

The combined use of compound 1 or a salt thereof and nivolumab may be more effective than the separate use of either of them, according to at least one of the following measured outcomes: reduction in the number of cancer cells, reduction in tumor size, reduction in the rate of infiltration of cancer cells into peripheral organs, reduction in the rate of tumor metastasis or tumor growth, objective response rate, and increased progression-free survival or overall survival.

Claims (25)

1. Use of an anti-PD-1 antibody, except 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 pharmaceutically acceptable salt thereof for the preparation of an antineoplastic agent for the treatment of cancer with resistance to immune checkpoint inhibitors, wherein the cancer is esophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer or urothelial cancer. 2. 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 pharmaceutically acceptable salt thereof for the preparation of an antitumor agent for administration in combination with an anti-PD-1 antibody, except pembrolizumab, to an oncology patient with resistance to immune checkpoint inhibitors, wherein the cancer is esophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer, or urothelial cancer. 3. Use of an anti-PD-1 antibody, except pembrolizumab, for the preparation of an antineoplastic agent 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 pharmaceutically acceptable salt thereof to a cancer patient with resistance to immune checkpoint inhibitors, wherein the cancer is esophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer, or urothelial cancer. 4. Use of an anti-PD-1 antibody, except 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 pharmaceutically acceptable salt thereof, for the treatment of cancer resistant to immune checkpoint inhibitors, wherein the cancer is esophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer, or urothelial cancer. 5. 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 pharmaceutically acceptable salt thereof for the treatment of cancer resistant to immune checkpoint inhibitors using combination therapy with an anti-PD-1 antibody, except for pembrolizumab, where the cancer is esophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer, or urothelial cancer. 6. Use of an anti-PD-1 antibody, other than pembrolizumab, for the treatment of immune checkpoint inhibitor-resistant cancer using 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 pharmaceutically acceptable salt thereof, wherein the cancer is esophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer, or urothelial cancer. 7. A method for treating cancer with resistance to immune checkpoint inhibitors, wherein the method comprises 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 pharmaceutically acceptable salt thereof and a therapeutically effective amount of an anti-PD-1 antibody, except pembrolizumab, to a human in need thereof, wherein the cancer is esophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer, or urothelial cancer. 8. Use of an anti-PD-1 antibody, except 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 pharmaceutically acceptable salt thereof, for the manufacture of an antineoplastic agent for the treatment of cancer in a cancer patient who has not been treated with immune checkpoint inhibitors, wherein the cancer is esophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer, or urothelial cancer. 9. 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 pharmaceutically acceptable salt thereof for the manufacture of an antineoplastic agent administered in combination with an anti-PD-1 antibody, except pembrolizumab, to a cancer patient who has not been treated with immune checkpoint inhibitors, wherein the cancer is esophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer, or urothelial cancer. 10. Use of an anti-PD-1 antibody, other than pembrolizumab, for the manufacture of an antineoplastic agent for administration 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 pharmaceutically acceptable salt thereof to a cancer patient who has not been treated with immune checkpoint inhibitors, wherein the cancer is esophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer, or urothelial cancer. 11. Use of an anti-PD-1 antibody, except 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 pharmaceutically acceptable salt thereof, for the treatment of cancer in a cancer patient who has not been treated with immune checkpoint inhibitors, wherein the cancer is esophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer, or urothelial cancer. 12. 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 pharmaceutically acceptable salt thereof for the treatment of cancer in a cancer patient who has not been treated with immune checkpoint inhibitors with combination therapy using an anti-PD-1 antibody, except pembrolizumab, wherein the cancer is esophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer, or urothelial cancer. 13. Use of an anti-PD-1 antibody, other than pembrolizumab, for the treatment of cancer in a cancer patient who has not been treated with immune checkpoint inhibitors, with 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 pharmaceutically acceptable salt thereof, wherein the cancer is esophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer, or urothelial cancer. 14. A method of treating cancer in a cancer patient who has not been administered immune checkpoint inhibitors, wherein the method comprises 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 pharmaceutically acceptable salt thereof and a therapeutically effective amount of an anti-PD-1 antibody, except pembrolizumab, to a human in need thereof, wherein the cancer is esophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer, or urothelial cancer. 15. Use of an anti-PD-1 antibody other than 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 pharmaceutically acceptable salt thereof for the manufacture of an antineoplastic agent for the treatment of cancer without aberrations in the FGFR pathway, 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 pharmaceutically acceptable salt thereof is administered once daily at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg and 20 mg, and where the cancer is oesophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer, or urothelial cancer. 16. 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 pharmaceutically acceptable salt thereof for the manufacture of an antineoplastic agent for administration in combination with an anti-PD-1 antibody, except pembrolizumab, to a cancer patient without aberrations in the FGFR pathway, 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 pharmaceutically acceptable salt thereof is administered once daily at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg and 20 mg, and where the cancer is oesophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer or urothelial cancer. 17. Use of an anti-PD-1 antibody, except pembrolizumab, for the manufacture of an antineoplastic agent 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 pharmaceutically acceptable salt thereof to a cancer patient without aberrations in the FGFR pathway, 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 pharmaceutically acceptable salt thereof is administered once daily at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg and 20 mg, and where the cancer is oesophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer or urothelial cancer. 18. Use of an anti-PD-1 antibody, except 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 pharmaceutically acceptable salt thereof, for the treatment of cancer without aberrations in the FGFR pathway, 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 pharmaceutically acceptable salt thereof, is administered once daily at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg, and 20 mg, and wherein the cancer is esophageal cancer, pancreatic cancer, bile duct cancer, lung cancer, head and neck cancer, or urothelial cancer. 19. 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 pharmaceutically acceptable salt thereof for the treatment of cancer without aberrations in the FGFR pathway with combination therapy with an anti-PD-1 antibody, except for pembrolizumab, 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 pharmaceutically acceptable salt thereof is administered once daily at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg and 20 mg, and where the cancer is oesophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer, or urothelial cancer. 20. Use of an anti-PD-1 antibody, except pembrolizumab, for the treatment of cancer without aberrations in the FGFR pathway by combination therapy with (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof, 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 pharmaceutically acceptable salt thereof is administered once daily at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg and 20 mg, and where the cancer is oesophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer, or urothelial cancer. 21. A method of treating cancer without aberrations in the FGFR pathway, wherein the method comprises 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 pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an anti-PD-1 antibody, except pembrolizumab, to a human in need thereof, wherein the (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 pharmaceutically acceptable salt thereof, is administered once daily at a dose selected from the group consisting of 4 mg, 8 mg, 12 mg, 16 mg and 20 mg, and where the cancer is oesophageal cancer, pancreatic cancer, biliary tract cancer, lung cancer, head and neck cancer or urothelial cancer. 22. The method according to claims 7, 14 and 21, 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 pharmaceutically acceptable salt thereof is administered simultaneously with or after an anti-PD-1 antibody. 23. The method according to claims 7 and 14, wherein (S)-1-(3-(4-amino-3((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable 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. 24. Use according to claims 1-6, 8-13 and 15-20, 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 pharmaceutically acceptable salt thereof is used simultaneously with or after an anti-PD-1 antibody. 25. Use according to paragraphs 1-6 and 8-13, wherein (S)-1-(3-(4-amino-3((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable 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.