FGFR tyrosine kinase inhibitors for the treatment of high-risk non-muscle-invasive bladder cancer

Abstract

Described herein are methods for treating high-risk non-muscle-invasive bladder cancer (HR-NMIBC) that involve administering a fibroblast growth factor receptor (FGFR) inhibitor. Also described are methods for treating intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC) that involve administering an FGFR inhibitor.

Description

[Technical Field]

[0001] Disclosed herein are methods for treating high-risk non-muscle invasive bladder cancer (HR-NMIBC) comprising administering a fibroblast growth factor receptor (FGFR) inhibitor. Also disclosed are methods for treating intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) comprising administering an FGFR inhibitor. [Background technology]

[0002] Early-stage non-muscle-invasive bladder cancer (NMIBC) is diagnosed in 70% of patients with bladder cancer (Isharwal S, Konety B. Indian J Urol. 2015;31(4):289-296), of which 25% have poorly differentiated, low-stage tumors, known as high-risk non-muscle-invasive bladder cancer (HR-NMIBC). Herr HW, Sogani PC. J Urol. 2001;166(4):1296-1299. HR-NMIBC is associated with a high rate of recurrence, progression to muscle invasion, and metastasis. Sylvester RJ et al. Eur Urol. 2006;49:466-477. Treatment failure with intravesical Bacillus Calmette-Guérin (BCG) therapy is high, with recurrence observed in approximately 30-40% of patients. Zlotta AR et al. Can Urol Assoc J. 2009:S199-S205. Erdafitinib, an oral pan-FGFR kinase inhibitor, is approved by the US FDA for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) harboring susceptible FGFR3 or FGFR2 mutations who have progressed during or after at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy (PCC). Loriot Y et al. N Engl J Med. 2019;381:338-348. New cancer treatments are needed for patients with FGFR mutation- or fusion-positive HR-NMIBC or IR-NMIBC who have relapsed after BCG therapy. Summary of the Invention [Means for solving the problem]

[0003] Described herein are methods for treating HR-NMIBC, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, more particularly erdafitinib, at a dose of about 8 mg / day, to a patient diagnosed with HR-NMIBC and having at least one FGFR2 genetic mutation and / or FGFR3 genetic mutation. In certain embodiments, the patient has undergone BCG therapy prior to the administration of the FGFR inhibitor. In further embodiments, the BCG therapy is adequate BCG therapy. In some embodiments, the patient is refractory to BCG therapy. In yet further embodiments, the patient has undergone BCG therapy. In certain embodiments, the patient has a papillary tumor. In further embodiments, the patient has carcinoma in situ. In some embodiments, the patient has not previously undergone cystectomy or is ineligible for cystectomy. In one embodiment, the FGFR inhibitor is or is to be administered at a dose of about 6 mg / day, particularly erdafitinib, and more particularly erdafitinib at a dose of about 6 mg / day.

[0004] Described herein are methods for treating IR-NMIBC, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, more particularly erdafitinib, at a dose of about 8 mg / day, to a patient diagnosed with IR-NMIBC and having at least one FGFR2 genetic mutation and / or FGFR3 genetic mutation. In certain embodiments, the patient has undergone BCG therapy prior to the administration of the FGFR inhibitor. In further embodiments, the BCG therapy is adequate BCG therapy. In some embodiments, the patient is refractory to BCG therapy. In yet further embodiments, the patient has undergone BCG therapy. In certain embodiments, the patient has a papillary tumor. In further embodiments, the patient has carcinoma in situ. In some embodiments, the patient has not previously undergone cystectomy or is ineligible for cystectomy. In one embodiment, the FGFR inhibitor is or is to be administered at a dose of about 6 mg / day, particularly erdafitinib, and more particularly erdafitinib at a dose of about 6 mg / day.

[0005] Described herein is the use of an FGFR inhibitor, particularly at a dose of about 8 mg / day, and particularly erdafitinib, more particularly at a dose of about 8 mg / day, for the manufacture of a medicament for the treatment of a patient diagnosed with HR-NMIBC and having at least one FGFR2 and / or FGFR3 gene mutation. In certain embodiments, the patient has received BCG therapy prior to the administration of the FGFR inhibitor. In further embodiments, the BCG therapy is adequate BCG therapy. In some embodiments, the patient is refractory to BCG therapy. In yet further embodiments, the patient has undergone BCG therapy. In certain embodiments, the patient has a papillary tumor. In further embodiments, the patient has carcinoma in situ. In some embodiments, the patient has not previously undergone a cystectomy or is ineligible for cystectomy. In one embodiment, the FGFR inhibitor is or is to be administered at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 6 mg / day.

[0006] Described herein is the use of an FGFR inhibitor for the manufacture of a medicament for the treatment of a patient diagnosed with HR-NMIBC and having at least one FGFR2 and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 8 mg / day. In certain embodiments, the patient has received BCG therapy prior to the administration of the FGFR inhibitor. In further embodiments, the BCG therapy is adequate BCG therapy. In some embodiments, the patient is refractory to BCG therapy. In yet further embodiments, the patient has been treated with BCG. In certain embodiments, the patient has a papillary tumor. In further embodiments, the patient has carcinoma in situ. In some embodiments, the patient has not previously undergone a cystectomy or is ineligible for cystectomy. In one embodiment, the FGFR inhibitor is or is to be administered at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib, at a dose of about 6 mg / day.

[0007] Described herein is the use of an FGFR inhibitor, particularly at a dose of about 8 mg / day, and particularly erdafitinib, more particularly at a dose of about 8 mg / day, for the manufacture of a medicament for the treatment of a patient diagnosed with IR-NMIBC and having at least one FGFR2 and / or FGFR3 gene mutation. In certain embodiments, the patient has received BCG therapy prior to the administration of the FGFR inhibitor. In further embodiments, the BCG therapy is adequate BCG therapy. In some embodiments, the patient is refractory to BCG therapy. In still further embodiments, the patient has undergone BCG therapy. In certain embodiments, the patient has a papillary tumor. In further embodiments, the patient has carcinoma in situ. In some embodiments, the patient has not previously undergone cystectomy or is ineligible for cystectomy. In one embodiment, the FGFR inhibitor is or is to be administered at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib, at a dose of about 6 mg / day.

[0008] Described herein is the use of an FGFR inhibitor for the manufacture of a medicament for the treatment of a patient diagnosed with IR-NMIBC and having at least one FGFR2 and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 8 mg / day. In certain embodiments, the patient has received BCG therapy prior to the administration of the FGFR inhibitor. In further embodiments, the BCG therapy is adequate BCG therapy. In some embodiments, the patient is refractory to BCG therapy. In yet further embodiments, the patient has undergone BCG therapy. In certain embodiments, the patient has papillary tumors. In further embodiments, the patient has carcinoma in situ. In some embodiments, the patient has not previously undergone cystectomy or is ineligible for cystectomy. In one embodiment, the FGFR inhibitor is or is to be administered at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib, at a dose of about 6 mg / day.

[0009] Described herein are FGFR inhibitors for use in treating patients diagnosed with HR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, particularly wherein the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 8 mg / day. In certain embodiments, the patient has received BCG therapy prior to the administration of the FGFR inhibitor. In further embodiments, the BCG therapy is suitable BCG therapy. In some embodiments, the patient is refractory to BCG therapy. In still further embodiments, the patient has undergone BCG therapy. In certain embodiments, the patient has papillary tumors. In further embodiments, the patient has carcinoma in situ. In some embodiments, the patient has not previously undergone cystectomy or is ineligible for cystectomy. In one embodiment, the FGFR inhibitor is or is to be administered at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib, at a dose of about 6 mg / day.

[0010] Described herein are FGFR inhibitors for use in treating patients diagnosed with IR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 8 mg / day. In certain embodiments, the patient has received BCG therapy prior to the administration of the FGFR inhibitor. In further embodiments, the BCG therapy is suitable BCG therapy. In some embodiments, the patient is refractory to BCG therapy. In yet further embodiments, the patient has undergone BCG therapy. In certain embodiments, the patient has papillary tumors. In further embodiments, the patient has carcinoma in situ. In some embodiments, the patient has not previously undergone cystectomy or is ineligible for cystectomy. In one embodiment, the FGFR inhibitor is or is to be administered at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib, at a dose of about 6 mg / day.

[0011] In further embodiments, the administration of an FGFR inhibitor results in increased recurrence-free survival compared to a patient population with HR-NMIBC receiving a placebo. In certain embodiments, the administration of an FGFR inhibitor results in increased recurrence-free survival compared to a patient population with HR-NMIBC receiving intravesical gemcitabine or intravesical mitomycin C (MMC) / hyperthermic MMC. In some embodiments, the patient exhibits a complete response to the FGFR inhibitor at about 6 months. In some embodiments, the administration of an FGFR inhibitor provides prevention or delay of disease recurrence in a non-muscle-invasive bladder cancer (NMIBC) population (HR-NMIBC or IR-NMIBC).

[0012] In certain embodiments, the FGFR2 gene mutation and / or FGFR3 gene mutation is an FGFR3 gene mutation, an FGFR2 gene fusion, or an FGFR3 gene fusion. In some embodiments, the FGFR3 gene mutation is R248C, S249C, G370C, Y373C, or any combination thereof. In still further embodiments, the FGFR2 gene fusion or FGFR3 gene fusion is FGFR3-TACC3, particularly FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

[0013] In some embodiments, the method or use further comprises evaluating a biological sample from the patient for the presence of at least one FGFR2 genetic mutation and / or FGFR3 genetic mutation prior to said administration of an FGFR inhibitor. In certain embodiments, the biological sample is blood, lymph, bone marrow, a solid tumor sample, urine, or any combination thereof. In certain embodiments, the biological sample is a blood sample. In certain embodiments, the biological sample is a urine sample.

[0014] In some embodiments, the FGFR inhibitor is erdafitinib. In further embodiments, erdafitinib is administered daily, specifically once daily. In yet further embodiments, erdafitinib is administered orally. In certain embodiments, erdafitinib is administered orally on a daily dosing schedule. In some embodiments, erdafitinib is administered orally at a dose of about 8 mg once daily. In some embodiments, erdafitinib is administered orally at a dose of about 8 mg once daily on a daily dosing schedule. In further embodiments, if the patient exhibits a serum phosphorus (PO4) level of less than about 5.5 mg / dL, the dose of erdafitinib is increased from 8 mg / day to 9 mg / day after initiation of treatment, specifically if the patient exhibits a serum phosphorus (PO4) level of less than about 5.5 mg / dL 14-21 days after initiation of treatment, the dose of erdafitinib is increased from 8 mg / day to 9 mg / day after initiation of treatment. In certain embodiments, erdafitinib is present in a solid dosage form. In further embodiments, the solid dosage form is a tablet.

[0015] In some embodiments, in the methods and uses described herein, the FGFR inhibitor, particularly erdafitinib, is administered at a dose of about 6 mg / day. In further embodiments, erdafitinib is administered at a dose of about 6 mg once a day. In even further embodiments, erdafitinib is administered orally. In certain embodiments, erdafitinib is administered orally on a daily dosing schedule. In some embodiments, erdafitinib is administered orally on a daily dosing schedule at a dose of about 6 mg once a day. In some embodiments, erdafitinib is administered orally on a daily dosing schedule at a dose of about 6 mg once a day. In a further embodiment, if the patient exhibits a serum phosphorus (PO4) level of less than about 5.5 mg / dL, the dose of erdafitinib is increased from 6 mg / day to 8 mg / day after initiation of treatment, specifically if the patient exhibits a serum phosphorus (PO4) level of less than about 5.5 mg / dL 14 to 21 days after initiation of treatment, the dose of erdafitinib is increased from 6 mg / day to 8 mg / day after initiation of treatment. In certain embodiments, erdafitinib is present in a solid dosage form. In a further embodiment, the solid dosage form is a tablet.

[0016] Also described herein is a method of treating HR-NMIBC, comprising: (a) assessing a biological sample from a patient diagnosed with HR-NMIBC for the presence of one or more FGFR gene mutations, particularly one or more FGFR2 or FGFR3 mutations; and (b) if one or more FGFR gene mutations are present in the sample, administering to the patient an FGFR inhibitor, particularly at a dose of about 8 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 8 mg / day.

[0017] Also described herein is a method of treating HR-NMIBC, comprising: (a) assessing a biological sample from a patient diagnosed with HR-NMIBC for the presence of one or more FGFR genetic mutations, particularly one or more FGFR2 or FGFR3 alterations; and (b) if one or more FGFR genetic mutations are present in the sample, administering to the patient an FGFR inhibitor, particularly at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 6 mg / day.

[0018] Also described herein is a method of treating IR-NMIBC, comprising: (a) assessing a biological sample from a patient diagnosed with IR-NMIBC for the presence of one or more FGFR gene mutations, particularly one or more FGFR2 or FGFR3 mutations; and (b) if one or more FGFR gene mutations are present in the sample, administering to the patient an FGFR inhibitor, particularly at a dose of about 8 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 8 mg / day.

[0019] Also described herein is a method of treating IR-NMIBC, comprising: (a) assessing a biological sample from a patient diagnosed with IR-NMIBC for the presence of one or more FGFR gene mutations, particularly one or more FGFR2 or FGFR3 mutations; and (b) if one or more FGFR gene mutations are present in the sample, administering to the patient an FGFR inhibitor, particularly at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 6 mg / day.

[0020] Described herein is the use of an FGFR inhibitor, particularly at a dose of about 8 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 8 mg / day, for the manufacture of a medicament for the treatment of a patient diagnosed with HR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is administered or to be administered after assessing a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample.

[0021] Described herein is the use of an FGFR inhibitor, particularly at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 6 mg / day, for the manufacture of a medicament for the treatment of a patient diagnosed with HR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is administered or to be administered after assessing a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample.

[0022] Described herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating a patient diagnosed with HR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is or will be administered at a dose of about 8 mg / day, and the FGFR inhibitor, particularly erdafitinib, is or will be administered after assessing a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations, and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample.

[0023] Described herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating a patient diagnosed with HR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein in particular the FGFR inhibitor, particularly erdafitinib, is or will be administered at a dose of about 6 mg / day, and the FGFR inhibitor, particularly erdafitinib, is or will be administered after assessing a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations, and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample.

[0024] Described herein is the use of an FGFR inhibitor, particularly at a dose of about 8 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 8 mg / day, for the manufacture of a medicament for the treatment of a patient diagnosed with IR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is administered or to be administered after assessing a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample.

[0025] Described herein is the use of an FGFR inhibitor, particularly at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 6 mg / day, for the manufacture of a medicament for the treatment of a patient diagnosed with IR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is administered or to be administered after assessing a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample.

[0026] Described herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating a patient diagnosed with IR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is or will be administered at a dose of about 8 mg / day, and the FGFR inhibitor, particularly erdafitinib, is or will be administered after assessing a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations, and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample.

[0027] Described herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating a patient diagnosed with IR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is or will be administered at a dose of about 6 mg / day, and the FGFR inhibitor, particularly erdafitinib, is or will be administered after assessing a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations, and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample.

[0028] Described herein is an FGFR inhibitor for use in treating a patient diagnosed with HR-NMIBC who has at least one FGFR2 gene mutation and / or FGFR3 gene mutation, in particular the FGFR inhibitor, particularly erdafitinib, is or will be administered at a dose of about 8 mg / day, and the FGFR inhibitor, particularly erdafitinib, is or will be administered after assessing a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations, and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample.

[0029] Described herein is an FGFR inhibitor for use in treating a patient diagnosed with HR-NMIBC who has at least one FGFR2 gene mutation and / or FGFR3 gene mutation, in particular the FGFR inhibitor, particularly erdafitinib, is or will be administered at a dose of about 6 mg / day, and the FGFR inhibitor, particularly erdafitinib, is or will be administered after assessing a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations, and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample.

[0030] Described herein is an FGFR inhibitor for use in treating a patient diagnosed with IR-NMIBC who has at least one FGFR2 gene mutation and / or FGFR3 gene mutation, in particular the FGFR inhibitor, particularly erdafitinib, is or will be administered at a dose of about 8 mg / day, and the FGFR inhibitor, particularly erdafitinib, is or will be administered after assessing a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations, and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample.

[0031] Described herein is an FGFR inhibitor for use in treating a patient diagnosed with IR-NMIBC who has at least one FGFR2 gene mutation and / or FGFR3 gene mutation, in particular the FGFR inhibitor, particularly erdafitinib, is or will be administered at a dose of about 6 mg / day, and the FGFR inhibitor, particularly erdafitinib, is or will be administered after assessing a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations, and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample.

[0032] Further provided herein is a method for treating intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC), comprising, consisting of, or consisting essentially of administering an FGFR inhibitor at a dose of about 8 mg / day to a patient diagnosed with IR-NMIBC, e.g., with at least one FGFR2 gene mutation and / or FGFR3 gene mutation. In certain embodiments, the patient has a papillary tumor. In some embodiments, the patient has an incomplete transurethral resection. In a further embodiment, the patient exhibits a complete response to the FGFR inhibitor at about 3 months.

[0033] Further provided herein is a method for treating intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC), comprising, consisting of, or consisting essentially of administering an FGFR inhibitor at a dose of about 6 mg / day to a patient diagnosed with IR-NMIBC, e.g., with at least one FGFR2 gene mutation and / or FGFR3 gene mutation. In certain embodiments, the patient has a papillary tumor. In some embodiments, the patient has an incomplete transurethral resection. In a further embodiment, the patient exhibits a complete response to the FGFR inhibitor at about 3 months.

[0034] In certain embodiments, the FGFR2 gene mutation and / or FGFR3 gene mutation is an FGFR3 gene mutation, or an FGFR2 gene fusion, or an FGFR3 gene fusion. In some embodiments, the FGFR3 gene mutation is R248C, S249C, G370C, Y373C, or any combination thereof. In still further embodiments, the FGFR2 gene fusion or FGFR3 gene fusion is FGFR3-TACC3, particularly FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof. In certain embodiments, the FGFR inhibitor is erdafitinib.

[0035] Also described herein is a method for treating BCG-treated HR-NMIBC in a patient with one or more FGFR2 or FGFR3 gene mutations, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, to the patient, wherein the treatment results in a 6-month recurrence-free survival rate of at least 90%, or at least 95%, particularly about 96%.

[0036] Also described herein is the use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-treated HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations, wherein the treatment results in a 6-month recurrence-free survival rate of at least 90%, or at least 95%, particularly about 96%.

[0037] Also described herein are FGFR inhibitors, particularly erdafitinib, for use in treating BCG-treated HR-NMIBC patients with one or more FGFR2 or FGFR3 gene mutations, wherein the treatment results in a 6-month recurrence-free survival rate of at least 90%, or at least 95%, particularly about 96%.

[0038] In certain embodiments, treatment results in a 6-month recurrence-free survival rate of about 96%. In some embodiments, the HR-NMIBC is papillary-only HR-NMIBC. In further embodiments, the FGFR inhibitor is erdafitinib. In certain embodiments, erdafitinib is administered or is to be administered at a dose of about 6 mg / day, particularly once daily.

[0039] Further provided herein is a method of treating BCG-treated HR-NMIBC in a patient with one or more FGFR2 or FGFR3 gene mutations, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, to the patient, wherein the treatment results in a 12-month recurrence-free survival rate of at least 70%, or at least 75%, particularly about 77%.

[0040] Further provided herein is the use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-treated HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations, wherein the treatment results in a 12-month recurrence-free survival rate of at least 70%, or at least 75%, particularly about 77%.

[0041] Further provided herein is an FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-treated HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations, wherein the treatment results in a 12-month recurrence-free survival rate of at least 70%, or at least 75%, particularly about 77%.

[0042] In certain embodiments, treatment results in a 12-month recurrence-free survival rate of about 77%. In further embodiments, the HR-NMIBC is papillary-only HR-NMIBC. In some embodiments, the FGFR inhibitor is erdafitinib. In certain embodiments, erdafitinib is administered or is to be administered at a dose of about 6 mg / day, particularly once daily.

[0043] Also described herein is a method for treating recurrent HR-NMIBC after BCG treatment in a patient with one or more FGFR2 or FGFR3 gene mutations, comprising, consisting of, or consisting essentially of administering to the patient an FGFR inhibitor, particularly erdafitinib, wherein the treatment results in a reduced recurrence or mortality rate compared to intravesical chemotherapy.

[0044] Also described herein is the use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of HR-NMIBC that has relapsed after BCG treatment and is associated with one or more FGFR2 or FGFR3 gene mutations, wherein the treatment results in a lower recurrence or mortality rate than intravesical chemotherapy.

[0045] Also described herein are FGFR inhibitors, particularly erdafitinib, for use in the treatment of HR-NMIBC that has relapsed after BCG treatment and has one or more FGFR2 or FGFR3 gene mutations, wherein the treatment results in a lower recurrence or mortality rate than intravesical chemotherapy.

[0046] In certain embodiments, the HR-NMIBC is Ta / T1 HR-NMIBC. In further embodiments, the HR-NMIBC is papillary-only HR-NMIBC. In some embodiments, the FGFR inhibitor is erdafitinib. In certain embodiments, erdafitinib is administered or is to be administered at a dose of about 6 mg / day, particularly once daily. In further embodiments, the treatment is for patients who have refused or are ineligible for radical cystectomy.

[0047] In further embodiments, the one or more FGFR2 or FGFR3 gene mutations are FGFR3 gene mutations, FGFR2 gene fusions, or FGFR3 gene fusions. In still further embodiments, the FGFR3 gene mutation is R248C, S249C, G370C, Y373C, or any combination thereof. In some embodiments, the FGFR2 or FGFR3 gene fusion is FGFR3-TACC3, particularly FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof. [Brief explanation of the drawings]

[0048] The Summary of the Invention, as well as the Detailed Description that follows, will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the methods or uses of the present disclosure, there are shown in the drawings exemplary embodiments of the methods or uses. However, it is not intended that the methods or uses be limited to the particular embodiments disclosed. [Figure 1] Figure 1 shows the clinical trial scheme for a phase 2, multicenter, open-label study evaluating the safety and efficacy of erdafitinib in subjects with HR-NMIBC harboring selected FGFR gene alterations (FGFR translocations or mutations) who relapsed after BCG therapy. Footnote (a) indicates the investigator's choice of intravesical gemcitabine / mitomycin C (MMC) / hyperthermic MMC therapy. Footnote (b) indicates 28-day cycles for up to 2 years until the patient experiences disease recurrence or progression, unacceptable toxicity, or withdraws consent. Footnote (c) indicates 28-day cycles for up to 2 years in Cohort 1 patients with confirmed high-grade recurrence at the investigator's option who can crossover to treatment with erdafitinib. Footnote (d) indicates treatment for up to 6 months, with discontinuation if CR is not observed within 3 months. As used in Figure 1, BCG stands for Mycobacterium Calmette-Guérin, CIS stands for carcinoma in situ, CR stands for complete response, ERDA stands for erdafitinib, FGFR stands for fibroblast growth factor receptor, HR stands for high risk, IC stands for intravesical chemotherapy, IR stands for intermediate risk, MMC stands for mitomycin C, NMIBC stands for non-muscle invasive bladder cancer, RFS stands for recurrence-free survival, and TUR stands for transurethral resection. [Figure 2] FIG. 1 depicts erdafitinib dose escalation from a 6 mg to an 8 mg daily regimen. [Figure 3] Figure 1 shows duration of response in evaluable patients in Cohort 2. CR, complete response; HGR, high-grade relapse; N / A, not applicable. a Patient is still on treatment. b Patient's duration of response is currently censored. [Figure 4]Figure 1 shows duration of response in evaluable patients in Cohort 3. CR, complete response; HGR, high-grade relapse; N / A, not applicable. a Patient is still on treatment. b Patient's duration of response is currently censored. [Figure 5] Figure 5: THOR-2 clinical trial design. Legend to Figure 5: a Number of patients randomized at the clinical cutoff of June 27, 2023, N=73. BCG, Mycobacterium Calmette-Guérin; CIS, carcinoma in situ; CR, complete response; FGFR, fibroblast growth factor receptor; GEM, gemcitabine; HR, high risk; IR, intermediate risk; MMC, mitomycin C; NMIBC, non-muscle invasive bladder cancer; R, randomized; TUR, transurethral resection. [Figure 6] CONSORT diagram showing trial and treatment trends for THOR-2 Cohort 1. Legend to Figure 6: a For patients crossing over from chemotherapy to erdafitinib treatment, this figure summarizes predisposing factors before crossover. b Patients were considered to have completed the trial if they died before the end of the trial, were not lost to follow-up, or did not withdraw consent to participate in the trial before the end of the trial. c Patients were considered to have completed treatment if they completed 2 years of erdafitinib or the maximum duration (minimum of at least 7 months) according to the local standard of care for gemcitabine or mitomycin C. ITT, intention to treat; MMC, mitomycin C. [Figure 7A] 1 is a graph showing recurrence-free survival. [Figure 7B] Graphs showing recurrence-free survival. Kaplan-Meier estimates of recurrence-free survival by treatment group (Figure 7A) and subgroups (Figure 7B). Subgroups were based on prior BCG therapy (BCG-experienced vs. BCG-refractory) and tumor stage (Ta vs. T1). Legend for Figures 7A and 7B: Hazard ratios and 95% CIs were estimated using stratified Cox proportional hazards regression models. Hazard ratios <1 indicate longer recurrence-free survival in the erdafitinib group compared with the chemotherapy (gemcitabine or mitomycin) group. BCG, Mycobacterium Calmette-Guérin; CI, confidence interval; HR, hazard ratio; NE, not estimable; RFS, recurrence-free survival. DETAILED DESCRIPTION OF THE INVENTION

[0049] It is understood that certain features of the invention that are described herein for clarity in the context of separate embodiments may also be provided in combination in a single embodiment. That is, unless expressly incompatible or specifically excluded, each individual embodiment is deemed combinable with any other embodiment, and such combination is deemed to be another embodiment. Conversely, different features of the invention that are described for brevity in the context of a single embodiment may also be provided separately or in any subcombination. Finally, while embodiments may be described as part of a series of steps or as part of a more general structure, each step may be deemed to be an independent embodiment in itself, combinable with the others.

[0050] Specific Terms The transitional phrases "comprising," "consisting essentially of," and "consisting" are intended to have their generally accepted meaning in patent terminology, i.e., (i) "comprising" is synonymous with "including," "containing," or "characterized by" and is inclusive or open-ended and does not exclude other unrecited elements or method steps; (ii) "consisting" excludes any element, step, or ingredient not specified in the claim; and (iii) "consisting essentially of" limits the scope of a claim or embodiment to the specified materials or steps and those that "do not materially affect the basic and novel characteristics" of the claimed invention or embodiment. More specifically, the basic and novel characteristics relate to the ability of the method or use to provide at least one of the benefits described herein, including, but not limited to, improved survival of a human population compared to survival of a human comparison population, as described elsewhere herein. Embodiments described with the term "comprising" (or its equivalents) also provide, as embodiments, those independently described with the terms "consisting of" and "consisting essentially of."

[0051] When values ​​are expressed as approximations, by use of the descriptor "about," it will be understood that the particular value forms another embodiment. Unless otherwise specified, the term "about" means a variation of ±10% of the associated value, although further embodiments include those where the variation can be ±5%, ±15%, ±20%, ±25%, or ±50%, and specifically, the term "about" means a variation of ±5% or ±10%, more specifically ±5% of the associated value.

[0052] Where lists are presented, it is to be understood that each individual element of that list and every combination of that list is a separate embodiment unless otherwise stated. For example, a list of embodiments presented as "A, B, or C" should be interpreted to include the embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0053] As used herein, the singular forms "a," "an," and "the" are intended to include plurals.

[0054] The following abbreviations are used throughout this disclosure: FGFR (fibroblast growth factor receptor); FGFR3-TACC3 V1 (a fusion of the gene encoding FGFR3 with the gene encoding transforming acidic coiled-coil-containing protein 3 variant 1); FGFR3-TACC3 V3 (a fusion of the gene encoding FGFR3 with the gene encoding transforming acidic coiled-coil-containing protein 3 variant 3); FGFR3-BAIAP2L1 (a fusion of the gene encoding FGFR3 with the gene encoding brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1); FGFR2-BICC1 (a fusion of the gene encoding FGFR2 with the gene encoding two-tailed C homolog 1); FGFR2-CASP7 (a fusion of the gene encoding FGFR2 with the gene encoding caspase 7).

[0055] As used herein, a "patient" is intended to mean any animal, particularly a mammal. Thus, the present method or use is applicable to human and non-human animals, but most preferably to humans. The terms "patient" and "subject" can be used interchangeably.

[0056] The terms "treat" and "treatment" refer to the treatment of a patient affected by a pathological condition, and refer not only to alleviating the condition by killing cancer cells, but also to inhibiting the progression of the condition, including slowing the rate of progression, stopping the rate of progression, ameliorating the condition, and curing the condition. Preventative treatment (i.e., prophylaxis) is also included.

[0057] A "therapeutically effective amount" refers to an amount effective to obtain a desired therapeutic result, at the dosage and for the duration necessary. A therapeutically effective amount may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improved health of the patient.

[0058] "Dosage" refers to information regarding the amount of a therapeutic agent taken by a subject and the frequency with which the therapeutic agent is taken by a subject.

[0059] The term "dose" refers to the amount or quantity of a therapeutic agent taken at each time.

[0060] As used herein, the term "cancer" refers to an abnormal growth of cells that tends to grow without control and in some cases to invade (spread).

[0061] As used herein, the term "co-administration" and the like is intended to encompass the administration of selected therapeutic agents to a single patient and includes therapeutic regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0062] As used herein, the term "pharmaceutical combination" refers to a product obtained by mixing or combining two or more active ingredients, including both fixed and non-fixed combinations of active ingredients.The term "fixed combination" means that both active ingredients, such as erdafitinib and co-agents, are administered to patients simultaneously in the form of a single unit or a single dosage form.The term "non-fixed combination" means that active ingredients, such as erdafitinib and co-agents, are administered to patients simultaneously, concurrently, or sequentially in separate units or separate dosage forms, without any specific time limit, and such administration provides a safe and effective level of the two active ingredients in the human body.The latter also applies to cocktail therapy, such as the administration of three or more active ingredients.

[0063] The term "continuous daily dosing schedule" refers to the administration of a particular therapeutic agent without any drug holidays for that particular therapeutic agent. In some embodiments, a continuous daily dosing schedule for a particular therapeutic agent comprises administering the particular therapeutic agent every day at approximately the same time each day.

[0064] The term "recurrence-free survival" (RSF) is defined as the time from the date of randomization to the date of recurrence of high-risk disease (high-grade Ta, T1, or CIS) or date of death, whichever is first reported. Patients who are alive without recurrence or whose status is unknown will be censored at the last tumor assessment. RFS will be assessed by central histopathological review.

[0065] The term "recurrence-free survival 2" (RFS2) is defined as the time from the date of randomization to the date of recurrence of high-risk disease on the first subsequent non-surgical anti-cancer treatment, or date of death, whichever is first reported. Patients who are alive without recurrence or whose status is unknown will be censored at the last tumor assessment.

[0066] The term "progression-free interval" is defined as the time from the date of randomization to the date of first recorded evidence of either progression or death. Patients who are alive without progression or whose status is unknown will be censored at the date of their last tumor assessment.

[0067] The term "time to disease progression" is defined as the time from the date of randomization to the date of the first documented evidence of a change in therapy indicating more advanced disease. Patients who are alive without disease progression or whose status is unknown will be censored at the last tumor assessment.

[0068] The term "time to disease progression" may also be defined as the time from the date of randomization to the date of first documented evidence of cystectomy, change in therapy (including systemic chemotherapy or radiation therapy) indicating more advanced disease. Patients who are alive without disease progression or whose status is unknown will be censored at the last tumor assessment.

[0069] The term "disease-specific survival" is defined as the time from the date of randomization to the date of the participant's death due to bladder cancer. Patients who are alive or whose vital status is unknown will be censored on the date the participant was last known to be alive. Participants who died from causes other than bladder cancer will be censored on the date of death.

[0070] The term "overall survival" (OS) is defined as the time from the date of randomization to the date of death of the participant from any cause. Patients who are alive or whose vital status is unknown will be censored at the date the participant was last known to be alive.

[0071] The term "complete response" (CR) is defined as disappearance of marker lesions with no remnants and no viable tumor on histopathological examination.

[0072] The term "partial response" (PR) includes at least a 30% reduction in the sum of the diameters of target lesions relative to the baseline sum of the diameters.

[0073] The term "adverse event" refers to any untoward medical occurrence in a subject receiving an investigational product, and does not necessarily refer only to events that have a clear causal relationship with the relevant investigational product.

[0074] As used herein, the term "placebo" refers to the administration of a pharmaceutical composition that does not contain an FGFR inhibitor.

[0075] The term "randomization," when applied to a clinical trial, refers to the point at which patients are identified as eligible for the clinical trial and assigned to a treatment group.

[0076] The terms "kit" and "article of manufacture" are used synonymously.

[0077] "Biological sample" refers to any sample obtained from a patient from which cancerous cells can be obtained and from which FGFR gene mutations can be detected. Suitable biological samples include, but are not limited to, blood, lymph, bone marrow, solid tumor samples, or any combination thereof. In some embodiments, the biological sample may be formalin-fixed paraffin-embedded tissue (FFPET).

[0078] "Cmax" is the maximum analytical concentration observed.

[0079] "Tmax" is the actual sampling time at which the maximum observed analyte concentration is reached.

[0080] "AUClast" is the time from time zero to the time of the last measurable (not below the limit of quantitation [BQL]) analyte concentration.

[0081] "AUCinfinity" is from time zero to infinity

[0082] FGFR gene mutations Described herein is a method or use for treating HR-NMIBC, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor at a dose of about 8 mg / day to a patient diagnosed with HR-NMIBC and having at least one FGFR2 genetic mutation and / or FGFR3 genetic mutation (i.e., one or more FGFR2 genetic mutations, one or more FGFR3 genetic mutations, or a combination thereof). Also described herein is a method or use for treating HR-NMIBC, comprising, consisting of, or consisting essentially of administering at least one fibroblast growth factor receptor (FGFR) inhibitor at a dose of about 8 mg / day to a patient diagnosed with HR-NMIBC and having at least one FGFR2 genetic mutation and / or FGFR3 genetic mutation. Further described herein is a method or use for treating HR-NMIBC, comprising, consisting of, or consisting essentially of administering two or more fibroblast growth factor receptor (FGFR) inhibitors at a dose of about 8 mg / day to a patient diagnosed with HR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation. The same method of treatment embodiments apply to the uses described herein. In one embodiment, in the method or use for treating HR-NMIBC, the FGFR inhibitor is or is to be administered at a dose of about 6 mg / day. In one embodiment, the FGFR inhibitor is erdafitinib.

[0083] Described herein is a method or use for treating IR-NMIBC, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor at a dose of about 8 mg / day to a patient diagnosed with IR-NMIBC and having at least one FGFR2 genetic mutation and / or FGFR3 genetic mutation (i.e., one or more FGFR2 genetic mutations, one or more FGFR3 genetic mutations, or a combination thereof). Also described herein is a method or use for treating IR-NMIBC, comprising, consisting of, or consisting essentially of administering at least one fibroblast growth factor receptor (FGFR) inhibitor at a dose of about 8 mg / day to a patient diagnosed with IR-NMIBC and having at least one FGFR2 genetic mutation and / or FGFR3 genetic mutation. Further described herein is a method or use for treating IR-NMIBC, comprising, consisting of, or consisting essentially of administering two or more fibroblast growth factor receptor (FGFR) inhibitors at a dose of about 8 mg / day to a patient diagnosed with IR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation. The same method of treatment embodiments apply to the uses described herein. In one embodiment, in the method or use for treating IR-NMIBC, the FGFR inhibitor is or is to be administered at a dose of about 6 mg / day. In one embodiment, the FGFR inhibitor is erdafitinib.

[0084] The fibroblast growth factor (FGF) family of protein tyrosine kinase (PTK) receptors regulates a wide variety of physiological functions, including mitogenesis, wound healing, cell differentiation and angiogenesis, and development. The growth and proliferation of normal and malignant cells are influenced by changes in the local concentrations of FGFs, extracellular signaling molecules that act as autocrine and paracrine factors. Autocrine FGF signaling may be particularly important in the progression of steroid hormone-dependent cancers to a hormone-independent state.

[0085] FGFs and their receptors are expressed at high levels in several tissues and cell lines, and their overexpression is thought to contribute to the malignant phenotype. Furthermore, many oncogenes are homologs of genes encoding growth factor receptors, which may aberrantly activate FGF-dependent signaling in human pancreatic cancer (Knight et al., Pharmacology and Therapeutics 2010 125:1(105-117); Korc M. et al. Current Cancer Drug Targets 2009 9:5(639-651)).

[0086] Acidic fibroblast growth factor (aFGF or FGF1) and basic fibroblast growth factor (bFGF or FGF2) are the two prototypic members, and at least 20 different FGF family members have been identified to date. Cellular responses to FGFs are mediated through four high-affinity transmembrane protein tyrosine kinase fibroblast growth factor receptors (FGFRs), numbered 1 to 4 (FGFR1 to FGFR4).

[0087] In certain embodiments, HR-NMIBC or IR-NMIBC is predisposed to FGFR2 and / or FGFR3 gene mutations.

[0088] As used herein, "FGFR gene mutation" refers to a mutation in a wild-type FGFR gene, including, but not limited to, an FGFR fusion gene, an FGFR mutation, an FGFR amplification, or any combination thereof. The terms "variant" and "alteration" are used interchangeably herein.

[0089] In certain embodiments, the FGFR2 gene mutation or FGFR3 gene mutation is an FGFR gene fusion. "FGFR fusion" or "FGFR gene fusion" refers to a gene encoding a portion of an FGFR (e.g., FGRF2 or FGFR3) and one or a portion of one of the fusion partners disclosed herein, which is created by a translocation between two genes. The terms "fusion" and "translocation" are used interchangeably herein. The presence of one or more of the following FGFR fusion genes in a biological sample from a patient: FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof, can be determined using the disclosed methods or uses or by methods well known to those skilled in the art. In certain embodiments, the FGFR3-TACC3 is FGFR3-TACC3 variant 1 (FGFR3-TACC3 V1) or FGFR3-TACC3 variant 3 (FGFR3-TACC3 V3). Table 1 shows the FGFR fusion genes and the FGFRs and fusion partner exons fused to each other. The sequences of the individual FGFR fusion genes are disclosed in Table 4.

[0090] [Table 1]

[0091] FGFR gene mutations include FGFR single nucleotide polymorphisms (SNPs). An "FGFR single nucleotide polymorphism" (SNP) refers to an FGFR2 or FGFR3 gene that differs by a single nucleotide between individuals. In certain embodiments, the FGFR2 gene mutation or FGFR3 gene mutation is an FGFR3 gene mutation. In particular, an "FGFR single nucleotide polymorphism" (SNP) refers to an FGFR3 gene that differs by a single nucleotide between individuals. The presence of one or more of the following FGFR SNPs in a biological sample from a patient can be determined by methods well known to those skilled in the art or by methods disclosed in WO 2016 / 048833. The sequences of the FGFR SNPs are shown in Table 2.

[0092] [Table 2] The sequence corresponds to nucleotides 920 to 1510 of FGFR3 (Genebank identification number NM_000142.4). Bold underlined nucleotides represent SNPs. * It is sometimes erroneously referred to as Y375C in the literature.

[0093] As used herein, an "FGFR gene mutation gene panel" includes one or more of the FGFR gene mutations listed above. In some embodiments, the FGFR gene mutation gene panel depends on the type of cancer of the patient.

[0094] The FGFR gene mutation gene panel used in the evaluation step of the disclosed methods is based in part on the patient's cancer type. For patients with HR-NMIBC or IR-NMIBC, a suitable FGFR gene mutation gene panel may include FGFR3-TACC3 V1, FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, or FGFR3 Y373C, or any combination thereof.

[0095] FGFR inhibitors for use in the disclosed methods or uses Provided herein are FGFR inhibitors suitable for use in the disclosed methods or uses. The FGFR inhibitors may be used alone or in combination for the treatment methods described herein.

[0096] In some embodiments, if one or more FGFR gene mutations are present in the sample, HR-NMIBC or IR-NMIBC can be treated with an FGFR inhibitor disclosed in U.S. Patent Application Publication No. 2013 / 0072457(A1), which is incorporated herein by reference, including any tautomers or stereochemical isomers thereof, and N-oxides thereof, pharmaceutically acceptable salts thereof, or solvates thereof.

[0097] In some aspects, for example, HR-NMIBC or IR-NMIBC may be treated with N-(3,5-dimethoxy-phenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine (referred to herein as "JNJ-42756493" or "JNJ493" or erdafitinib), including any tautomeric form thereof, its N-oxide, its pharmaceutically acceptable salt, or its solvate. In some embodiments, the FGFR inhibitor is a compound of Formula (I), also referred to as erdafitinib:

[0098] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is an HCl salt. In preferred embodiments, erdafitinib base is used.

[0099] Erdafitinib (also known as ERDA), a once-daily oral pan-FGFR kinase inhibitor, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with locally advanced UC or mUC harboring a susceptible FGFR3 or FGFR2 gene mutation who have progressed during or after at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. (Loriot Y et al., NEJM. 2019;381:338-48.) Erdafitinib has demonstrated clinical efficacy and tolerability in patients with mUC and FGFR expression mutations. Tabernero J,et al.,J Clin Oncol.2015;33:3401-3408;Soria JC,et al.,Ann Oncol.2016;27(Suppl 6):vi266-vi295.Abstract 781PD;Siefker-Radtke AO,et al.,ASCO 2018.Abstract 4503;Siefker-Radtke A,et al.,ASCO-GU 2018.Abstract 450. In some embodiments, HR-NMIBC or IR-NMIBC can be treated with an FGFR inhibitor, where the FGFR inhibitor is N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,5-diemthylpiperazin-1-yl)benzamide (AZD4547); Gavine, P.R., et al., AZD4547: An Orally Bioavailable, Potent, and Selective Inhibitor of the Fibroblast Growth Factor Receptor Tyrosine Kinase Family, Cancer Res. April 15, 2012 72;2045:

[0100] [ka] and includes, where chemically possible, any tautomers or stereochemical isomers thereof, and N-oxides thereof, pharmaceutically acceptable salts thereof, or solvates thereof.

[0101] In some embodiments, HR-NMIBC or IR-NMIBC can be treated with an FGFR inhibitor, where the FGFR inhibitor is 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-l-{6-[4-(4-ethyl-piperazin-l-yl)-phenylamino]-pyrimidin-4-yl}-methyl-urea (NVP-BGJ398), as described in WO 2006 / 000420.

[0102] [ka] and includes, where chemically possible, any tautomers or stereochemical isomers thereof, as well as its N-oxides, its pharmaceutically acceptable salts, or its solvates.

[0103] In some embodiments, HR-NMIBC or IR-NMIBC can be treated with an FGFR inhibitor, where the FGFR inhibitor is 4-amino-5-fluoro-3-[6-(4-methylpiperazin-l-yl)-lH-benzimidazol-2-yl]-lH-quinolin-2-one (dovitinib), as described in WO 2006 / 127926.

[0104] [ka] and includes, where chemically possible, any tautomers or stereochemical isomers thereof, as well as its N-oxides, its pharmaceutically acceptable salts, or its solvates.

[0105] In some embodiments, HR-NMIBC or IR-NMIBC can be treated with an FGFR inhibitor, where the FGFR inhibitor is 6-(7-((1-aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide (AL3810) (lucitanib; E-3810), as described in Bello, E. et al., E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models, Cancer Res February 15, 2011 71(A)1396-1405, and WO 2008 / 112408.

[0106] [ka] and includes, where chemically possible, any tautomers or stereochemical isomers thereof, as well as its N-oxides, its pharmaceutically acceptable salts, or its solvates.

[0107] In some embodiments, HR-NMIBC or IR-NMIBC may be treated with an FGFR inhibitor, and the FGFR inhibitor is pemigatinib (11-(2,6-difluoro-3,5-dimethoxy-phenyl)-13-ethyl-4-(morpholin-4-ylmethyl)-5,7,11,13-tetraazatricyclo[7.4.0.0] 2,6 ]Trideca-1,3,6,8-tetraen-12-one:

[0108] [ka] and includes, where chemically possible, any tautomers or stereochemical isomers thereof, as well as its N-oxides, its pharmaceutically acceptable salts, or its solvates.

[0109] Further suitable FGFR inhibitors include BAY1163877 (Bayer), BAY1179470 (Bayer), TAS-120 (Taiho), ARQ087 (ArQule), ASP5878 (Astellas), FF284 (Chugai), FP-1039 (GSK / FivePrime), Blueprint, LY-2874455 (Lilly), RG-7444 (Roche), or any combination thereof, including, where chemically possible, any tautomers or stereochemical isomers thereof, and N-oxides thereof, pharmaceutically acceptable salts thereof, or solvates thereof.

[0110] In one embodiment, the FGFR inhibitor, more specifically erdafitinib, is generally administered as a pharmaceutically acceptable salt. In a preferred embodiment, the FGFR inhibitor, more specifically erdafitinib, is generally administered in base form. In one embodiment, the FGFR inhibitor, more specifically erdafitinib, is generally administered as a pharmaceutically acceptable salt in an amount equivalent to 8 mg of base equivalent or an amount equivalent to 9 mg of base equivalent. In one embodiment, the FGFR inhibitor, more specifically erdafitinib, is generally administered as a pharmaceutically acceptable salt in an amount equivalent to 6 mg of base equivalent. In one embodiment, the FGFR inhibitor, more specifically erdafitinib, is generally administered in base form in an amount of 8 mg or 9 mg. In one embodiment, the FGFR inhibitor, more specifically erdafitinib, is generally administered in base form in an amount of 6 mg.

[0111] These salts can be prepared, for example, by reacting an FGFR inhibitor in general, and more specifically erdafitinib, with a suitable acid in a suitable solvent.

[0112] Acid addition salts may be formed with both inorganic and organic acids. Examples of acid addition salts include salts formed with acids selected from the group consisting of acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid (mesylate), ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propanoic acid, butanoic acid, malonic acid, glucuronic acid, and lactobionic acid. Another group of acid addition salts includes salts formed with acetic acid, adipic acid, ascorbic acid, aspartic acid, citric acid, DL-lactic acid, fumaric acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloric acid, glutamic acid, DL-malic acid, methanesulfonic acid, sebacic acid, stearic acid, succinic acid, and tartaric acid.

[0113] In one embodiment, generally, FGFR inhibitors, more specifically, erdafitinib, are administered in the form of a solvate. As used herein, the term "solvate" refers to the physical association of erdafitinib with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, such as hydrogen bonding. In certain cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be isolated. The term "solvate" encompasses both solution-phase solvates and isolable solvates. Non-limiting examples of solvents that can form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

[0114] Solvates are well known in pharmaceutical chemistry. Solvates can be important in processes for preparing substances (e.g., in connection with their purification), for storage of substances (e.g., their stability), and for ease of handling, and are often formed as part of an isolation or purification step in a chemical synthesis. Those skilled in the art can determine whether hydrates or other solvates are formed by the isolation or purification conditions used to prepare a given compound using standard and long-established techniques. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g., single-crystal X-ray crystallography or X-ray powder diffraction), and solid-state NMR (Solid-State NMR, SS-NMR, also known as Magic Angle Spinning NMR or Magic Angle Spinning NMR, MAS-NMR). These techniques, along with NMR, IR, HPLC, and MS, are part of the standard analytical toolkit of a skilled chemist. Alternatively, one skilled in the art can intentionally form a solvate using crystallization conditions that include the amount of solvent required for the particular solvate. The standard methods described above can then be used to determine whether a solvate has formed. Also included are any complexes (e.g., inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals).

[0115] Additionally, the compounds may have one or more polymorphic (crystalline) or amorphous forms.

[0116] Compounds include compounds with one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of that element. For example, a reference to hydrogen includes within its scope 1 H, 2 H(D), and 3 Similarly, references to carbon and oxygen include within their scope 12 C. 13 C and 14 C, and 16 O and18 Each of the compounds includes O. Such isotopes may be radioactive or non-radioactive isotopes. In one embodiment, the compound does not contain a radioisotope. Such compounds are preferred for therapeutic use. However, in another embodiment, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in diagnostic situations.

[0117] Treatment Methods and Uses Described herein are methods for treating HR-NMIBC, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor at a dose of about 8 mg / day to a patient diagnosed with HR-NMIBC who has at least one FGFR2 and / or FGFR3 gene mutation.

[0118] Described herein are methods for treating HR-NMIBC, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor at a dose of about 6 mg / day to a patient diagnosed with HR-NMIBC who has at least one FGFR2 and / or FGFR3 gene mutation.

[0119] Further provided herein is a method of treating IR-NMIBC, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor at a dose of about 8 mg / day to a patient diagnosed with IR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation.

[0120] Further provided herein is a method of treating IR-NMIBC, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor at a dose of about 6 mg / day to a patient diagnosed with IR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation.

[0121] Described herein is the use of an FGFR inhibitor, particularly erdafitinib at a dose of about 8 mg / day, more particularly erdafitinib at a dose of about 8 mg / day, for the manufacture of a medicament for the treatment of patients diagnosed with HR-NMIBC who have at least one FGFR2 gene mutation and / or FGFR3 gene mutation.

[0122] Described herein is the use of an FGFR inhibitor, particularly erdafitinib at a dose of about 6 mg / day, more particularly erdafitinib at a dose of about 6 mg / day, for the manufacture of a medicament for the treatment of patients diagnosed with HR-NMIBC who have at least one FGFR2 gene mutation and / or FGFR3 gene mutation.

[0123] Described herein is the use of an FGFR inhibitor for the manufacture of a medicament for the treatment of patients diagnosed with HR-NMIBC who have at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 8 mg / day.

[0124] Described herein is the use of an FGFR inhibitor for the manufacture of a medicament for the treatment of patients diagnosed with HR-NMIBC who have at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 6 mg / day.

[0125] Described herein is the use of an FGFR inhibitor, particularly erdafitinib at a dose of about 8 mg / day, more particularly erdafitinib at a dose of about 8 mg / day, for the manufacture of a medicament for the treatment of patients diagnosed with IR-NMIBC who have at least one FGFR2 gene mutation and / or FGFR3 gene mutation.

[0126] Described herein is the use of an FGFR inhibitor, particularly erdafitinib, at a dose of about 6 mg / day, more particularly erdafitinib, for the manufacture of a medicament for the treatment of patients diagnosed with IR-NMIBC who have at least one FGFR2 gene mutation and / or FGFR3 gene mutation.

[0127] Described herein is the use of an FGFR inhibitor for the manufacture of a medicament for the treatment of patients diagnosed with IR-NMIBC who have at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 8 mg / day.

[0128] Described herein is the use of an FGFR inhibitor for the manufacture of a medicament for the treatment of patients diagnosed with IR-NMIBC who have at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 6 mg / day.

[0129] Described herein are FGFR inhibitors for use in treating patients diagnosed with HR-NMIBC who have at least one FGFR2 gene mutation and / or FGFR3 gene mutation, in particular wherein the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 8 mg / day.

[0130] Described herein are FGFR inhibitors for use in treating patients diagnosed with HR-NMIBC who have at least one FGFR2 gene mutation and / or FGFR3 gene mutation, in particular wherein the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 6 mg / day.

[0131] Described herein are FGFR inhibitors for use in treating patients diagnosed with IR-NMIBC who have at least one FGFR2 gene mutation and / or FGFR3 gene mutation, in particular wherein the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 8 mg / day.

[0132] Described herein are FGFR inhibitors for use in treating patients diagnosed with IR-NMIBC who have at least one FGFR2 gene mutation and / or FGFR3 gene mutation, in particular wherein the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 6 mg / day.

[0133] The methods and uses also include administering at least one, one, two, three or four FGFR inhibitors to a patient diagnosed with HR-NHIMB or IR-NMIBC.

[0134] In certain embodiments, the patient has received at least one therapy prior to administration of said FGFR inhibitor. In further embodiments, the patient has received BCG therapy prior to said administration of said FGFR inhibitor.

[0135] In some embodiments, the BCG therapy is adequate BCG therapy. The minimum requirements for adequate BCG therapy include (1) at least five of six total doses of an initial induction course and at least one maintenance (two of three total weekly doses) in a six-month period, or (2) at least five of six total doses of an initial induction course and at least two of six total doses of a second induction course. The total dose BCG is at least 1 x 10 8 Defined as one total vial containing a colony forming unit (CFU).

[0136] In some embodiments, a patient is refractory to BCG therapy. A patient is refractory to BCG therapy if they have one of the following recurrent disease states and if they have received adequate BCG therapy: (1) persistent or recurrent carcinoma in situ (CIS) alone or with recurrent Ta / T1 (non-invasive papillary disease / tumor invades subepithelial connective tissue) disease within 12 months of completing adequate BCG therapy, (2) recurrent high-grade Ta / T1 disease within 6 months of completing adequate BCG therapy, or (3) high-grade T1 at the first disease assessment after the introduction of a BCG course.

[0137] In yet a further embodiment, the patient is BCG-experienced. A patient is BCG-experienced if they have recurrent high-grade Ta / T1 disease within 12 months of completing BCG therapy and their previous BCG therapy was the minimum treatment requirement. The minimum treatment requirement is (1) at least five of the six total doses of the initial induction course in a six-month period, and (2) at least five of the six total doses of the initial induction course plus at least one maintenance (two of the three weekly doses). Half doses or one-third doses are allowed during maintenance.

[0138] In certain embodiments, the patient has a papillary tumor, which can grow from tissue lining an organ and can occur in the bladder, thyroid, and breast.

[0139] In further embodiments, the patient has carcinoma in situ. In certain embodiments, carcinoma in situ refers to a group of abnormal cells that remain where they originally formed. In certain embodiments, the patient has stage 0 disease.

[0140] In some embodiments, the patient has not previously undergone or is ineligible for a cystectomy, i.e., surgery to remove all or part of the bladder or to remove a cyst within the body. Determination of eligibility may be made, for example, by the treating physician.

[0141] In some embodiments, the patient undergoes an incomplete transurethral resection, for example, a procedure to remove tissue using a special instrument inserted through the urethra.

[0142] In certain embodiments, the administration of an FGFR inhibitor results in an increase in RFS, time to progression, time to disease progression, disease-specific survival, OS, RFS rate, RFS2, or CR compared to a patient population with HR-NMIBC or IR-NMIBC receiving a placebo. In certain embodiments, the administration of an FGFR inhibitor results in an increase in RFS compared to a patient population with HR-NMIBC or IR-NMIBC receiving a placebo. In certain embodiments, the administration of an FGFR inhibitor results in an increase in time to progression compared to a patient population with HR-NMIBC or IR-NMIBC receiving a placebo. In certain embodiments, the administration of an FGFR inhibitor results in an increase in disease-specific survival compared to a patient population with HR-NMIBC or IR-NMIBC receiving a placebo. In certain embodiments, the administration of an FGFR inhibitor results in an increased OS compared to a patient population with HR-NMIBC or IR-NMIBC receiving a placebo. In certain embodiments, the administration of an FGFR inhibitor results in an increased RFS rate compared to a patient population with HR-NMIBC or IR-NMIBC receiving a placebo. In certain embodiments, the administration of an FGFR inhibitor results in an increased RFS2 compared to a patient population with HR-NMIBC or IR-NMIBC receiving a placebo. In certain embodiments, the administration of an FGFR inhibitor results in an increased CR compared to a patient population with HR-NMIBC or IR-NMIBC receiving a placebo.

[0143] In certain embodiments, the increase in RFS rate is determined at 6 months. In certain embodiments, the increase in RFS rate is determined at 12 months. In certain embodiments, the increase in RFS rate is determined at 24 months.

[0144] In certain embodiments, the improved anti-tumor activity is compared to placebo treatment. In certain embodiments, the improved anti-tumor activity is compared to no treatment. In certain embodiments, the improved anti-tumor activity is compared to standard of care. In certain embodiments, the improved anti-tumor activity is compared to investigator's choice. In certain embodiments, the improved anti-tumor activity is compared to a patient population with HR-NMIBC or IR-NMIBC receiving intravesical gemcitabine. In certain embodiments, the improved anti-tumor activity is compared to a patient population with HR-NMIBC or IR-NMIBC receiving intravesical mitomycin C (MMC) / hyperthermic MMC.

[0145] Gemcitabine, the active ingredient in gemcitabine hydrochloride (also known as GEMZAR®), is a nucleoside metabolic inhibitor that can be administered intravesically, for example, to the bladder via a urinary catheter. Gemcitabine may be administered as 200 mg / single-use vial or 1 g / single-use vial. Gemcitabine HCl is 2'-deoxy-2',2'-difluorocytidine monohydrochloride (β-isomer).

[0146] Mitomycin C (also known as MUTAMYCIN®) is a methylazirinopyrrolo-indoledione anti-neoplastic antibiotic isolated from Streptomyces caespitosus and other Streptomyces species and may be administered by intravesical administration. Intravesical administration of MMC may optionally be accompanied by simultaneous intravesical administration of hyperthermia, e.g., microwave-induced hyperthermia. To achieve microwave-induced hyperthermia, an applicator may deliver hyperthermia to the bladder wall via direct irradiation.

[0147] In some embodiments, the patient exhibits a CR to the FGFR inhibitor at about month 6. In some embodiments, the patient exhibits a CR to the FGFR inhibitor at about month 3.

[0148] In some embodiments, methods are provided for treating BCG-refractory HR-NMIBC in a patient with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitininb, to the patient, particularly a patient who refuses or is ineligible for cystectomy, wherein the treatment results in a CR rate of about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, about 100%, or a CR rate of 100% at about 8 weeks from the start of treatment, or a CR rate in the range of 75% to 100%, or in the range of 80% to 100%, or in the range of 90% to 100%, or in the range of 95% to 100% at about 8 weeks from the start of treatment. In one embodiment, there is provided use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-refractory HR-NMIBC harboring one or more FGFR2 or FGFR3 gene mutations that presents as carcinoma in situ with or without papillary neoplasia, wherein the treatment results in a CR rate of about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, about 100%, or a CR rate of 100% at about 8 weeks from the start of treatment, particularly in patients who refuse cystectomy or are ineligible for cystectomy, or in a range of 75% to 100%, or a range of 80% to 100%, or a range of 90% to 100%, or a range of 95% to 100% at about 8 weeks from the start of treatment.In one embodiment, there is provided an FGFR inhibitor, particularly erdafitinib, for use in treating BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations that presents as carcinoma in situ with or without papillary neoplasia, wherein the treatment results in a CR rate of about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, about 100%, or a CR rate of 100% at about 8 weeks from the start of treatment, particularly in patients who refuse cystectomy or are ineligible for cystectomy, or in the range of 75% to 100%, or 80% to 100%, or 90% to 100%, or 95% to 100% at about 8 weeks from the start of treatment.

[0149] In one embodiment, the treatment is for patients who refuse or are ineligible for cystectomy. In one embodiment, the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 6 mg / day, particularly once daily. The CR rate reported above is for treated patients at week 8. That is, the number of patients who report a CR after week 9 of treatment (including the 7-day window for scheduled evaluation) is divided by the number of treated patients and multiplied by 100.

[0150] In some embodiments, a method of treating BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia in a patient, particularly in a patient who refuses or is ineligible for cystectomy, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, to the patient, wherein treatment results in a reduction of about 50%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75 ... Methods are provided that result in a CR rate of about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate that is 80%, or a CR rate in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80% at about 20 weeks from the start of treatment. In one embodiment, the present invention relates to the use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment achieves a reduction in urinary tract infections of about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 65%, at least ... Uses are provided which result in a CR rate of 0%, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate that is 80%, or which result in a CR rate at about 20 weeks from the start of treatment in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80%.In one embodiment, an FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment provides a cystectomy improvement of about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65% or more at about 20 weeks from the start of treatment, particularly in patients who refuse cystectomy or are ineligible for cystectomy. Provided are FGFR inhibitors that result in a CR rate of at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate that is 80%, or that result in a CR rate in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80% at about 20 weeks from the start of treatment.

[0151] In one embodiment, the treatment is for patients who refuse or are ineligible for cystectomy. In one embodiment, the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 6 mg / day, particularly once daily. The CR rate reported above is for treated patients at week 20. That is, the number of patients who report a CR after week 19 of treatment (including the 7-day window for scheduled evaluation) is divided by the number of treated patients, and multiplied by 100.

[0152] In some embodiments, a method of treating BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia in patients, particularly patients who refuse cystectomy or are ineligible for cystectomy, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, to the patient, wherein the treatment results in a reduction of about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 50%, at least about 5 ... Methods are provided that result in a CR rate of 5%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate that is about 78%, or that results in a CR rate at about 31 weeks from the start of treatment in the range of 43% to 88%, or in the range of 45% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80%. In one embodiment, the present invention relates to the use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment provides a cystectomy improvement of about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, at about 31 weeks from the start of treatment, particularly in patients who refuse cystectomy or are ineligible for cystectomy. %, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate that is about 78%, or a CR rate at about 31 weeks from the start of treatment that is in the range of 43% to 88%, or in the range of 45% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80%.In one embodiment, an FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment improves the survival rate by about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65% or more at about 31 weeks from the start of treatment, particularly in patients who refuse cystectomy or are ineligible for cystectomy. or a CR rate of at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or about 78%, or a CR rate in the range of 43% to 88%, or in the range of 45% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80% at about 31 weeks from the start of treatment.

[0153] In some embodiments, a method of treating BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia in patients, particularly patients who refuse cystectomy or are ineligible for cystectomy, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, to the patient, wherein treatment results in a reduction of about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, at about 32 weeks from the start of treatment. %, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or about 78%, or at about 32 weeks from the start of treatment in the range of 43% to 88%, or in the range of 45% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80%, particularly in the range of 70% to 88%, particularly about 73% at about 32 weeks from the start of treatment.In one embodiment, there is provided the use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment results in an improvement in urinary tract infection rate of about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, at about 32 weeks from the start of treatment, particularly in patients who refuse cystectomy or are ineligible for cystectomy. %, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or about 78%, or at about 32 weeks from the start of treatment in the range of 43% to 88%, or in the range of 45% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80%, particularly in the range of 70% to 88%, particularly about 73% at about 32 weeks from the start of treatment.In one embodiment is an FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment provides an improvement in urinary tract infections of about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, at about 32 weeks from the start of treatment, particularly in patients who refuse cystectomy or are ineligible for cystectomy. Provided are FGFR inhibitors that result in a CR rate of about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate that is about 78%, or in the range of 43% to 88%, or in the range of 45% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80%, particularly in the range of 70% to 88%, and particularly a CR rate of about 73% at about 32 weeks from the start of treatment.

[0154] In one embodiment, the treatment is for patients who refuse or are ineligible for cystectomy. In one embodiment, the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 6 mg / day, particularly once daily. The CR rate reported above is for treated patients at 31 weeks. That is, the number of patients who report a CR after 30 weeks (including the 7-day window for scheduled evaluation) or at 32 weeks from the start of treatment is divided by the number of treated patients, and multiplied by 100.

[0155] In some embodiments, a method of treating BCG-refractory HR-NMIBC in a patient with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia comprises, consists of, or consists essentially of administering an FGFR inhibitor, particularly erdafitinib, to the patient, wherein the treatment achieves about 30%, at least about 30%, about 35%, at least about 35%, about 40%, at least about 40%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 75 ... Methods are provided that result in a CR rate of 5%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate that is about 71% or 71.4%, or result in a CR rate at about 43 weeks from the start of treatment in the range of 30% to 88%, or in the range of 35% to 88%, or in the range of 40% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 60% to 88%, or in the range of 75% to 88%, or in the range of 60% to 80%, or in the range of 65% to 80%, or in the range of 75% to 80%, or in the range of 70% to 80%, or in the range of 70% to 75%.In one embodiment, the present invention provides the use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ, with or without papillary neoplasia, wherein the treatment provides a cystectomy improvement of about 30%, at least about 30%, about 35%, at least about 35%, about 40%, at least about 40%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 70%, about 75% or more at about 43 weeks from the start of treatment, particularly in patients who refuse cystectomy or are ineligible for cystectomy. or a CR rate at about 43 weeks from the start of treatment in the range of 30% to 88%, or in the range of 35% to 88%, or in the range of 40% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 60% to 88%, or in the range of 75% to 88%, or in the range of 60% to 80%, or in the range of 65% to 80%, or in the range of 75% to 80%, or in the range of 70% to 80%, or in the range of 70% to 75%.In one embodiment is an FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment provides a cystectomy-refractory HR-NMIBC response rate of about 30%, at least about 30%, about 35%, at least about 35%, about 40%, at least about 40%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about Provided are FGFR inhibitors that result in a CR rate of 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate of about 71% or 71.4%, or a CR rate at about 43 weeks from the start of treatment in the range of 30% to 88%, or in the range of 35% to 88%, or in the range of 40% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 60% to 88%, or in the range of 75% to 88%, or in the range of 60% to 80%, or in the range of 65% to 80%, or in the range of 75% to 80%, or in the range of 70% to 80%, or in the range of 70% to 75%.

[0156] In one embodiment, the treatment is for patients who refuse or are ineligible for cystectomy. In one embodiment, the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 6 mg / day, particularly once daily. The CR rate reported above is for treated patients at week 43. That is, the number of patients who report a CR after week 42 (including the 7-day window for scheduled evaluation) from the start of treatment is divided by the number of treated patients, and multiplied by 100.

[0157] In some embodiments, a method of treating IR-NMIBC in patients, particularly in patients where all previous tumors were low grade (grade 1-2), Ta / T1, and no previous carcinoma in situ, who have one or more FGFR2 or FGFR3 gene mutations (no previous BCG treatment required), and who have a marker lesion after incomplete TUR (transurethral resection), particularly a single, untreated bladder tumor (marker lesion), comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, to the patient. Methods are provided wherein the treatment results in a CR rate of about 72%, at least about 72%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, or about 100%, or a CR rate in the range of 72% to 100%, or in the range of 75% to 100%, or in the range of 80% to 100%, or in the range of 70% to 95%, or in the range of 70% to 90%, or in the range of 70% to 80%, or a CR rate that is about 72% or 72.2%. In one embodiment, the CR rate is in the range of 80% to 90% or is about 83%, e.g., 83.3%. In one embodiment, the use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of IR-NMIBC with one or more FGFR2 or FGFR3 gene mutations (not requiring previous BCG treatment) and with a marker lesion after incomplete TUR (transurethral resection), particularly with a single, untreated bladder tumor (marker lesion) remaining, wherein the treatment is at least about 72%, at least about 72%, at least about 75%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 10 ... Uses are provided which result in a CR rate of at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, or about 100%, or a CR rate in the range of 72% to 100%, or in the range of 75% to 100%, or in the range of 80% to 100%, or in the range of 70% to 95%, or in the range of 70% to 90%, or in the range of 70% to 80%, or a CR rate of about 72% or 72.2%.In one embodiment, the CR rate is in the range of 80% to 90% or about 83%, for example, 83.3%. In one embodiment, the treatment is for patients with all previous tumors being low grade (grade 1-2), Ta / T1, and no previous carcinoma in situ. In one embodiment, an FGFR inhibitor, particularly erdafitinib, for use in the treatment of IR-NMIBC with one or more FGFR2 or FGFR3 gene mutations (no previous BCG treatment required) and residual marker lesion after incomplete TUR (transurethral resection), particularly a single, untreated 5-10 mm bladder tumor (marker lesion), wherein the treatment is for a CR rate of about 72%, at least about 72%, about 75%, at least about 75%, about 80%, at least about 80%, or about FGFR inhibitors are provided that result in a CR rate of 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, or about 100%, or a CR rate in the range of 72% to 100%, or in the range of 75% to 100%, or in the range of 80% to 100%, or in the range of 70% to 95%, or in the range of 70% to 90%, or in the range of 70% to 80%, or a CR rate of about 72% or 72.2%. In one embodiment, the CR rate is in the range of 80% to 90% or about 83%, for example, 83.3%.

[0158] In one embodiment, the treatment is for patients in which all previous tumors are low grade (grade 1-2), Ta / T1, and there is no previous carcinoma in situ.

[0159] In one embodiment, the FGFR inhibitor, particularly erdafitinib, is or will be administered at a dose of about 6 mg / day, particularly once a day.The CR rate reported above is for treated patients.That is, the number of patients who report a best overall response of CR is divided by the number of treated patients, and multiplied by 100.

[0160] Also provided herein is a method or use for improving RFS, time to progression, time to disease progression, disease-specific survival, OS, RFS rate, RFS2, or CR in patients diagnosed with HR-NMIBC or IR-NMIBC, compared to patients diagnosed with HR-NMIBC or IR-NMIBC who have not been treated with an FGFR inhibitor, the method comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly at a dose of about 8 mg / day, or particularly at a dose of about 6 mg / day, in particular erdafitinib, more particularly erdafitinib at a dose of about 8 mg / day, or more particularly erdafitinib at a dose of about 6 mg / day, to a patient diagnosed with HR-NMIBC or IR-NMIBC and having at least one FGFR2 genetic mutation and / or FGFR3 genetic mutation. In certain embodiments, provided herein is a method or use for improving RFS in patients diagnosed with HR-NMIBC compared to patients diagnosed with HR-NMIBC who have not been treated with an FGFR inhibitor, the method comprising administering an FGFR inhibitor, particularly at a dose of about 8 mg / day, or particularly at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 8 mg / day, or more particularly erdafitinib at a dose of about 6 mg / day, to a patient diagnosed with HR-NMIBC or IR-NMIBC who has at least one FGFR2 genetic mutation and / or FGFR3 genetic mutation.In certain embodiments, provided herein is a method or use for improving time to progression in patients diagnosed with HR-NMIBC or IR-NMIBC compared to patients diagnosed with HR-NMIBC or IR-NMIBC who have not been treated with an FGFR inhibitor, the method comprising administering an FGFR inhibitor, particularly at a dose of about 8 mg / day, or particularly at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 8 mg / day, or more particularly erdafitinib at a dose of about 6 mg / day, to a patient diagnosed with HR-NMIBC or IR-NMIBC who has at least one FGFR2 genetic mutation and / or FGFR3 genetic mutation. In certain embodiments, provided herein is a method or use for improving time to disease progression in a patient diagnosed with HR-NMIBC compared to a patient diagnosed with HR-NMIBC who has not been treated with an FGFR inhibitor, the method comprising administering to a patient diagnosed with HR-NMIBC or IR-NMIBC who has at least one FGFR2 genetic mutation and / or FGFR3 genetic mutation an FGFR inhibitor, particularly at a dose of about 8 mg / day, or particularly at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 8 mg / day, or more particularly erdafitinib at a dose of about 6 mg / day. In certain embodiments, provided herein is a method or use for improving disease-specific survival in patients diagnosed with HR-NMIBC or IR-NMIBC compared to patients diagnosed with HR-NMIBC who have not been treated with an FGFR inhibitor, the method comprising administering to a patient diagnosed with HR-NMIBC and having at least one FGFR2 genetic mutation and / or FGFR3 genetic mutation an FGFR inhibitor, particularly at a dose of about 8 mg / day, or particularly at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 8 mg / day or more, more particularly erdafitinib at a dose of about 6 mg / day.In certain embodiments, provided herein is a method or use for improving OS in patients diagnosed with HR-NMIBC or IR-NMIBC compared to patients diagnosed with HR-NMIBC or IR-NMIBC who have not been treated with an FGFR inhibitor, the method comprising administering an FGFR inhibitor, particularly at a dose of about 8 mg / day, or particularly at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 8 mg / day, or more particularly erdafitinib at a dose of about 6 mg / day, to a patient diagnosed with HR-NMIBC or IR-NMIBC who has at least one FGFR2 genetic mutation and / or FGFR3 genetic mutation. In certain embodiments, provided herein is a method or use for improving RFS rates in patients diagnosed with HR-NMIBC or IR-NMIBC compared to patients diagnosed with HR-NMIBC or IR-NMIBC who have not been treated with an FGFR inhibitor, the method or use comprising administering an FGFR inhibitor, particularly at a dose of about 8 mg / day, or particularly at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 8 mg / day, or more particularly erdafitinib at a dose of about 6 mg / day, to a patient diagnosed with HR-NMIBC or IR-NMIBC who has at least one FGFR2 genetic mutation and / or FGFR3 genetic mutation. In certain embodiments, provided herein is a method or use for improving RFS2 in a patient diagnosed with HR-NMIBC or IR-NMIBC compared to a patient diagnosed with HR-NMIBC or IR-NMIBC who has not been treated with an FGFR inhibitor, the method comprising administering an FGFR inhibitor, particularly at a dose of about 8 mg / day, or particularly at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 8 mg / day, or more particularly erdafitinib at a dose of about 6 mg / day, to a patient diagnosed with HR-NMIBC or IR-NMIBC who has at least one FGFR2 genetic mutation and / or FGFR3 genetic mutation.In certain embodiments, provided herein is a method or use for improving CR in patients diagnosed with HR-NMIBC or IR-NMIBC compared to patients diagnosed with HR-NMIBC or IR-NMIBC who have not been treated with an FGFR inhibitor, the method comprising administering an FGFR inhibitor, particularly at a dose of about 8 mg / day, or particularly at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 8 mg / day, or more particularly erdafitinib at a dose of about 6 mg / day, to a patient diagnosed with HR-NMIBC or IR-NMIBC who has at least one FGFR2 genetic mutation and / or FGFR3 genetic mutation.

[0161] In certain embodiments, the improvement is compared to treatment with a placebo. In certain embodiments, the improvement in anti-tumor activity is compared to no treatment. In certain embodiments, the improvement in anti-tumor activity is compared to standard of care. In certain embodiments, the improvement in anti-tumor activity is compared to investigator's choice. In certain embodiments, the improvement in anti-tumor activity is compared to a patient population with HR-NBMIBC receiving intravesical gemcitabine. In certain embodiments, the improvement in anti-tumor activity is compared to a patient population with HR-NMIBC or IR-NMIBC receiving intravesical mitomycin C (MMC) / hyperthermic MMC.

[0162] Also described herein is a method for treating BCG-treated HR-NMIBC in a patient with one or more FGFR2 or FGFR3 gene mutations, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, to the patient, wherein the treatment results in a 6-month recurrence-free survival rate of at least 90%, or at least 95%, particularly about 96%.

[0163] Also described herein is the use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-treated HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations, wherein the treatment results in a 6-month recurrence-free survival rate of at least 90%, or at least 95%, particularly about 96%.

[0164] Also described herein are FGFR inhibitors, particularly erdafitinib, for use in treating BCG-treated HR-NMIBC patients with one or more FGFR2 or FGFR3 gene mutations, wherein the treatment results in a 6-month recurrence-free survival rate of at least 90%, or at least 95%, particularly about 96%.

[0165] In certain embodiments, treatment results in a 6-month recurrence-free survival rate of about 96%. In some embodiments, the HR-NMIBC is papillary-only HR-NMIBC. In further embodiments, the FGFR inhibitor is erdafitinib. In certain embodiments, erdafitinib is administered or is to be administered at a dose of about 6 mg / day, particularly once daily.

[0166] Further provided herein is a method of treating BCG-treated HR-NMIBC in a patient with one or more FGFR2 or FGFR3 gene mutations, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, to the patient, wherein the treatment results in a 12-month recurrence-free survival rate of at least 70%, or at least 75%, particularly about 77%.

[0167] Further provided herein is the use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-treated HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations, wherein the treatment results in a 12-month recurrence-free survival rate of at least 70%, or at least 75%, particularly about 77%.

[0168] Further provided herein is an FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-treated HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations, wherein the treatment results in a 12-month recurrence-free survival rate of at least 70%, or at least 75%, particularly about 77%.

[0169] In certain embodiments, treatment results in a 12-month recurrence-free survival rate of about 77%. In further embodiments, the HR-NMIBC is papillary-only HR-NMIBC. In some embodiments, the FGFR inhibitor is erdafitinib. In certain embodiments, erdafitinib is administered or is to be administered at a dose of about 6 mg / day, particularly once daily.

[0170] Also described herein is a method for treating recurrent HR-NMIBC after BCG treatment in a patient with one or more FGFR2 or FGFR3 gene mutations, comprising, consisting of, or consisting essentially of administering to the patient an FGFR inhibitor, particularly erdafitinib, wherein the treatment results in a reduced recurrence or mortality rate compared to intravesical chemotherapy.

[0171] Also described herein is the use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of HR-NMIBC that has relapsed after BCG treatment and is associated with one or more FGFR2 or FGFR3 gene mutations, wherein the treatment results in a lower recurrence or mortality rate than intravesical chemotherapy.

[0172] Also described herein are FGFR inhibitors, particularly erdafitinib, for use in the treatment of HR-NMIBC that has relapsed after BCG treatment and has one or more FGFR2 or FGFR3 gene mutations, wherein the treatment results in a lower recurrence or mortality rate than intravesical chemotherapy.

[0173] In certain embodiments, the HR-NMIBC is Ta / T1 HR-NMIBC. In further embodiments, the HR-NMIBC is papillary-only HR-NMIBC. In some embodiments, the FGFR inhibitor is erdafitinib. In certain embodiments, erdafitinib is administered or is to be administered at a dose of about 6 mg / day, particularly once daily. In further embodiments, the treatment is for patients who have refused or are ineligible for radical cystectomy.

[0174] In further embodiments, the one or more FGFR2 or FGFR3 gene mutations are FGFR3 gene mutations, FGFR2 gene fusions, or FGFR3 gene fusions. In still further embodiments, the FGFR3 gene mutation is R248C, S249C, G370C, Y373C, or any combination thereof. In some embodiments, the FGFR2 or FGFR3 gene fusion is FGFR3-TACC3, particularly FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

[0175] Evaluation of the sample for the presence of one or more FGFR gene mutations Also described herein is a method of treating HR-NMIBC comprising, consisting of, or consisting essentially of: (a) evaluating a biological sample from a patient diagnosed with HR-NMIBC for the presence of one or more fibroblast growth factor receptor (FGFR) genetic mutations; and (b) if one or more FGFR genetic mutations are present in the sample, administering to the patient an FGFR inhibitor, particularly at a dose of about 8 mg / day, or particularly at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 8 mg / day, or more particularly erdafitinib at a dose of about 6 mg / day.

[0176] Also described herein is a method of treating IR-NMIBC, comprising: (a) assessing a biological sample from a patient diagnosed with IR-NMIBC for the presence of one or more FGFR gene mutations, particularly one or more FGFR2 or FGFR3 mutations; and (b) if one or more FGFR gene mutations are present in the sample, administering to the patient an FGFR inhibitor, particularly at a dose of about 8 mg / day, or particularly at a dose of about 6 mg / day, particularly erdafitinib, more particularly erdafitinib at a dose of about 8 mg / day, or more particularly erdafitinib at a dose of about 6 mg / day.

[0177] Described herein is the use of an FGFR inhibitor, particularly erdafitinib, more particularly at a dose of about 8 mg / day, or more particularly at a dose of about 6 mg / day, for the manufacture of a medicament for the treatment of a patient diagnosed with HR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is administered or is to be administered after assessing a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample.

[0178] The present specification describes the use of an FGFR inhibitor for the manufacture of a medicament for treating a patient diagnosed with HR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is or will be administered at a dose of about 8 mg / day, and the FGFR inhibitor, particularly erdafitinib, is or will be administered after evaluating a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations, and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample. In one embodiment, the FGFR inhibitor, particularly erdafitinib, is or will be administered at a dose of about 6 mg / day.

[0179] Described herein is the use of an FGFR inhibitor, particularly erdafitinib, more particularly at a dose of about 8 mg / day, or more particularly at a dose of about 6 mg / day, for the manufacture of a medicament for the treatment of a patient diagnosed with IR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is administered or is to be administered after assessing a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations, and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample.

[0180] The present specification describes the use of an FGFR inhibitor for the manufacture of a medicament for treating a patient diagnosed with IR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is or will be administered at a dose of about 8 mg / day, and the FGFR inhibitor, particularly erdafitinib, is or will be administered after evaluating a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations, and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample. In one embodiment, the FGFR inhibitor, particularly erdafitinib, is or will be administered at a dose of about 6 mg / day.

[0181] Described herein is an FGFR inhibitor for use in treating patients diagnosed with HR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 8 mg / day, and the FGFR inhibitor, particularly erdafitinib, is or is to be administered after evaluating a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations, and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample. In one embodiment, the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 6 mg / day.

[0182] Described herein is an FGFR inhibitor for use in treating patients diagnosed with IR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 8 mg / day, and the FGFR inhibitor, particularly erdafitinib, is or is to be administered after evaluating a biological sample from the patient for the presence of one or more FGFR2 gene mutations or FGFR3 gene mutations, and if one or more FGFR2 gene mutations or FGFR3 gene mutations are present in the sample. In one embodiment, the FGFR inhibitor, particularly erdafitinib, is or is to be administered at a dose of about 6 mg / day.

[0183] The following method for assessing a biological sample for the presence of one or more FGFR gene mutations applies equally to any of the methods of treatment and uses disclosed above.

[0184] The disclosed methods are suitable for treating cancer in patients when one or more FGFR gene mutations are present in a biological sample from the patient. In some embodiments, the FGFR gene mutations can be one or more FGFR fusion genes, particularly one or more FGFR2 or FGFR3 fusion genes. In some embodiments, the FGFR gene mutations can be one or more FGFR mutations, particularly one or more FGFR3 mutations. In some embodiments, the FGFR gene mutations can be one or more FGFR amplifications. In some embodiments, a combination of one or more FGFR gene mutations can be present in a biological sample from a patient. For example, in some embodiments, the FGFR gene mutations can be one or more FGFR fusion genes and one or more FGFR mutations. In some embodiments, the FGFR gene mutations can be one or more FGFR fusion genes and one or more FGFR amplifications. In some embodiments, the FGFR gene mutations can be one or more FGFR mutations and one or more FGFR amplifications. In still other embodiments, the FGFR gene mutations can be one or more FGFR fusion genes, mutations, and amplifications. Exemplary FGFR fusion genes are provided in Table 1 and include, but are not limited to, FGFR2-BICC1; FGFR2-CASP7; FGFR3-BAIAP2L1; FGFR3-TACC3 V1; FGFR3-TACC3 V3; or combinations thereof.

[0185] Suitable methods for evaluating a biological sample for the presence of one or more FGFR genetic mutations are described in the methods section herein and in International Publication No. 2016 / 048833 and U.S. Patent Application No. 16 / 723,975, which are incorporated herein in their entireties. For example, and without intending to be limiting, evaluating a biological sample for the presence of one or more FGFR genetic mutations may include any combination of isolating RNA from the biological sample, synthesizing cDNA from the RNA, and amplifying the cDNA (pre-amplified or not). In some embodiments, evaluating a biological sample for the presence of one or more FGFR genetic mutations may include amplifying cDNA from the patient using a primer pair that binds to and amplifies one or more FGFR genetic mutations and determining whether one or more FGFR genetic mutations are present in the sample. In some aspects, the cDNA may be pre-amplified. In some aspects, the evaluating step may include isolating RNA from the sample, synthesizing cDNA from the isolated RNA, and pre-amplifying the cDNA.

[0186] Suitable primer pairs for carrying out the amplification step include, but are not limited to, those disclosed in WO 2016 / 048833, as exemplified in Table 3 below.

[0187] [Table 3]

[0188] The presence of one or more FGFR gene mutations can be assessed at any suitable time point, including at the time of diagnosis, following tumor removal, following first-line therapy, during clinical treatment, or any combination thereof.

[0189] For example, a biological sample taken from a patient can be analyzed to determine whether a condition or disease, such as cancer, that the patient is suffering from or may be suffering from is characterized by genetic abnormalities or aberrant protein expression that result in upregulation of FGFR levels or activity, or sensitization of pathways to normal FGFR activity, or upregulation of these growth factor signaling pathways, such as growth factor ligand levels or growth factor ligand activity, or upregulation of biochemical pathways downstream of FGFR activation.

[0190] Examples of such abnormalities that lead to activation or sensitization of FGFR signaling include loss or inhibition of apoptosis pathways, upregulation of receptors or ligands, or genetic mutations of receptors or ligands, such as the presence of PTK variants. Tumors with genetic mutations of FGFR1, FGFR2, FGFR3, or FGFR4, or upregulation, particularly overexpression, of FGFR1, or gain-of-function genetic mutations of FGFR2 or FGFR3 may be particularly sensitive to FGFR inhibitors.

[0191] The methods, approved formulations, and uses may further comprise assessing the presence of one or more FGFR gene mutations in the biological sample prior to the administering step.

[0192] Diagnostic tests and screenings are typically performed on biological samples selected from tumor biopsy samples, blood samples (isolation and enrichment of sloughed tumor cells), fecal biopsies, sputum, chromosome analysis, pleural effusion, ascites, buccal spears, biopsies, circulating DNA, or urine. In certain embodiments, the biological sample is blood, lymph, bone marrow, a solid tumor sample, or any combination thereof. In certain embodiments, the biological sample is a solid tumor sample. In certain embodiments, the biological sample is a blood sample. In certain embodiments, the biological sample is a urine sample.

[0193] Methods for identifying and analyzing gene mutations and protein upregulation are known to those skilled in the art. Screening methods may include standard methods such as, but not limited to, reverse transcriptase polymerase chain reaction (RT PCR) or in situ hybridization, such as fluorescent in situ hybridization (FISH).

[0194] Identification of individuals carrying FGFR genetic mutations, particularly those described herein, may mean that the patient is particularly suitable for treatment with erdafitinib. Tumors may be selectively screened for the presence of FGFR variants prior to treatment. Screening processes typically involve direct sequencing, oligonucleotide microarray analysis, or mutant-specific antibodies. Diagnosis of tumors carrying such genetic mutations can be performed using methods such as RT-PCR and FISH, which are well known to those skilled in the art and are described herein.

[0195] In addition, for example, genetic mutations of FGFR can be identified by, for example, direct sequencing of tumor biopsies using PCR and the method for directly sequencing PCR products as described above. Those skilled in the art will recognize that any of these well-known techniques for detecting overexpression, activation or mutation of the above proteins can be applied in the present invention.

[0196] In RT-PCR screening, the level of mRNA in tumors is assessed by generating a cDNA copy of the mRNA and then amplifying the cDNA by PCR. PCR amplification methods, primer selection, and amplification conditions are well known to those skilled in the art. Nucleic acid manipulation and PCR are performed by standard methods described, for example, in Ausubel, FM et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc., or Innis, MA et al., eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al., (2001), 3rd Ed., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, commercially available kits for RT-PCR (e.g., Roche Molecular Biochemicals) may be used, or the methodology set forth in U.S. Patent Nos. 4,666,828, 4,683,202, 4,801,531, 5,192,659, 5,272,057, 5,882,864, and 6,218,529 may be used, which are incorporated herein by reference. An example of an in situ hybridization technique for assessing mRNA expression is fluorescent in situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152:649).

[0197] Generally, in situ hybridization involves the following major steps: (1) fixation of the tissue to be analyzed, (2) prehybridization treatment of the sample to increase the accessibility of the target nucleic acid and reduce nonspecific binding, (3) hybridization of the mixture of nucleic acids with nucleic acids in the biological structure or tissue, (4) posthybridization washes to remove nucleic acid fragments not bound by hybridization, and (5) detection of the hybridized nucleic acid fragments. Probes used in such applications are typically labeled, for example, with radioisotopes or fluorescent reporters. Preferred probes are sufficiently long, for example, from about 50, 100, or 200 nucleotides to about 1,000 nucleotides or more, to enable specific hybridization with the target nucleic acid under stringent conditions. Standard methods for performing FISH are described in Ausubel, F. M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc. and Fluorescence In Situ Hybridization: Technical Overview, Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed. ISBN: 1-59259-760-2; March 2004, pp. 077-088; Series: Methods in Molecular Medicine.

[0198] The method for gene expression profiling is described in (DePrimo et al., (2003), BMC Cancer, 3:3). Briefly, the protocol is as follows: double-stranded cDNA is synthesized from total RNA using a (dT)24 oligomer (SEQ ID NO: 38: tttttttttt tttttttttt tttt) to prime first-strand cDNA synthesis, followed by second-strand cDNA synthesis with a random hexamer primer. This double-stranded cDNA is used as a template for in vitro transcription of cRNA using biotinylated ribonucleotides. The cRNA is then chemically fragmented according to the protocol described by Affymetrix (Santa Clara, CA, USA) and then hybridized overnight on a Human Genome Array.

[0199] Alternatively, the protein products expressed from mRNA may be assayed by immunohistochemistry of tumor samples, solid-phase immunoassays using microtiter plates, Western blotting, two-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry, and other methods known in the art for detecting specific proteins. Detection methods include the use of site-specific antibodies. Those skilled in the art will recognize that any of these well-known techniques for detecting FGFR upregulation or FGFR variants or mutations may be applicable in the context of the present invention.

[0200] Abnormal levels of proteins such as FGFR can be measured using standard enzyme assays, such as those described herein. Activation or overexpression can also be detected in tissue samples (e.g., tumor tissues) by measuring tyrosine kinase activity using assays such as those from Chemicon International. The tyrosine kinase of interest is immunoprecipitated from the sample lysate and its activity is measured.

[0201] Another method for measuring the overexpression or activation of FGFR, including its isoforms, is to measure microvessel density, which can be measured, for example, using the method described by Orre and Rogers (Int J Cancer (1999), 84(2)101-8). Assay methods also include the use of markers.

[0202] Thus, any of these techniques can also be used to identify tumors particularly suitable for treatment with the compounds of the invention.

[0203] Erdafitinib is particularly useful for treating patients with genetically mutated FGFRs, particularly mutated FGFRs. In certain embodiments, HR-NMIBC or IR-NMIBC is prone to FGFR2 and / or FGFR3 gene mutations. In certain embodiments, the FGFR2 or FGFR3 gene mutation is an FGFR3 gene mutation or an FGFR2 or FGFR3 gene fusion. In some embodiments, the FGFR3 gene mutation is R248C, S249C, G370C, Y373C, or any combination thereof. In further embodiments, the FGFR2 or FGFR3 gene fusion is FGFR3-TACC3, particularly FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

[0204] In certain embodiments, FGFR2 and / or FGFR3 gene mutations can be identified using commercially available kits, including, but not limited to, the QIAGEN therascreen® FGFR RGQ RT-PCR kit.

[0205] Pharmaceutical Compositions and Routes of Administration Given their useful pharmacological properties, FGFR inhibitors in general, and erdafitinib more specifically, can be formulated into various pharmaceutical forms for administration purposes.

[0206] In one embodiment, a pharmaceutical composition (e.g., formulation) comprises at least one active compound of the invention together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants, or other materials known to those of skill in the art, and optionally other therapeutic or prophylactic agents.

[0207] To prepare a pharmaceutical composition, an effective amount of an FGFR inhibitor, more specifically erdafitinib, as an active ingredient is generally combined with a pharmaceutically acceptable carrier, which can take various forms depending on the desired dosage form. The pharmaceutical composition can be in any form suitable for oral, parenteral, topical, intranasal, ocular, otic, rectal, vaginal, or transdermal administration. These pharmaceutical compositions are preferably in a unit dosage form suitable for oral, rectal, transdermal, or parenteral injection administration. For example, when preparing an inhibitor as an oral dosage form, any of the usual pharmaceutical media can be used, such as water, glycols, oils, and alcohols for oral liquid preparations such as suspensions, syrups, elixirs, and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, and disintegrants for powders, pills, capsules, and tablets.

[0208] The pharmaceutical compositions of the present invention, particularly capsules and / or tablets, can include one or more pharmaceutically acceptable excipients (pharmaceutically acceptable carriers), such as disintegrants, diluents, fillers, binders, buffers, glidants, glidants, thickeners, sweeteners, flavoring agents, coloring agents, preservatives, etc. Some excipients can serve multiple purposes.

[0209] Suitable disintegrants have a large swelling coefficient. Examples include hydrophilic cross-linked polymers that are insoluble or poorly soluble in water, such as crospovidone (cross-linked polyvinylpyrrolidone) and croscarmellose sodium (cross-linked sodium carboxymethylcellulose). The amount of disintegrant in the tablet of the present invention may conveniently be in the range of about 2.5 to about 15% (w / w), preferably in the range of about 2.5 to 7% (w / w), and particularly in the range of about 2.5 to 5% (w / w). Since disintegrants inherently result in sustained-release formulations when used in large amounts, it is advantageous to dilute the disintegrant with an inert substance called a diluent or filler.

[0210] A variety of materials can be used as diluents or fillers. Examples include lactose monohydrate, anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (e.g., microcrystalline cellulose (Avicel™), silicified microcrystalline cellulose), dihydrate or anhydrous dibasic calcium phosphate, and others known in the art, as well as mixtures thereof (e.g., the spray-dried mixture of lactose monohydrate (75%) and microcrystalline cellulose (25%) commercially available as Microcelac™). Microcrystalline cellulose and mannitol are preferred. The total amount of diluent or filler in the pharmaceutical compositions of the present invention may conveniently range from about 20% to about 95% (w / w), preferably from about 55% to about 95% (w / w), or from about 70% to about 95% (w / w), or from about 80% to about 95% (w / w), or from about 85% to about 95%.

[0211] Lubricants and glidants can be used in the manufacture of certain dosage forms, and are usually used when manufacturing tablets. Examples of lubricants and glidants include hydrogenated vegetable oils, such as hydrogenated cottonseed oil, magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silica, colloidal anhydrous silica, talc, mixtures thereof, and others known in the art. Interesting lubricants are magnesium stearate and mixtures of magnesium stearate and colloidal silica, with magnesium stearate being preferred. A preferred lubricant is colloidal anhydrous silica.

[0212] When present, the lubricant generally comprises 0.2-7.0% (w / w) of the total inhibitor weight, specifically 0.5-1.5% (w / w), and more specifically 1-1.5% (w / w).

[0213] When present, lubricants generally constitute 0.2 to 7.0% (w / w) of the total composition weight, specifically 0.2 to 2% (w / w), or 0.5 to 2% (w / w), or 0.5 to 1.75% (w / w), or 0.5 to 1.5% (w / w).

[0214] A binder can be optionally used in the pharmaceutical composition of the present invention. Suitable binders include water-soluble polymers, for example, alkylcelluloses such as methylcellulose; hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxybutylcellulose; hydroxyalkylalkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose; carboxyalkylcelluloses such as carboxymethylcellulose; alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylethylcellulose; carboxyalkylalkylcelluloses such as carboxymethylethylcellulose; carboxyalkylcelluloses Examples of suitable water-soluble polymers include: starch, pectins such as sodium carboxymethyl amylopectin, chitin derivatives such as chitosan, disaccharides, oligosaccharides, and polysaccharides such as trehalose, cyclodextrin, and its derivatives, alginic acid, its alkali metal salts and ammonium salts, carrageenan, galactomannan, tragacanth, agar, gum arabic, guar gum, and xanthan gum, polyacrylic acid and its salts, polymethacrylic acid, its salts and esters, methacrylate copolymers, and copolymers thereof such as polyvinylpyrrolidone (PVP), polyvinylalcohol (PVA), and PVP-VA. Preferably, the water-soluble polymer is a hydroxyalkyl alkylcellulose, such as hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose 15 cps).

[0215] Other excipients, such as colorants and pigments, can also be added to the compositions of the present invention. Colorants and pigments include titanium dioxide and food-grade dyes. Colorants or pigments are optional ingredients in the formulations of the present invention, but if used, the colorant can be present in an amount of up to 3.5% (w / w) based on the total composition weight.

[0216] Flavoring agents are optional in the composition and can be selected from synthetic flavor oils and flavoring aromatics or natural oils, extracts from plant leaves, flowers, fruits, and the like, and combinations thereof. These can include cinnamon oil, oil of wintergreen, peppermint oil, bay oil, anise oil, eucalyptus oil, and thyme oil. Also useful as flavoring agents are vanilla, citrus oils such as lemon, orange, grape, lime, and grapefruit, and fruit essences such as apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, and the like. The amount of flavoring agent can depend on several factors, including the desired organoleptic effect. Generally, flavoring agents will be present in an amount of about 0% to about 3% (w / w).

[0217] Formaldehyde scavengers are compounds capable of absorbing formaldehyde. Formaldehyde scavengers include compounds containing a nitrogen center reactive with formaldehyde, forming one or more reversible or irreversible bonds between the formaldehyde scavenger and formaldehyde. For example, formaldehyde scavengers contain one or more nitrogen atoms / centers that react with formaldehyde to form a Schiff base imine that can subsequently bind to formaldehyde. For example, formaldehyde scavengers contain one or more nitrogen centers that react with formaldehyde to form one or more 5- to 8-membered rings. Formaldehyde scavengers preferably contain one or more amine or amide groups. For example, formaldehyde scavengers can be amino acids, amino sugars, α-amine compounds, or conjugates or derivatives thereof, or mixtures thereof. Formaldehyde scavengers may contain two or more amines and / or amides.

[0218] Formaldehyde scavengers include, for example, glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, aspartic acid, glutamic acid, arginine, lysine, ornithine, citrulline, taurine, pyrrolysine, meglumine, histidine, aspartame, proline, tryptophan, citrulline, pyrrolysine, asparagine, glutamine, or conjugates or mixtures thereof; or, where possible, pharmaceutically acceptable salts thereof.

[0219] In one aspect of the invention, the formaldehyde scavenger is meglumine or a pharmaceutically acceptable salt thereof, specifically meglumine base.

[0220] In one embodiment, in the methods and uses described herein, erdafitinib is or should be administered as a pharmaceutical composition, particularly a tablet or capsule, comprising erdafitinib or a pharmaceutically acceptable salt thereof, particularly erdafitinib base, a formaldehyde scavenger, particularly meglumine or a pharmaceutically acceptable salt thereof, particularly meglumine base, and a pharmaceutically acceptable carrier.

[0221] Another object of the present invention is to provide a process for preparing the pharmaceutical composition described herein, particularly in the form of a tablet or capsule, characterized by blending a formaldehyde scavenger, particularly meglumine, and erdafitinib, a pharmaceutically acceptable salt thereof or a solvate thereof, particularly erdafitinib base, with a pharmaceutically acceptable carrier, and compressing the blend into a tablet or filling the blend into a capsule.

[0222] Because of their ease of administration, tablets and capsules are the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously used. For parenteral compositions, the carrier usually comprises, at least in large part, sterile water, although other ingredients, for example, to aid solubility, may be included. For example, injectable solutions may be prepared in which the carrier comprises saline, glucose solution, or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents, and the like may be used. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and / or a suitable humectant, optionally in combination with a small amount of any suitable additive that does not cause significant adverse effects on the skin. Such additives may facilitate application to the skin and / or aid in formulating the desired composition. These compositions can be administered in a variety of ways, for example, as a transdermal patch, a spot-on, or an ointment. It is particularly advantageous to formulate the above pharmaceutical compositions into dosage unit forms for ease of administration and uniformity of dosage. As used in this specification and claims, unit dosage form refers to physically discrete units suitable as single dosages, each containing a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoons, tablespoons, and the like, and multiples thereof.

[0223] It is particularly advantageous to formulate the above-mentioned pharmaceutical composition into unit dosage form for ease of administration and uniform dosage.As used herein, unit dosage refers to a physically discrete unit suitable as a single dose, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect together with necessary pharmacological carriers.Examples of such unit dosage forms are tablets (including scored tablets or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoons, tablespoons, etc., and multiple portions thereof.Preferred forms are tablets and capsules.

[0224] In certain embodiments, the FGFR inhibitor is present in a solid unit dosage form and is suitable for oral administration. The unit dosage form may contain about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg of the FGFR inhibitor per unit dosage form, or an amount within a range defined by two of these values, particularly an amount of 3, 4, or 5 mg per unit dose.

[0225] Depending on the mode of administration, the pharmaceutical composition will preferably contain 0.05 to 99% by weight, more preferably 0.1 to 70% by weight, even more preferably 0.1 to 50% by weight of a compound of the invention and 1 to 99.95% by weight, more preferably 30 to 99.9% by weight, even more preferably 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

[0226] The tablets or capsules of the present invention may be further film-coated to improve taste, ease of swallowing, and provide an elegant appearance. Polymer-based film coating materials are well known in the art. A water-based film coating is preferred over a solvent-based film coating, as the latter may contain more trace aldehydes. A preferred film coating material is the Opadry® II aqueous film coating system, e.g., Opadry II 85F, such as Opadry II 85F92209. Further preferred film coatings are water-based film coatings that protect against environmental moisture, such as aqueous moisture-proof film coating systems, such as Readilycoat® (e.g., Readilycoat® D), AquaPolish® MS, Opadry® amb, and Opadry® amb II. A preferred film coating is Opadry® amb II, a high-performance moisture-proof film coating that is a polyethylene glycol-free PVA-based immediate-release system.

[0227] In tablets according to the invention, the film coat preferably comprises by weight no more than about 4% (w / w) of the total tablet weight.

[0228] Of the capsules according to the present invention, hypromellose (HPMC) capsules are preferred over gelatin capsules.

[0229] In one aspect of the present invention, the pharmaceutical compositions described herein, specifically in capsule or tablet form, contain 0.5 mg to 20 mg base equivalent, or 2 mg to 20 mg base equivalent, or 0.5 mg to 12 mg base equivalent, or 2 mg to 12 mg base equivalent, or 2 mg to 10 mg base equivalent, or 2 mg to 6 mg base equivalent, or 2 mg base equivalent, 3 mg base equivalent, 4 mg base equivalent, 5 mg base equivalent, 6 mg base equivalent, 7 mg base equivalent, 8 mg base equivalent, 9 mg base equivalent, 10 mg base equivalent, 11 mg base equivalent, or 12 mg base equivalent of erdafitinib, a pharmaceutically acceptable salt thereof, or a solvate thereof. Specifically, the pharmaceutical compositions described herein contain 3 mg base equivalent, 4 mg base equivalent, or 5 mg base equivalent of erdafitinib, a pharmaceutically acceptable salt thereof, or a solvate thereof, specifically 3 mg, 4 mg, or 5 mg of erdafitinib base.

[0230] In one aspect of the invention, particularly in capsule or tablet form, the pharmaceutical compositions described herein contain 0.5 mg to 20 mg, or 2 mg to 20 mg, or 0.5 mg to 12 mg, or 2 mg to 12 mg, or 2 mg to 10 mg, or 2 mg to 6 mg, or 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, or 12 mg of erdafitinib base. Specifically, the pharmaceutical compositions described herein contain 3 mg, 4 mg, or 5 mg of erdafitinib base. Specifically, the pharmaceutical compositions described herein contain 3 mg, 4 mg, or 5 mg of erdafitinib base and about 0.5 to about 5% (w / w), about 0.5 to about 3% (w / w), about 0.5 to about 2% (w / w), about 0.5 to about 1.5% (w / w), or about 0.5 to about 1% (w / w) of a formaldehyde scavenger, specifically meglumine. Specifically, the pharmaceutical compositions described herein contain 3 mg, 4 mg, or 5 mg of erdafitinib base and about 0.5 to about 1.5% (w / w) or about 0.5 to about 1% (w / w) of a formaldehyde scavenger, specifically meglumine.

[0231] In one embodiment of the present invention, multiple (e.g., two) pharmaceutical compositions described herein can be administered to obtain a desired dose, e.g., a daily dose. For example, for a daily dose of erdafitinib of 8 mg base equivalent, two tablets or capsules each containing 4 mg of erdafitinib base equivalent can be administered. Alternatively, a tablet or capsule containing 3 mg of erdafitinib base equivalent and a tablet or capsule containing 5 mg of base equivalent can be administered. For example, for a daily dose of erdafitinib of 9 mg base equivalent, three tablets or capsules each containing 3 mg of erdafitinib base equivalent can be administered, or a tablet or capsule containing 4 mg of erdafitinib base equivalent and a tablet or capsule containing 5 mg of base equivalent can be administered. For example, for a daily dose of erdafitinib of 6 mg base equivalent, two tablets or capsules each containing 3 mg of erdafitinib base equivalent can be administered.

[0232] The amount of formaldehyde scavenger, in particular meglumine, in the pharmaceutical composition according to the present invention may be in the range of about 0.1 to about 10% by weight, about 0.1 to about 5% by weight, about 0.1 to about 3% by weight, about 0.1 to about 2% by weight, about 0.1 to about 1.5% by weight, about 0.1 to about 1% by weight, about 0.5 to about 5% by weight, about 0.5 to about 3% by weight, about 0.5 to about 2% by weight, about 0.5 to about 1.5% by weight, or about 0.5 to about 1% by weight.

[0233] According to certain embodiments, erdafitinib is supplied as 3 mg, 4 mg, or 5 mg film-coated tablets for oral administration containing the following inactive ingredients or their equivalents: tablet core: croscarmellose sodium, magnesium stearate, mannitol, meglumine, and microcrystalline cellulose; and film coating: Opadry amb II: glycerol monocaprylocaprate type I, partially hydrolyzed polyvinyl alcohol, sodium lauryl sulfate, talc, titanium dioxide, yellow iron oxide, red iron oxide (for orange and brown tablets), triiron tetroxide / black iron oxide (for brown tablets).

[0234] Safety studies seek to identify any potential adverse effects that may result from exposure to a drug. Efficacy is often measured by determining whether an active pharmaceutical ingredient demonstrates health benefits greater than a placebo or other intervention when tested in the appropriate context, e.g., in a rigorously controlled clinical trial.

[0235] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that the beneficial effects of the formulation, composition, or ingredient on the overall health of the person being treated substantially outweigh its detrimental effects.

[0236] All formulations for oral administration are in a form suitable for such administration.

[0237] Dosage and Treatment Regimen In one aspect, described herein is a method for treating HR-NMIBC or IR-NMIBC, comprising, consisting of, or consisting essentially of administering a therapeutically effective amount of an FGFR inhibitor to a patient diagnosed with HR-NMIBC or IR-NMIBC, wherein the FGFR inhibitor is administered orally. In some embodiments, the FGFR inhibitor, particularly erdafitinib, is generally administered daily, specifically once daily. In some embodiments, the FGFR inhibitor, particularly erdafitinib, is generally administered twice daily. In some embodiments, the FGFR inhibitor, particularly erdafitinib, is generally administered three times daily. In some embodiments, the FGFR inhibitor, particularly erdafitinib, is generally administered four times daily. In some embodiments, the FGFR inhibitor, particularly erdafitinib, is generally administered every other day. In some embodiments, the FGFR inhibitor, particularly erdafitinib, is generally administered once weekly. In some embodiments, the FGFR inhibitor, particularly erdafitinib, is generally administered twice a week. In some embodiments, the FGFR inhibitor, particularly erdafitinib, is generally administered every other week. In some embodiments, the FGFR inhibitor, particularly erdafitinib, is generally orally administered on a daily dosing schedule.

[0238] Generally, the dose of an FGFR inhibitor, specifically erdafitinib, used to treat the diseases or conditions described herein in humans typically ranges from about 1 to 20 mg / day. In some embodiments, an FGFR inhibitor, specifically erdafitinib, is orally administered to a human at a dose of about 1 mg / day, about 2 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 6 mg / day, about 7 mg / day, about 8 mg / day, about 9 mg / day, about 10 mg / day, about 11 mg / day, about 12 mg / day, about 13 mg / day, about 14 mg / day, about 15 mg / day, about 16 mg / day, about 17 mg / day, about 18 mg / day, about 19 mg / day, or about 20 mg / day.

[0239] In some embodiments, erdafitinib is administered orally. In certain embodiments, erdafitinib is administered orally at a dose of about 8 mg once daily. In further embodiments, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily. In still further embodiments, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily 14 to 21 days after initiation of treatment if (a) the patient exhibits a serum phosphate (PO4) level of less than about 5.5 mg / dL 14 to 21 days after initiation of treatment and administration of erdafitinib at 8 mg once daily does not cause eye disorders, or (b) administration of erdafitinib at 8 mg once daily does not cause grade 2 or higher adverse reactions. In certain embodiments, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily 14 days after initiation of treatment. In certain embodiments, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily 15 days after the start of treatment. In certain embodiments, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily 16 days after the start of treatment. In certain embodiments, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily 17 days after the start of treatment. In certain embodiments, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily 18 days after the start of treatment. In certain embodiments, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily 19 days after the start of treatment. In certain embodiments, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily 20 days after the start of treatment. In one particular embodiment, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily after 21 days of treatment.

[0240] In one embodiment, erdafitinib is administered at a dose of 8 mg, particularly 8 mg once daily. In one embodiment, erdafitinib is administered at a dose of 8 mg, particularly 8 mg once daily, and may be increased to 9 mg depending on the serum phosphate level (e.g., if the serum phosphate level is less than 5.5 mg / dL, or less than 7 mg / dL, or in the range of 7 mg / dL to 9 mg / dL or less, or 9 mg / dL or less) and depending on the observed treatment-related adverse events. In one embodiment, the serum phosphate level for determining whether to increase the dose is measured on the treatment day during the first cycle of erdafitinib treatment, particularly on day 14±2 of erdafitinib administration, more particularly on day 14.

[0241] In one embodiment, erdafitinib is administered at a dose of 6 mg, particularly 6 mg once daily, particularly on a continuous schedule.

[0242] In one embodiment, erdafitinib is administered at a dose of 6 mg, specifically 6 mg once daily. In one embodiment, erdafitinib is administered at a dose of 6 mg, specifically 6 mg once daily, with the option of increasing the dose to 8 mg depending on serum phosphate levels (e.g., serum phosphate levels less than 5.5 mg / dL) and depending on observed treatment-related adverse events. In one embodiment, the serum phosphate level for determining whether to increase the dose is measured on the treatment day, at the end of the treatment period of cycle 1, particularly on day 1 (C2D1) ± 7 of cycle 2 of erdafitinib administration, or on day 1 (C2D1) ± 3 of cycle 2, more particularly on C2D1.

[0243] In certain embodiments, the dose of erdafitinib is increased from 6 mg once daily to 8 mg once daily at the end of the cycle 1 treatment period, particularly on day 1 (C2D1) ± 7 days of cycle 2, or on day 1 (C2D1) ± 3 days of cycle 2, more particularly on C2D1.

[0244] In some embodiments, erdafitinib is orally administered.In certain embodiments, erdafitinib is orally administered at a dose of about 6 mg once a day.In further embodiments, the dose of erdafitinib is increased from 6 mg once a day to 8 mg once a day. In yet a further embodiment, the dose of erdafitinib is increased from 6 mg once daily to 8 mg once daily at the end of the cycle 1 treatment period, particularly on day 1 (C2D1) ± 7 days of cycle 2 or on day 1 (C2D1) ± 3 days of cycle 2, more particularly on C2D1, if, after initiating treatment, (a) the patient exhibits a serum phosphate (PO4) level of less than about 5.5 mg / dL at the end of the cycle 1 treatment period, particularly on day 1 (C2D1) ± 7 days of cycle 2 or on day 1 (C2D1) ± 3 days of cycle 2, more particularly on C2D1, and no significant toxicity, e.g., ocular disorders, occurs with administration of 6 mg of erdafitinib once daily, or (b) no adverse reactions of grade 2 or higher occur with administration of 6 mg of erdafitinib once daily.

[0245] In some embodiments, erdafitinib is administered orally. In certain embodiments, erdafitinib is administered orally at a dose of about 6 mg once daily. In a further embodiment, erdafitinib continues to be administered orally at a dose of about 6 mg once daily at the end of the cycle 1 treatment period, particularly on day 1 (C2D1) ±7 days of cycle 2 or day 1 (C2D1) ±3 days of cycle 2, more particularly on C2D1, after initiating treatment if: (a) the patient exhibits a serum phosphate (PO4) level of 5.5 mg / dL to 6.99 mg / dL at the end of the cycle 1 treatment period, particularly on day 1 (C2D1) ±7 days of cycle 2 or day 1 (C2D1) ±3 days of cycle 2, more particularly on C2D1, after initiating treatment, and administration of 6 mg of erdafitinib once daily does not result in significant toxicity, e.g., eye disorders; or (b) administration of 6 mg of erdafitinib once daily does not result in grade 2 or higher adverse reactions. In one embodiment, phosphate intake is limited to 600-800 mg / day.

[0246] In some embodiments, erdafitinib is administered orally. In certain embodiments, erdafitinib is administered orally at a dose of about 6 mg once daily. In further embodiments, erdafitinib continues to be administered orally at a dose of about 6 mg once daily after initiating treatment if (a) the patient exhibits a serum phosphate PO4 level of ≥ 7 mg / dL at the end of the cycle 1 treatment period, particularly on day 1 (C2D1) of cycle 2 ± 7 days or on day 1 (C2D1) of cycle 2 ± 3 days, more specifically on C2D1, after initiating treatment, or (b) the patient exhibits the presence of other toxicity at the end of the cycle 1 treatment period, particularly on day 1 (C2D1) of cycle 2 ± 7 days or on day 1 (C2D1) of cycle 2 ± 3 days, more specifically on C2D1, and the serum phosphate (PO4) toxicity management in Table 7 is applied.

[0247] [Table 4] NOTE: These are general guidelines. The treating physician must use clinical judgment and local standard of care to determine the best way to manage elevated phosphate. If sevelamer hydrochloride (Renagel®) is unavailable, the use of other phosphate binders (calcium-free) based on local standards is recommended, including sevelamer carbonate (Renvela) or lanthanum carbonate (Fosrenol®). Further information regarding phosphorus in foods by food category can also be found at www.permanente.net / homepage / kaiser / pdf / 42025.pdf. Further information regarding phosphate management and diet can be found on the National Kidney Foundation website at http: / / www.kidney.org / atoz / content / phosphorus.cfm a. Persistent hyperphosphatemia is considered to be a continuous phosphate value greater than 1 above the cutoff. b. Interruption of study drug for hyperphosphatemia is suggested for 7 consecutive days. TID = 3 times a day

[0248] Table 7 reports guidelines for the clinical management of elevated serum phosphate levels during erdafitinib treatment.

[0249] Table 8 reports the 6 mg daily dosing schedule (with dose escalation) and dose reductions.

[0250] [Table 5]

[0251] In one embodiment, a treatment cycle as used herein is a 28-day cycle. In certain embodiments, a treatment cycle is a 28-day cycle for up to two years.

[0252] In one embodiment, the desired dose is conveniently given in a single dose, or in divided doses administered simultaneously (or closely), or at appropriate intervals, for example, two, three, four or more sub-doses per day. In some embodiments, the FGFR inhibitor is conveniently given in divided doses administered simultaneously (or closely), once a day. In some embodiments, the FGFR inhibitor, particularly erdafitinib, is conveniently given in divided doses administered equally twice a day. In some embodiments, the FGFR inhibitor, particularly erdafitinib, is conveniently given in divided doses administered equally three times a day. In some embodiments, the FGFR inhibitor is conveniently given in divided doses administered equally four times a day.

[0253] In certain embodiments, the desired dose can be delivered in 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fractional unit doses throughout the day, such that the total amount of FGFR inhibitor, specifically erdafitinib, delivered by the fractional unit doses throughout the day is the total daily dose.

[0254] In some embodiments, the amount of FGFR inhibitor generally, and erdafitinib specifically, given to a human will vary depending on factors such as, but not limited to, the state and severity of the disease or condition, as well as the characteristics of the human (e.g., body weight), and the particular additional therapeutic agent (if applicable) being administered.

[0255] In yet further embodiments, erdafitinib is not administered with a strong CYP3A4 inhibitor or inducer or a moderate CYP3A4 inducer. In certain embodiments, erdafitinib is not administered with a strong CYP3A4 inhibitor or inducer or a moderate CYP3A4 inducer within 14 days or 5 half-lives prior to the first dose of the investigational drug.

[0256] Non-limiting examples of strong CYP3A4 inhibitors include boceprevir, aprepitant, clarithromycin, conivaptan, grapefruit juice, indinavir, lopinavir, itraconazole, mibefradil ketoconazole, nefazodone, ritonavir, posaconazole, nelfinavir, saquinavir, conivaptan, telaprevir, boceprevir, telithromycin, clarithromycin, voriconazole, clotrimazole, diltiazem, erythromycin, fluconazole, verapamil, and troleandomycin.

[0257] Non-limiting examples of moderate to strong CYP3A4 inducers include avasimibe, St. John's wort, carbamazepine, efavirenz, phenytoin, etravirine, bosentan, nafcillin, rifampicin, modafinil, rifabutin, and barbiturates.

[0258] Kits / Products Kits and articles for use in the uses or methods described herein are also described. Such kits include a package or container that is divided to receive one or more doses of the pharmaceutical compositions disclosed herein. Suitable containers include, for example, bottles. In one embodiment, the container is made of various materials, such as glass or plastic.

[0259] The articles of manufacture provided herein include packaging materials. Packaging materials for use in packaging pharmaceutical products include, for example, those described in U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for the selected formulation and the intended mode of administration and treatment.

[0260] Kits typically include a label listing the contents and / or instructions for use, as well as a package insert with instructions for use. A set of instructions is also typically included.

[0261] In one embodiment, a label is on or associated with a container. In one embodiment, a label is on a container when letters, numbers, or other characters forming the label are affixed to, molded into, or inscribed into the container itself; a label is associated with a container when the label is present in a receptacle or carrier that also holds the container, for example, as a package insert.

[0262] In one embodiment, the label indicates that the contents are to be used for a particular therapeutic application. The label also indicates how to use the contents, for example, in the methods described herein.

[0263] In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device containing one or more unit dosage forms containing a compound provided herein. The pack comprises metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is accompanied by a notice on the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects approval by that agency of the drug form for administration to humans or animals. Such notice may be, for example, a package insert approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. In one embodiment, compositions containing a compound described herein formulated in a compatible pharmaceutical carrier are also dispensed for treatment of a designated medical condition, placed in an appropriate container, and labeled.

[0264] Nucleotide sequence of the FGFR fusion gene The nucleotide sequences of the FGFR fusion cDNAs are shown in Table 4. The underlined sequences correspond to either FGFR3 or FGFR2, and the sequences in black represent the fusion partners.

[0265] [Table 6-1]

[0266] [Table 6-2]

[0267] [Table 6-3]

[0268] [Table 6-4]

[0269] [Table 6-5]

[0270] [Table 6-6]

[0271] [Table 6-7] [Example]

[0272] These examples are presented for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0273] Example 1: Sensitivity of bladder cancer cell lines to erdafitinib Cell viability assays were performed to test the efficacy of erdafitinib in vitro. The cell lines shown in Table 5 were used in either the MTT or CellTiter-Glo assays, as described below. Both assays measure the metabolic activity of cells but use different reagents to determine cell viability.

[0274] MTT assay Cells were seeded into 96-well culture plates in 180 μL of growth medium as recommended by the supplier at a density ensuring continuous logarithmic growth over a 4-day incubation period. Cells were incubated for 24 hours in a humidified incubator at 37°C and 5% CO2. A range of erdafitinib concentrations was prepared in growth medium, and 20 μL was added to the cells in each well. The cells were incubated for an additional 4 days, after which 25 μL of MTT (5 mg / mL in phosphate-buffered saline) was added to each well. The cells were incubated for 2 hours at 37°C and 5% CO2, after which the growth medium was removed. Residual crystals were dissolved in 125 μL of glycine / DMSO buffer, and the optical density was determined at 540 nm. Cells incubated without erdafitinib served as the untreated control and were defined as 100%. The effect of erdafitinib was determined as a percentage of the control, and IC was calculated as shown in Table 5. 50 Values ​​were determined from curve fitting of the dose-response effect.

[0275] CellTiter-Glo assay Cells were seeded into 96-well culture plates in 180 μL of growth medium recommended by the supplier at a density ensuring continuous logarithmic growth over a 4-day incubation period. Cells were incubated for 24 hours in a humidified incubator at 37°C and 5% CO2. A range of erdafitinib concentrations was prepared in growth medium, and 20 μL was added to the cells in each well. The cells were incubated for an additional 4 days, after which 100 μL of CellTiter-Glo reagent (Promega) was added to each well, the plate was shaken at 500 rpm for 5 minutes, and luminescence was detected using an Envision plate reader (Perkin Elmer). Cells incubated without erdafitinib served as the untreated control and were defined as 100%. The effect of erdafitinib was determined as a % of the control, and IC was calculated as shown in Table 5. 50 Values ​​were determined from curve fitting of the dose-response effect.

[0276] [Table 7]

[0277] conclusion Cell viability assays demonstrated that several NMIBC cell lines (MGH-U3, RT4, and 97-7) containing FGFR3 mutations (mutation or fusion) were sensitive to low nanomolar concentrations of erdafitinib. Two cell lines with either WT (T24) or unknown FGFR3 status (EJ28) were not sensitive to erdafitinib.

[0278] Example 2: Phase 2, Multicenter, Open-Label Study (NCT04172675) A non-limiting example of a Phase 2, multicenter, open-label study to evaluate recurrence-free survival (RFS) in participants treated with erdafitinib versus investigator's choice for participants with high-risk non-muscle-invasive bladder cancer (NMIBC) harboring a fibroblast growth factor receptor (FGFR) mutation or fusion and who relapsed after Mycobacterium Calmette-Guérin (BCG) therapy.

[0279] the purpose The primary objective of this trial is to evaluate RFS in patients with HR-NMIBC harboring FGFR mutations or fusions and those with HR-NMIBC that has relapsed after BCG therapy, treated with erdafitinib compared with investigator's choice of intravesical gemcitabine / mitomycin C (MMC) / hyperthermic MMC therapy.

[0280] method Clinical trial overview Eligible patients will be screened for the presence of FGFR mutations or fusions and assigned to one of three cohorts. See Figure 1 for a schematic of this trial design.

[0281] Cohort 1 (erdafitinib and active comparator) (n=240) includes HR-NMIBC patients with papillary tumors only (no carcinoma in situ (CIS)), disease recurrence after BCG therapy, and refusing or ineligible for cystectomy. Patients may be BCG-refractory or BCG-experienced.

[0282] Cohort 2 (experimental) (n=20) includes HR-NMIBC, BCG-refractory patients who presented with carcinoma in situ (CIS) with or without concomitant papillary neoplasia and either refused cystectomy or were ineligible for cystectomy. This cohort is exploratory.

[0283] Cohort 3 (experimental) (n=20) includes IR-NMIBC patients presenting only with papillary disease. There is no predefined requirement for BCG or intravesical chemotherapy. Patients had all visible bladder tumors removed by resection or fulguration, except for one 5-10 mm bladder tumor (marker lesion). This cohort is exploratory.

[0284] Patients in Cohort 1 may be randomized in a 2:1 ratio to receive either oral erdafitinib or intravesical gemcitabine or intravesical mitomycin C (MMC) / hyperthermic MMC. Participants randomized to gemcitabine or MMC / hyperthermic MMC in Cohort 1 who demonstrate recurrence via investigator disease assessment will have the opportunity to crossover to treatment with erdafitinib. Randomization will be stratified by tumor stage (Ta vs. T1) and type of previous BCG therapy (BCG-refractory vs. BCG-experienced).

[0285] All patients enrolled in cohorts 2 and 3 will receive erdafitinib treatment. Erdafitinib will be discontinued in cohort 2 if a CR is not observed within 3 months. Erdafitinib will be discontinued in cohort 3 if a partial response (PR) or CR is not observed within 3 months. For cohort 2, a CR is defined as at least one of the following: 1) a negative cystoscopy and negative (including atypical) urine cytology, or 2) a positive cystoscopy and negative cytology in patients with biopsy-proven benign or low-grade NMIBC. The CR rate at 6 months is calculated with its two-sided 95% exact CI. For cohort 3, a CR is defined as the disappearance of marker lesions without new lesions; if marker lesions persist, histopathological examination should reveal no viable tumor. Cystoscopy was performed on day 1 of cycles 2, 3, and 4, or until complete response (CR), if earlier. If a CR was achieved, urine cytology was performed. CR rates were calculated using their two-sided 95% exact CI. Patients with a partial response (PR) or CR within 3 months of treatment initiation continued erdafitinib for up to 2 years or until high-risk disease recurrence, intolerable toxicity, withdrawal of consent, investigator decision, or end of the study.

[0286] The follow-up phase includes a 30-day safety follow-up visit, disease assessment follow-up, and survival follow-up.

[0287] In Cohort 1 (erdafitinib), participants may receive oral erdafitinib starting on Day 1 of Cycle 1 until completion of 2 years of treatment, until disease recurrence, unacceptable toxicity, withdrawal of consent, investigator decision to discontinue treatment, or study termination, whichever occurs first. Each cycle is 28 days. The dose is 8 mg daily, with the option to increase to 9 mg daily based on phosphate levels on Day 14 of Cycle 1. Per protocol amendment, the dose may be changed to 6 mg daily, with the option to increase to 8 mg daily based on phosphate levels at the end of the Cycle 1 treatment period (Day 1 of Cycle 2). In Cohort 1 (investigator's choice), gemcitabine will be given weekly (2,000 mg) for at least four doses of induction, followed by monthly maintenance for at least six months. In Cohort 1 (investigator's choice), mitomycin C will be given weekly (40 mg dose) for at least four doses of induction, followed by monthly maintenance for at least six months. In Cohort 2, participants will receive oral erdafitinib starting on Day 1 of Cycle 1 until completion of 2 years of treatment, until disease recurrence, intolerable toxicity, withdrawal of consent, investigator decision to discontinue treatment, or study termination, whichever occurs first. Each cycle will be 28 days. The dose will be 8 mg daily, with the option to increase to 9 mg daily based on phosphate levels on Day 14 of Cycle 1. A protocol amendment will change the dose to 6 mg daily, with the option to increase to 8 mg daily based on phosphate levels at the end of the Cycle 1 treatment period (Day 1 of Cycle 2). In Cohort 3, participants will receive oral erdafitinib starting on Day 1 of Cycle 1 until completion of 2 years of treatment, until disease recurrence, unacceptable toxicity, withdrawal of consent, investigator decision to discontinue treatment, or study termination, whichever occurs first. Each cycle is 28 days. The dose is 8 mg daily, with the option to increase to 9 mg daily based on phosphate levels on Day 14 of Cycle 1. Per protocol amendment, the dose will change to 6 mg daily, with the option to increase to 8 mg daily based on phosphate levels at the end of the Cycle 1 treatment period (Day 1 of Cycle 2).

[0288] Inclusion and Exclusion Criteria The trial will enroll patients across sites in 14 countries, including the United States, according to the following inclusion and exclusion criteria:

[0289] Inclusion criteria 1. Age 18 or older. Eastern Cooperative Oncology Group (ECOG) status of 2.1 or less. 3. Histologically confirmed recurrent non-muscle invasive urothelial carcinoma of the bladder (for Cohort 3, histologically confirmed intermediate-risk (IR) NMIBC and recurrent IR disease), Cohort 1: High-grade papillary disease Ta / T1 lesions, b. Cohort 2: CIS with or without nipple disease, c. Cohort 3: low grade (G1-G2), Ta / T1 marker lesions, no previous intraepithelial carcinoma. 4. Tumors with one or more predetermined FGFR2 or FGFR3 gene mutations (including mutations and fusions). Specifically, patients must have at least one of the following FGFR3 gene mutations: R248C, S249C, G370C, Y373C, or at least one of the following FGFR2 or FGFR3 gene fusions: FGFR2-BICC1, FGFR2-CASP7, FGFR3-TACC3, FGFR3-BAIAP2L1. 5. Refuses or is ineligible for cystectomy (Cohorts 1 and 2 only). 6. Risk of progression <5% and risk of recurrence >50% over the next 2 years using the European Organisation for Research and Treatment of Cancer risk calculator (Cohort 3 only) 7. A signed informed consent form indicating that each individual understands the purpose of the study and the procedures involved, and is willing to participate in the study. 8. Women of childbearing potential must have a negative pregnancy test (β-hCG [β-human chorionic gonadotropin]) (urine or serum) within 7 days prior to randomization (Cohort 1) or first dose of study drug (Cohort 2 and Cohort 3). 9. Adequate bone marrow, liver, and kidney function: 10. BCG-refractory or BCG-experienced participants after appropriate BCG therapy BCG Refractory: Patient has one of the following recurrent disease states and is receiving adequate BCG treatment as defined below: a. Persistent or recurrent CIS with isolated or recurrent Ta / T1 (non-invasive papillary disease / tumor invading the subepithelial connective tissue) disease within 12 months of completing appropriate BCG therapy (Cohort 2 only), b. Recurrent high-grade Ta / T1 disease within 6 months of completing adequate BCG therapy, c. High grade T1 at first disease evaluation following the introduction of a BCG course.

[0290] Appropriate BCG (minimum treatment requirements) a. At least 5 of 6 total doses of the initial induction course and at least 1 maintenance (2 of 3 total weekly doses) in a 6-month period (BCG total dose must be at least 1 x 10 8 (must contain one complete vial with colony forming units (CFU)), or b. At least 5 of the 6 total doses of the initial induction course and at least 2 of the 6 total doses of the second induction course.

[0291] BCG-experienced: Patients have recurrent high-grade Ta / T1 disease within 12 months of completing BCG therapy, and their prior BCG therapy is the minimum treatment requirement, as described below. d. At least 5 of the 6 total doses of the initial induction course; or e. At least five of the six total doses of the induction course and at least one maintenance (two of the three weekly doses) over a six-month period. Half-dose or one-third-dose is allowed during maintenance.

[0292] Exclusion criteria 1. Histologically confirmed muscle-invasive (stage T2 or higher) urothelial carcinoma of the bladder. 2. Histopathology with small cell component, pure adenocarcinoma, pure squamous cell carcinoma, or pure squamous cell CIS of the bladder. 3. Other active malignancies. The only permitted exceptions are (a) skin cancer treated within the last 24 months that is considered completely cured, (b) adequately treated lobular carcinoma in situ (LCIS) and ductal CIS, and (c) a history of localized breast cancer and administration of antihormonal agents, or a history of localized prostate cancer (N0M0) and administration of androgen deprivation therapy. 4. Previous treatment with an FGFR inhibitor. 5. Major surgery within 4 weeks prior to Cycle 1 Day 1 (C1D1). 6. No recovery from the toxicity of previous anticancer therapy. 7. Central serous retinopathy or retinal pigment epithelial detachment of any grade.

[0293] Clinical trial objectives For Cohort 1, the primary objective is to evaluate RFS in patients treated with erdafitinib compared to investigator's choice for patients with high-risk NMIBC harboring FGFR mutations or fusions who relapsed after BCG therapy. Secondary objectives are to evaluate other measures of efficacy.

[0294] For Cohort 2, the exploratory objective is to evaluate the efficacy of erdafitinib in terms of CR rate at 6 months in patients with high-risk BCG-refractory NMIBC and FGFR mutations or fusions.

[0295] For Cohort 3, the exploratory objective is to evaluate the efficacy of erdafitinib in terms of CR rate for marker lesions in patients with intermediate-risk NMIBC and FGFR mutations or fusions.

[0296] Primary and exploratory endpoints / evaluations For Cohort 1, the primary endpoint is RFS with a time frame of up to 4 years. Secondary endpoints, time frames, and descriptions are provided in Table 6.

[0297] [Table 8-1]

[0298] [Table 8-2]

[0299] For Cohort 2, the exploratory endpoints are CR rate at 6 months, or CR rate and DOR (duration of response) at weeks 8 and 32. The key secondary endpoint is safety.

[0300] For Cohort 3, the exploratory endpoints are CR rate, BOR, and DOR. The key secondary endpoint is safety.

[0301] Results: Part 1 Safety evaluation Safety assessments will be based on medical review of adverse event reports and results of vital sign measurements, 12-lead ECG, physical examination, laboratory tests, ophthalmologic examination, and other safety assessments from baseline through 30 days after the last dose of study drug. All adverse events, serious adverse events, and special reporting circumstances, whether serious or non-serious, will be reported.

[0302] For Cohort 2, among the 10 enrolled patients, at the first evaluation (approximately C3D1), the CR rate for disease-evaluable patients was 100% (9 / 9 of evaluable patients), and at the second evaluation (approximately C6D1), the CR rate for disease-evaluable patients was 75% (6 / 8 of evaluable patients). The median follow-up period from first dose was 9.2 months, and patients received erdafitinib for a median of 5.9 months. The median DOR was not reached. Safety data in Cohort 2 were consistent with the known safety profile of erdafitinib.

[0303] For Cohort 2, at the time of final analysis, among the 16 enrolled patients, the CR rate for disease-evaluable patients at approximately week 8 was 100% (12 / 12 evaluable patients), at approximately week 32 the CR rate for disease-evaluable patients was 80% (8 / 10 evaluable patients), at approximately C9D1 the CR rate for disease-evaluable patients was 77.8% (7 / 9 evaluable patients), and at approximately C12D1 the CR rate for disease-evaluable patients was 71.4% (5 / 7 evaluable patients).

[0304] For Cohort 2, at the time of final analysis (median study follow-up of 14.8 months), 16 patients (median age: 68.5 years [range, 35–83]; tumor stage: 100% CIS; >90% of patients with FGFR3 mutations) had received treatment for a median duration of 6.7 months (range, 1.9–18.6). Table 9A provides baseline and disease characteristics. CR rates among disease-evaluable patients were 93.8% (15 / 16) and 72.7% (8 / 11) at weeks 8 and 32, respectively (see Table 9B below). Twelve responses were ongoing, and the median duration of response was not reached (see Figure 3). Common treatment-emergent adverse events (TEAEs) were mostly grade 1-2: dry mouth (56%; n=9), hyperphosphatemia (56%; n=9), diarrhea (56%; n=9), stomatitis, dysgeusia, and dry skin (44%; n=7 each). One patient (6.3%) reported grade 2 treatment-related retinal detachment, which led to treatment discontinuation, and one patient (6.3%) had grade 1 treatment-related subretinal fluid, both of which resolved. Six patients (37.5%) had grade ≥3 treatment-related TEAEs (onychia, acute kidney injury, increased alanine aminotransferase, chronic kidney disease, dry mouth, hypotension, nail disorder, stomatitis, and sepsis). One patient (6.3%) discontinued treatment due to a treatment-related TEAE. No treatment-related deaths occurred.

[0305] [Table 9] ECOG PS, Eastern Cooperative Oncology Group performance status; ITT, intention to treat. a Other FGFR3 mutations screened for: R248C. b Other gene fusions screened: FGFR2:BICC1, FGFR2:CASP7, FGFR3:BAIAP2L1, FGFR3:TACC3_V3, FGFR3:TACC3_Other

[0306] [Table 10] aCR was defined as at least one of the following: (1) negative cystoscopy and negative (including atypical) urinary cytology, or 2) positive cystoscopy and negative cytology in biopsy-proven benign or low-grade NMIBC. b 16 evaluable patients. Disease-evaluable patients at week 8 included only patients who met any of the following criteria: (1) disease assessment after the week 8 window, (2) documented recurrence, progression, death, or study discontinuation at any time, or (3) initiation of subsequent anticancer therapy at any time. c 95% CIs were calculated using the Clopper-Pearson method. d 11 evaluable patients. Disease-evaluable patients at week 32 included only patients who met any of the following criteria: (1) disease assessment after the week 32 window, (2) documented recurrence, progression, death, or study discontinuation at any time, or (3) initiation of subsequent anticancer therapy at any time.

[0307] In cohort 2, patients received oral erdafitinib 6 mg once daily without dose escalation.

[0308] Data from this study demonstrate promising and durable efficacy of FGFR inhibitors, such as erdafitinib, in patients with BCG-refractory CIS and FGFR alterations. The two longest response durations were observed in patients who discontinued treatment relatively early, highlighting the durability of treatment-free responses. Safety data were consistent with the known safety profile of erdafitinib. For Cohort 2: Disease-evaluable patients were all subjects who met three criteria: they met all eligibility criteria for the study, received at least one dose of study drug, and underwent a baseline assessment and at least one appropriate post-treatment disease assessment.

[0309] For Cohort 3, 10 of 11 enrolled patients received erdafitinib; the CR rate for disease-evaluable patients was 75% (6 / 8 evaluable patients), with one patient experiencing a PR. The median follow-up period from first dose was 5.7 months, and patients received erdafitinib for a median of 2.9 months. The median DOR was not reached. Safety data for Cohort 3 were consistent with the known safety profile of erdafitinib.

[0310] For Cohort 3, further evaluation revealed that among the 18 enrolled patients who received erdafitinib, the CR rate for disease-evaluable patients was 81.3% (13 / 16 evaluable patients).

[0311] For Cohort 3, at the time of final analysis (median follow-up 10.0 months), 18 patients were enrolled (median age: 63.5 years [range, 47-77]; tumor stage: n = 13 Ta, n = 5 unstaged) and received erdafitinib for a median of 7.1 months (range, 0.7-17.4). All patients had FGFR3 mutations. Table 10A provides baseline and disease characteristics. Of the 18 patients, 15 had a CR (CR rate, 83.3%), 2 had a PR (11.1%), and 1 had a BOR with high-grade recurrence (HGR). The median time to response was 1.15 months, and 1 had a high-grade recurrence (see Table 10B below). Among the 17 responders, the median DOR was 12.7 months; 12 responses were ongoing, 3 were discontinued, and 2 were terminated due to relapse / progression / death (1 low-grade, 1 high-grade) (see Figure 4). The most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (100%; n = 18), diarrhea (83%; n = 15), dry mouth (72%; n = 13), dry skin (50%; n = 9), and dysgeusia (50%; n = 9). Grade 3 TEAEs (n = 1 each) included abdominal pain, diarrhea, dysuria, and gastritis. Two (11.1%) patients each had grade 1 treatment-related central serous chorioretinopathy and retinal pigment epithelial detachment; two resolved and two did not. Three (16.7%) patients had treatment-related TEAEs leading to discontinuation. No treatment-related deaths occurred. Most treatment-related adverse events (TRAEs) were grade 1 or 2.

[0312] [Table 11] ECOG PS, Eastern Cooperative Oncology Group performance status; ITT, intention to treat. a Other FGFR3 mutations screened for: G370C. b Other gene fusions screened: FGFR2:BICC1, FGFR2:CASP7, FGFR3:BAIAP2L1, FGFR3:TACC3_V1, FGFR3:TACC3_Other

[0313] [Table 12] a CR is defined as disappearance of marker lesions without new lesions, and if marker lesions persist, no viable tumor is seen on histopathological examination. PR in Cohort 3 is defined as a 50% reduction in marker lesions. Stable disease in Cohort 3 is defined as less than a 50% reduction in marker lesions. Progressive disease in Cohort 3 is defined as any marker lesion growth above baseline. b 95% CIs were calculated using the Clopper-Pearson method. c Best overall response (BOR) is defined as the best response recorded after the start of study treatment. d One patient (5.6%) had a BOR of HGR.

[0314] In cohort 3, patients received oral erdafitinib 6 mg once daily without dose escalation.

[0315] In this marker lesion trial of FGFR-targeted therapy, erdafitinib demonstrated efficacy in all treated patients with IR NMIBC with FGFR alterations. Data from this study demonstrate the rapid onset and durability of response after treatment with erdafitinib in patients with IR NMIBC. Safety data were consistent with the known safety profile of erdafitinib.

[0316] For Cohort 3: Disease-evaluable patients were all subjects who met three criteria: met all eligibility criteria for the study, received at least one dose of study drug, and underwent a baseline assessment and at least one adequate post-treatment disease assessment.

[0317] Results: Part 2 Updated methods and final results from Cohort 1 are presented here.

[0318] Patients and Treatment Cohort 1 was designed to enroll approximately 240 patients, but enrollment for this trial was terminated early due to insufficient accrual.

[0319] Patients were randomized 2:1 to receive oral erdafitinib or the investigator's choice of intravesical chemotherapy (Figure 5). Erdafitinib dosing was 6 mg daily without dose escalation in 28-day cycles for up to 2 years. Initially, patients received 8 mg daily with individual dose escalation. An independent data monitoring committee reviewed safety data from the first four patients treated with erdafitinib and recommended changing the dose to 6 mg daily without dose escalation, with the goal of improving tolerability and maintaining activity while preventing early treatment discontinuation. Intravesical chemotherapy included weekly infusions of mitomycin C / hyperthermic mitomycin C 40 mg or gemcitabine 2000 mg for at least four induction doses, followed by monthly maintenance for at least 6 months. Additional doses of intravesical chemotherapy were permitted according to local standard of care. Gemcitabine and mitomycin C were selected as comparators to erdafitinib in this setting based on treatment guidelines and clinical data. Patients with confirmed high-risk recurrence in the chemotherapy group were crossed over to erdafitinib. Randomization was stratified by tumor stage (Ta vs. T1) and type of previous BCG therapy (BCG-refractory vs. BCG-experienced; see also Table 11). However, due to the completion of enrollment in Cohort 1 and a smaller-than-planned sample size, the primary analysis was not stratified for recurrence-free survival (RFS).

[0320] endpoint The primary endpoint was RFS, defined as the time from randomization to recurrence of histologically proven high-risk disease (high-grade Ta / T1 or CIS) or death. Secondary and exploratory endpoints included 6- and 12-month RFS rates, safety, time to progression, overall survival, and time to cystectomy. The efficacy endpoints of time to progression, time to cystectomy, and overall survival were not assessed due to an insufficient number of events observed at the clinical cutoff.

[0321] evaluation Disease response was assessed by cystoscopy, bladder mapping (if there was a history of CIS), urine cytology, and computed tomography / magnetic resonance imaging urography. Cystoscopy was performed on day 1 of cycle 3, then every 12 weeks for up to 2 years of treatment, and then every 24 weeks for an additional 2 years or until high-risk disease recurrence or progression. Adverse events were recorded from the date of informed consent until the end of the 30-day safety follow-up period and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Ophthalmological examinations (including optical coherence tomography and Amsler grid examination) were performed at screening and at pre-specified time points during treatment.

[0322] statistical analysis Cohort 1 was designed to enroll approximately 240 patients (randomized 2:1), and the primary efficacy analysis was planned when approximately 160 RFS events were observed. This statistically assumed a 67% improvement in median RFS for the erdafitinib group compared with the chemotherapy group (i.e., a hazard ratio of 0.60 for erdafitinib compared with chemotherapy and an increase in median RFS from 6 to 10 months). However, due to the end of enrollment in Cohort 1 and the resulting sample size of 73 patients, the statistical analysis plan was modified to eliminate all pre-specified hypothesis testing. All reported P values ​​are nominal. Descriptive subgroup analyses were performed, but no adjustment for multiplicity was made. 95% confidence intervals are presented but should not be used as a substitute for hypothesis testing.

[0323] result patient Of the total 1,092 patients screened for molecular eligibility in Cohort 1, 882 (81%) had sufficient tumor samples for study inclusion, and 336 had FGFR alterations (positive rate, 38%; Table 12). At clinical cutoff, 73 patients were randomized in Cohort 1: 49 to erdafitinib and 24 to chemotherapy (Figure 6). One patient in the chemotherapy group was randomized but did not receive any treatment due to treatment refusal and was excluded from the safety population. At clinical cutoff, one patient (2%) in the erdafitinib group and seven (29%) in the chemotherapy group completed study treatment, while 28 patients (57%) in the erdafitinib group and 14 (58%) in the chemotherapy group discontinued study treatment. The most frequent reasons for discontinuation were adverse events in the erdafitinib group and high-risk recurrent disease in the chemotherapy group. Baseline demographic and clinical characteristics were generally balanced between treatment groups (Tables 12 and 13). Only two black patients were enrolled, likely due to limited enrollment in the United States (Table 14). At baseline, 57% and 58% of patients were BCG-refractory, and 59% and 58% had tumor stage Ta in the erdafitinib and chemotherapy groups, respectively. Ninety-four percent of patients in Cohort 1 had FGFR3 mutations, and 10% had FGFR gene fusions. The FGFR3-S249C mutation was the most common alteration, followed by the FGFR3-Y373C mutation (Table 15).

[0324] Effectiveness The median follow-up for RFS was 13.4 months in both treatment groups. At the clinical cutoff, a total of 25 RFS events had occurred (11, erdafitinib; 14, chemotherapy). The Kaplan-Meier estimate (95% confidence interval [CI]) of median RFS was not reached in the erdafitinib group (16.9 months to not estimable) and was 11.6 (6.4-20.1) months in the chemotherapy group (Figure 7A and Table 16). The hazard ratio based on the Cox proportional hazards model was 0.28 (95% CI, 0.1-0.6) (nominal two-sided log-rank test P = 0.0008). The 6- and 12-month RFS rates (95% CI) were 96% (83.7-98.9) and 77% (60.0-87.4), respectively, for erdafitinib compared with 73% (50.1-87.1) and 41% (18.9-61.7) for chemotherapy.

[0325] Nine patients (38%) crossed over from chemotherapy to receive erdafitinib. The RFS benefit observed with erdafitinib was generally consistent across subgroups based on prior BCG therapy (BCG-experienced vs. BCG-refractory) and tumor stage (Ta vs. T1) (Figure 7B; Table 17).

[0326] safety The safety analysis set included 72 patients (49 in the erdafitinib group and 23 in the chemotherapy group) who received at least one study treatment. The median exposure duration (range) was 9.0 (1.0-23.1) months for erdafitinib and 6.4 (1.1-14.2) months for chemotherapy.

[0327] As shown in Table 18, adverse events of any cause were reported in 100% and 83% of patients in the erdafitinib and chemotherapy groups, respectively (overall safety in Table 19). The most frequent grade 3 or higher treatment-related adverse events were stomatitis (10%), nail dystrophy (4%), and glossitis (4%) in the erdafitinib group, and increased alanine aminotransferase (4%) in the chemotherapy group (Table 20). Serious adverse events occurred in 11 (22%) and 3 (13%) patients in the erdafitinib and chemotherapy groups, respectively (Table 21).

[0328] No treatment-emergent adverse events leading to death were reported. After treatment discontinuation, three deaths occurred in the erdafitinib group: two due to disease progression (395 and 249 days after discontinuation) and one due to a second malignancy (relapse of a previous diffuse large B-cell lymphoma); all three were considered unrelated to treatment.

[0329] Adverse events of any cause led to treatment discontinuation in 14 patients (29%) in the erdafitinib group and in none in the chemotherapy group (Table 22). The most frequent adverse event leading to erdafitinib discontinuation was stomatitis (6%).

[0330] Based on the known safety profile of erdafitinib, adverse events of interest included nail disorders (78%), hyperphosphatemia (74%), ophthalmologic disorders (excluding central serous retinopathy, 59%), skin disorders (51%), dry mouth (47%), mucositis (41%), and central serous retinopathy (39%) (Table 23). Most central serous retinopathy adverse events were either grade 1 or 2, with two patients in the erdafitinib group reporting grade 3 events (one patient had resolved the event and the other was resolving at the clinical cutoff). Central serous retinopathy events (central serous chorioretinopathy, macular retinal pigment epithelial detachment, maculopathy, and macular detachment) led to treatment discontinuation in six patients.

[0331] The main results are as follows: Trial enrollment was halted due to slow accrual.

[0332] Seventy-three patients were randomized 2:1 to receive erdafitinib (n = 49) or chemotherapy (n = 24). The median follow-up for RFS was 13.4 months in both groups. Median RFS was not reached for erdafitinib (95% confidence interval [CI] 16.9-not estimable) and 11.6 months for chemotherapy (95% CI 6.4-20.1), with an estimated hazard ratio of 0.28 (95% CI 0.1-0.6; nominal P = 0.0008).

[0333] In this population, safety results were generally consistent with the known profiles for erdafitinib and chemotherapy.

[0334] In conclusion, erdafitinib prolonged RFS compared with intravesical chemotherapy in patients with papillary-only high-risk NMIBC and FGFR alterations who had disease recurrence after BCG therapy and who refused or were ineligible for radical cystectomy.

[0335] Highlights include: · Erdafitinib prolonged RFS versus intravesical chemotherapy in papillary-only FGFR-altered BCG-treated high-risk NMIBC; With a median follow-up of 13.4 months, median RFS was not reached with erdafitinib and was 11.6 months with chemotherapy. The RFS benefit observed with erdafitinib was further reflected by the 6- and 12-month RFS rates and subgroups studied. In this population, safety results were generally consistent with the known profiles of erdafitinib and chemotherapy. This study demonstrated an innovative application of precision medicine to explore FGFR inhibition as a treatment option in NMIBC.

[0336] Consideration With a median follow-up of 13.4 months, the median RFS was not reached in the erdafitinib group and was 11.6 months in the chemotherapy group, yielding a hazard ratio of 0.28. The observed hazard ratio reflects the long-term RFS of erdafitinib treatment compared with standard-of-care chemotherapy in patients with papillary-only high-risk NMIBC with selected FGFR alterations and disease recurrence after BCG therapy who refused or were ineligible for radical cystectomy. The RFS curves show a clear early separation supporting early clinical benefit, and the separation continues over longer follow-up. By approximately 15 months, the RFS curves demonstrate sustained disease control with erdafitinib. Notably, the RFS benefit of erdafitinib over chemotherapy was consistent across evaluated subgroups, including prior BCG therapy (BCG-experienced vs. BCG-refractory) and tumor stage (Ta vs. T1).

[0337] In this patient population, safety results were consistent with the known safety profiles of erdafitinib and intravesical chemotherapy, with no new safety signals observed. The adverse events observed with erdafitinib and the higher rate of treatment-related adverse events of grade ≥ 3 were consistent with the on-target effect of FGFR inhibition, mechanism of action, and systemic exposure to erdafitinib. Most adverse events in the erdafitinib group were grade 1 or 2 and were managed with dose reduction and interruption. Discontinuation due to treatment-related adverse events was more frequent with erdafitinib (29%) compared with intravesical chemotherapy (0%). No treatment-related deaths were reported in either group. However, three deaths unrelated to treatment occurred after discontinuation in the erdafitinib group.

[0338] Of note, central serous retinopathy events, a known class effect of FGFR inhibitors, were more frequent in the erdafitinib group in this trial (6 mg daily) than previously reported for 8 mg erdafitinib with dose escalation in patients with locally advanced or metastatic urothelial carcinoma (39% vs. 27%), likely as a result of prior optical coherence tomography surveillance, despite symptoms and the longer treatment duration in this trial. Most events of central serous retinopathy had resolved at the time of clinical cutoff.

[0339] Of the first four patients treated with erdafitinib at 8 mg daily with dose escalation to 9 mg, three discontinued erdafitinib due to grade 2 toxicity, and two of those three discontinued erdafitinib (one due to grade 2 toxicity), highlighting the low tolerability of systemic toxicity in patients with NMIBC. The 6 mg dose in this trial resulted in manageable toxicity while maintaining efficacy, and the median treatment duration was 9.0 months for erdafitinib.

[0340] [Table 13] BCG, Mycobacterium Calmette-Guérin tuberculosis.

[0341] [Table 14] Data are in n (%) unless otherwise stated. a All patients screened for Cohort 1 signed a Molecular Eligibility Study Informed Consent Form (ICF) or a Full Study ICF for molecular eligibility screening. b All patients screened for Cohort 1 who signed the molecular eligibility test ICF. The N from "patients entered molecular screening" was used as the denominator to calculate the percentages for "patients molecularly tested" and "patients not molecularly tested." cThe N from "molecularly tested patients" was used as the denominator to calculate the percentage for that subcategory. d The N from "numerally untested patients" was used as the denominator to calculate the percentage for that subcategory. e This includes "insufficient tumor cells," "insufficient RNA," and "insufficient quantity." f All patients who were screened for Cohort 1, were FGFR positive, and signed the full study ICF. The N from "Patients who entered full study screening" was used as the denominator to calculate the percentages for "Passed full study screening" and "Failed full study screening." g The N from "failed all study screening" was used as the denominator to calculate the percentage for that subcategory.

[0342] [Table 15] Data are in n (%) unless otherwise stated. a N for each parameter reflects non-missing values. Percentages are calculated using the number of patients in each treatment group with available data as the denominator. b Scores on the ECOG scale range from 0 (no disability) to 5 (death). c One patient was found to have a false-positive QIAGEN test and received chemotherapy. d Patients may have both FGFR3 mutations and gene fusions. BCG, Mycobacterium Calmette-Guérin; ECOG, Eastern Cooperative Oncology Group.

[0343] [Table 16] SEER, The Surveillance, Epidemiology, and End Results Program.

[0344] [Table 17] Data are in n (%). a The denominator was based on the total number of FGFR-positive patients in the FGFR panel. b One patient was found to have a false-positive QIAGEN test and received chemotherapy.

[0345] [Table 18] a RFS in months was calculated as (date of RFS event or censoring - date of randomization + 1) / (365.25 / 12). If the patient was relapse-free, alive, or had an unknown status at the assessment cutoff date, RFS was censored at the date of the last tumor assessment. Patients without post-baseline disease assessments were censored at the date of randomization. Patients who withdrew consent before an RFS event were censored at the last tumor assessment. Patients who were lost to follow-up were censored at the last tumor assessment before being lost to follow-up. Patients who initiated subsequent anticancer therapy without an RFS event were censored at the last disease assessment before the initiation of subsequent anticancer therapy. b HRs and 95% CIs were estimated using stratified Cox proportional hazards regression models. A hazard ratio of less than 1 indicates a longer RFS in the erdafitinib group compared with the chemotherapy (gemcitabine or mitomycin) group. c P values ​​comparing RFS between treatment groups were based on the unstratified log-rank test. CI, confidence interval; HR, hazard ratio; NE, not estimable; RFS, recurrence-free survival

[0346] [Table 19] a Hazard ratios and 95% CIs were estimated using stratified Cox proportional hazards regression models. A hazard ratio of less than 1 indicates a longer RFS in the erdafitinib group compared with the chemotherapy (gemcitabine or mitomycin) group. b P values ​​comparing RFS between treatment groups were based on the unstratified log-rank test. BCG, Mycobacterium Calmette-Guérin; CI, confidence interval; max, maximum; min, minimum; NE, not estimable; RFS, recurrence-free survival.

[0347] [Table 20] Data are in n (%). a Adverse events of any cause reported in more than 15% of patients in either treatment group are listed by preferred duration and worst toxicity grade. For patients crossing over from chemotherapy to erdafitinib treatment, this table summarizes adverse events prior to crossover. b Patients are counted only once for any given event, regardless of the number of times they actually experience that event. The event experienced by the patient with the worst toxicity is used. If a patient lacks toxicity for a particular adverse event, they are counted only in the total column for that adverse event. Adverse events are coded using MedDRA Version 26.0.

[0348] [Table 21] Data are in n (%). a For patients crossing over from chemotherapy to erdafitinib treatment, this table summarizes adverse events prior to crossover. bCOVID-19 related adverse events are based on events coded to COVID-19 MedDRA terms and events identified via COVID-19 adverse event case forms.

[0349] [Table 22] Data are N (%). a All treatment-related adverse events reported in patients in either treatment group are listed by preferred duration and worst toxicity grade. For patients crossing over from chemotherapy to erdafitinib treatment, this table summarizes adverse events prior to crossover. b Patients are counted only once for any given event, regardless of the number of times they actually experience that event. The event experienced by the patient with the worst toxicity is used. If a patient lacks toxicity for a particular adverse event, they are counted only in the total column for that adverse event. Adverse events are coded using MedDRA Version 26.0.

[0350] [Table 23] Data are in n (%). a All adverse events of any cause reported in more than 2% of patients in either treatment group are listed by preferred duration and worst toxicity grade. For patients crossing over from chemotherapy to erdafitinib treatment, this table summarizes adverse events prior to crossover. b A patient is counted only once for any given event, regardless of the number of times they actually experienced that event. The event experienced by the patient with the worst toxicity is used. If a patient lacks toxicity for a particular adverse event, they are counted only in the total column for that adverse event. Adverse events are coded using MedDRA version 26.0.

[0351] [Table 24] Data are in n (%). a For patients crossing over from chemotherapy to erdafitinib treatment, this table summarizes adverse events prior to crossover. b Patients are counted only once for any given event, regardless of the number of times they actually experience that event. The event experienced by the patient with the worst toxicity is used. If a patient lacks toxicity for a particular adverse event, they are counted only in the total column for that adverse event. Adverse events are coded using MedDRA Version 26.0.

[0352] [Table 25-1]

[0353] [Table 25-2] Data are in n (%). a All adverse events of any cause by category of particular interest, preferred term, and worst toxicity grade reported in more than 5% of patients in either treatment group for nail disorders, hyperphosphatemia, ophthalmopathy, skin disorders, dry mouth, and mucositis, and in more than 2% of patients for central serous retinopathy events are listed. For patients crossing over from chemotherapy to erdafitinib treatment, this table summarizes adverse events before crossover. b Patients are counted only once for any given event, regardless of the number of times they actually experience that event. The event experienced by the patient with the worst toxicity is used. If a patient lacks toxicity for a particular adverse event, they are counted only in the total column for that adverse event. Adverse events are coded using MedDRA Version 26.0.

[0354] The following sections describe specific embodiments of the present invention. 1. A method for treating high-risk non-muscle-invasive bladder cancer (HR-NMIBC), comprising administering a fibroblast growth factor receptor (FGFR) inhibitor at a dose of about 6 mg / day to a patient diagnosed with HR-NMIBC and having at least one FGFR2 and / or FGFR3 gene mutation. 2. The method according to item 1, wherein prior to said administration of said FGFR inhibitor, the patient has undergone Mycobacterium Calmette-Guerin (BCG) therapy. 3. The method according to item 2, wherein the BCG therapy is a suitable BCG therapy. 4. The method according to item 2 or 3, wherein the patient is refractory to BCG therapy. 5. The method according to item 2 or 3, wherein the patient has undergone BCG vaccination. 6. The method of any one of items 1 to 5, wherein the patient has a papillary tumor. 7. The method of any one of items 1 to 6, wherein the patient has carcinoma in situ. 8. The method of any one of items 1 to 7, wherein the patient has not previously undergone cystectomy or is ineligible for cystectomy. 9. The method according to any one of items 1 to 8, wherein said administration of an FGFR inhibitor results in an increase in recurrence-free survival compared to a patient population with HR-NMIBC receiving a placebo. 10. The method of any one of items 1 to 8, wherein said administration of an FGFR inhibitor results in increased recurrence-free survival compared to a patient population with HR-NMIBC treated with intravesical gemcitabine or intravesical mitomycin C (MMC) / hyperthermic MMC. 11. The method of any one of items 1 to 10, wherein the patient exhibits a complete response to the FGFR inhibitor at about 6 months. 12. The method according to any one of items 1 to 11, wherein the FGFR2 gene mutation and / or FGFR3 gene mutation is an FGFR3 gene mutation, an FGFR2 gene fusion, or an FGFR3 gene fusion. 13. The method of item 12, wherein the FGFR3 gene mutation is R248C, S249C, G370C, Y373C, or any combination thereof. 14. The method of item 12, wherein the FGFR2 gene fusion or FGFR3 gene fusion is FGFR3-TACC3, in particular FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof. 15. The method of any one of items 1 to 14, further comprising assessing a biological sample from the patient for the presence of at least one of an FGFR2 genetic mutation and / or an FGFR3 genetic mutation prior to said administration of an FGFR inhibitor. 16. The method according to item 15, wherein the biological sample is a blood, lymph, bone marrow, solid tumor sample, or any combination thereof. 17. The method according to any one of items 1 to 16, wherein the FGFR inhibitor is erdafitinib. 18. The method of item 17, wherein erdafitinib is administered daily. 19. The method according to item 17 or 18, wherein erdafitinib is administered orally. 20. The method of any one of items 17 to 19, wherein erdafitinib is administered orally on a daily dosing schedule. 21. The method of any one of items 17 to 19, wherein erdafitinib is administered at a dose of about 6 mg once daily. 22. The method of any one of items 17 to 19, wherein the dose of erdafitinib is increased from 6 mg / day to 8 mg / day after initiating treatment if the patient exhibits a serum phosphate (PO4) level of less than about 5.5 mg / dL. 23. The method of any one of items 17 to 22, wherein erdafitinib is administered in a solid dosage form. 24. The method according to item 23, wherein the solid dosage form is a tablet. 25. A method of treating high-risk non-muscle-invasive bladder cancer (HR-NMIBC), comprising: (a) assessing a biological sample from a patient diagnosed with HR-NMIBC for the presence of one or more fibroblast growth factor receptor (FGFR) gene mutations; (b) administering to the patient a fibroblast growth factor receptor (FGFR) inhibitor at a dose of about 6 mg / day if one or more FGFR gene mutations are present in the sample. 26. A method for treating intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC), comprising administering a fibroblast growth factor receptor (FGFR) inhibitor at a dose of about 6 mg / day to a patient diagnosed with IR-NMIBC and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation. 27. The method according to item 26, wherein the patient has a papillary tumor. 28. The method according to item 26 or 27, wherein the patient has an incomplete transurethral resection. 29. The method of any one of items 26 to 28, wherein the patient exhibits a complete response to the FGFR inhibitor at about 3 months. 30. The method according to any one of items 26 to 29, wherein the FGFR2 gene mutation and / or FGFR3 gene mutation is an FGFR3 gene mutation, an FGFR2 gene fusion, or an FGFR3 gene fusion. 31. The method of item 30, wherein the FGFR3 gene mutation is R248C, S249C, G370C, Y373C, or any combination thereof. 32. The method of item 30, wherein the FGFR2 gene fusion or FGFR3 gene fusion is FGFR3-TACC3, in particular FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof. 33. The method according to any one of items 26 to 32, wherein the FGFR inhibitor is erdafitinib. 34. A fibroblast growth factor receptor (FGFR) inhibitor for use in the treatment of high-risk non-muscle-invasive bladder cancer (HR-NMIBC) in patients with at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor is administered at a dose of about 6 mg / day. 35. A fibroblast growth factor receptor (FGFR) inhibitor for use in the treatment of intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC) in patients with at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor is administered at a dose of about 6 mg / day. 36. Use of a fibroblast growth factor receptor (FGFR) inhibitor for the manufacture of a medicament for the treatment of patients diagnosed with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) with at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor is administered at a dose of about 6 mg / day. 37. Use of a fibroblast growth factor receptor (FGFR) inhibitor for the manufacture of a medicament for the treatment of patients diagnosed with intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC) with at least one FGFR2 gene mutation and / or FGFR3 gene mutation, wherein the FGFR inhibitor is administered at a dose of about 6 mg / day. 38. The use of a fibroblast growth factor receptor (FGFR) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor for use according to any one of items 34 to 37, wherein the patient has received Mycobacterium Calmette-Guérin (BCG) therapy prior to administration of the FGFR inhibitor. 39. The use of a fibroblast growth factor receptor (FGFR) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor for use according to item 38, wherein the BCG therapy is a suitable BCG therapy. 40. The use of a fibroblast growth factor receptor (FGFR) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor for use according to item 38 or 39, wherein the patient is refractory to BCG therapy. 41. The use of a fibroblast growth factor receptor (FGFR) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor for use according to item 38 or 39, wherein the patient has undergone BCG therapy. 42. The use of a fibroblast growth factor receptor (FGFR) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor for use according to any one of items 34 to 41, wherein the patient has a papillary tumor. 43. The use of a fibroblast growth factor receptor (FGFR) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor for use according to any one of items 34 to 42, wherein the patient has carcinoma in situ. 44. The use of a fibroblast growth factor receptor (FGFR) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor for use according to any one of items 34 to 43, wherein the patient has not previously undergone a cystectomy or is ineligible for a cystectomy. 45. Use of a fibroblast growth factor receptor (FGFR) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor for use according to any one of items 34 to 44, wherein the FGFR2 gene mutation and / or FGFR3 gene mutation is an FGFR3 gene mutation, an FGFR2 gene fusion, or an FGFR3 gene fusion. 46. ​​The fibroblast growth factor receptor (FGFR) inhibitor for use according to item 45 or the use of a fibroblast growth factor receptor (FGFR) inhibitor, wherein the FGFR3 gene mutation is R248C, S249C, G370C, Y373C, or any combination thereof. 47. The use of a fibroblast growth factor receptor (FGFR) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor for use according to item 45, wherein the FGFR2 gene fusion or FGFR3 gene fusion is FGFR3-TACC3, in particular FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof. 48. A fibroblast growth factor receptor (FGFR) inhibitor or a fibroblast growth factor receptor (FGFR) inhibitor for use according to any one of items 34 to 47, wherein the FGFR inhibitor is erdafitinib.

[0355] The following items describe the subject matter of the present invention. 1. A method of treating BCG-refractory HR-NMIBC in a patient with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, comprising, consisting of, or consisting essentially of administering to the patient an FGFR inhibitor, particularly erdafitinib, wherein the treatment results in a CR rate of about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, a CR rate of about 100%, or a CR rate of 100% at about 8 weeks from the start of treatment, or a CR rate in the range of 75%-100%, or in the range of 80%-100%, or in the range of 90%-100%, or in the range of 95%-100% at about 8 weeks from the start of treatment. 2. Use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-refractory HR-NMIBC harboring one or more FGFR2 or FGFR3 gene mutations that present as carcinoma in situ with or without papillary neoplasia, wherein the treatment results in a CR rate of about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, a CR rate of about 100%, or a CR rate of 100% at about 8 weeks from the start of treatment, or a CR rate in the range of 75% to 100%, or in the range of 80% to 100%, or in the range of 90% to 100%, or in the range of 95% to 100% at about 8 weeks from the start of treatment. 3. An FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment results in a CR rate of about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, a CR rate that is about 100% or is 100% at about 8 weeks from the start of treatment, or a CR rate in the range of 75% to 100%, or in the range of 80% to 100%, or in the range of 90% to 100%, or in the range of 95% to 100% at about 8 weeks from the start of treatment. 4. The method or use according to any one of items 1 to 3, wherein the CR rate is in the range of 75% to 100%, or in the range of 80% to 100%, or in the range of 90% to 100%, or in the range of 95% to 100%, or 100%. 5. The method or use according to item 4, wherein the CR rate is 100%. 6. The method or use according to any one of items 1 to 5, wherein the treatment is for patients who refuse cystectomy or are ineligible for cystectomy. 7. The method or use according to any one of items 1 to 6, wherein the FGFR inhibitor is erdafitinib. 8. The method or use according to item 7, wherein erdafitinib is or is to be administered in a dose of about 6 mg / day, in particular once a day. 9. A method of treating BCG-refractory HR-NMIBC in a patient with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, to the patient, wherein the treatment results in a reduction of about 50%, at least about 50%, at least about 55%, at least about 55%, at least about 60 ... 0%, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or an 80% CR rate, or a CR rate in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80% at about 20 weeks from the start of treatment. 10. Use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-refractory HR-NMIBC harboring one or more FGFR2 or FGFR3 gene mutations and presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment results in a CR rate of about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate that is 80%, or a CR rate in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80% at about 20 weeks from the start of treatment. 11. An FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment results in a CR rate of about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate that is 80%, or a CR rate in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80% at about 20 weeks from the start of treatment. 12. The method or use according to any one of items 9 to 11, wherein the CR rate is about 75%. 13. The method or use according to any one of items 9 to 11, wherein the CR rate is about 80%. 14. The method or use according to any one of items 9 to 13, wherein the treatment is for patients who refuse cystectomy or are ineligible for cystectomy. 15. The method or use according to any one of items 9 to 14, wherein the FGFR inhibitor is erdafitinib. 16. The method or use according to item 15, wherein erdafitinib is or is to be administered in a dose of about 6 mg / day, in particular once a day. 17. A method of treating BCG-refractory HR-NMIBC in a patient with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, to the patient, wherein the treatment achieves a remission rate of about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 65%, at about 31 weeks from the start of treatment. %, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or about 78%, or at about 31 weeks from the start of treatment, a CR rate in the range of 43% to 88%, or in the range of 45% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80%. 1. A method of treating BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without head tumors, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, to a patient, wherein the treatment results in a reduction of about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, or at least about 65% of the total BCG-refractory HR-NMIBC at about 32 weeks from the start of treatment. or a CR rate of about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or about 78%, or a CR rate at about 32 weeks from the start of treatment that is in the range of 43% to 88%, or in the range of 45% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80%, particularly in the range of 70% to 88%, particularly about 73%. 18. Use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein treatment achieves about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, or about 70% success rate at about 31 weeks from the start of treatment. or a CR rate that is at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or about 78%, or a CR rate that is in the range of 43% to 88%, or in the range of 45% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80% at about 31 weeks from the start of treatment. 1. Use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without associated HBsAg, wherein treatment achieves a survival benefit of about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 75 ... Use that results in a CR rate of about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate that is about 78%, or that results in a CR rate at about 32 weeks from the start of treatment that is in the range of 43% to 88%, or in the range of 45% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80%, particularly in the range of 70% to 88%, particularly about 73%. 19. An FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-refractory HR-NMIBC patients with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment achieves a survival rate of about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 75 ... or a CR rate of about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or about 78%, or a CR rate in the range of 43% to 88%, or in the range of 45% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80%, at about 31 weeks from the start of treatment. 1. An FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without associated FGFR2 or FGFR3 gene mutations, wherein the treatment achieves a survival benefit of about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, or at least about 80% at about 32 weeks from the start of treatment. or a CR rate at about 32 weeks from the start of treatment that is in the range of 43% to 88%, or in the range of 45% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80%, particularly in the range of 70% to 88%, particularly about 73%. 20. The method or use according to any one of items 17 to 19, wherein the CR rate is about 78%, in particular 77.8%. 21. The method or use according to any one of items 17 to 20, wherein the treatment is for patients who refuse cystectomy or are ineligible for cystectomy. 22. The method or use according to any one of items 17 to 21, wherein the FGFR inhibitor is erdafitinib. 23. The method or use according to item 22, wherein erdafitinib is or is to be administered in a dose of about 6 mg / day, in particular once a day. 24. A method of treating BCG-refractory HR-NMIBC in a patient with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, to the patient, wherein the treatment achieves a reduction in BCG-refractory HR-NMIBC of about 30%, at least about 30%, about 35%, at least about 35%, about 40%, at least about 40%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at about 43 weeks from the start of treatment. A method that results in a CR rate of at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate of about 71% or 71.4%, or a CR rate at about 43 weeks from the start of treatment in the range of 30% to 88%, or in the range of 35% to 88%, or in the range of 40% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 60% to 88%, or in the range of 75% to 88%, or in the range of 60% to 80%, or in the range of 65% to 80%, or in the range of 75% to 80%, or in the range of 70% to 80%, or in the range of 70% to 75%. 25. Use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein treatment achieves about 30%, at least about 30%, about 35%, at least about 35%, about 40%, at least about 40%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, or Use that results in a CR rate of at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate that is about 71%, or 71.4%, or that results in a CR rate at about 43 weeks from the start of treatment in the range of 30% to 88%, or in the range of 35% to 88%, or in the range of 40% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 60% to 88%, or in the range of 75% to 88%, or in the range of 60% to 80%, or in the range of 65% to 80%, or in the range of 75% to 80%, or in the range of 70% to 80%, or in the range of 70% to 75%. 26. An FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-refractory HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment results in a reduction of about 30%, at least about 30%, about 35%, at least about 35%, about 40%, at least about 40%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 85%, or at least about 87% of patients with BCG-refractory HR-NMIBC at about 43 weeks from the start of treatment. an FGFR inhibitor that results in a CR rate of 0%, about 85%, at least about 85%, about 87%, or a CR rate of about 71% or 71.4%, or that results in a CR rate at about 43 weeks from the start of treatment in the range of 30% to 88%, or in the range of 35% to 88%, or in the range of 40% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 60% to 88%, or in the range of 75% to 88%, or in the range of 60% to 80%, or in the range of 65% to 80%, or in the range of 75% to 80%, or in the range of 70% to 80%, or in the range of 70% to 75%. 27. The method or use according to any one of items 24 to 26, wherein the CR rate is about 71%, in particular 71.4%. 28. The method or use according to any one of items 24 to 17, wherein the treatment is for patients who refuse cystectomy or are ineligible for cystectomy. 29. The method or use according to any one of items 24 to 28, wherein the FGFR inhibitor is erdafitinib. 30. The method or use according to item 29, wherein erdafitinib is or is to be administered in a dose of about 6 mg / day, in particular once a day. 31. A method for treating IR-NMIBC in patients with one or more FGFR2 or FGFR3 gene mutations (no prior BCG treatment required), particularly in patients where all previous tumors were low grade (grade 1-2), Ta / T1, and there was no previous carcinoma in situ, and where a marker lesion remains after incomplete TUR (transurethral resection), particularly a single, untreated bladder tumor (marker lesion) of 5-10 mm, comprising, consisting of, or consisting essentially of, administering to the patient an FGFR inhibitor, particularly erdafitinib, and whereby the treatment is successful. wherein the treatment results in a CR rate of about 72%, at least about 72%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, or about 100%, or a CR rate in the range of 72% to 100%, or in the range of 75% to 100%, or in the range of 80% to 100%, or in the range of 70% to 95%, or in the range of 70% to 90%, or in the range of 70% to 80%, or a CR rate that is about 72% or 72.2%. 32. Use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of IR-NMIBC with one or more FGFR2 or FGFR3 gene mutations (not requiring previous BCG treatment) and marker lesions after incomplete TUR (transurethral resection), particularly a single, untreated bladder tumor (marker lesion) of 5-10 mm, wherein treatment is effective in about 72%, at least about 72%, about 75%, at least about 75%, about 80%, or at least or results in a CR rate of about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, or about 100%, or a CR rate in the range of 72% to 100%, or in the range of 75% to 100%, or in the range of 80% to 100%, or in the range of 70% to 95%, or in the range of 70% to 90%, or in the range of 70% to 80%, or a CR rate that is about 72% or 72.2%. 33. An FGFR inhibitor, particularly erdafitinib, for use in the treatment of IR-NMIBC with one or more FGFR2 or FGFR3 gene mutations (not requiring previous BCG treatment) and marker lesions after incomplete TUR (transurethral resection), particularly a single, untreated bladder tumor (marker lesion) of 5-10 mm, wherein treatment achieves an improvement of about 72%, at least about 72%, about 75%, at least about 75%, about 80%, at least about 80%, An FGFR inhibitor that results in a CR rate of about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, or about 100%, or a CR rate in the range of 72% to 100%, or in the range of 75% to 100%, or in the range of 80% to 100%, or in the range of 70% to 95%, or in the range of 70% to 90%, or in the range of 70% to 80%, or a CR rate that is about 72% or 72.2%. 34. The method or use according to any one of items 31 to 33, wherein the CR rate is about 72%, in particular 72.2%. 35. The method or use according to any one of items 31 to 34, wherein the treatment is for patients in whom all previous tumors are low grade (grade 1-2), Ta / T1, and there is no previous carcinoma in situ. 36. The method or use according to any one of items 31 to 35, wherein the FGFR inhibitor is erdafitinib. 37. The method or use according to any one of items 31 to 36, wherein erdafitinib is or is to be administered in a dose of about 6 mg / day, in particular once a day. 38. The method or use according to any one of items 1 to 37, wherein the one or more FGFR2 gene mutations or FGFR3 gene mutations are FGFR3 gene mutations, FGFR2 gene fusions, or FGFR3 gene fusions. 39. The method or use according to item 38, wherein the FGFR3 gene mutation is R248C, S249C, G370C, Y373C, or any combination thereof. 40. The method or use according to item 38, wherein the FGFR2 gene fusion or FGFR3 gene fusion is FGFR3-TACC3, in particular FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

[0356] The examples and embodiments described herein are for illustrative purposes only, and various modifications or alterations will be suggested to those skilled in the art and are within the spirit and scope of this application and the accompanying clauses.

Claims

1. 1. A method of treating BCG-refractory HR-NMIBC in a patient with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, comprising, consisting of, or consisting essentially of administering to said patient an FGFR inhibitor, particularly erdafitinib, wherein said treatment results in a CR rate of about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, a CR rate of about 100% or is 100%, or a CR rate in the range of 75% to 100%, or in the range of 80% to 100%, or in the range of 90% to 100%, or in the range of 95% to 100% at about 8 weeks from the start of treatment.

2. 1. Use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-refractory HR-NMIBC harboring one or more FGFR2 or FGFR3 gene mutations and presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment results in a CR rate of about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, a CR rate of about 100% or is 100%, or a CR rate in the range of 75% to 100%, or in the range of 80% to 100%, or in the range of 90% to 100%, or in the range of 95% to 100% at about 8 weeks from the start of treatment.

3. 1. An FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-refractory HR-NMIBC harboring one or more FGFR2 or FGFR3 gene mutations and presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment results in a CR rate of about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, a CR rate of about 100% or is 100%, or a CR rate in the range of 75% to 100%, or in the range of 80% to 100%, or in the range of 90% to 100%, or in the range of 95% to 100% at about 8 weeks from the start of treatment.

4. 4. The method or use according to any one of claims 1 to 3, wherein the CR rate is in the range of 75% to 100%, or in the range of 80% to 100%, or in the range of 90% to 100%, or in the range of 95% to 100%, or 100%, particularly the CR rate is in the range of 90% to 95%, particularly about 94%.

5. The method or use of claim 4, wherein the CR rate is 100%.

6. The method or use of any one of claims 1 to 5, wherein the treatment is for patients who refuse or are ineligible for cystectomy.

7. The method or use according to any one of claims 1 to 6, wherein the FGFR inhibitor is erdafitinib.

8. 8. The method or use according to claim 7, wherein erdafitinib is or is to be administered in a dose of about 6 mg / day, in particular once a day.

9. 1. A method of treating BCG-refractory HR-NMIBC in a patient with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, to said patient, wherein said treatment results in a reduction of about 50%, at least about 50%, at least about 55%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75 ... A method that results in a CR rate of 60%, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or an 80% CR rate, or a CR rate in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80% at about 20 weeks from the start of treatment.

10. 1. Use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-refractory HR-NMIBC harboring one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment results in a reduction of about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, at about 20 weeks from the start of treatment. %, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate that is 80%, or a CR rate in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80% at about 20 weeks from the start of treatment.

11. 1. An FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-refractory HR-NMIBC harboring one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment results in a reduction of about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, An FGFR inhibitor that results in a CR rate of at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate that is 80%, or that results in a CR rate in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80% at about 20 weeks from the start of treatment.

12. The method or use according to any one of claims 9 to 11, wherein the CR rate is about 75%.

13. The method or use according to any one of claims 9 to 11, wherein the CR rate is about 80%.

14. The method or use of any one of claims 9 to 13, wherein the treatment is for patients who refuse or are ineligible for cystectomy.

15. The method or use according to any one of claims 9 to 14, wherein the FGFR inhibitor is erdafitinib.

16. 16. The method or use according to claim 15, wherein erdafitinib is or is to be administered in a dose of about 6 mg / day, in particular once a day.

17. 1. A method of treating BCG-refractory HR-NMIBC in a patient with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, to said patient, wherein said treatment results in a remission rate of about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60% at about 31 weeks from the start of treatment. or a CR rate of about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or about 78%, or a CR rate of 43% to 88%, or 45% to 88%, or 50% to 88%, or 60% to 88%, or 70% to 88%, or 75% to 88%, or 75% to 80% at about 31 weeks from the start of treatment; 1. A method of treating BCG-refractory HR-NMIBC in a patient with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, to said patient, wherein said treatment results in an improvement of about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, or at least about 70% at about 32 weeks from the start of treatment. or a CR rate of about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or about 78%, or a CR rate at about 32 weeks from the start of treatment that is in the range of 43% to 88%, or in the range of 45% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80%, particularly in the range of 70% to 88%, particularly about 73%.

18. 1. Use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-refractory HR-NMIBC harboring one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment results in a reduction of about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, or a use that results in a CR rate of about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate that is about 78%, or that results in a CR rate at about 31 weeks from the start of treatment in the range of 43% to 88%, or in the range of 45% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80%; 1. Use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-refractory HR-NMIBC harboring one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment results in a reduction of about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 75 ... Use which results in a CR rate of about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate that is about 78%, or which results in a CR rate at about 32 weeks from the start of treatment that is in the range of 43% to 88%, or in the range of 45% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80%, particularly in the range of 70% to 88%, particularly about 73%.

19. 1. An FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-refractory HR-NMIBC harboring one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment results in a reduction of about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, or at least about 80% at about 31 weeks from the start of treatment. an FGFR inhibitor that results in a CR rate of at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate that is about 78%, or that results in a CR rate at about 31 weeks from the start of treatment in the range of 43% to 88%, or in the range of 45% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80%; or 1. An FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-refractory HR-NMIBC harboring one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment results in a reduction of about 43%, at least about 43%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least ... an FGFR inhibitor that results in a CR rate of 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate that is about 78%, or that results in a CR rate at about 32 weeks from the start of treatment that is in the range of 43% to 88%, or in the range of 45% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 75% to 88%, or in the range of 75% to 80%, particularly in the range of 70% to 88%, particularly about 73%.

20. The method or use according to any one of claims 17 to 19, wherein the CR rate is about 78%, in particular 77.8%.

21. 21. The method or use of any one of claims 17 to 20, wherein the treatment is for patients who refuse or are ineligible for cystectomy.

22. The method or use of any one of claims 17 to 21, wherein the FGFR inhibitor is erdafitinib.

23. 23. The method or use according to claim 22, wherein erdafitinib is or is to be administered in a dose of about 6 mg / day, in particular once a day.

24. 1. A method of treating BCG-refractory HR-NMIBC in a patient with one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor, particularly erdafitinib, to said patient, wherein said treatment results in a reduction of about 30%, at least about 30%, at least about 35%, at least about 35%, at least about 43 ... or results in a CR rate of 0%, at least about 40%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 87%, or a CR rate of about 71% or 71.4%; or A method which results in a CR rate at about 43 weeks from the start of treatment in the range of 30% to 88%, or in the range of 35% to 88%, or in the range of 40% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 60% to 88%, or in the range of 75% to 88%, or in the range of 60% to 80%, or in the range of 65% to 80%, or in the range of 75% to 80%, or in the range of 70% to 80%, or in the range of 70% to 75%.

25. 1. Use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-refractory HR-NMIBC harboring one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, said treatment resulting in a reduction in the incidence of BCG-refractory HR-NMIBC of about 30%, at least about 30%, about 35%, at least about 35%, about 40%, at least about 40%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, or at least about 90% of patients at about 43 weeks from the start of treatment. or a CR rate of at least about 80%, about 85%, at least about 85%, about 87%, or about 71% or 71.4%, or a CR rate of 30% to 88%, or 35% to 88%, or 40% to 88%, or 50% to 88%, or 60% to 88%, or 70% to 88%, or 60% to 88%, or 75% to 88%, or 60% to 80%, or 65% to 80%, or 75% to 80%, or 70% to 80%, or 70% to 75% at about 43 weeks from the start of treatment.

26. 1. An FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-refractory HR-NMIBC harboring one or more FGFR2 or FGFR3 gene mutations presenting as carcinoma in situ with or without papillary neoplasia, wherein the treatment results in a reduction of about 30%, at least about 30%, about 35%, at least about 35%, about 40%, at least about 40%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 85%, or at least about 90% of patients with BCG-refractory HR-NMIBC at about 43 weeks from the start of treatment. an FGFR inhibitor that results in a CR rate of 0%, about 85%, at least about 85%, about 87%, or a CR rate that is about 71% or 71.4%, or that results in a CR rate at about 43 weeks from the start of treatment in the range of 30% to 88%, or in the range of 35% to 88%, or in the range of 40% to 88%, or in the range of 50% to 88%, or in the range of 60% to 88%, or in the range of 70% to 88%, or in the range of 60% to 88%, or in the range of 75% to 88%, or in the range of 60% to 80%, or in the range of 65% to 80%, or in the range of 75% to 80%, or in the range of 70% to 80%, or in the range of 70% to 75%.

27. The method or use according to any one of claims 24 to 26, wherein the CR rate is about 71%, in particular 71.4%.

28. The method or use of any one of claims 24 to 17, wherein the treatment is for patients who refuse or are ineligible for cystectomy.

29. The method or use of any one of claims 24 to 28, wherein the FGFR inhibitor is erdafitinib.

30. 30. The method or use according to claim 29, wherein erdafitinib is or is to be administered in a dose of about 6 mg / day, in particular once a day.

31. 1. A method for treating IR-NMIBC in patients, particularly in patients where all previous tumors have been low grade (grade 1-2), Ta / T1, no previous carcinoma in situ, harboring one or more FGFR2 or FGFR3 gene mutations (no previous BCG treatment required), and where a marker lesion remains after incomplete TUR (transurethral resection), particularly a single, untreated bladder tumor (marker lesion) of 5-10 mm, comprising, consisting of, or consisting essentially of, administering to said patient an FGFR inhibitor, particularly erdafitinib, wherein said treatment wherein the treatment results in a CR rate of about 72%, at least about 72%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, or about 100%, or a CR rate in the range of 72% to 100%, or in the range of 75% to 100%, or in the range of 80% to 100%, or in the range of 70% to 95%, or in the range of 70% to 90%, or in the range of 70% to 80%, or a CR rate that is about 72% or 72.2%.

32. 1. Use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of IR-NMIBC patients with one or more FGFR2 or FGFR3 gene mutations (not requiring previous BCG treatment) and marker lesions after incomplete TUR (transurethral resection), particularly those with a single, untreated bladder tumor (marker lesion) of 5-10 mm, wherein said treatment results in a 90% or greater improvement in about 72%, at least about 72%, about 75%, at least about 75%, about 80%, at least about 90%, or at least about 100% of patients. or about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, or about 100%, or a CR rate in the range of 72% to 100%, or in the range of 75% to 100%, or in the range of 80% to 100%, or in the range of 70% to 95%, or in the range of 70% to 90%, or in the range of 70% to 80%, or a CR rate that is about 72% or 72.2%.

33. 1. An FGFR inhibitor, particularly erdafitinib, for use in the treatment of IR-NMIBC patients with one or more FGFR2 or FGFR3 gene mutations (no previous BCG treatment required) and a marker lesion after incomplete TUR (transurethral resection), particularly a single, untreated bladder tumor (marker lesion) of 5-10 mm, wherein said treatment achieves a survival rate of about 72%, at least about 72%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 90%, at least about 95 ... 95%, at least about 95%, or about 100%, or a CR rate in the range of 72% to 100%, or in the range of 75% to 100%, or in the range of 80% to 100%, or in the range of 70% to 95%, or in the range of 70% to 90%, or in the range of 70% to 80%, or a CR rate that is about 72% or 72.2%, particularly wherein the CR rate is in the range of 70% to 90%, particularly about 83%.

34. 34. The method or use according to any one of claims 31 to 33, wherein the CR rate is about 72%, in particular 72.2%, or the CR rate is about 83%, in particular about 83.3%.

35. 35. The method or use of any one of claims 31 to 34, wherein the treatment is for patients in whom all previous tumors have been low grade (grade 1-2), Ta / T1, and there has been no previous carcinoma in situ.

36. 36. The method or use of any one of claims 31 to 35, wherein the FGFR inhibitor is erdafitinib.

37. 37. The method or use according to any one of claims 31 to 36, wherein erdafitinib is or is to be administered in a dose of about 6 mg / day, in particular once a day.

38. The method or use according to any one of claims 1 to 37, wherein the one or more FGFR2 gene mutations or FGFR3 gene mutations are FGFR3 gene mutations, FGFR2 gene fusions, or FGFR3 gene fusions.

39. 39. The method or use according to claim 38, wherein the FGFR3 gene mutation is R248C, S249C, G370C, Y373C, or any combination thereof.

40. 39. The method or use of claim 38, wherein the FGFR2 gene fusion or the FGFR3 gene fusion is FGFR3-TACC3, in particular FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

41. 1. A method of treating BCG-treated HR-NMIBC in a patient with one or more FGFR2 or FGFR3 gene mutations, comprising, consisting of, or consisting essentially of administering to said patient an FGFR inhibitor, particularly erdafitinib, wherein said treatment results in a 6-month recurrence-free survival rate of at least 90%, or at least 95%, particularly about 96%.

42. 1. Use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-treated HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations, wherein said treatment results in a 6-month recurrence-free survival rate of at least 90%, or at least 95%, particularly about 96%.

43. 1. An FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-treated HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations, wherein said treatment results in a 6-month recurrence-free survival rate of at least 90%, or at least 95%, particularly about 96%.

44. 44. The method or use of any one of claims 41 to 43, wherein the treatment results in a 6-month recurrence-free survival rate of about 96%.

45. 45. The method or use of any one of claims 41 to 44, wherein the HR-NMIBC is nipple-only HR-NMIBC.

46. 46. ​​The method or use of any one of claims 41 to 45, wherein the FGFR inhibitor is erdafitinib.

47. 47. The method or use according to any one of claims 41 to 46, wherein erdafitinib is or is to be administered in a dose of about 6 mg / day, in particular once a day.

48. 1. A method of treating BCG-treated HR-NMIBC in a patient with one or more FGFR2 or FGFR3 gene mutations, comprising, consisting of, or consisting essentially of administering to said patient an FGFR inhibitor, particularly erdafitinib, wherein said treatment results in a 12-month recurrence-free survival rate of at least 70%, or at least 75%, particularly about 77%.

49. 1. Use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of BCG-treated HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations, wherein said treatment results in a 12-month recurrence-free survival rate of at least 70%, or at least 75%, particularly about 77%.

50. 1. An FGFR inhibitor, particularly erdafitinib, for use in the treatment of BCG-treated HR-NMIBC with one or more FGFR2 or FGFR3 gene mutations, wherein said treatment results in a 12-month recurrence-free survival rate of at least 70%, or at least 75%, particularly about 77%.

51. 51. The method or use of any one of claims 48 to 50, wherein the treatment results in a 12-month recurrence-free survival rate of about 77%.

52. 52. The method or use of any one of claims 48 to 51, wherein the HR-NMIBC is nipple-only HR-NMIBC.

53. 53. The method or use of any one of claims 48 to 52, wherein the FGFR inhibitor is erdafitinib.

54. 54. The method or use according to any one of claims 48 to 53, wherein erdafitinib is or is to be administered in a dose of about 6 mg / day, in particular once a day.

55. 1. A method of treating recurrent HR-NMIBC after BCG treatment with one or more FGFR2 or FGFR3 gene mutations in a patient, comprising, consisting of, or consisting essentially of administering to said patient an FGFR inhibitor, particularly erdafitinib, wherein said treatment results in a reduced recurrence or mortality rate compared to intravesical chemotherapy.

56. Use of an FGFR inhibitor, particularly erdafitinib, for the manufacture of a medicament for the treatment of HR-NMIBC that has relapsed after BCG treatment and is associated with one or more FGFR2 or FGFR3 gene mutations, wherein the treatment results in a lower recurrence or mortality rate than intravesical chemotherapy.

57. An FGFR inhibitor, particularly erdafitinib, for use in the treatment of HR-NMIBC that has relapsed after BCG treatment and is associated with one or more FGFR2 or FGFR3 gene mutations, wherein said treatment results in a lower recurrence or mortality rate than intravesical chemotherapy.

58. 58. The method or use of any one of claims 55 to 57, wherein the HR-NMIBC is Ta / T1 HR-NMIBC.

59. 59. The method or use of any one of claims 55 to 58, wherein the HR-NMIBC is nipple-only HR-NMIBC.

60. 60. The method or use of any one of claims 55 to 59, wherein the FGFR inhibitor is erdafitinib.

61. 61. The method or use according to any one of claims 55 to 60, wherein erdafitinib is or is to be administered in a dose of about 6 mg / day, in particular once a day.

62. 62. The method or use of any one of claims 55 to 61, wherein the treatment is for patients who have refused or are ineligible for radical cystectomy.

63. 63. The method or use of any one of claims 1 to 62, wherein the one or more FGFR2 gene mutations or FGFR3 gene mutations are FGFR3 gene mutations, FGFR2 gene fusions, or FGFR3 gene fusions.

64. 64. The method or use of claim 63, wherein the FGFR3 gene mutation is R248C, S249C, G370C, Y373C, or any combination thereof.

65. 64. The method or use of claim 63, wherein the FGFR2 gene fusion or the FGFR3 gene fusion is FGFR3-TACC3, in particular FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

Images