FGFR tyrosine kinase inhibitors and anti-PD1 agents for the treatment of urothelial carcinoma

Abstract

This invention provides a novel cancer treatment method for patients with urothelial carcinoma who are positive for fibroblast growth factor receptor (FGFR) mutations or FGFR fusions. [Solution] A method for treating urothelial carcinoma is provided, comprising administering a fibroblast growth factor receptor (FGFR) inhibitor at a dose of approximately 8 mg per day in combination with an anti-PD1 antibody or its antigen-binding fragment at a dose of approximately 240 mg to a patient diagnosed with urothelial carcinoma who has at least one FGFR2 gene mutation and / or FGFR3 gene mutation. The FGFR is preferably the inhibitor erdafitinib, and the anti-PD1 antibody is preferably cetrelimab. The treatment method may be used in combination with platinum-based chemotherapy (e.g., cisplatin, carboplatin).

Claims

1. A fibroblast growth factor receptor (FGFR) inhibitor at a dose of approximately 8 mg per day for approximately 24 In combination with a 0 mg dose of anti-PD1 antibody or its antigen-binding fragment, urothelial carcinoma Diagnosed with at least one FGFR2 gene mutation and / or FGFR3 gene mutation A method for treating urothelial carcinoma, including administering to a patient having the disease.

2. The method according to claim 1, further comprising administering platinum chemotherapy.

3. The method according to claim 1, wherein the urothelial carcinoma is locally advanced or metastatic.

4. The FGFR inhibitor combined with the anti-PD1 antibody or its antigen-binding fragment When administration is measured by objective response rate, FGFR inhibitors and anti-PD1 antibodies or their anti- Compared to patients diagnosed with urothelial carcinoma who have not received treatment with primordial fragments The method according to any one of claims 1 to 3, which provides improved antitumor activity.

5. The FGFR inhibitor combined with the anti-PD1 antibody or its antigen-binding fragment The administration does not cause hematological toxicity of grade 3 or higher, as described in any one of claims 1 to 4. Method of loading.

6. The patient has the FGFR inhibitor and the anti-PD1 antibody or its antigen-binding fragment. Before administering this drug, the patient must have received at least one systemic therapy to treat urothelial carcinoma. The method according to any one of claims 1 to 5.

7. The at least one systemic therapy for treating urothelial carcinoma is a platinum-containing chemotherapy The method according to claim 6.

8. The urothelial carcinoma is diagnosed during or after at least one line of platinum-containing chemotherapy. The method according to claim 7, further developed.

9. The platinum-containing chemotherapy is neoadjuvant platinum-containing chemotherapy or adjuvant chemotherapy. The method according to claim 8, which is a toplatinum-containing chemotherapy.

10. The urothelial carcinoma is a neoadjuvant platinum-containing chemical of at least one line The disease progressed within 12 months after therapy or adjuvant platinum-containing chemotherapy, as per claim 9. Method of description.

11. The patient has the FGFR inhibitor and the anti-PD1 antibody or its antigen-binding fragment. Prior to administration, the patient has not received systemic therapy for the treatment of urothelial carcinoma, according to claims 1 to 5. The method described in any one of the items.

12. The method according to claim 11, wherein the patient is unsuitable for cisplatin.

13. The patient described in any one of claims 1 to 12 has an ECOG general status of 2 or less. Method of loading.

14. The aforementioned FFFR2 gene mutation and / or FFFR3 gene mutation may be a mutation in the FFFR3 gene. A mutation, an FGFR2 gene fusion, or an FGFR3 gene fusion, according to any of claims 1 to 13 The method described in any one of the items.

15. The aforementioned FGFR3 gene mutations are R248C, S249C, G370C, Y373C The method according to claim 14, or any combination thereof.

16. The aforementioned FGFR2 or FGFR3 gene fusion is FGFR3-TACC3, FGFR3- BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any of the above. The method according to claim 14, which is a combination.

17. Before administering the FGFR inhibitor and the anti-PD1 antibody or its antigen-binding fragment In addition, the patient-derived biological sample was found to contain one or more FGFR2 gene mutations and / or FGFR3 mutations. The present invention further includes evaluating the presence of genetic mutations, as described in any one of claims 1 to 16. Method of loading.

18. The aforementioned biological sample is blood, lymph, bone marrow, solid tumor sample, or any combination thereof. A method according to claim 17.

19. The FGFR inhibitor is erdafitinib, as described in any one of claims 1 to 18. Method of loading.

20. The method according to claim 19, wherein erdafitinib is administered orally.

21. The erdafitinib is administered orally on a daily schedule, according to claim 19 or 20. Method of description.

22. Erdafitinib is administered once daily at a dose of approximately 8 mg, according to claims 19 to 21. The method described in any one of the items.

23. The aforementioned dose of erdafitinib may change from 8 mg per day to 9 mg per day after the start of treatment. The method according to any one of claims 19 to 22, which is increased to

24. The aforementioned patient had a serum phosphate level (PO) of less than approximately 5.5 mg / dL. ４ ) When indicating the level, In more detail, the aforementioned patient had a serum phosphorus level of less than approximately 5.5 mg / dL on the 14th to 21st day after the start of treatment. acid salt (PO ４ ) showed a level and administration of erdafitinib at 8 mg once daily was ocular If no adverse effect occurs; or (b) administration of erdafitinib at 8 mg once daily If the administration does not cause a Grade 2 or higher adverse reaction, the use of erdafitinib Claim 23 states that the dose is increased from 8 mg per day to 9 mg per day after the start of treatment. Method of loading.

25. Erdafitinib is administered in a solid dosage form, as described in any one of claims 19 to 24. Method of loading.

26. The method according to claim 25, wherein the solid dosage form is a tablet.

27. The aforementioned anti-PD1 antibody or its antigen-binding fragment is administered at a dose of approximately 240 mg every two weeks. The method according to any one of claims 1 to 26, administered as a single dose.

28. Claims 1 to 1, wherein the anti-PD1 antibody or its antigen-binding fragment is cetrelimab. The method described in any one of paragraphs 26.

29. The method according to claim 28, wherein the cetrelimab is administered by intravenous infusion.

30. The aforementioned cetrelimab is administered at a dose of approximately 240 mg. (a) once every two weeks, once every three weeks, once every four weeks, once every five weeks, or 6 Once a week; (b) Once every two weeks; (c) Once every three weeks; (d) Once every four weeks; (e) Once every five weeks; or (f) The method according to claim 28 or 29, administered once every six weeks.

31. Claim 30, wherein the cetrelimab is administered once every two weeks at a dose of approximately 240 mg. Method of description.

32. The platinum chemotherapy is cisplatin, as described in any one of claims 2 to 31. The method.

33. The aforementioned cisplatin is approximately 50 mg / m² ２ The method according to claim 32, administered in the dose of 。

34. The aforementioned cisplatin is approximately 60 mg / m² ２ The method according to claim 32, administered in the dose of 。

35. The platinum chemotherapy is carboplatin, as described in any one of claims 2 to 31. Method of loading.

36. Claim 35, in which the carboplatin is administered at an AUC of approximately 4 mg / mL / min Methods used.

37. Claim 35, in which the carboplatin is administered at an AUC of approximately 5 mg / mL / min Methods used.

38. A fibroblast growth factor receptor (FGFR) inhibitor at a dose of approximately 8 mg per day for approximately 24 Combined with a 0 mg dose of anti-PD1 antibody or its antigen-binding fragment, further... In combination with Tina chemotherapy, it is administered to patients diagnosed with urothelial carcinoma, including the urinary tract Methods for treating epithelial cancer.

39. Treatment with FGFR inhibitors or anti-PD1 antibodies or their antigen-binding fragments Compared to patients diagnosed with urothelial carcinoma, the objectives of patients diagnosed with urothelial carcinoma A method for improving the response rate, comprising approximately 240 mg of anti-PD1 antibody or its antigen conjugate. Fibroblast growth factor receptor (FIBC) in combination with the fragment at a daily dose of approximately 8 mg. FGFR inhibitors target at least one FGFR2 gene mutation and / or FGFR3 gene mutation. A method comprising administering to a patient diagnosed with urothelial carcinoma who has a sub-mutation.

40. A method for treating urothelial carcinoma, (a) A biological sample from a patient diagnosed with urothelial carcinoma is administered to one or more fibroblast growth factors. To evaluate the presence of mutations in the Physiolytic (FGFR) gene; and (b) If one or more FGFR gene mutations are present in the sample, approximately 8 mg per day A dose of FGFR inhibitor, approximately 240 mg of anti-PD1 antibody or its antigen-binding fragment. A method comprising administering to the patient in combination with a substance.

41. Patients with at least one FGFR2 gene mutation and / or FGFR3 gene mutation Fibroblast growth factor receptor (FGFR) inhibitors and for use in the treatment of urothelial carcinoma The anti-PD1 antibody or its antigen-binding fragment, wherein the FGFR inhibitor is present in a daily dose. It should be administered in doses of approximately 8 mg, and the anti-PD1 antibody or its antigen-binding flag should be used. Menthol should be administered at a dose of approximately 240 mg, along with FGFR inhibitors and anti-PD1 inhibitors. A body or its antigen-binding fragment.

42. Patients with at least one FGFR2 gene mutation and / or FGFR3 gene mutation FG, a drug for manufacturing a medicine for treating urothelial carcinoma, at a dose of approximately 8 mg per day. The use of an FR inhibitor, wherein the FR inhibitor is an anti-PD1 antibody in a dose of approximately 240 mg. Or, an FGFR inhibitor which should be used in combination with its antigen-binding fragment. use.

43. Patients with at least one FGFR2 gene mutation and / or FGFR3 gene mutation A drug for manufacturing a medicine to treat urothelial carcinoma, with a dose of approximately 240 mg of anti-PD1 anti Use of the body or its antigen-binding fragment, wherein the anti-PD1 antibody or its antigen-binding fragment Lagment should be used in combination with an FGFR inhibitor at a dose of approximately 8 mg per day. The use of an anti-PD1 antibody or its antigen-binding fragment.

44. Patients with at least one FGFR2 gene mutation and / or FGFR3 gene mutation For use in the treatment of urothelial carcinoma, an anti-PD1 antibody or its antigen-binding fragment is combined with A fibroblast growth factor receptor (FGFR) inhibitor for use in combination, the aforementioned FGFR inhibitors should be administered at a dose of approximately 8 mg per day, and the aforementioned anti-PD1 inhibitors The body or its antigen-binding fragment should be administered in a dose of approximately 240 mg, FG FR inhibitors.

45. Patients with at least one FGFR2 gene mutation and / or FGFR3 gene mutation Fibroblast growth factor receptor (FGFR) inhibitors and for use in the treatment of urothelial carcinoma An anti-PD1 antibody or its antigen-binding fragment for use in combination, the The anti-PD1 antibody or its antigen-binding fragment should be administered at a dose of approximately 240 mg. Yes, the FGFR inhibitor should be administered at a dose of approximately 8 mg per day, anti-P D1 antibody or its antigen-binding fragment.

46. The aforementioned anti-PD1 antibody or its antigen-binding fragment is administered at a dose of approximately 240 mg every two weeks. A single dose of the method or use according to any one of claims 39 to 45.

47. Any one of claims 39 to 46, to be used in combination with platinum chemotherapy. Methods or uses of the above.

48. The FGFR inhibitor is erdafitinib, according to any one of claims 39 to 47. The method or use described.

49. Claim 39, wherein the anti-PD1 antibody or its antigen-binding fragment is cetrelimab. The method or use described in any one of paragraphs 48.

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