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KR-20260062972-A - Cancer treatment methods comprising 3,5-2-substituted benzenealkynyl compounds and immune checkpoint inhibitors

KR20260062972AKR 20260062972 AKR20260062972 AKR 20260062972AKR-20260062972-A

Abstract

The problem to be solved by the present invention is to provide a new combination therapy that exhibits excellent antitumor effects. The present invention provides an antitumor agent (not containing pembrolizumab as an active ingredient) comprising putivatinib or its salt as an active ingredient, which is administered to cancer patients in combination with an immune checkpoint inhibitor (excluding CD155/TIGIT pathway antagonists) and at least one other antitumor agent.

Inventors

  • 히라야마, 나오키

Assignees

  • 다이호야쿠힌고교 가부시키가이샤

Dates

Publication Date
20260507
Application Date
20240830
Priority Date
20230831

Claims (20)

  1. Antitumor agents of any of the following (i) to (iii) (provided that antitumor agents containing pembrolizumab as an active ingredient and antitumor agents used to be administered in combination with pembrolizumab). (i) An antitumor agent comprising putivatinib or a pharmaceutically acceptable salt thereof as an active ingredient, which is used to be administered to cancer patients in combination with an immune checkpoint inhibitor and at least one other antitumor agent. (ii) an antitumor agent comprising an immune checkpoint inhibitor as an active ingredient, which is used to be administered to cancer patients in combination with putivatinib or its pharmaceutically acceptable salt and at least one other antitumor agent. (iii) said antitumor agent comprising at least one other antitumor agent as an active ingredient, which is used to be administered to cancer patients in combination with putivatinib or its pharmaceutically acceptable salt and an immune checkpoint inhibitor.
  2. An antitumor agent according to claim 1, wherein the immune checkpoint inhibitor is at least one selected from the group consisting of anti-PD-1 antibody, anti-PD-L1 antibody, and anti-PD-L2 antibody.
  3. An antitumor agent according to claim 1 or 2, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.
  4. An antitumor agent according to claim 2 or 3, wherein the anti-PD-1 antibody is at least one selected from the group consisting of nivolumab, cemiplimab, spartalizumab, tisrelizumab, BI754091, dostalimab, sasanlimab, MGA-012, setrelimab, AGEN-2034, zimberelimab, camrelizumab, budigalimab, and valstilimab.
  5. In paragraph 4, an antitumor agent in which the anti-PD-1 antibody is zimberelimab.
  6. An antitumor agent according to any one of paragraphs 1 to 5, wherein the other antitumor agent is a chemotherapy agent.
  7. In paragraph 6, the antitumor agent is at least one selected from the group consisting of metabolic antagonists, alkaloid antitumor agents, platinum preparations, immune checkpoint inhibitors, molecular targeted agents, antitumor antibiotics, and alkylating agents.
  8. In paragraph 6, the antitumor agent is at least one selected from the group consisting of metabolic antagonists, alkaloid antitumor agents, platinum preparations, and immune checkpoint inhibitors.
  9. In paragraph 6, the chemotherapy agents are in the group consisting of fludarabine, cladribine, nerarabine, 5-fluorouracil, tegafur/gimeracil/oteracil potassium, tegafur/uracil, trifluridine/tipiracil hydrochloride, capecitabine, doxifluridine, 5-fluoro-2'-deoxyuridine, gemcitabine, cytarabine, pemetrexed, methotrexate, paclitaxel, albumin suspension paclitaxel, docetaxel, cabazitaxel, eribulin, irinotecan, nogitecan (topotecan), etoposide, tenifoside, vinorelbine, vincristine, vinblastine, cisplatin, carboplatin, oxaliplatin, nedaplatin, dombanalimab, AB308, vivostolimab, ociperlimab, and tiragolumab At least one selected antitumor agent.
  10. An antitumor agent according to claim 6, wherein the chemotherapy agent is at least one selected from the group consisting of 5-fluorouracil, gemcitabine, albumin suspension paclitaxel, irinotecan, cisplatin, carboplatin, dombanalimab, and AB308.
  11. In claim 6, the antitumor agent is at least one selected from the group consisting of 5-fluorouracil, gemcitabine, albumin suspension paclitaxel, cisplatin, carboplatin, and dombanalimab.
  12. An antitumor agent according to any one of claims 1 to 11, wherein the cancer is at least one selected from the group consisting of lung cancer, esophageal cancer, stomach cancer, duodenal cancer, liver cancer, hepatocellular carcinoma, biliary tract cancer, pancreatic cancer, colorectal cancer, breast cancer, uterine cancer, ovarian cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumor, thyroid cancer, bone and soft tissue tumor, leukemia, malignant lymphoma, multiple myeloma, head and neck cancer, brain tumor, mesothelioma, skin cancer, and cancer of unknown primary origin.
  13. An antitumor agent according to any one of claims 1 to 11, wherein the cancer is at least one selected from the group consisting of pancreatic cancer, lung cancer, esophageal cancer, bile duct cancer, and head and neck cancer.
  14. An antitumor agent according to any one of claims 1 to 13, wherein the cancer patient has no history of prior treatment for advanced cancer or has a history of prior treatment with one line of chemotherapy.
  15. An antitumor agent characterized by repeating an administration cycle of 21 days or 28 days one or more times in any one of claims 1 to 14.
  16. An antitumor agent according to claim 15, wherein putivatinib is administered once daily on each day of a 21-day or 28-day administration cycle.
  17. An antitumor agent according to claim 15, wherein zimberelimab is administered for 1 to 2 days during a 21-day or 28-day administration cycle.
  18. In claim 15, an antitumor agent administered for 1 to 5 days during a 21-day or 28-day administration cycle.
  19. In paragraph 15, an antitumor agent in which another antitumor agent is administered once on Day 1 during a 21-day or 28-day administration cycle.
  20. In paragraph 15, an antitumor agent in which another antitumor agent is administered once each on Day 1 and Day 8 during a 21-day or 28-day administration cycle.

Description

Cancer treatment methods comprising 3,5-2-substituted benzenealkynyl compounds and immune checkpoint inhibitors The present invention relates to an antitumor agent, an antitumor effect enhancer, and a kit formulation. Fibroblast growth factor (FGF) is expressed in a wide range of tissues and is one of the growth factors responsible for cell proliferation and differentiation. The physiological activity of FGF is mediated by the fibroblast growth factor receptor (FGFR), a specific cell surface receptor. FGFR belongs to the receptor-type protein tyrosine kinase family and consists of an extracellular ligand binding domain, a once-transmembrane domain, and an intracellular tyrosine kinase domain; to date, four types of FGFR have been identified (FGFR1, FGFR2, FGFR3, and FGFR4). FGFR forms a dimer upon binding to FGF and is activated by phosphorylation. Activation of the receptor induces the recruitment and activation of specific downstream signaling molecules, thereby manifesting physiological functions. Abnormalities in FGF/FGFR signaling have been reported to be associated with various human tumors. Abnormal activation of FGF/FGFR signaling in human tumors is known to be due to autocrine or paracrine mechanisms caused by the overexpression of FGFR and/or gene amplification, gene mutation, chromosomal translocation, insertion, or inversion, gene fusion, or the overproduction of the ligand FGF (Non-patent Literature 1, 2, 3 and 4). Meanwhile, the development of cancer immunotherapy is underway as a new cancer treatment method. The activation of the adaptive immune response is initiated by the binding of the antigen-peptide-MHC complex to the T cell receptor (TCR). This binding is further defined by costimulation or coinhibition resulting from the binding between the B7 family, which are co-stimulatory molecules, and their receptor, the CD28 family. In other words, for T cells to be antigen-specifically activated, two characteristic signaling events are required; T cells that receive only antigen stimulation without co-stimulation from the B7 family become anergy-free, thereby inducing immune tolerance. Cancer cells utilize this structure to evade immune surveillance mechanisms and continue to proliferate by suppressing the activation of antigen-specific T cells. Therefore, it is considered effective in cancer treatment to control the immune escape of tumors by inducing an in vivo anti-tumor immune response in cancer patients through the enhancement of costimulation or the blocking of coinhibitory; thus, various cancer immunotherapies targeting costimulatory molecules or coinhibitory molecules have been proposed (Non-patent Literature 5). For example, nivolumab (a humanized IgG4 monoclonal antibody against human PD-1) is used in the treatment of malignant melanoma and the like as an immune checkpoint inhibitor that activates T cells by inhibiting the binding of PD-1 to its ligands (PD-L1 and PD-L2) (Patent Literature 1, Non-patent Literature 6). In addition, zimberelimab (AB122) is known as a novel immune checkpoint inhibitor and is used in the treatment of Hodgkin lymphoma, etc. (Non-patent document 7). (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethinyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pyrrolidin-1-yl)propa-2-en-1-one (hereinafter referred to as "Futivatinib"), a 3,5-2-substituted benzeallkynyl compound, or its salts are known as FGFR inhibitors, and combinations of FGFR inhibitors with other antitumor agents have been reported to date (Patent Documents 2, 3). In addition, a clinical trial regarding the combination administration of Putivatinib and Zimberellimab in patients with non-small cell lung cancer (jRCT No.: jRCT2011210020) is being conducted (Non-Patent Document 8). Figure 1 shows an overview of the clinical trial design of a combination therapy including putivatinib. The present invention relates to providing putivatinib or its salt, an immune checkpoint inhibitor (excluding pembrolizumab and CD155/TIGIT pathway antagonists), and at least one other antitumor agent in combination. In the present invention, putivatinib, which produces an excellent antitumor effect when used in combination with an immune checkpoint inhibitor, is a disubstituted benzenealkinyl compound having the following structure. Putivatinib is described as Example Compound 2 in the above-mentioned Patent Document 2. Putivatinib or its salt has been reported to have an excellent FGFR inhibitory activity and to inhibit the phosphorylation ability of tyrosine in the substrate peptide sequences of the receptor proteins tyrosine kinases of FGFR1, FGFR3, and FGFR4, respectively (Patent Document 2). The putivatinib or its pharmaceutically acceptable salt in the present invention may be synthesized based on, for example, the manufacturing method described in Patent Document 2, although not specifically limited thereto. In the present invention, putivatinib may be used as is or in the form of a pharmaceutically acceptable salt. Pharmaceutica