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

Abstract

This invention provides a novel cancer treatment method for patients with high-risk bladder cancer in situ (HR-NMIBC) or intermediate-risk bladder cancer in situ (IR-NMIBC) who have fibroblast growth factor receptor (FGFR) mutations or fusion positivity and experience relapse after Bacillus subtilis (BCG) therapy. [Solution] A method for treating HR-NMIBC is provided, comprising administering a fibroblast growth factor receptor (FGFR) inhibitor at a dose of approximately 8 mg per day to a patient diagnosed with HR-NMIBC who has at least one FGFR2 gene mutation and / or FGFR3 gene mutation.

Description

[Technical Field]

[0001] High-risk muscle tissue non-surgery, including administration of fibroblast growth factor receptor (FGFR) inhibitors. A method for treating invasive bladder cancer (HR-NMIBC) is disclosed herein. Treatment of intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC), including the administration of harmful drugs. The method will also be disclosed. [Background technology]

[0002] Early-stage non-muscle-invasive bladder cancer (NMIBC) is diagnosed in 70% of bladder cancer patients (I sharwal S,Konety B.Indian J Urol.2015;31 (4):289-296), of which 25% of patients had high-risk nonmuscle-invasive bladder cancer. This refers to a poorly differentiated, early-stage tumor known as HR-NMIBC. ,Sogani PC.J Urol.2001;166(4):1296-1299. HR-NMIBC is associated with a high rate of recurrence and progression of muscle invasion and muscle metastases. . Sylvester RJ et al.Eur Urol.2006;49:466 -477. The failure rate of treatment with Bacillus Calmette-Guérin (BCG) therapy in the bladder is high, and patients Recurrence is observed in approximately 30-40% of patients. (Zlotta AR et al. Can U) rol Assoc J.2009;S199-S205. It is an oral pan-FGFR inhibitor. Erdafitinib is for patients with susceptible FGFR3 or FGFR2 gene mutations within 12 months. This includes neoadjuvant or adjuvant platinum-containing chemotherapy (PCC), and at least Also, locally advanced or metastatic urothelial carcinoma that has progressed during or after one line of prior PCC ( Loriot is approved by the US FDA for the treatment of adult patients with mUC. Y et al. N Engl J Med.2019;381:338-348.

[0003] HR-NMIB positive for FGFR mutation or FGFR fusion that relapses after BCG therapy. There is a need for new cancer treatment methods for patients with C or IR-NMIBC. [Overview of the project] [Means for solving the problem]

[0004] For example, in detail, an FGFR inhibitor at a dose of approximately 8 mg per day, in detail, erdafiti Nib, more specifically erdafitinib at a dose of approximately 8 mg per day, at least one HR-NMIBC and having FGFR2 gene mutations and / or FGFR3 gene mutations HR, consisting of or essentially comprising administering to diagnosed patients -Methods for treating NMIBC are described herein. In certain embodiments, patients In a further embodiment, the patient has received BCG therapy prior to the administration of the FGFR inhibitor. BCG therapy is sufficient BCG therapy. In some embodiments, patients receive BCG therapy. In a further embodiment, the patient is a BCG survivor. In one embodiment, the patient has a papillary tumor. In a further embodiment, the patient has carcinoma in situ. In some embodiments, the patient has not previously undergone cystectomy or is ineligible. In one embodiment, an FGFR inhibitor is administered at a dose of approximately 6 mg per day, and in detail, Rudafitinib, more specifically, erdafitinib administered at a dose of approximately 6 mg per day. It should be administered or administered.

[0005] For example, in detail, an FGFR inhibitor at a dose of approximately 8 mg per day, in detail, erdafiti Nib, more specifically erdafitinib at a dose of approximately 8 mg per day, at least one IR-NMIBC and having FGFR2 gene mutations and / or FGFR3 gene mutations IR, consisting of or essentially derived from, including administering to diagnosed patients. -Methods for treating NMIBC are described herein. In certain embodiments, patients In a further embodiment, the patient has received BCG therapy prior to the administration of the FGFR inhibitor. BCG therapy is sufficient BCG therapy. In some embodiments, patients receive BCG therapy. In a further embodiment, the patient is a BCG survivor. In one embodiment, the patient has a papillary tumor. In a further embodiment, the patient has carcinoma in situ. In some embodiments, the patient has not previously undergone cystectomy or is ineligible. In one embodiment, an FGFR inhibitor is administered at a dose of approximately 6 mg per day, and in detail, Rudafitinib, more specifically, erdafitinib administered at a dose of approximately 6 mg per day. It should be administered or administered.

[0006] H For details on manufacturing medicine to treat patients diagnosed with R-NMIBC, please see below. An FGFR inhibitor administered at a dose of approximately 8 mg per day, specifically erdafitinib, and more specifically, 1 day. The use of erdafitinib at a dose of approximately 8 mg per unit is described herein. In this administration method, the patient has received BCG therapy prior to the administration of the FGFR inhibitor. In certain embodiments, the BCG therapy is a sufficient BCG therapy. In some embodiments , the patient is non-responsive to the BCG therapy. In still further embodiments, the patient is a BCG experienced patient. 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, an FGFR inhibitor is administered or to be administered at a dose of about 6 mg per day, specifically erdafitinib, more specifically erdafitinib at a dose of about 6 mg per day.

[0007] Use of an FGFR inhibitor for the manufacture of a medicament for treating a patient diagnosed with HR-NMIBC having at least one FGFR2 gene mutation and / or FGFR3 gene mutation is described herein, specifically an FGFR inhibitor, specifically erdafitinib, is to be administered or administered at a dose of about 8 mg per 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 a sufficient BCG therapy. In some embodiments , the patient is non-responsive to the BCG therapy. In still further embodiments, the patient is a BCG experienced patient. 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, an FGFR inhibitor is administered or to be administered at a dose of about 6 mg per day, specifically erdafitinib, more specifically erdafitinib at a dose of about 6 mg per day.

[0008] I have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. For details on manufacturing medicine to treat patients diagnosed with R-NMIBC, please see below. An FGFR inhibitor administered at a dose of approximately 8 mg per day, specifically erdafitinib, and more specifically, 1 day. The use of erdafitinib at a dose of approximately 8 mg per unit is described herein. In this administration method, the patient has received BCG therapy prior to the administration of the FGFR inhibitor. In some embodiments, BCG therapy is sufficient. The patient is unresponsive to BCG therapy. In a further embodiment, the patient is a BCG survivor. Yes. In certain embodiments, the patient has a papillary tumor. In further embodiments, the patient It has carcinoma in situ. In some embodiments, the patient has previously undergone cystectomy. It is either not present or is unsuitable. In one embodiment, an FGFR inhibitor is administered at a dose of approximately 6 mg per day. Regarding dosage, more specifically erdafitinib, and more specifically erdafitinib at a dose of approximately 6 mg per day. itinib should be administered or should be administered.

[0009] I have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. FGFR inhibitors for manufacturing medicines to treat patients diagnosed with R-NMIBC The use of the agent is described herein, in detail, FGFR inhibitors, in detail, erdafitinib However, it should be administered at a dose of approximately 8 mg per day. In this embodiment, the patient has received BCG therapy prior to the administration of the FGFR inhibitor. In further embodiments, BCG therapy is sufficient BCG therapy. In some embodiments In a further embodiment, the patient is unresponsive to BCG therapy. In certain embodiments, the patient has a papillary tumor. In further embodiments, the patient The patient has carcinoma in situ. In some embodiments, the patient has previously undergone cystectomy. They are either absent or ineligible. In one embodiment, an FGFR inhibitor is administered at a dose of approximately 6 mg per day. In terms of dosage, more specifically erdafitinib, more specifically erdafitinib at a dose of approximately 6 mg per day Fitinib should be administered or should be administered.

[0010] H FGFR inhibitors for use in the treatment of patients diagnosed with R-NMIBC are described herein. It is stated that, in detail, the FGFR inhibitor, specifically erdafitinib, is administered at approximately 8 mg per day. It is administered or should be administered in the following dose. In certain embodiments, the patient Prior to the administration of the FGFR inhibitor, the patient has received BCG therapy. In a further embodiment, BCG therapy is sufficient BCG therapy. In some embodiments, patients undergo BCG therapy. No response. In further embodiments, the patient is a BCG survivor. In a particular implementation Morphologically, the patient has a papillary tumor. In a further embodiment, the patient has carcinoma in situ. In some embodiments, the patient has not previously undergone cystectomy or is ineligible. Yes. In one embodiment, an FGFR inhibitor is administered at a dose of approximately 6 mg per day, in detail, Dafitinib, more specifically, erdafitinib at a dose of approximately 6 mg per day, is administered. Or, it should be administered.

[0011] I have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. FGFR inhibitors for use in the treatment of patients diagnosed with R-NMIBC are described herein. It is stated that, in detail, the FGFR inhibitor, specifically erdafitinib, is administered at approximately 8 mg per day. It is administered or should be administered in the following dose. In certain embodiments, the patient Prior to the administration of the FGFR inhibitor, the patient has received BCG therapy. In a further embodiment, BCG therapy is sufficient BCG therapy. In some embodiments, patients undergo BCG therapy. No response. In further embodiments, the patient is a BCG survivor. In a particular implementation Morphologically, the patient has a papillary tumor. In a further embodiment, the patient has carcinoma in situ. In some embodiments, the patient has not previously undergone cystectomy or is ineligible. Yes. In one embodiment, an FGFR inhibitor is administered at a dose of approximately 6 mg per day, in detail, Dafitinib, more specifically, erdafitinib at a dose of approximately 6 mg per day, is administered. Or, it should be administered.

[0012] In a further embodiment, the administration of the FGFR inhibitor is performed on HR-N patients who have been given a placebo. This results in improved recurrence-free survival compared to the MIBC patient population. In certain embodiments, The aforementioned administration of an FGFR inhibitor is either by intravesical administration of gemcitabine or mitomeycete. Compared to the HR-NMIBC patient population that received intravesical administration of SynC(MMC) / thermal MMC This leads to improved recurrence-free survival. In some embodiments, patients undergo FG at approximately 6 months. It shows complete response to FR inhibitors. In some embodiments, the FGFR inhibitor is administered This refers to the population of nonmuscle-invasive bladder cancer (NMIBC) (HR-NMIBC or IR-NMIBC). ) This prevents or delays disease recurrence.

[0013] In a particular embodiment, FGFR2 gene mutations and / or FGFR3 gene mutations are This is due to an FGFR3 gene mutation, an FGFR2 gene fusion, or an FGFR3 gene fusion. In some embodiments, the FGFR3 gene mutations are R248C, S249C, G370 C, Y373C, or any combination thereof. In further embodiments, FGF R2 or FGFR3 gene fusion is FGFR3-TACC3, more specifically FGFR3-TA CC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FG FR2-BICC1, FGFR2-CASP7, or any combination thereof.

[0014] In some embodiments, the method or use is performed before administering the FGFR inhibitor to the patient. Biological samples from individuals were found to have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. Further includes evaluating a single entity. In a particular embodiment, the biological sample is Blood, lymph, bone marrow, solid tumor samples, urine, or any combination thereof. In some embodiments, the biological sample is a blood sample. In certain embodiments, the biological sample is urine. This is a sample.

[0015] In some embodiments, the FGFR inhibitor is erdafitinib. Further implementation In terms of dosage, erdafitinib is administered daily, or more precisely, once daily. Further implementation In terms of form, erdafitinib is administered orally. In certain embodiments, erdafi Tinib is administered orally on a daily dosing schedule. In some embodiments, eldaf itinib is administered orally once daily at a dose of approximately 8 mg. In some embodiments, Dafitinib is administered orally once daily at a dose of approximately 8 mg, following a daily dosing schedule. In a further embodiment, the dose of erdafitinib is such that the patient has blood levels less than approximately 5.5 mg / dL. If the phosphate (PO4) level is elevated, the dose should be increased from 8 mg per day to 8 mg per day after the start of treatment. The dose was increased to 9 mg, and in detail, the dose of erdafitinib was increased to 14-2 mg after the start of treatment in patients. If serum phosphate (PO4) levels are less than approximately 5.5 mg / dL on day 1, initiate treatment. Later, the dose is increased from 8 mg per day to 9 mg per day. In certain embodiments, Rudafitinib is present in a solid dosage form. In further embodiments, the solid dosage form is a tablet. be.

[0016] In some embodiments, the methods and uses described herein involve FGFR inhibition. The drug, specifically erdafitinib, is administered at a dose of approximately 6 mg per day. Further details... In terms of administration, erdafitinib is administered once daily at a dose of approximately 6 mg. In some embodiments, erdafitinib is administered orally. In certain embodiments, erda Fitinib is administered orally on a daily dosing schedule. In some embodiments, El Dafitinib is administered orally once daily at a dose of approximately 6 mg. In some embodiments, Erdafitinib is administered orally once daily at a dose of approximately 6 mg, following a daily dosing schedule. In further embodiments, the dose of erdafitinib is less than approximately 5.5 mg / dL for patients. If serum phosphate (PO4) levels are present, start with 6 mg per day after initiating treatment. The dose was increased to 8 mg, and in detail, the dose of erdafitinib was increased to 14 mg after the start of treatment in the patient. If serum phosphate (PO4) levels are less than approximately 5.5 mg / dL on day 21, treatment The dosage is increased from 6 mg per day to 8 mg per day after initiation. In certain embodiments, Erdafitinib is present in a solid dosage form. In further embodiments, the solid dosage form is a tablet. It is a drug.

[0017] (a) A biological sample from a patient diagnosed with HR-NMIBC is taken from one or more FGFR genes. Evaluate for submutations, specifically the presence of one or more FGFR2 or FGFR3 mutations. , and (b) if one or more FGFR gene mutations are present in the sample, in detail per day A dose of approximately 8 mg of an FGFR inhibitor, more specifically erdafitinib, more specifically per day Administer erdafitinib at a dose of approximately 8 mg per day to the patient. Methods for treating HR-NMIBC, including the above, are also provided herein.

[0018] (a) A biological sample from a patient diagnosed with HR-NMIBC is taken from one or more FGFR genes. Evaluate for submutations, specifically the presence of one or more FGFR2 or FGFR3 mutations. , and (b) if one or more FGFR gene mutations are present in the sample, in detail per day A dose of approximately 6 mg of an FGFR inhibitor, more specifically erdafitinib, more specifically per day Administer erdafitinib at a dose of approximately 6 mg per day to the patient. Methods for treating HR-NMIBC, including the above, are also provided herein.

[0019] (a) A biological sample from a patient diagnosed with IR-NMIBC is taken from one or more FGFR genes. Evaluate for submutations, specifically the presence of one or more FGFR2 or FGFR3 mutations. , and (b) if one or more FGFR gene mutations are present in the sample, in detail per day A dose of approximately 8 mg of an FGFR inhibitor, more specifically erdafitinib, more specifically per day IR-NMIBC, which includes administering approximately 8 mg of erdafitinib to the patient. Methods for treating this condition are also provided herein.

[0020] (a) A biological sample from a patient diagnosed with IR-NMIBC is taken from one or more FGFR genes. Evaluate for submutations, specifically the presence of one or more FGFR2 or FGFR3 mutations. , and (b) if one or more FGFR gene mutations are present in the sample, in detail per day A dose of approximately 6 mg of an FGFR inhibitor, more specifically erdafitinib, more specifically per day IR-NMIBC, which includes administering a dose of approximately 6 mg of erdafitinib to the patient. Methods for treating this condition are also provided herein.

[0021] H For details on manufacturing medicine to treat patients diagnosed with R-NMIBC, please see below. An FGFR inhibitor administered at a dose of approximately 8 mg per day, specifically erdafitinib, and more specifically, 1 day. The use of erdafitinib at a dose of approximately 8 mg per gram is described herein, and it is an FGFR inhibitor. In more detail, erdafitinib uses one or more patient-derived biological samples containing FGFR2 or FGF After evaluating the presence of R3 gene mutations, and after the sample contains one or more FGFR2 or FGF It should be administered, or should be administered, if an R3 gene mutation is present.

[0022] H For details on manufacturing medicine to treat patients diagnosed with R-NMIBC, please see below. A dose of approximately 6 mg per day of FGFR inhibitors, specifically erdafitinib, and more specifically, 1 day The use of erdafitinib at a dose of approximately 6 mg per gram is described herein, and it is an FGFR inhibitor. In more detail, erdafitinib uses one or more patient-derived biological samples containing FGFR2 or FGF After evaluating the presence of R3 gene mutations, and after the sample contains one or more FGFR2 or FGF It should be administered, or should be administered, if an R3 gene mutation is present.

[0023] H FGFR inhibitors for manufacturing medicines to treat patients diagnosed with R-NMIBC The use of the agent is described herein, in detail, FGFR inhibitors, in detail, erdafitinib It should be administered or should be administered at a dose of approximately 8 mg per day, and FGFR inhibition The harmful agent, specifically erdafitinib, is derived from a patient's biological sample containing one or more FGFR2 or F After evaluating the presence of GFR3 gene mutations, and after the sample contains one or more FGFR2 or F It should be administered, or should be administered, in cases where a GFR3 gene mutation is present.

[0024] H FGFR inhibitors for manufacturing medicines to treat patients diagnosed with R-NMIBC The use of the agent is described herein, in detail, FGFR inhibitors, in detail, erdafitinib It should be administered or should be administered at a dose of approximately 6 mg per day, and FGFR inhibition The harmful agent, specifically erdafitinib, is derived from a patient's biological sample containing one or more FGFR2 or F After evaluating the presence of GFR3 gene mutations, and after the sample contains one or more FGFR2 or F It should be administered, or should be administered, in cases where a GFR3 gene mutation is present.

[0025] I have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. For details on manufacturing medicine to treat patients diagnosed with R-NMIBC, please see below. An FGFR inhibitor administered at a dose of approximately 8 mg per day, specifically erdafitinib, and more specifically, 1 day. The use of erdafitinib at a dose of approximately 8 mg per gram is described herein, and it is an FGFR inhibitor. In more detail, erdafitinib uses one or more patient-derived biological samples containing FGFR2 or FGF After evaluating the presence of R3 gene mutations, and after the sample contains one or more FGFR2 or FGF It should be administered, or should be administered, if an R3 gene mutation is present.

[0026] I have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. For details on manufacturing medicine to treat patients diagnosed with R-NMIBC, please see below. A dose of approximately 6 mg per day of FGFR inhibitors, specifically erdafitinib, and more specifically, 1 day The use of erdafitinib at a dose of approximately 6 mg per gram is described herein, and it is an FGFR inhibitor. In more detail, erdafitinib uses one or more patient-derived biological samples containing FGFR2 or FGF After evaluating the presence of R3 gene mutations, and after the sample contains one or more FGFR2 or FGF It should be administered, or should be administered, if an R3 gene mutation is present.

[0027] I have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. FGFR inhibitors for manufacturing medicines to treat patients diagnosed with R-NMIBC The use of the agent is described herein, in detail, FGFR inhibitors, in detail, erdafitinib It should be administered or should be administered at a dose of approximately 8 mg per day, and FGFR inhibition The harmful agent, specifically erdafitinib, is derived from a patient's biological sample containing one or more FGFR2 or F After evaluating the presence of GFR3 gene mutations, and after the sample contains one or more FGFR2 or F It should be administered, or should be administered, in cases where a GFR3 gene mutation is present.

[0028] I have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. FGFR inhibitors for manufacturing medicines to treat patients diagnosed with R-NMIBC The use of the agent is described herein, in detail, FGFR inhibitors, in detail, erdafitinib It should be administered or should be administered at a dose of approximately 6 mg per day, and FGFR inhibition The harmful agent, specifically erdafitinib, is derived from a patient's biological sample containing one or more FGFR2 or F After evaluating the presence of GFR3 gene mutations, and after the sample contains one or more FGFR2 or F It should be administered, or should be administered, in cases where a GFR3 gene mutation is present.

[0029] H FGFR inhibitors for use in the treatment of patients diagnosed with R-NMIBC are described herein. It is stated that, in detail, FGFR inhibitors, specifically erdafitinib, are administered at approximately 8 mg per day. It should be administered or should be administered in the dose of an FGFR inhibitor, specifically Eldaf itinib is used to test patient-derived biological samples for the presence of one or more FGFR2 or FGFR3 gene mutations. After evaluation, if one or more FGFR2 or FGFR3 gene mutations are present in the sample It should be administered or should be administered at the appropriate time.

[0030] H FGFR inhibitors for use in the treatment of patients diagnosed with R-NMIBC are described herein. It is stated that, in detail, FGFR inhibitors, specifically erdafitinib, are administered at approximately 6 mg per day. It should be administered or should be administered in the dose of an FGFR inhibitor, specifically Eldaf itinib is used to test patient-derived biological samples for the presence of one or more FGFR2 or FGFR3 gene mutations. After evaluation, if one or more FGFR2 or FGFR3 gene mutations are present in the sample It should be administered or should be administered at the appropriate time.

[0031] I have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. FGFR inhibitors for use in the treatment of patients diagnosed with R-NMIBC are described herein. It is stated that, in detail, FGFR inhibitors, specifically erdafitinib, are administered at approximately 8 mg per day. It should be administered or should be administered in the dose of an FGFR inhibitor, specifically Eldaf itinib is used to test patient-derived biological samples for the presence of one or more FGFR2 or FGFR3 gene mutations. After evaluation, if one or more FGFR2 or FGFR3 gene mutations are present in the sample It should be administered or should be administered at the appropriate time.

[0032] I have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. FGFR inhibitors for use in the treatment of patients diagnosed with R-NMIBC are described herein. It is stated that, in detail, FGFR inhibitors, specifically erdafitinib, are administered at approximately 6 mg per day. It should be administered or should be administered in the dose of an FGFR inhibitor, specifically Eldaf itinib is used to test patient-derived biological samples for the presence of one or more FGFR2 or FGFR3 gene mutations. After evaluation, if one or more FGFR2 or FGFR3 gene mutations are present in the sample It should be administered or should be administered at the appropriate time.

[0033] For example, an FGFR inhibitor at a dose of approximately 8 mg per day is administered to at least one FGFR2 Intermediate-risk nonmuscle-invasive bladder cancer (I) with gene mutations and / or FGFR3 gene mutations. A method comprising or from administering to a patient diagnosed with R-NMIBC Essentially, methods for treating IR-NMIBC are further described herein. In certain embodiments, the patient has a papillary tumor. In some embodiments, the patient has an incomplete It involves transurethral resection. In a further embodiment, the patient is treated with an FGFR inhibitor for about 3 months. And it shows a complete remission.

[0034] For example, an FGFR inhibitor at a dose of approximately 6 mg per day is administered to at least one FGFR2 Intermediate-risk nonmuscle-invasive bladder cancer (I) with gene mutations and / or FGFR3 gene mutations. A method comprising or from administering to a patient diagnosed with R-NMIBC Essentially, methods for treating IR-NMIBC are further described herein. In certain embodiments, the patient has a papillary tumor. In some embodiments, the patient has an incomplete It involves transurethral resection. In a further embodiment, the patient is treated with an FGFR inhibitor for about 3 months. And it shows a complete remission.

[0035] In a particular embodiment, FGFR2 gene mutations and / or FGFR3 gene mutations are This is due to an FGFR3 gene mutation, an FGFR2 gene fusion, or an FGFR3 gene fusion. In some embodiments, the FGFR3 gene mutations are R248C, S249C, G370 C, Y373C, or any combination thereof. In further embodiments, FGF R2 or FGFR3 gene fusion is FGFR3-TACC3, more specifically FGFR3-TA CC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FG It is FR2-BICC1, FGFR2-CASP7, or any combination thereof. In certain embodiments, the FGFR inhibitor is erdafitinib.

[0036] The overview and the detailed description below will be better understood when read in conjunction with the attached drawings. To illustrate the method or use, the drawings show exemplary embodiments of the method or use. However, the methods or uses are not limited to the specific embodiments disclosed. . [Brief explanation of the drawing]

[0037] [Figure 1]This describes the study scheme for a phase 2, multicenter, open-label trial evaluating the safety and efficacy of erdafitinib in patients with HR-NMIBC who have relapsed after BCG therapy and have selected FGFR gene mutations (FGFR metastases or mutations). Footnote (a) refers to investigator-selected treatment with intravesical gemcitabine / mitomycin C (MMC) / hyperthermic MMC therapy. Footnote (b) refers to a maximum of two years in 28-day cycles until the patient experiences disease relapse or progression, unacceptable toxicity, or withdrawal of consent. Footnote (c) refers to a maximum of two years in 28-day cycles in patients in Cohort 1 who have confirmed high-grade relapse in investigator-selected treatment and may be crossed over to erdafitinib treatment. Footnote (d) refers to a maximum of six months of treatment, but will be discontinued if complete response (CR) is not observed within three months. When used in Figure 1, BCG represents Bacillus calmette-Guérin, CIS represents carcinoma in situ, CR represents complete response, ERDA represents erdafitinib, FGFR represents fibroblast growth factor receptor, HR represents high risk, IC represents intravesical chemotherapy, IR represents intermediate risk, MMC represents mitomycin C, NMIBC represents nonmuscle-invasive bladder cancer, RFS represents recurrence-free survival, and TUR represents transurethral resection. [Figure 2] This shows a dose escalation regimen of erdafitinib at 6 mg to 8 mg per day. [Modes for carrying out the invention]

[0038] For clarity, several aspects of the present invention are described herein in the context of separate embodiments. It should be understood that the features may also be provided in combination in a single embodiment. That is to say, unless otherwise explicitly stated, each individual embodiment is, It is considered to be combinable with other embodiments of the intent, and such combination is a different embodiment. It is considered a form. Conversely, a book described in the context of a single embodiment for the sake of brevity. The various features of the invention can also be provided separately or in any subordinate combination. Finally, A particular embodiment may be described as part of a series of steps or as part of a more general structure. However, each of the aforementioned steps is also an independent embodiment in itself and can be combined with others. It can be considered possible.

[0039] Specific Terminology The transitional terms "contains," "essentially consists of," and "consist of" are used in patent applications. The word is intended to include those generally accepted meanings. That is, ( i) "including," "containing," or "characterized by" "Comprising," which is synonymous with "including," means comprehensive or open-ended. (ii) "consists of ~" Any element, process, or component not specified in the claims shall be excluded, and ( iii) "Essentially made from" refers to the material specified in the claimed invention or embodiment. Or the scope of the claims in a process "that does not substantially affect the basic and novel features". This limits the scope or embodiments. More specifically, the basic and novel features are not covered by other documents in this specification. Compared to the survivability of comparative human populations described in the section, the ability to improve the survivability of human populations. Providing at least one of the advantages described herein, including but not limited to force Regarding methods or the ability to use. Described in terms including (or synonyms for) the phrase "~including". The embodiments described also include, as embodiments, "consisting of" and "essentially consisting of". Provides terms that are independently defined.

[0040] When a value is represented as an approximation by the use of the descriptive word "approximately", a particular value may be represented by a different implementation. It will be understood that it forms a shape. Unless otherwise specified, the term "approximately" refers to This means a variation of ±10% in the consecutive values, but in additional embodiments, the variation can be ±5%, ±1 This includes things that may be 5%, ±20%, ±25%, or ±50%, and in detail, The term "approximately" means a variation of ±5% or ±10% of the associated value, or more specifically, ±5%.

[0041] If a list is provided, unless otherwise stated, each individual element of that list, and It should be understood that all combinations of the list represent separate embodiments. For example, the list of embodiments shown as "A, B, or C" is an example of an embodiment "A", B", C, A or B, A or C, B or C, or A, B or C It should be interpreted as including it.

[0042] As used herein, the singular forms "a," "an," and "that" are used. "(the)" can include plural forms.

[0043] Throughout this disclosure, the following abbreviation will be used: FGFR (Fibroblast Growth Factor Receptor) ;FGFR3-TACC3 V1 (the gene encoding FGFR3 and the transformed acid coil) Fusion between 3 variants of the docile-containing protein); FGFR3-TACC3 V3( The gene encoding FGFR3 and the transformed acid coiled-coil-containing protein 3Varian Fusion between (T3); FGFR3-BAIAP2L1 (the gene encoding FGFR3 and the brain) Fusion between specific angiogenesis inhibitor 1-related protein 2-like protein 1); FGFR2-B ICC1 (fusion between the gene encoding FGFR2 and bicaudal C homolog 1) );FGFR2-CASP7(fusion between the gene encoding FGFR2 and caspase 7) ).

[0044] As used herein, “patient” means any animal, more specifically, a mammal. This is intended. Therefore, the method or use is applicable to humans and non-human animals. Being human is most preferable. The terms "patient," "subject," and "human" are interchangeable. It can be used.

[0045] The terms "to treat" and "treatment" refer to the treatment of patients suffering from a disease, and cancer cells. This refers to the effect of alleviating the condition by killing off the organisms, but also to the effect of inhibiting the progression of the condition. This also includes, and encompasses a decrease in the rate of progression, a cessation of the rate of progression, remission of the condition, and a cure of the condition. This also includes treatment as a preventative measure (i.e., prevention of onset).

[0046] The "therapeutic effective dose" is the dose and duration required to obtain the desired therapeutic outcome. This refers to the effective dose. The therapeutically effective dose is determined by factors such as the individual's disease state, age, sex, and weight. Furthermore, the effectiveness of the drug or combination of drugs varies depending on their ability to induce the desired response in the individual. It is possible. Exemplary indicators of an effective treatment or combination of treatments include, for example, improvement. This includes the health of the patients.

[0047] The term "dosage" refers to the amount of medication that should be taken depending on the subject, and the amount taken depending on the subject. This refers to information about the frequency of administration of the medication.

[0048] The term "dosage" refers to the amount or quantity of medication that should be taken each time.

[0049] As used herein, the term "cancer" refers to a growth that occurs in an uncontrolled manner and may occur in some cases. This refers to the abnormal proliferation of cells that have a tendency to metastasize (spread).

[0050] As used herein, terms such as "simultaneous administration" refer to selected therapeutic agents administered to a single patient. This includes the administration of drugs via the same or different routes of administration or at the same or different times. It is intended to include a treatment regimen in which [the drug] is administered.

[0051] As used herein, the term “combination of therapeutic agents” refers to a mixture of two or more active ingredients. Or it refers to the products resulting from the combination, including fixed and non-fixed combinations of active ingredients. This includes both combinations. The term "fixed combination" refers to the active ingredients, e.g., erdafitinib and This means that both the adjuvant and the adjuvant are administered to the patient simultaneously in the form of a single unit or a single dosage form. The term "non-fixed combination" refers to a combination of the active ingredient, e.g., erdafitinib and an adjuvant. Without specific time constraints, separate units or separate agents can be administered simultaneously, in parallel, or sequentially. It means that it is administered to the patient in a tangible form, and by administering it in this way, it is safe. Furthermore, two active ingredients are delivered to the human body at effective levels. The latter is also a cocktail. This also applies to therapeutic interventions, such as the administration of three or more active ingredients.

[0052] The term "daily administration schedule" refers to a schedule in which a specific therapeutic agent is administered, with days off from that agent. This refers to administration without accompanying medication. In some embodiments, the daily administration schedule of a particular therapeutic agent The plan involves administering a specific therapeutic agent daily at approximately the same time each day.

[0053] The term "recurrence-free survival" (RSF) is defined as the period from the date of randomization to the date of diagnosis of a high-risk disease (high-risk malignancy). Until the date of recurrence of (T1, CIS) or the date of death (whichever was reported first) This is defined as the time. Patients who have survived without recurrence, or whose condition is unknown, are considered to have reached their final stage. The evaluation will be terminated upon assessment of the tumor. RFS will be evaluated by central histopathological examination. ru.

[0054] The term "relapse-free survival 2" (RFS2) refers to the period from the date of randomization to the first subsequent non-relapse-free survival. In medical anti-cancer treatment, the date of recurrence of a high-risk disease or the date of death (whichever was first reported) This is defined as the time until the person who has not relapsed. Participants who have survived without relapse, or whose condition is unknown. Participants will be terminated after their final tumor assessment.

[0055] The term "progression-free period" refers to the period from the randomization date to the date on which there is no evidence of progression or death. Defined as the time until the first recorded date. Patients who are alive and have no progression, or those whose condition For patients whose condition is unclear, treatment will be terminated on the last tumor evaluation date.

[0056] The term "disease exacerbation period" refers to the period from the randomization date to the date the disease has progressed further with the treatment. This is defined as the time until the first recorded evidence of the change. Patients who are still alive or whose condition is unknown will be terminated at the time of the last tumor assessment. .

[0057] The term "disease exacerbation period" also refers to the period from the randomization date to cystectomy and further progression of the disease. The evidence for the change in therapies (including systemic chemotherapy or radiotherapy) that demonstrates this was first described. It can be defined as the time up to the date recorded. A patient or condition in which the disease has not worsened and the patient is still alive. For patients whose status is unclear, treatment will be terminated after the final tumor evaluation.

[0058] The term "disease-specific survival" refers to the period from the randomization date to the date of death of participants due to bladder cancer. Defined as time up to [date]. Patients who are alive or whose life status is unknown are considered participants. The treatment will be terminated on the day the patient's survival was last confirmed. Death due to causes other than bladder cancer. Participation will be terminated on the date of the participant's death.

[0059] The term "overall survival" (OS) refers to the period from the day of randomization to the end of participation for any reason. This is defined as the time until the date of death of the person. For patients whose survival status or life condition is unknown, The trial will be terminated on the day the participant's survival is last confirmed.

[0060] The term "complete response" (CR) refers to the absence of residual tissue and the presence of viable tumor tissue as determined by histopathological examination. It is defined as the absence of marker lesions.

[0061] The term "partial response" (PR) refers to a situation where the sum of diameters of target lesions is smaller than the sum of diameters at baseline. It is defined as something that decreases by at least 30%.

[0062] The term "adverse event" refers to any adverse medical event that occurs in a participant who has been administered an investigational drug. Therefore, this does not necessarily mean that only events with a clear causal relationship to the investigational drug in question are shown.

[0063] As used herein, the term "placebo" refers to a pharmaceutical composition that does not contain an FGFR inhibitor. This means administering [the drug].

[0064] The term "randomization," when referring to a clinical trial, means that the patient has been confirmed to be eligible for the clinical trial. This refers to the time when the arm is assigned to a treatment arm.

[0065] The terms "kit" and "manufactured product" are used as synonyms.

[0066] "Biological samples" can be used to obtain cancer cells and to detect FGFR gene mutations. This refers to any sample from a patient. Suitable biological samples include blood, lymph, bone marrow, and solid waste. Examples include, but are not limited to, tumor specimens or any combination thereof. In that embodiment, the biological sample is formalin-fixed paraffin-embedded tissue (FFPET). It is possible.

[0067] "Cmax" is the maximum observed analyte concentration.

[0068] "Tmax" is the actual sampling time until the maximum observed analyte concentration is reached. It is in between.

[0069] "AUClast" allows you to measure the analyte concentration from 0 hours until the last time it can be measured (limit of quantification [BQL]). It is a time (less than ).

[0070] "AUCinfinity" represents time from 0 hours to infinity.

[0071] FGFR gene mutation FGFR inhibitors at a dose of approximately 8 mg per day, diagnosed with HR-NMIBC, and less Both one FGFR2 gene mutation and / or one FGFR3 gene mutation (i.e., one or more) (Having an FGFR2 gene mutation, one or more FGFR3 gene mutations, or a combination thereof) HR-NMI consisting of or essentially derived from, including administration to patients who... Methods or uses for treating BC are described herein. A dose of approximately 8 mg per day. At least one fibroblast growth factor receptor (FGFR) inhibitor is used in HR-NMIBC Diagnosed with at least one FGFR2 gene mutation and / or FGFR3 gene mutation HR-NM consisting of or essentially derived from, including administration to patients having Methods or uses for treating IBC are also described herein. Approximately 8 mg per day In addition to two or more fibroblast growth factor receptor (FGFR) inhibitors, HR-NMIBC is diagnosed as a serious condition. The patient is diagnosed and has at least one FGFR2 gene mutation and / or FGFR3 gene mutation. HR-NMIB, consisting of or essentially derived from, including administration to patients. Methods or uses for treating C are further described herein. Implementation of the same treatment method. The form is applicable to the use described herein. In one embodiment, HR-NMIBC is In the method or use for treatment, FGFR inhibitors are administered at a dose of approximately 6 mg per day. It is administered or should be administered. In one embodiment, the FGFR inhibitor is It is rudafitinib.

[0072] FGFR inhibitors at a dose of approximately 8 mg per day, diagnosed with IR-NMIBC, and less Both one FGFR2 gene mutation and / or one FGFR3 gene mutation (i.e., one or more) (Having an FGFR2 gene mutation, one or more FGFR3 gene mutations, or a combination thereof) IR-NMI consisting of or essentially derived from, including administration to patients who... Methods or uses for treating BC are described herein. A dose of approximately 8 mg per day. At least one fibroblast growth factor receptor (FGFR) inhibitor is used in IR-NMIBC Diagnosed with at least one FGFR2 gene mutation and / or FGFR3 gene mutation IR-NM consisting of or essentially derived from, including administration to patients having Methods or uses for treating IBC are also described herein. Approximately 8 mg per day In addition to two or more fibroblast growth factor receptor (FGFR) inhibitors, IR-NMIBC is diagnosed as a serious condition. The patient is diagnosed and has at least one FGFR2 gene mutation and / or FGFR3 gene mutation. IR-NMIB, consisting of or essentially derived from, including administration to patients. Methods or uses for treating C are further described herein. Implementation of the same treatment method. The form is applicable to the use described herein. In one embodiment, IR-NMIBC is In the method or use for treatment, FGFR inhibitors are administered at a dose of approximately 6 mg per day. It is administered or should be administered. In one embodiment, the FGFR inhibitor is It is rudafitinib.

[0073] Protein tyrosine kinase (PTK) receptor fibroblast growth factor (FGF) Lee's work encompasses a wide range of processes, including mitosis induction, wound healing, cell differentiation and angiogenesis, and development. It controls physiological functions. Cell growth and proliferation are controlled whether the cells are normal or malignant. FGF, an extracellular signaling molecule that acts as an autocrine and paracrine factor, local concentration It is affected by changes in the degree. Autocrine FGF signaling is involved in steroid hormone-dependent cancer. This can be particularly important when progressing to a hormone-independent state.

[0074] FGF and its receptors are expressed at increased levels in several tissues and cell lines. Overexpression is thought to be one of the causes of malignant phenotypes. Furthermore, several oncogenes It is a homolog of the gene encoding the growth factor receptor, and in human pancreatic cancer, FGF-dependent Existential signaling may be abnormally activated (Knights et al., P pharmacology and therapeutics 2010 125:1( 105-117);Korc M.et al Current Cancer Dru g Targets 2009 9:5(639-651)).

[0075] The two prototype members are acid fibroblast growth factor (aFGF or FGF1). and basic fibroblast growth factor (bFGF or FGF2), and to date at least Twenty different FGF family members have been identified. The cellular response to FGF is Four types of high-affinity transmembrane protein tyrosine kinases, numbered 1 to 4, are fibroblasts. It is transmitted via cell growth factor receptors (FGFRs) (FGFR1-FGFR4).

[0076] In certain embodiments, HR-NMIBC or IR-NMIBC is an FGFR2 gene. It is susceptible to submutations and / or FGFR3 gene mutations.

[0077] As used herein, "FGFR gene mutation" refers to an FGFR fusion gene, FGFR This includes, but is not limited to, mutations, FGFR amplification, or any combination thereof. This refers to mutations in the biomorphic FGFR gene. The terms "variant" and "mutation" are defined herein. It is used interchangeably.

[0078] In certain embodiments, FGFR2 or FGFR3 gene mutations result in FGFR gene fusion. It is a fusion. "FGFR fusion" or "FGFR gene fusion" is a fusion of FGFR (for example, FGR). It is caused by a gene that codes for part of F2 or FGFR3 and by a transposition between two genes. This refers to one or more of the Fusion Partners disclosed herein. The terms "Fusion" and The term "transfer" is used interchangeably herein. The following FGFs in patient-derived biological samples. R-fusion genes: FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2- The presence of one or more of BICC1, FGFR2-CASP7, or any combination thereof, Determining by the methods or uses disclosed, or by methods known to those skilled in the art Yes, it is possible. In a particular embodiment, FGFR3-TACC3 is FGFR3-TACC3 Variant 1 (FGFR3-TACC3 V1) or FGFR3-TACC3 Variant 3 (FGFR3-TACC3 V3). Table 1 shows the FGFR fusion gene and the fused gene. The FGFR and the exons of the fusion partner are shown. The sequence of each FGFR fusion gene is This is disclosed in Table 4.

[0079] [Table 1]

[0080] FGFR gene mutations include FGFR single nucleotide polymorphisms (SNPs). A (SNP) refers to a single nucleotide polymorphism in the FGFR2 or FGFR3 gene that differs by one nucleotide between individuals. In certain embodiments, FGFR2 or FGFR3 gene mutations result in FGFR3 gene mutations. They are different. In particular, "FGFR single nucleotide polymorphisms" (SNPs) are FGFs that differ by one nucleotide between individuals. This refers to the R3 gene. The following FGFR SNPs in patient-derived biological samples: FGFR3 R2 48C, FGFR3 S249C, FGFR3 G370C, FGFR3 Y373C, The existence of one or more of any combination thereof is known to those skilled in the art or as described in International Publication No. 20 This can be determined by the method disclosed in pamphlet No. 16 / 048833. F The sequences of GFR SNPs are shown in Table 2.

[0081] [Table 2]

[0082] When used herein, "FGFR gene mutation panel" refers to the FGFR gene mutations listed above. It includes one or more GFR gene mutations. In some embodiments, the FGFR gene mutation is inherited. The sub-panel depends on the patient's cancer type.

[0083] The FGFR gene mutation gene panel used in the evaluation step of the disclosed method is for patients Partially based on the patient's cancer type. Suitable for HR-NMIBC or IR-NMIBC patients. The FGFR gene mutation panel includes FGFR3-TACC3 Vl and FGFR3-TA CC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2- CASP7, FGFR3 R248C, FGFR3 S249C, FGFR3 G370 It may include C, or FGFR3 Y373C, or any combination thereof.

[0084] FGFR inhibitors for use in the disclosed method or use The methods disclosed or suitable FGFR inhibitors for use are provided herein. FGFR inhibitors may be used alone for the therapeutic methods described herein. Alternatively, they may be used in combination.

[0085] In some embodiments, if one or more FGFR gene mutations are present in the sample, H R-NMIBC or IR-NMIBC is a U.S. Patent Application Publication No. 2013 / 0072457 FGFR inhibitors disclosed in Specification A1 (incorporated herein by reference) (either of the tautomerized or stereochemical isomerized forms, and their N-oxides, so It may be treated with a pharmaceutically acceptable salt of or a solvate thereof.

[0086] In some embodiments, for example, HR-NMIBC or IR-NMIBC is N-(3, 5-Dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1 H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine (Honmei The detailed inscription is "JNJ-42756493" or "JNJ493", or Erdafitini (referred to as 'bu') (one of its tautomer forms, its N-oxide, its pharmaceutically acceptable form) It can be treated with a salt or solvate thereof. In some embodiments, FGFR The inhibitor, also known as erdafitinib, is given by formula (I): [ka] It may be a compound or a pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutically acceptable The salt used is an HCl salt. In a preferred embodiment, erdafitinib base is used.

[0087] Erdafitinib (also known as ERDA) is a pan-FGFR-12 ozant administered orally once daily. It is a rhezase inhibitor and is used in individuals with susceptible FGFR3 or FGFR2 gene mutations within 12 months. At least one line of treatment including neoadjuvant or adjuvant platinum-containing chemotherapy. Locally progressive ulcerative colitis (UC) or mesenteric ulcerative colitis (MUC) that progressed during or after prior platinum-containing chemotherapy. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients. riot Y et al. NEJM. 2019;381:338-48. Eldafiti Nib has clinical utility and tolerability in mUC patients and in mutations in FGFR expression. This is shown in Tabernero J, et al. J Clin Oncol. 20. 15;33:3401-3408;Soria JC,et al.Ann Onco l.2016;27(Suppl 6):vi266-vi295.Abstract 781PD;Siefker-Radtke AO,et al.ASCO 2018. Abstract 4503;Siefker-Radtke A,et al.ASC O-GU 2018. Abstract 450.

[0088] In some embodiments, HR-NMIBC or IR-NMIBC is an FGFR inhibitor. It may be treated with FGFR inhibitors, such as Gavine, PR, et al., AZ. D4547;An Orally Bioavailable, Potent, and Selective Inhibitor of the Fibroblast Gr owth Factor Receptor Tyrosine Kinase Fam ily, Cancer Res. April 15, 2012 72;2045 N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazole [3-yl]-4-(3,5-dimethylpiperazine-1-yl)benzamide (AZD 4547): [ka] And, if chemically possible, any of its tautomers or stereochemical variants This includes the sexual form, its N-oxide, its pharmaceutically acceptable salt, or its solvate.

[0089] In some embodiments, HR-NMIBC or IR-NMIBC is an FGFR inhibitor. It may be treated with FGFR inhibitors, as described in International Publication No. 2006 / 000420. 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1 -{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimido-4 -yl-methylurea (NVP-BGJ398): [ka] And, if chemically possible, any of its tautomers or stereochemical variants This includes the sexual form, its N-oxide, its pharmaceutically acceptable salt, or its solvate.

[0090] In some embodiments, HR-NMIBC or IR-NMIBC is an FGFR inhibitor. It may be treated with FGFR inhibitors, as described in International Publication No. 2006 / 127926. 4-amino-5-fluoro-3-[6-(4-methylpiperazine) as described in the book -1-yl)-1H-benzimidazole-2-yl]-1H-quinoline-2-one(do Vitinib): [ka] And, if chemically possible, any of its tautomers or stereochemical variants This includes the sexual form, its N-oxide, its pharmaceutically acceptable salt, or its solvate.

[0091] In some embodiments, HR-NMIBC or IR-NMIBC is an FGFR inhibitor. It may be treated with FGFR inhibitors, 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 F February 15, 2011 71(A)1396-1405 and International Publication No. 200 As described in the 8 / 112408 pamphlet, 6-(7-((l-aminocyclop Ropil)-methoxy)-6-methoxyquinoline-4-yloxy)-N-methyl-1-na Phthaamide (AL3810) (Lucitanib; E-3810): [ka] And, if chemically possible, any of its tautomers or stereochemical variants This includes the sexual form, its N-oxide, its pharmaceutically acceptable salt, or its solvate.

[0092] In some embodiments, HR-NMIBC or IR-NMIBC is an FGFR inhibitor. It may also be treated with FGFR inhibitors, such as pemigatinib (11-(2,6-difluoro- 3,5-Dimethoxyphenyl)-13-ethyl-4-(morpholine-4-ylmethyl)- 5,7,11,13-Tetrazatricyclo[7.4.0.0 2,6 ]Trideca-1,3, 6,8-tetraen-12-one: [ka] And, if chemically possible, any of its tautomers or stereochemical variants This includes the sexual form, its N-oxide, its pharmaceutically acceptable salt, or its solvate.

[0093] Further suitable FGFR inhibitors include BAY1163877 (Bayer), BA Y1179470 (Bayer), TAS-120 (Taiho), ARQ087 (Ar Quele), ASP5878 (Astellas), FF284 (Chugai Pharmaceutical Co., Ltd.), FP-1039(GSK / FivePrime), Blueprint, LY-2874 Examples include 455 (Lilly), RG-7444 (Roche), or any combination thereof. If possible, and if chemically feasible, any tautomer or stereochemical isomer thereof This includes N-oxides, pharmaceutically acceptable salts thereof, or solvates thereof.

[0094] In one embodiment, FGFR inhibitors in general, and more specifically erdafitinib, are drugs. It is administered as a scientifically acceptable salt. In preferred embodiments, generally an FGFR inhibitor, And more specifically, erdafitinib is administered in nucleotide form. In one embodiment, generally FGFR inhibitors, and more specifically erdafitinib, are equivalent to 8 mg of base equivalent. It is administered as a pharmaceutically acceptable salt in an amount equivalent to 9 mg of base equivalent. In terms of administration, FGFR inhibitors, and more specifically erdafitinib, are generally administered in 6 mg doses. It is administered as a pharmaceutically acceptable salt in an amount equivalent to the base equivalent. In one embodiment, generally FGFR inhibitors, and more specifically erdafitinib, are administered in amounts of 8 mg or 9 mg of salt. It is administered in its base form. In one embodiment, generally an FGFR inhibitor, and more specifically, an ELF Dafitinib is administered in a 6 mg dose in its base form.

[0095] Salts are generally used as FGFR inhibitors, and more specifically as eldaf, in a suitable solvent. It can be prepared by reacting itinib with a suitable acid.

[0096] Acid addition salts can be formed by both inorganic and organic acids. Examples of acid addition salts include: Acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, ma Leic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfone Acids, methanesulfonic acid (mesylates), ethanesulfonic acid, naphthalenesulfonic acid, valerian Acids, acetic acid, propionic acid, butanoic acid, malonic acid, glucuronic acid, and lactobionic acid Examples of salts formed by acids selected from the group include vinegar. Another group of acid addition salts includes vinegar. Acids, 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, meta Examples include salts formed from sulfonic acid, sebacic acid, stearic acid, succinic acid, and tartaric acid. It is possible.

[0097] In one embodiment, FGFR inhibitors in general, and more specifically erdafitinib, are soluble It is administered in the form of a solvate. As used herein, the term “solvate” means Eldafi This refers to the physical association of tinib with one or more solvent molecules. This physical association involves hydrogen bonding. It includes ionic and covalent bonds of varying degrees. In certain cases, for example, one or more solvents When a medium molecule is incorporated into the crystal lattice of a crystalline solid, it is possible to isolate the solvate. It is intended that the term "solvate" encompasses both the solution phase and isolable solvates. Non-limiting examples of solvents that can form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine, among others.

[0098] Solvates are well-known in pharmaceutical chemistry. They can be important for processes for the preparation of substances (e.g., in relation to their purification), the storage of substances (e.g., their stability), and the ease of handling of substances, and are often formed as part of the isolation or purification step of chemical synthesis. One of ordinary skill in the art can determine whether a hydrate or other solvate has been formed by standard and long-established techniques depending on the isolation or purification conditions used to prepare a given compound. 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 (also known as SS-NMR, magic angle spinning NMR, or MAS-NMR). Such techniques are part of the standard analytical toolkit of one of ordinary skill in the art, along with NMR, IR, HPLC, and MS. Alternatively, one of ordinary skill in the art can intentionally form a solvate using crystallization conditions that include the amount of solvent required for a particular solvate.

[0099] Furthermore, the compound may have one or more polymorphic (crystalline) or amorphous forms.

[0100] The compound includes compounds having one or more isotope substitutions, and reference to a particular element includes all isotopes of that element within its scope. For example, reference to hydrogen includes within its scope, 1 H , 2 H(D), and 3 H(T). Similarly, reference to carbon and oxygen includes within their scope respectively 12 C, 13 C, and 14 C, as well as 16 O and 18 O. Isotopes can be radioactive or non-radioactive. In one embodiment, the compound does not contain radioactive isotopes. Such compounds are preferred for therapeutic use. However, in another embodiment, the compound may contain one or more radioactive isotopes. Such compounds containing radioactive isotopes may be useful from a diagnostic perspective.

[0101] Therapeutic Methods and Uses A method of treating HR-NMIBC, consisting of, consisting essentially of, or including administering to a patient diagnosed with HR-NMIBC having at least one FGFR2 gene variant and / or FGFR3 gene variant, a dose of an FGFR inhibitor of about 8 mg per day. One is described herein. A method of treating HR-NMIBC, consisting of, consisting essentially of, or including administering to a patient diagnosed with HR-NMIBC having at least one FGFR2 gene

[0102] variant and / or FGFR3 gene variant, a dose of an FGFR inhibitor of about 6 mg per day. One is described herein. variant and / or FGFR3 gene variant, a dose of an FGFR inhibitor of about 6 mg per day. One is described herein.

[0103] A dose of approximately 8 mg of an FGFR inhibitor per day is administered to at least one FGFR2 gene mutation. To be administered to patients diagnosed with IR-NMIBC who have different and / or FGFR3 gene mutations. Treating IR-NMIBC, including, consisting of, or essentially derived from Methods for doing so are further described herein.

[0104] A dose of approximately 6 mg of an FGFR inhibitor per day is administered to at least one FGFR2 gene mutation. To be administered to patients diagnosed with IR-NMIBC who have different and / or FGFR3 gene mutations. Treating IR-NMIBC, including, consisting of, or essentially derived from Methods for doing so are further described herein.

[0105] H For details on manufacturing medicine to treat patients diagnosed with R-NMIBC, please see below. An FGFR inhibitor administered at a dose of approximately 8 mg per day, specifically erdafitinib, and more specifically, 1 day. The use of erdafitinib at a dose of approximately 8 mg per gram is described herein.

[0106] H For details on manufacturing medicine to treat patients diagnosed with R-NMIBC, please see below. A dose of approximately 6 mg per day of FGFR inhibitors, specifically erdafitinib, and more specifically, 1 day The use of erdafitinib at a dose of approximately 6 mg per gram is described herein.

[0107] H Use of an FGFR inhibitor for manufacturing a medicament for treating a patient diagnosed with HR-NMIBC is described herein, in particular an FGFR inhibitor, in particular erdafitinib is to be administered or should be administered at a dose of about 8 mg per day.

[0108] Use of an FGFR inhibitor for manufacturing a medicament for treating a patient diagnosed with HR-NMIBC having at least one FGFR2 gene mutation and / or FGFR3 gene mutation is described herein, in particular an FGFR inhibitor, in particular erdafitinib is to be administered or should be administered at a dose of about 6 mg per day.

[0109] Use of an FGFR inhibitor for manufacturing a medicament for treating a patient diagnosed with HR-NMIBC having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, in particular an FGFR inhibitor at a dose of about 8 mg per day, in particular erdafitinib, more particularly erdafitinib at a dose of about 8 mg per day is described herein.

[0110] Use of an FGFR inhibitor for manufacturing a medicament for treating a patient diagnosed with HR-NMIBC having at least one FGFR2 gene mutation and / or FGFR3 gene mutation, in particular an FGFR inhibitor at a dose of about 6 mg per day, in particular erdafitinib, more particularly erdafitinib at a dose of about 6 mg per day is described herein.

[0111] Use of an FGFR inhibitor for manufacturing a medicament for treating a patient diagnosed with HR-NMIBC having at least one FGFR2 gene mutation and / or FGFR3 gene mutation The use of the agent is described herein, in detail, FGFR inhibitors, in detail, erdafitinib However, it should be administered at a dose of approximately 8 mg per day.

[0112] I have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. FGFR inhibitors for manufacturing medicines to treat patients diagnosed with R-NMIBC The use of the agent is described herein, in detail, FGFR inhibitors, in detail, erdafitinib However, it should be administered at a dose of approximately 6 mg per day.

[0113] H FGFR inhibitors for use in the treatment of patients diagnosed with R-NMIBC are described herein. It is stated that, in detail, the FGFR inhibitor, specifically erdafitinib, is administered at approximately 8 mg per day. It should be administered or should be administered in the following dose.

[0114] H FGFR inhibitors for use in the treatment of patients diagnosed with R-NMIBC are described herein. It is stated that, in detail, the FGFR inhibitor, specifically erdafitinib, is administered at approximately 6 mg per day. It should be administered or should be administered in the following dose.

[0115] I have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. FGFR inhibitors for use in the treatment of patients diagnosed with R-NMIBC are described herein. It is stated that, in detail, the FGFR inhibitor, specifically erdafitinib, is administered at approximately 8 mg per day. It should be administered or should be administered in the following dose.

[0116] I have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. FGFR inhibitors for use in the treatment of patients diagnosed with R-NMIBC are described herein. It is stated that, in detail, the FGFR inhibitor, specifically erdafitinib, is administered at approximately 6 mg per day. It should be administered or should be administered in the following dose.

[0117] The aforementioned method and use also involve at least one, one, two, three, or four FGFR inhibitors. This includes administering the drug to patients diagnosed with HR-NHIMB or IR-NMIBC. ru.

[0118] In a particular embodiment, the patient undergoes at least one FGFR inhibitor before administration. The patient is receiving therapy. In a further embodiment, the patient is receiving the FGFR inhibitor before the administration of the FGFR inhibitor. , has received BCG vaccination.

[0119] In some embodiments, BCG therapy is sufficient BCG therapy. The minimum requirements include (1) at least 5 doses out of the total 6 doses in the initial introductory course, plus (2) Initially, maintenance (2 doses out of 3 per week) should be performed at least once over a period of 6 months. At least 5 of the 6 doses in the first introductory course, plus all 6 doses in the second introductory course. It includes at least two doses of the BCG. The total dose of BCG is at least 1 x 10 8 Includes the entire vial containing colony-forming units (CFUs).

[0120] In some embodiments, the patient is unresponsive to BCG therapy. The patient has the following recurrent disease If a patient has one of the conditions and has received sufficient BCG therapy, The patient is unresponsive to BCG therapy. The relapsing disease state is defined as follows: (1) sufficient B Single persistent or recurrent carcinoma in situ (CIS) within 12 months of completing CG therapy, young Alternatively, it may be accompanied by recurrent Ta / T1 (non-invasive papillary disease / tumor invading subepithelial connective tissue) disease. (1) Persistent or recurrent carcinoma in situ (CIS), (2) Six months after completion of adequate BCG therapy. (3) Recurrent high-grade Ta / T1 disease within the specified period, or the first disease assessment after initiation of the BCG course. The tumor is T1 (high malignancy) at that time.

[0121] In further embodiments, the patient is a BCG veteran. The patient has completed BCG therapy. Patients who have relapsed high-grade Ta / T1 disease within the last 12 months and whose previous BCG therapy was the most severe For patients with minimal treatment requirements, the patient must have received the BCG vaccine. The minimum treatment requirements are as follows: As per the following: (1) at least 5 doses out of the total 6 doses in the initial introductory course, and (2) initial At least 5 of the 6 doses in the introductory course, plus at least one dose over a 6-month period. Maintenance (2 out of 3 doses per week). During maintenance, 1 / 2 or 1 / 3 of the dose may be permitted. It will be done.

[0122] In certain embodiments, the patient has a papillary tumor. The papillary tumor lines the inside of the organ. It can grow from existing tissue and can occur in the bladder, thyroid gland, and breasts.

[0123] In further embodiments, the patient has carcinoma in situ. In certain embodiments, carcinoma in situ This refers to the group of abnormal cells that remain in the site where they were initially formed. In certain embodiments, the affected The individual has a stage 0 disease.

[0124] In some embodiments, the patient undergoes cystectomy, i.e., removal of all or part of the bladder. Either you have never undergone surgery to remove a cyst from your body, or you are ineligible for the procedure. The determination of eligibility can be made, for example, by the physician involved in the treatment.

[0125] In some embodiments, patients undergo incomplete transurethral resection, for example, insertion through the urethra. They are undergoing surgery to remove tissue using a special instrument.

[0126] In a particular embodiment, the administration of the FGFR inhibitor is compared to HR-14, which is administered with placebo. Compared to the NMIBC or IR-NMIBC patient population, FRS, progression-free survival, and disease exacerbation period were compared to the NMIBC or IR-NMIBC patient population. During this time, it leads to improvements in disease-specific survival, OS, RFS rate, RFS2, or CR. In certain embodiments, the administration of an FGFR inhibitor is compared to HR-NMI administered with a placebo. It results in improved RFS compared to the BC or IR-NMIBC patient population. In the administration method, the administration of the FGFR inhibitor is performed on HR-NMIBC or patients who have been given a placebo. Compared to the IR-NMIBC patient population, it results in improved progression-free survival. In this state, the administration of the FGFR inhibitor is performed on HR-NMIBC or IR patients who have been given a placebo. -Results in improved disease exacerbation duration compared to the NMIBC patient population. (In certain embodiments) Therefore, the administration of the FGFR inhibitor is performed on HR-NMIBC or IR-24 patients who have been given a placebo. This results in improved disease-specific survival compared to the NMIBC patient population. In terms of form, the administration of the FGFR inhibitor is compared to HR-NMIBC or I given a placebo. This results in improved OS compared to the R-NMIBC patient population. In certain embodiments, The aforementioned administration of an FGFR inhibitor is performed on HR-NMIBC or IR-NMIBC patients who have been given a placebo. This results in an improved RFS rate compared to the BC patient population. In certain embodiments, FGF The aforementioned administration of the R inhibitor is performed on HR-NMIBC or IR-NMIBC patients who have been given a placebo. This results in improved RFS2 compared to the group of individuals. In certain embodiments, FGFR inhibition The aforementioned administration of the agent was performed on a population of HR-NMIBC or IR-NMIBC patients who received a placebo. Compared to that, it leads to an improvement in CR.

[0127] In a particular embodiment, the improvement in RFS rate is determined in 6 months. Therefore, the improvement in the RFS rate is determined in 12 months. In a particular embodiment, the improvement in the RFS rate The upper limit is determined at 24 months.

[0128] In a particular embodiment, the improvement in antitumor activity compared to treatment with placebo was observed. In certain embodiments, the improvement in antitumor activity is compared to the case without treatment. This is a comparison. In certain embodiments, the improvement in antitumor activity is compared with standard treatment. This is a comparison. In a particular embodiment, the improvement in antitumor activity was selected by the investigator. This is a comparison with alternative therapies. In certain embodiments, improvement in antitumor activity is observed. Compared to a population of HR-NMIBC or IR-NMIBC patients who received mucitabine intravesically. In a particular embodiment, the improvement in antitumor activity is due to mitomycin C (MMC) / HR-NMIBC or IR-NMIBC patients who received intravesical administration of thermal MMC. This is a comparison with a group.

[0129] Gemcitabine is the active ingredient of gemcitabine hydrochloride (also known as GEMZAR®). Nu is an ingredient that can be administered into the bladder by indwelling in the bladder, for example, through a urinary catheter. It is a cleoside metabolism inhibitor. Gemcitabine is 200 mg per single-use vial, It can be administered as 1 g per single-use vial. Gemcitabine HCl is 2'-deodorant. It is xi-2',2'-difluorocytidine monohydrochloride (β-isomer).

[0130] Mitomycin C (also known as MUTAMYCIN®) is used for intravesical placement in the bladder. The bacterium Streptomyces caespitosus can be administered more effectively. Streptomyces caespitosus and other Streptomyces species Methylazirinopyrroloindoldione, isolated from the bacterial species *Omyces*, is an anti-malignant tumor compound. It is a ulcerative antibiotic. Intravesical administration of MMC may be optionally administered with heat, such as microwave induction. It may be administered simultaneously in the bladder with microwave-induced thermotherapy. By direct irradiation, thermotherapy can be delivered to the bladder wall by an applicator.

[0131] In some embodiments, patients show complete response (CR) to FGFR inhibitors within approximately 6 months. In some embodiments, patients achieve a complete response (CR) to FGFR inhibitors in approximately 3 months.

[0132] HR-NMIBC or IR-NMIBC patients who have not received treatment with FGFR inhibitors. Compared to patients who were not diagnosed, the R of patients diagnosed with HR-NMIBC or IR-NMIBC FS, progression-free survival, disease-specific survival, OS, RFS rate, RFS2, or Methods or uses for improving CR are also provided herein, and such methods are, in detail, 1 day A dose of approximately 8 mg of an FGFR inhibitor per day, or more specifically, a dose of approximately 6 mg of F per day. A GFR inhibitor, specifically erdafitinib, more specifically, a dose of approximately 8 mg per day. Erdafitinib, or more specifically, erdafitinib at a dose of approximately 6 mg per day. This refers to having at least one FGFR2 gene mutation and / or FGFR3 gene mutation. This includes administering it to patients diagnosed with HR-NMIBC or IR-NMIBC, or Consists of, or essentially consists of. In certain embodiments, by an FGFR inhibitor Compared to patients diagnosed with HR-NMIBC who have not received treatment, HR-NMIBC Methods or uses for improving RFS in patients diagnosed with the aforementioned method are provided herein. The law specifies, in detail, a dose of approximately 8 mg of an FGFR inhibitor per day, or in detail, per day A dose of approximately 6 mg of an FGFR inhibitor, more specifically erdafitinib, more specifically per day A dose of approximately 8 mg of erdafitinib, or more specifically, a dose of approximately 6 mg per day. Erdafitinib is used to treat at least one FGFR2 gene mutation and / or FGFR3 gene mutation. This drug is administered to patients diagnosed with HR-NMIBC or IR-NMIBC who have a genetic mutation. This includes the following: In certain embodiments, HR- Compared to patients diagnosed with NMIBC or IR-NMIBC, HR-NMIBC or I Methods or uses for improving progression-free survival in patients diagnosed with R-NMIBC are described herein. The method is provided as follows, and more specifically, involves administering an FGFR inhibitor at a dose of approximately 8 mg per day, or More specifically, an FGFR inhibitor at a dose of approximately 6 mg per day, more specifically, erdafitinib, More specifically, erdafitinib at a dose of approximately 8 mg per day, or more specifically, per day A dose of approximately 6 mg of erdafitinib is administered to patients with at least one FGFR2 gene mutation and / or diagnosed with HR-NMIBC or IR-NMIBC with an FGFR3 gene mutation This includes administering to patients who have been treated with FGFR inhibitors. In certain embodiments, treatment with FGFR inhibitors is Compared to patients diagnosed with HR-NMIBC who did not receive the test, Methods or uses for improving the duration of disease exacerbation in patients are provided herein, and the method Specifically, this involves an FGFR inhibitor at a dose of approximately 8 mg per day, or specifically, approximately A 6 mg dose of an FGFR inhibitor, specifically erdafitinib, and more specifically, per day A dose of approximately 8 mg of erdafitinib, or more specifically, a dose of approximately 6 mg per day. Erdafitinib is used to treat at least one FGFR2 gene mutation and / or FGFR3 gene mutation. This medication is administered to patients diagnosed with HR-NMIBC or IR-NMIBC who have a sub-mutation. This includes, in a particular embodiment, HR-N who have not been treated with an FGFR inhibitor. Compared to patients diagnosed with MIBC, patients diagnosed with HR-NMIBC or IR-NMIBC Methods or uses for improving disease-specific survival in patients are provided herein, prior The method of administration involves administering an FGFR inhibitor at a dose of approximately 8 mg per day, or, in detail, per day A dose of approximately 6 mg of an FGFR inhibitor, more specifically erdafitinib, more specifically 1 A dose of approximately 8 mg of erdafitinib per day, or more specifically, approximately 6 mg per day. A dose of erdafitinib is administered to at least one FGFR2 gene mutation and / or FGFR This includes administering the drug to patients diagnosed with HR-NMIBC who have three gene mutations. In certain embodiments, HR-NMIBC or I who have not been treated with an FGFR inhibitor Compared to patients diagnosed with R-NMIBC, those diagnosed with HR-NMIBC or IR-NMIBC Methods or uses for improving the OS of diagnosed patients are provided herein, and the method More specifically, an FGFR inhibitor at a dose of approximately 8 mg per day, or more specifically, approximately 6 mg per day. A dose of mg of an FGFR inhibitor, more specifically erdafitinib, more specifically per day Approximately 8 mg of erdafitinib, or more specifically, approximately 6 mg per day. Rudafitinib is used to treat at least one FGFR2 gene mutation and / or FGFR3 gene mutation. Administer to patients diagnosed with HR-NMIBC or IR-NMIBC who have a mutation. This includes, in certain embodiments, HR-NM that have not been treated with an FGFR inhibitor. Compared to patients diagnosed with IBC or IR-NMIBC, HR-NMIBC or IR- Methods or uses for improving the rate of recurrent fasting (RFS) in patients diagnosed with NMIBC are provided herein. The method, in particular, involves administering an FGFR inhibitor at a dose of approximately 8 mg per day, or in detail This involves an FGFR inhibitor administered at a dose of approximately 6 mg per day, specifically erdafitinib, and more specifically... More specifically, a dose of approximately 8 mg of erdafitinib per day, or more specifically, approximately A 6 mg dose of erdafitinib is administered to patients with at least one FGFR2 gene mutation and / or Patients diagnosed with HR-NMIBC or IR-NMIBC who have an FGFR3 gene mutation. This includes administering to a person who has been treated with an FGFR inhibitor. In certain embodiments, the person is being treated with an FGFR inhibitor. Compared to patients diagnosed with HR-NMIBC or IR-NMIBC who do not have HR-NM Methods or uses for improving RFS2 in patients diagnosed with IBC or IR-NMIBC This specification provides for a method of FGFR inhibition at a dose of approximately 8 mg per day. The drug, or more specifically, an FGFR inhibitor at a dose of approximately 6 mg per day, more specifically, Eldafi Tinib, or more specifically, erdafitinib at a dose of approximately 8 mg per day, or more For this, erdafitinib is administered at a dose of approximately 6 mg per day, and at least one FGFR2 gene is present. HR-NMIBC or IR-NMIB with submutations and / or FGFR3 gene mutations. This includes administering to patients diagnosed with C. In certain embodiments, an FGFR inhibitor is used. Compared to patients diagnosed with HR-NMIBC or IR-NMIBC who have not received treatment. Therefore, to improve CR in patients diagnosed with HR-NMIBC or IR-NMIBC Methods or uses are provided herein, and the method, in particular, involves a dose of approximately 8 mg per day. FGFR inhibitors, or more specifically, FGFR inhibitors at a dose of approximately 6 mg per day, in detail This refers to erdafitinib, more specifically, erdafitinib at a dose of approximately 8 mg per day. Or, more specifically, erdafitinib at a dose of approximately 6 mg per day, with at least one F HR-NMIBC or I have a GFR2 gene mutation and / or an FGFR3 gene mutation. This includes administering the drug to patients diagnosed with R-NMIBC.

[0133] In certain embodiments, the improvement is compared to treatment with a placebo. In a given embodiment, the improvement in antitumor activity is compared to the case without treatment. In certain embodiments, the improvement in antitumor activity is compared to standard treatment. In certain embodiments, the improvement in antitumor activity was compared to the investigator's choice treatment. In a particular embodiment, the improvement in antitumor activity is achieved by administering gemcitabine intravesically. This is compared to the HR-NMIBC patient population that received the treatment. In a particular embodiment, Improvement in antitumor activity was observed when mitomycin C (MMC) / thermal MMC was administered intravesically. This was compared to a population of HR-NMIBC or IR-NMIBC patients.

[0134] Evaluation of the sample for the presence of one or more FGFR gene mutations (a) Biopsy of one or more fibroblasts in biological samples from patients diagnosed with HR-NMIBC To evaluate the presence of frogent receptor (FGFR) gene mutations, and (b) to put 1 in the sample If more than one FGFR gene mutation is present, the specific dose of FG is approximately 8 mg per day. FR inhibitors, or more specifically, FGFR inhibitors at a dose of approximately 6 mg per day, more specifically, Rudafitinib, more specifically, erdafitinib at a dose of approximately 8 mg per day, or More specifically, this involves administering erdafitinib to the patient at a dose of approximately 6 mg per day. This specification also includes methods for treating HR-NMIBC that consist of or are essentially derived from it. Provided for publication.

[0135] (a) A biological sample from a patient diagnosed with IR-NMIBC is taken from one or more FGFR genes. Evaluate for submutations, specifically the presence of one or more FGFR2 or FGFR3 mutations. , and (b) if one or more FGFR gene mutations are present in the sample, in detail per day Approximately 8 mg of an FGFR inhibitor, or more specifically, approximately 6 mg of FGFR per day The inhibitor, more specifically erdafitinib, more specifically erdafitinib at a dose of approximately 8 mg per day The patient was given dafitinib, or more specifically, erdafitinib at a dose of approximately 6 mg per day. Methods for treating IR-NMIBC, including administration to the patient, are also provided herein.

[0136] H For details on manufacturing medicine to treat patients diagnosed with R-NMIBC, please see below. A dose of approximately 8 mg of an FGFR inhibitor per day, or more specifically, a dose of approximately 6 mg of FGFR inhibitor per day. FR inhibitors, more specifically erdafitinib, more specifically erdafitinib at a dose of approximately 8 mg per day The use of dafitinib, or more specifically, erdafitinib at a dose of approximately 6 mg per day. As described herein, FGFR inhibitors, in particular erdafitinib, are used in patient-derived biopsies. After evaluating the sample for the presence of one or more FGFR2 or FGFR3 gene mutations, and one in the sample This drug is administered or should be administered if any of the above FGFR2 or FGFR3 gene mutations are present. That is the case.

[0137] H FGFR inhibitors for manufacturing medicines to treat patients diagnosed with R-NMIBC The use of the agent is described herein, in detail, FGFR inhibitors, in detail, erdafitinib It should be administered or should be administered at a dose of approximately 8 mg per day, and FGFR inhibition The harmful agent, specifically erdafitinib, is derived from a patient-derived biological sample containing one or more FGFR2 or 3 After evaluating the presence of gene mutations, if the sample contains one or more FGFR2 or FGFR3 gene mutations, It should be administered or should be administered if abnormalities are present. In one embodiment, FGF R inhibitors, specifically erdafitinib, are administered at a dose of approximately 6 mg per day, or It should be administered.

[0138] I have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. For details on manufacturing medicine to treat patients diagnosed with R-NMIBC, please see below. A dose of approximately 8 mg of an FGFR inhibitor per day, or more specifically, a dose of approximately 6 mg of FGFR inhibitor per day. FR inhibitors, more specifically erdafitinib, more specifically erdafitinib at a dose of approximately 8 mg per day The use of dafitinib, or more specifically, erdafitinib at a dose of approximately 6 mg per day. As described herein, FGFR inhibitors, in particular erdafitinib, are used in patient-derived biopsies. After evaluating the sample for the presence of one or more FGFR2 or FGFR3 gene mutations, and one in the sample This drug is administered or should be administered if any of the above FGFR2 or FGFR3 gene mutations are present. That is the case.

[0139] I have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. FGFR inhibitors for manufacturing medicines to treat patients diagnosed with R-NMIBC The use of the agent is described herein, in detail, FGFR inhibitors, in detail, erdafitinib It should be administered or should be administered at a dose of approximately 8 mg per day, and FGFR inhibition The harmful agent, specifically erdafitinib, is derived from a patient-derived biological sample containing one or more FGFR2 or 3 After evaluating the presence of gene mutations, if the sample contains one or more FGFR2 or FGFR3 gene mutations, It should be administered or should be administered if abnormalities are present. In one embodiment, FGF R inhibitors, specifically erdafitinib, are administered at a dose of approximately 6 mg per day, or It should be administered.

[0140] H FGFR inhibitors for use in the treatment of patients diagnosed with R-NMIBC are described herein. It is stated that, in detail, FGFR inhibitors, specifically erdafitinib, are administered at approximately 8 mg per day. It should be administered or should be administered in the dose of an FGFR inhibitor, specifically Eldaf itinib is used to test patient-derived biological samples for the presence of one or more FGFR2 or FGFR3 gene mutations. After evaluation, if one or more FGFR2 or FGFR3 gene mutations are present in the sample, administration is performed. It should be done or administered. In one embodiment, an FGFR inhibitor, in particular, Dafitinib should be administered or should be administered at a dose of approximately 6 mg per day. .

[0141] I have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. FGFR inhibitors for use in the treatment of patients diagnosed with R-NMIBC are described herein. It is stated that, in detail, FGFR inhibitors, specifically erdafitinib, are administered at approximately 8 mg per day. It should be administered or should be administered in the dose of an FGFR inhibitor, specifically Eldaf itinib is used to test patient-derived biological samples for the presence of one or more FGFR2 or FGFR3 gene mutations. After evaluation, if one or more FGFR2 or FGFR3 gene mutations are present in the sample, administration is performed. It should be done or administered. In one embodiment, an FGFR inhibitor, in particular, Dafitinib should be administered or should be administered at a dose of approximately 6 mg per day. .

[0142] The following methods for evaluating the presence of one or more FGFR gene mutations in biological samples This applies equally to any of the treatment methods and methods of use disclosed above.

[0143] The disclosed method is used when one or more FGFR gene mutations are present in a patient-derived biological sample. In general, it is suitable for treating cancer in patients. In some embodiments, FGFR gene mutation This refers to one or more FGFR fusion genes, specifically one or more FGFR2 or FGFR3 fusions. It can be a gene. In some embodiments, an FGFR gene mutation is one or more FGF The R mutation, more specifically, may be one or more FGFR3 mutations. In some embodiments, In some embodiments, an FGFR gene mutation can result in one or more FGFR amplifications. Therefore, a combination of one or more FGFR gene mutations may be present in patient-derived biological samples. For example, in some embodiments, an FGFR gene mutation is one or more FGFR fusion genes. It may be a child and one or more FGFR mutations. In some embodiments, FGFR inheritance Sub-mutations may include one or more FGFR fusion genes and one or more FGFR amplifications. In some embodiments, the FGFR gene mutation is one or more FGFR mutations and one or more This can be FGFR amplification. In yet another embodiment, there may be one or more FGFR gene mutations. These may be FGFR fusion genes, mutations, and amplifications. Exemplary FGFR fusion genes are Table 1 shows these, and they include FGFR2-BICC1;FGFR2-CASP7;FGFR 3-BAIAP2L1;FGFR3-TACC3 V1;FGFR3-TACC3 V3 ; or combinations thereof, but not limited to these.

[0144] A preferred method for evaluating a biological sample for the presence of one or more FGFR gene mutations is The section on methods in this specification, and the entirety thereof, are incorporated herein by International Publication No. 2016 / As described in Brochure No. 048833 and U.S. Patent Application No. 16 / 723,975 For example, although not intended to be limiting, biological samples are found to have one or more FGFR gene mutations. Evaluating the existence of RNA may involve any combination of the following steps: The process of isolating from the sample; the process of synthesizing cDNA from RNA; and the process of amplifying cDNA. (Pre-amplification or not pre-amplification). In some embodiments, one or more biological samples are used. Evaluating the presence of FGFR gene mutations is important for determining whether one or more FGFR gene mutations are present. Combine and amplify patient-derived cDNA with a pair of primers that amplify this; and one This may include determining whether the above FGFR gene mutations are present in the sample. In one embodiment, cDNA may be pre-amplified. In some embodiments, the evaluation step is performed on the sample or The process involves isolating RNA, synthesizing cDNA from the isolated RNA, and synthesizing cDNA This may include a step of pre-amplifying the signal.

[0145] Suitable primer pairs for carrying out the amplification process are exemplified in Table 3 below, This is one example of what is disclosed in the International Publication No. 2016 / 048833 pamphlet, but It is not limited to them.

[0146] [Table 3]

[0147] The presence of one or more FGFR gene mutations indicates that, at the time of diagnosis, after tumor resection, the first-line treatment is... It can then be evaluated at any suitable point in time, including during clinical treatment or any combination thereof.

[0148] For example, a biological sample taken from a patient may indicate whether the patient has or is susceptible to cancer. Which pathological conditions or diseases cause upregulation of FGFR levels or activity, or normalization of FGFR activity? Sensitization of the sexual pathway, or growth factor ligand levels or growth factor ligand activity, etc. Upregulation of growth factor signaling pathways, or downstream biochemical pathways of FGFR activation Does it feature a genetic abnormality or abnormal protein expression that leads to upregulation? It can be analyzed to determine whether or not.

[0149] Examples of such abnormalities that lead to activation or sensitization of FGFR signaling include apothesis Loss or inhibition of the cis pathway, upregulation of the receptor or ligand, or the receptor or One example is the presence of a ligand gene mutation, such as a PTK variant. FGFR1, F Genetic mutations or upregulation of GFR2, FGFR3, or FGFR4, specifically F GFR1 overexpression, or gain-of-function gene mutations in FGFR2 or FGFR3. These tumors may be particularly sensitive to FGFR inhibitors.

[0150] The method, approved formulation, and use further include one or more of the following in a biological sample prior to the administration step: This may include evaluating the presence of FGFR gene mutations.

[0151] Diagnostic tests and screenings typically involve tumor biopsy samples and blood samples (for shed tumor cells). Isolation and concentration of (stool biopsy, sputum, chromosome analysis, pleural fluid, ascites, oral puncture, biopsy, circulatory D This procedure is performed on a biological sample selected from NA or urine. In certain embodiments, Body samples include blood, lymph, bone marrow, solid tumor samples, or any combination thereof. In certain embodiments, the biological sample is a solid tumor sample. The body sample is a blood sample. In certain embodiments, the biological sample is a urine sample.

[0152] Methods for identifying and analyzing gene mutations and upregulations in proteins are known to those skilled in the art. Cleaning methods include reverse transcriptase polymerase chain reaction (RT-PCR) or injection Situ hybridization, for example, fluorescence in situ hybridization (F Standard methods such as ISH (Instructional Standards) are examples, but are not limited to these.

[0153] Genetic mutations in FGFR, specifically FGFR gene mutations as described herein. Identifying individuals with differences indicates whether this patient is particularly suitable for treatment with erdafitinib. This could mean that the tumor should be prioritized for the presence of FGFR variants before treatment. Screening can be performed using direct sequencing, oligonucleotide sequencing, etc. The screening process typically involves direct sequencing, oligonucleotide sequencing, etc. This will involve nucleotide microarray analysis or mutant-specific antibodies. Diagnosis of tumors with such gene mutations is performed by those skilled in the art, using methods such as RT-PCR and FISH. This is publicly known and can be carried out using the methods described herein.

[0154] In addition, for example, FGFR gene mutations are, for example, PCR and as previously described herein. Direct sequencing of tumor biopsies using the method for directly sequencing the PCR products described. It can be identified by... A person skilled in the art can detect the overexpression, activation, or mutation of the aforementioned protein... We recognize that all such well-known methods are applicable to this case. Ro.

[0155] Screening by RT-PCR showed that the level of mRNA in tumors was c It is evaluated by generating a DNA copy and then amplifying the cDNA by PCR. The CR amplification method, primer selection, and amplification conditions are known to those skilled in the art. Nucleic acid manipulation and P CR is, for example, Ausubel, FM et al., eds. (2004) Cur rent 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 Dieg The procedure is carried out according to the standard method described in o. Reactions and operations related to nucleic acid methods are as follows: ambrook et al.,(2001),3rd Ed,Molecular C loning:A Laboratory Manual,Cold Spring H It is also mentioned in Arbor Laboratory Press. Alternatively, RT-P Commercially available CR kits (e.g., Roche Molecular Biochemica) ls), or U.S. Patent No. 4,666,828; U.S. Patent No. 4,683,202 ; Specification No. 4,801,531; Specification No. 5,192,659, No. 5,272 Specification No. 057, Specification No. 5,882,864, and Specification No. 6,218,529 Methods such as those described in the details (which are incorporated herein by reference) may be used. An example of an in situ hybridization method for evaluating mRNA expression is fluorescence This is likely cytohybridization (FISH) (Angerer (1987)). See Meth.Enzymol., 152:649.

[0156] In general, in situ hybridization involves the following main steps: (1) Analyze what (2) Immobilization of tissues; (3) Experiments to increase the reachability of target nucleic acids and reduce nonspecific binding. (3) Pre-hybridization treatment of materials; (4) Biological structure of nucleic acid mixture or nuclei in tissue Hybridization to acid; (4) Nucleic acid that did not bind by hybridization Post-hybridization washing to remove lagging, and (5) hybrid This includes the detection of fused nucleic acid fragments. Probes used for such applications are typical. They are typically labeled with, for example, a radioactive isotope or a fluorescent reporter. Preferred probes are... To enable specific hybridization with target nucleic acids under trigger conditions Sufficiently long, for example, about 50, 100, or 200 nucleotides to about 1000 nucleotides. It is above. The standard method for performing FISH is Ausubel, FMet a l.,eds.(2004)Current Protocols in Molecule lar Biology, John Wiley & Sons Inc and Fluor escence In Situ Hybridization:Technical Overview by John MS Bartlett in Molecule ar Diagnosis of Cancer,Methods and Proto cols,2nd ed.;ISBN:1-59259-760-2;March 20 04,pps.077-088;Series:Methods in Molecule It is listed in ar Medicine.

[0157] The method for gene expression profiling is (DePrimo et al. (2003) This is described by BMC Cancer, 3:3). In short, this pro The tocologne is as follows: To prime the synthesis of the first strand of cDNA, (dT) 24 oligomer (SEQ ID NO: 38: tttttttttt tttttttttt ttt After synthesizing double-stranded cDNA from total RNA using t), random hexamer primer - This synthesizes the second strand of cDNA. The double-stranded cDNA is biotinylated ribonucleotides. Use as a template for in vitro transcription of cRNA using Affy. The protocol described by metrix (Santa Clara, CA, USA) Therefore, it is chemically fragmented, and then hives overnight on a Human Genome Array. Reduce.

[0158] Alternatively, protein products expressed from mRNA can be used in immunohistochemical examination of tumor samples. Microtiter plate solid-phase immunoassay, Western blotting, 2D SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry, and this technique The assay may be performed by other methods known in the field for detecting specific proteins. The detection method would involve the use of site-specific antibodies. Those skilled in the art will know how to upcontrol FGFR. All such well-known methods for detection, or for the detection of FGFR variants or mutations. They will recognize that the method described is applicable to this case.

[0159] Abnormal levels of proteins such as FGFR can be detected by standard enzyme assays, e.g., this specification. It can be measured using the assay described in the book. Activation or overexpression can also be measured. It can be detected in tissue samples, such as tumor tissue. For example, Chemicon In By measuring tyrosine kinase activity using the international assay... The target tyrosine kinase is immunoprecipitated from the sample lysate, and its activity is measured.

[0160] As an alternative method for measuring FGFR overexpression or activation, including isoforms One example is the measurement of microvascular density. This is done, for example, by Orre and Roger This is described in s(Int J Cancer(1999),84(2)101-8). It can be measured using the assay method. The assay method also includes the use of markers.

[0161] Therefore, in order to identify tumors that are particularly suitable for treatment with the compounds of the present invention, You can also use all of the techniques.

[0162] Erdafitinib is used to treat genetically mutated FGFRs, specifically mutated FGFRs. It is particularly useful in the treatment of patients who have HR-NMIBC or IR-NMIBC is susceptible to FGFR2 gene mutations and / or FGFR3 gene mutations. In a particular embodiment, a mutation in the FGFR2 or FGFR3 gene is FGFR3 This is a gene mutation or a fusion of the FGFR2 or FGFR3 gene. In some embodiments, FGFR3 gene mutations include R248C, S249C, G370C, Y373C, or any combination thereof. In further embodiments, FGFR2 or FGFR3 The gene fusion is FGFR3-TACC3, specifically FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC 1. FGFR2-CASP7, or any combination thereof.

[0163] In a particular embodiment, FGFR2 and / or FGFR3 gene mutations are QIAGE Includes N therascreen® FGFR RGQ RT-PCR kit However, identification can be performed using commercially available kits, which are not limited to these.

[0164] Pharmaceutical composition and route of administration Considering their useful pharmacological properties, FGFR inhibitors in general, and more specifically, erdafiti Nib can be formulated into various pharmaceutical forms for administration purposes.

[0165] In one embodiment, the pharmaceutical composition (e.g., a formulation) contains at least one activated compound of the present invention. A substance is used as one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, or saturates. Auxiliaries, stabilizers, preservatives, lubricants, or other substances well known to those skilled in the art, and optionally Included together with other therapeutic or prophylactic agents.

[0166] To prepare a pharmaceutical composition, the active ingredient is generally an FGFR inhibitor, and more specifically... In essence, the effective dose of erdafitinib is homogeneously mixed with a pharmaceutically acceptable carrier. The carrier can take on a wide variety of forms depending on the desired form of the preparation for administration. The pharmaceutical composition is suitable for oral, parenteral, topical, intranasal, ocular, ocular, ocular, rectal, vaginal, or transdermal administration. It may be any suitable form. These pharmaceutical compositions are preferably administered orally, rectally, It is desirable that the unit dosage form be suitable for transdermal administration or parenteral injection. For example, When preparing a composition into an oral dosage form, such as a suspension, syrup, elixir, and solution, For oral liquid formulations, for example, water, glycol, oil, alcohol, etc.; or powders, pills, In the case of capsules and tablets, a solid carrier is used, such as starch, sugars, kaolin, lubricant, etc. Any of the usual pharmaceutical media, such as combination drugs or disintegrants, can be used.

[0167] The pharmaceutical composition of the present invention, more particularly capsules and / or tablets, comprises one or more pharmaceutically acceptable materials. Excipients (pharmaceutically acceptable carriers), such as disintegrants, diluents, fillers, binders, It may contain buffering agents, lubricants, flow enhancers, thickeners, sweeteners, flavorings, colorings, preservatives, etc. Some excipients can serve multiple purposes.

[0168] Suitable disintegrants are those with a high expansion rate. Examples include hydrophilic, insoluble, or water-soluble disintegrants. Poorly soluble crosslinked polymers, such as crospovidone (crosslinked polyvinylpyrrolidone) and clo This is scalmellose sodium (cross-linked carboxymethylcellulose sodium). For convenience, the amount of disintegrant in the tablets according to the formula is in the range of approximately 2.5 to approximately 15 w / w%, preferably. The range is approximately 2.5-7 w / w%, and more specifically, it may be in the range of approximately 2.5-5 w / w%. Disintegrants, when used in large quantities, naturally result in sustained-release formulations, so disintegrants are used as diluents or fillers. It is advantageous to dilute it with an inert substance called [name of substance].

[0169] Various materials may be used as diluents or fillers. For example, lactose monohydrate, Water, lactose, sucrose, dextrose, mannitol, sorbitol, starch, Cellulose (e.g., microcrystalline cellulose (Avicel®), silicified microcrystalline cellulose) Calcium hydrogen phosphate (-), dihydrate or anhydrous calcium hydrogen phosphate, and other substances known in the art. , as well as mixtures thereof (for example, rac sold as Microcelac (trademark) It is a spray-dried mixture of tox monohydrate (75%) and microcrystalline cellulose (25%). Microcrystalline cellulose and mannitol are preferred. Diluents or fillers in the pharmaceutical compositions of the present invention. For convenience, the total amount of the agent should be in the range of approximately 20 to approximately 95 w / w%, preferably approximately 55 to approximately 95 w / w In the range of %, or in the range of approximately 70 to approximately 95 w / w%, or in the range of approximately 80 to approximately 95 w / w%, The percentage can range from approximately 85% to approximately 95% w / w%.

[0170] Lubricants and flow enhancers can be used in the manufacture of specific dosage forms, typically tablets. It is used in such cases. Examples of lubricants and flow promoters include hydrogenated vegetable oils, for example, hydrogenated cotton. Fruit oil, magnesium stearate, stearic acid, sodium lauryl sulfate, lauryl sulf Magnesium oxide, colloidal silica, colloidal anhydrous silica, talc, mixtures thereof, and Other than those known in the art, an interesting lubricant is magnesium stearate. It is a mixture of magnesium stearate and colloidal silica, and stearic acid Magnesium is preferred. A preferred flow promoter is colloidal anhydrous silica.

[0171] If present, the flow accelerator is generally present in an amount of 0.2-7.0 w / w% of the total weight of the composition, details This includes 0.5-1.5 w / w%, and more specifically, 1-1.5 w / w%.

[0172] If present, the lubricant is generally present in an amount of 0.2-7.0 w / w% of the total weight of the composition, in detail 0.2~2 w / w%, or 0.5~2 w / w%, or 0.5~1.75 w / w%, or 0 Contains 0.5-1.5 w / w%.

[0173] A binder can be optionally used in the pharmaceutical composition of the present invention. The binder is a water-soluble polymer, such as alkylcellulose such as methylcellulose; Roxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxyalkylcellulose such as hydroxybutylcellulose: hydroxyethyl Hydroxyalkyl cellulose such as methylcellulose and hydroxypropylmethylcellulose. Alkylcellulose; carboxymethylcellulose and other carboxyalkylcelluloses. ; Sodium carboxymethylcellulose and other carboxyalkylcellulose alkalis Metallic salts; such as carboxymethyl ethyl cellulose and other carboxyalkyl alkyl cellulose -; carboxyalkylcellulose ester; starch; sodium carboxymethyl Pectins such as amylopectin; chitin derivatives such as chitosan; trehalose, cyclodextrin Disaccharides such as chistrin and its derivatives, oligosaccharides and polysaccharides, alginic acid, and its alkali gold Genus and ammonium salts, carrageenan, galactomannan, tragacanth, agar, arabic Guar gum and xanthan gum; polyacrylic acid and its salts; polymethacrylic acid, etc. Salts and esters of polyvinylpyrrolidone (PVP), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone (PVP) PVA (Vitamin A) and its copolymers, for example, PVP-VA. Preferably For example, water-soluble polymers include hydroxypropyl methylcellulose, for example, Hydro Hydroxyalkylalkylcellulose such as 15cps of hydroxypropylmethylcellulose That is the case.

[0174] Other excipients, such as colorants and pigments, may also be added to the composition of the present invention. It contains titanium dioxide and food-grade dyes. The coloring agent or pigment in the formulation of the present invention Although optional, if used, the colorant may be used in the maximum amount based on the total weight of the composition. It can be present in an amount of 3.5 w / w%.

[0175] The fragrance is optional in the composition and may be synthetic flavoring oils and aromatic compounds for flavoring or natural It can be selected from oils, extracts from plant leaves, flowers, fruits, etc., and combinations thereof. These contain cinnamon oil, wintergreen oil, peppermint oil, bay oil, anise oil, eucalyptus oil, and thyme oil. Obtain vanilla, citrus oils, e.g., lemon, orange, grape, lime and grapefruit. Fruits such as apple, banana, pear, peach, and strawberry extracts. Raspberries, cherries, plums, pineapples, and apricots are also useful as flavorings. Yes, the amount of fragrance can depend on several factors, including the desired sensory receptor effect. In general, fragrance The substance will be present in an amount of approximately 0% to approximately 3% (w / w).

[0176] Formaldehyde scavengers are compounds that can absorb formaldehyde. One or more reversible or irreversible bonds are formed between the formaldehyde scavenger and formaldehyde. It contains compounds that have a nitrogen center that is reactive with formaldehyde, such as by forming a compound. For example, Formaldehyde scavengers are reactive with formaldehyde and form Schiff base imines. It then contains one or more nitrogen atoms / centers that can subsequently bond with formaldehyde. For example, a formaldehyde scavenger is reactive with formaldehyde and contains one or more 5- It contains one or more nitrogen centers that form an 8-membered ring. The formaldehyde scavenger is preferably, It contains one or more amine or amide groups. For example, formaldehyde scavengers contain amino acids, Amino sugars, α-amine compounds, or their conjugates or derivatives, or mixtures thereof It is possible. The formaldehyde scavenger may contain two or more amines and / or amides.

[0177] Formaldehyde scavengers include, for example, glycine, alanine, serine, threonine, and cis. Theine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, Aspartic acid, glutamic acid, arginine, lysine, ornithine, citrulline, tauri Pyrrolidine, meglumine, histidine, aspartame, proline, tryptophan , citrulline, pyrrolidine, asparagine, glutamine, or their conjugates or This includes a mixture; or, where possible, a pharmaceutically acceptable salt thereof.

[0178] In one aspect of the present invention, the formaldehyde scavenger is meglumine or a pharmaceutically acceptable formaldehyde. The salt is, more specifically, a meglumine base.

[0179] In one embodiment, in the method and use described herein, Erdafitini Br or its pharmaceutically acceptable salts, specifically erdafitinib base; formaldehyde capture Captive agents, more specifically meglumine or its pharmaceutically acceptable salts, more specifically meglumine bases; and More specifically, in the form of tablets or capsules containing erdafitinib, which includes a pharmaceutically acceptable carrier. It should be administered or be administered as a pharmaceutical composition.

[0180] Another object of the present invention is to provide pharmaceutical compositions as described herein, more specifically in the form of tablets or capsules. A process for preparing a formaldehyde scavenger in capsule form, specifically a formaldehyde scavenger, and more specifically, a Meguru Min, and erdafitinib, its pharmaceutically acceptable salts or solvates, in particular E Mixing rudafitinib base with a pharmaceutically acceptable carrier, and forming the mixture into tablets. The present invention provides a process characterized by compression or filling the mixture into capsules. That is what it is.

[0181] Tablets and capsules are the most advantageous oral dosage forms because they are easy to administer. In that case, a solid pharmaceutical carrier is naturally used. In the case of parenteral compositions, the carrier is usually made of solid material. It will contain bacterial water in at least a large portion, but for example, it will also contain other components that aid in dissolution. This is also acceptable. For example, the carrier may be physiological saline, glucose solution, or physiological saline and glucose solution. An injectable solution containing a mixture of the above may be prepared. An injectable suspension may also be prepared, and In such cases, appropriate liquid carriers, suspensions, etc., may be used. In compositions suitable for transdermal administration, The carrier is a combination of suitable additives having any desired properties in low proportions, selected by arbitrary means, and is permeable. The product optionally contains accelerators and / or suitable wetting agents, but these additives may be of significant harmful effects. It does not cause any effect on the skin. The additive may facilitate administration to the skin, and These compositions may be useful in preparing and / or desired compositions in various ways. For example, it can be administered as a transdermal patch, a spot-on formulation, or an ointment. To facilitate administration and ensure uniformity of dosage, the aforementioned pharmaceutical composition is formulated into a unit dosage form. This is particularly advantageous. The unit dosage form, when used in this specification and the claims, is a unit This refers to physically individual units suitable for dosage, each unit being provided with the necessary pharmaceutical carrier, as desired. It contains a predetermined amount of the active ingredient calculated to produce the therapeutic effect. Examples include tablets (including scored tablets or coated tablets), capsules, pills, and fractions. Powders, cachet preparations, injectable solutions or suspensions, teaspoon and tablespoon amounts, and the like. There are variations that are formed by dividing and combining these elements.

[0182] To facilitate administration and ensure uniformity of dosage, the aforementioned pharmaceutical composition is formulated into a single dosage form. This is particularly advantageous. The unit dosage forms used herein are physically suitable as unit doses. It refers to individual units, and each unit, along with the necessary drug carrier, produces the desired therapeutic effect. It contains a predetermined amount of the active ingredient calculated accordingly. An example of such a unit dosage form is a tablet. (Including scored tablets or coated tablets), capsules, pills, powdered preparations, cachet preparations, injections Injectable solutions or suspensions, teaspoon and tablespoon amounts, and compound forms thereof. There are such forms. The preferred forms are tablets and capsules.

[0183] In certain embodiments, the FGFR inhibitor is available in solid unit dosage form and suitable for oral administration. It is present in the unit dosage form. The unit dosage form contains approximately 1, 2, 3, 4, 5, 6, 7 units per unit dose. 8, 9, or 10 mg of an FGFR inhibitor, or limited by two of these values. The amount may be in the range of 3, 4, or 5 mg per unit dose.

[0184] The pharmaceutical composition is preferably 0.05 to 99% by weight, and more preferably, depending on the mode of administration. The compound of the present invention is present in an amount of 0.1 to 70% by weight, more preferably 0.1 to 50% by weight, and 1 to 99.95% by weight, more preferably 30 to 99.9% by weight, even more preferably It contains 50-99.9% by weight of pharmaceutically acceptable carriers, all percentages being part of the composition. The total weight is used as the basis.

[0185] The tablets or capsules of the present invention may be further film-coated to improve, for example, the taste. This may provide ease of swallowing and a superior appearance. Polymer film coating The materials are known in the art. A preferred film coating is a water-based film. It is a film coating, in contrast to solvent-based film coatings, but this is because This is because it may contain more trace amounts of aldehyde. Preferred film The coating material is Opadry(registered trademark) II water-based film coating system, for example Opadry(registered trademark) II 85F92209 and other Opadry(registered trademarks) II 85F. A more preferred film coating is an aqueous moisture barrier film. Readilycoat® (registered trademark), a coating system (for example, Readilyc oat(registered trademark) D), AquaPolish(registered trademark) MS, Opadry(registered trademark) Protects against environmental moisture, including trademarks amb and Opadry® amb II. It is a water-based film coating. A preferred film coating is polyethylene glycerin. High-performance moisture barrier film coatings that are PVA-based and free of coal, with an immediate release system. This is Opadry(registered trademark) amb II.

[0186] In the tablet according to the present invention, the film coating is approximately 4% (w / ) of the total weight of the tablet in terms of weight. It is preferable that the amount is less than or equal to w.

[0187] In the case of the capsule formulation according to the present invention, hypromellose (HPMC) is more effective than gelatin capsule formulations. Capsules are preferred.

[0188] In one aspect of the present invention, a medical device described herein, more specifically in the form of a capsule or tablet, The drug composition contains 0.5 mg to 20 mg base equivalents, or 2 mg to 20 mg base equivalents, or 0. 5 mg to 12 mg base equivalent, or 2 mg to 12 mg base equivalent, or 2 mg to 10 mg base Equivalents, or 2mg to 6mg base equivalents, or 2mg base equivalents, 3mg base equivalents, 4mg base equivalents 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 erdafitini This includes β, its pharmaceutically acceptable salts or solvates. Details are provided herein. The pharmaceutical composition contains 3 mg base equivalent, 4 mg base equivalent, or 5 mg base equivalent of erdafitin. b, its pharmaceutically acceptable salt or solvate, specifically 3 mg, 4 mg, or 5 mg Contains erdafitinib base.

[0189] In one aspect of the present invention, a medical device described herein, more specifically in the form of a capsule or tablet, The drug composition is 0.5 mg to 20 mg, or 2 mg to 20 mg, or 0.5 mg to 12 mg , or 2mg-12mg, or 2mg-10mg, or 2mg-6mg, or 2mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg or Contains 12 mg of erdafitinib base. More specifically, the pharmaceutical compositions described herein It contains 3 mg, 4 mg, or 5 mg of erdafitinib base. See details herein. The pharmaceutical composition contains 3 mg, 4 mg, or 5 mg of erdafitinib base, and about 0.5 ~5w / w%, approximately 0.5~3w / w%, approximately 0.5~2w / w%, approximately 0.5~1. 5 w / w%, or approximately 0.5 to 1 w / w%, formaldehyde scavenger, see Megurumi for details. Contains. More specifically, the pharmaceutical compositions described herein contain 3 mg, 4 mg, or 5 mg Erdafitinib base, and approximately 0.5 to 1.5 w / w%, or approximately 0.5 to 1 w / w% It contains formaldehyde scavenging agents, specifically meglumine.

[0190] In one aspect of the present invention, two or more pharmaceutical compositions, for example, two pharmaceutical compositions described herein, It may be administered to obtain a desired dose, for example, a daily dose. For example, a daily dose of 8 mg of salt For the base equivalent of erdafitinib, two tablets of 4 mg of erdafitinib are used. Alternatively, capsules may be administered separately, or the base equivalent of 3 mg of erdafitinib Even if tablets or capsules containing 5 mg of base equivalent are administered, Good. For example, if the daily dose of erdafitinib is 9 mg base equivalent, then 3 mg of erdafitinib The three tablets or capsules containing the base equivalents of itinib may be administered separately, or 4 Tablets or capsules containing the base equivalent of mg of erdafitinib and tablets containing the base equivalent of 5 mg. A drug or capsule may be administered. For example, Eldaf with a daily dose of 6 mg base equivalent. In the case of erdafitinib, two tablets or capsules containing the base equivalent of 3 mg of erdafitinib. Each of these may be administered separately.

[0191] The amount of the formaldehyde scavenger, specifically meglumine, in the pharmaceutical composition according to the present invention is approximately 0.1 to about 10w / w%, about 0.1 to about 5w / w%, about 0.1 to about 3w / w%, about 0.1 ~2w / w%, approx. 0.1~1.5w / w%, approx. 0.1~1w / w%, approx. 0.5~approx. 5w / w%, about 0.5 to about 3w / w%, about 0.5 to about 2w / w%, about 0.5 to about 1.5w / w%, which can range from approximately 0.5% to approximately 1 w / w%.

[0192] According to a particular embodiment, erdafitinib is administered orally in doses of 3 mg, 4 mg, or Supplied as 5 mg film-coated tablets, containing the following inactive ingredients or their equivalents: Tablet core: Croscarmellose sodium, magnesium stearate, mannitol Cellulose, meglumine, and microcrystalline cellulose; and film coatings: Opadory amb II: Glycerol monocaprylic plate type I, polyvinyl alcohol portion Iron oxide, sodium lauryl sulfate, talc, titanium dioxide, yellow iron oxide, red iron oxide (orange For colored and brown tablets, triiron tetroxide / black iron oxide (for brown tablets).

[0193] In safety-focused trials, all potential adverse effects that may arise from exposure to the drug are considered. It is necessary to identify adverse effects. Efficacy is often determined through strictly controlled clinical trials. When tested under appropriate conditions such as those mentioned above, the active drug component may have a greater health effect than placebo or other interventions. It is measured by determining whether it demonstrates a benefit.

[0194] The term “acceptable” in relation to a formulation, composition, or component means “treatment” as used herein. The beneficial effects of the preparation, composition, or component on the overall health of the person being treated are present. It means that, to a certain extent, it substantially outweighs the harmful effects.

[0195] All formulations for oral administration are in dosage forms suitable for such administration.

[0196] Administration method and treatment regimen In one embodiment, a therapeutically effective amount of an FGFR inhibitor is administered as HR-NMIBC or IR-NMIBC. This includes, consists of, or essentially involves administering to a patient diagnosed with BC. A method for treating HR-NMIBC or IR-NMIBC is described herein, FG FR inhibitors are administered orally. In some embodiments, FGFR inhibitors are generally used, and Physically, erdafitinib is administered daily, or more precisely, once daily. Several embodiments Generally, FGFR inhibitors, and specifically erdafitinib, are administered twice a day. In some embodiments, FGFR inhibitors in general, and specifically erdafitinib, It is administered three times a day. In some embodiments, FGFR inhibitors are used in general, and specifically Erdafitinib is administered four times a day. In some embodiments, FGFR is generally used. The inhibitor, and specifically erdafitinib, is administered every other day. Several implementations In general, FGFR inhibitors, and specifically erdafitinib, are administered once a week. In some embodiments, FGFR inhibitors are used in general, and specifically erdafitinib. It is administered twice a week. In some embodiments, FGFR inhibitors are used in general, and specific In some embodiments, erdafitinib is administered every other week. The inhibitor, specifically erdafitinib, is administered orally on a daily schedule.

[0197] Generally, F is used in humans for the treatment of diseases or conditions described herein. The dosage of GFR inhibitors, and specifically erdafitinib, is typically about 1 / 20 per day. The range is 20 mg. In some embodiments, FGFR inhibitors, and specifically, el Dafitinib is administered at approximately 1 mg per day, approximately 2 mg per day, approximately 3 mg per day, and daily Approximately 4 mg per serving, approximately 5 mg per day, approximately 6 mg per day, approximately 7 mg per day, 1 day Approximately 8 mg per serving, approximately 9 mg per day, approximately 10 mg per day, approximately 11 mg per day, Approximately 12 mg per day, approximately 13 mg per day, approximately 14 mg per day, approximately 1 5 mg, approximately 16 mg per day, approximately 17 mg per day, approximately 18 mg per day, per day It is administered orally to humans at a dose of approximately 19 mg per day or approximately 20 mg per day.

[0198] In some embodiments, erdafitinib is administered orally. Erdafitinib is administered orally once daily at a dose of approximately 8 mg. Further implementation In this case, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily. In further embodiments, (a) the patient receives approximately 5.5 mg / 14 to 21 days after the start of treatment. Patients with serum phosphate (PO4) levels less than dL and who are receiving 8 mg of erdafitin once daily. If administration of b does not cause ocular damage; or (b) 8 mg of erdafi once daily If tinib administration does not cause a grade 2 or higher adverse reaction, 1 From day 4 to 21, increase the dose of erdafitinib from 8 mg once daily to 9 mg once daily. In one particular embodiment, on the 14th day after the start of treatment, the dose of erdafitinib is increased daily. The dose is increased from 8 mg once daily to 9 mg once daily. In certain embodiments, after the start of treatment... On day 5, increase the dose of erdafitinib from 8 mg once daily to 9 mg once daily. In one particular embodiment, on the 16th day after the start of treatment, a dose of erdafitinib is administered once daily. The dose is increased from 8 mg to 9 mg once daily. In certain embodiments, 17 days after the start of treatment. For the eye, increase the dose of erdafitinib from 8 mg once daily to 9 mg once daily. In a specific embodiment, on day 18 after the start of treatment, the dose of erdafitinib was 8 mg once daily. The dose is increased from g to 9 mg once daily. In a particular embodiment, on the 19th day after the start of treatment... The dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily. In this embodiment, on the 20th day after the start of treatment, the dose of erdafitinib is 8 mg once daily. Then increase to 9 mg once a day. In a particular embodiment, on the 21st day after the start of treatment, Increase the dose of rudafitinib from 8 mg once daily to 9 mg once daily.

[0199] In one embodiment, erdafitinib is administered at a dose of 8 mg, specifically 8 mg once daily. In one embodiment, erdafitinib is administered at a dose of 8 mg, specifically 8 mg once daily. It is administered when serum phosphate levels (for example, when serum phosphate levels are <5.5 mg / dL) It is present, or <7 mg / dL, or in the range of 7 mg / dL to ≤9 mg / dL. Depending on whether the dose is within that range or ≤9 mg / dL, observed treatment-related adverse effects Depending on the situation, there is an option to gradually increase the dose to 9 mg. In one embodiment, whether to gradually increase the dose or not Serum phosphate levels to determine this during the first cycle of erdafitinib treatment The measurement was taken on the day of treatment, specifically on day 14±2 of erdafitinib administration, and more specifically on day 14. It will be done.

[0200] In one embodiment, erdafitinib is administered at a dose of 6 mg, specifically 6 mg once daily. It is administered in a continuous schedule.

[0201] 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. It is administered to monitor serum phosphate levels (e.g., serum phosphate levels <5.5 mg / dL). Depending on the observed treatment-related adverse events, there is an option to gradually increase the dose to 8 mg. In one embodiment, the serum phosphate level used to determine whether to gradually increase is erda The last treatment day of cycle 1 of fitinib administration, specifically day 1 of cycle 2 ( Day 7 of Cycle 2 (C2D1), or Day 1 of Cycle 2 (C2D1) ± Day 3, or more specifically, Day 2 Measured on D1.

[0202] In a particular embodiment, the dose of erdafitinib is at the end of the treatment period of cycle 1. More specifically, day 1 of cycle 2 (C2D1) ± 7 days, or day 1 of cycle 2 (C2D 1) On ±3 days, more specifically on C2D1, increase the dose from 6 mg once daily to 8 mg once daily. ru.

[0203] In some embodiments, erdafitinib is administered orally. Erdafitinib is administered orally once daily at a dose of approximately 6 mg. Further implementation In this case, the dose of erdafitinib is increased from 6 mg once daily to 8 mg once daily. In further embodiments, (a) the patient at the end of the treatment period of cycle 1 after the start of treatment More specifically, day 1 of cycle 2 (C2D1) ± 7 days, or day 1 of cycle 2 (C2D 1) On days ±3, more specifically on C2D1, serum phosphate (PO) levels less than approximately 5.5 mg / dL 4) The level is shown, and administration of 6 mg of erdafitinib once daily is serious toxicity, for example If no ocular impairment occurs; or (b) administration of 6 mg of erdafitinib once daily If the dose does not cause a Grade 2 or higher adverse reaction, then the first cycle of treatment after the start of treatment At the end of the treatment period, specifically on day 1 (C2D1) ± day 7 of cycle 2, or cycle 2 On day 1 (C2D1) ± day 3, more specifically on C2D1, the dose of erdafitinib was increased by 1 Increase the dosage from 6 mg once daily to 8 mg once daily.

[0204] In some embodiments, erdafitinib is administered orally. Erdafitinib is administered orally once daily at a dose of approximately 6 mg. Further implementation In this case, (a) the patient, at the end of the treatment period of cycle 1 after the start of treatment, in detail cycle Day 1 of cycle 2 (C2D1) ± 7 days, or Day 1 of cycle 2 (C2D1) ± 3 days, In detail, C2D1 showed serum phosphate (PO4) levels of 5.5 mg / dL to 6.99 mg / dL. The level indicated that administration of 6 mg of erdafitinib once daily was serious toxicity, such as ocular toxicity. If no adverse effect occurs; or (b) administration of 6 mg of erdafitinib once daily If no adverse reactions of Grade 2 or higher occur, treatment for cycle 1 after the start of treatment will be discontinued. At the end of the period, specifically on day 1 of cycle 2 (C2D1) ± 7 days, or day 1 of cycle 2 Day 1 (C2D1) ± 3, more specifically on C2D1, approximately 6 mg of erdafitinib was administered. Maintain an oral dose of 600g once daily. In one embodiment, phosphate intake is 600g It is limited to ~800mg / day.

[0205] In some embodiments, erdafitinib is administered orally. Erdafitinib is administered orally once daily at a dose of approximately 6 mg. Further implementation In this case, (a) the patient, at the end of the treatment period of cycle 1 after the start of treatment, in detail cycle Day 1 of cycle 2 (C2D1) ± 7 days, or Day 1 of cycle 2 (C2D1) ± 3 days, In detail, if C2D1 shows a serum phosphate (PO4) level of ≥7 mg / dL, or (b) If other toxicities are present and serum phosphate (PO4) toxicity control as set forth in Table 7 is applicable, At the end of the treatment period of Cycle 1 after the start of treatment, more specifically on Day 1 of Cycle 2 (C2D1) ±7 days, or day 1 of cycle 2 (C2D1) ±3 days, more specifically on C2D1, Maintain a dose of rudafitinib of approximately 6 mg once daily orally.

[0206] [Table 4]

[0207] Table 7 provides guidelines for the clinical management of high serum phosphate levels during erdafitinib treatment. This is a report of the line.

[0208] Table 8 reports the daily administration schedule of 6 mg (with dose escalation) and dose reduction. be.

[0209] [Table 5]

[0210] In one embodiment, the treatment cycle used herein is a 28-day cycle. In a specific embodiment, the treatment cycle is a 28-day cycle over a maximum of two years.

[0211] In one embodiment, the desired dose is, for convenience, a single dose, or simultaneously (or over a short period of time) ) In divided doses, or at appropriate intervals, for example, 2, 3, or 4 times per day. It is provided in the lower doses shown above. In some embodiments, the FGFR inhibitor is, for convenience, 1 day It is provided in divided doses that are administered all at once (or over a short period of time). In some embodiments, Generally, FGFR inhibitors, and specifically erdafitinib, are administered in equal doses twice daily for convenience. It is provided in divided doses to be administered. In some embodiments, generally an FGFR inhibitor, Specifically, erdafitinib is offered in a divided dose, administered three times a day in equal amounts, for convenience. In some embodiments, the FGFR inhibitor is administered in equal doses four times a day for convenience. It is provided in divided doses.

[0212] In a particular embodiment, the desired dose is delivered by partial unit doses over a day. Generally, the total amount of FGFR inhibitors, and specifically erdafitinib, is the total daily dose. To bring about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 1 throughout the day It can be delivered in zero partial doses.

[0213] In some embodiments, a generally FGFR inhibitor is administered to humans, and specifically The dosage of erdafitinib depends on the disease or condition and its severity, as well as the identity of the person (e.g., These include, but are not limited to, body weight, and any additional therapeutic agents administered (if applicable). It fluctuates depending on factors that are not limited to these.

[0214] In further embodiments, erdafitinib is a potent CYP3A4 inhibitor or Do not administer concurrently with inducers or moderate CyP3A4 inducers. In certain embodiments, Erdafitinib is effective in producing potent C14 within 14 days or within 5 half-lives prior to the first dose of the study drug. Do not administer concurrently with YP3A4 inhibitors or inducers, or moderate CyP3A4 inducers.

[0215] Non-exclusive examples of potent CYP3A4 inhibitors include boceprevir and aprepitant. Clarithromycin, conivaptan, grapefruit juice, indinavir, lopina Viru, itraconazole, mibefurazil, ketoconazole, nefazodone, ritonavir, Posaconazole, nelfinavir, saquinavir, conivaptan, telaprevir, bocepre Viru, telithromycin, clarithromycin, voriconazole, clotrimazole, di Lutiazem, erythromycin, fluconazole, verapamil, and troleandmycin One example is n.

[0216] Non-exclusive examples of moderate to potent CYP3A4 inducers include abasimib and sentegyl. Jones wort, carbamazepine, efavirenz, phenytoin, etravirine, bosom Ntan, nafcillin, rifampin, modafinil, rifabutin, and barbiturates These are some examples.

[0217] Kit / Manufactured product The methods or kits and products for use described herein are also described herein. Such kits are described in the section below. Such kits provide one or more doses of the pharmaceutical compositions disclosed herein. Includes packaging containers or containers that are compartmentalized to accept quantities. Suitable containers include: For example, a bottle can be used. In one embodiment, the container may be made of glass or plastic. It is formed from various materials.

[0218] The products provided herein include packaging materials. Packaging used for packaging pharmaceuticals. Examples of materials include those specified in U.S. Patent No. 5,323,907 and No. 5,052,55 Examples include those specified in Specification No. 8 and Specification Nos. 5,033,252. Examples of pharmaceutical packaging materials This is not limited to blister packs, bottles, tubes, bags, etc. Containers, bottles, and any packaging materials suitable for the selected formulation and the intended mode of administration and treatment. The amount is listed.

[0219] The kit typically includes a label listing the contents and / or instructions for use, as well as instructions for use. Includes accompanying documentation. A complete set of instructions is also typically included.

[0220] In one embodiment, the label is present on or attached to the container. Then, the letters, numbers, or other symbols that form the label are affixed, molded, or etched onto the container itself. If so, the label is present on the container and also within the receptacle or carrier that holds the container. If present, the label is attached to the container (for example, as part of the accompanying leaflet).

[0221] In one embodiment, the label is used to indicate that the contents are intended for a specific therapeutic use. The label also indicates how to use the contents, for example, how to use the method described herein.

[0222] In a particular embodiment, the pharmaceutical composition contains one of the compounds provided herein. The above unit dosage forms are provided in a pack or dispenser device. For example, it contains metal foil or plastic foil, for example, a blister pack. In one embodiment, the pack or dispenser device is fitted with instructions for administration. In one embodiment, the pack or dispenser also contains instructions for the manufacture, use, or sale of pharmaceuticals. A warning label will be attached to the container in the form specified by the regulating government agency. The statement indicates that the form of the drug for administration to humans or animals has been approved by the regulatory authority. This reflects the fact that such warnings are used, for example, in the U.S. Food and Drug Administration regarding prescription drugs. This refers to labeling information approved by the bureau, or an approved product insert. In one embodiment, Compositions containing the compounds provided herein, formulated in a compatible pharmaceutical carrier, may also be prepared. It is then placed in an appropriate container and labeled with information about the treatment of the condition as instructed.

[0223] Nucleotide sequence of FGFR fusion gene Table 4 shows the nucleotide sequences of FGFR fusion cDNA. The underlined sequences are FGF This corresponds to either R3 or FGFR2, and the sequence in black represents the fusion partner.

[0224] [Table 6]

[0225] [Table 7]

[0226] [Table 8]

[0227] [Table 9]

[0228] [Table 10]

[0229] [Table 11]

[0230] [Table 12]

[0231] [Table 13]

[0232] [Table 14] [Examples]

[0233] These examples are provided for illustrative purposes only and are not part of the claims provided herein. This does not limit it.

[0234] Example 1: Sensitivity of bladder cancer cell lines to erdafitinib To test the efficacy of erdafitinib in vitro, a cell viability assay was performed. The cell lines shown in Table 5 were subjected to MTT or CellTiter- as described below. It was used in one of the Glo assays. Both assays measure the metabolic activity of cells. However, different reagents are used to measure cell viability.

[0235] MTT assay In a 96-well culture plate containing 180 μl of growth medium as recommended by the provider, Cells were seeded at a density that ensured continuous logarithmic growth over a 4-day culture period. 37 The cells were incubated for 24 hours in a humidified incubator with °C and 5% CO2. A range of rudafitinib concentrations was prepared in growth medium, and 20 μl was added to each well of cells. The cells were incubated for another 4 days, followed by 25 μl of MTT (phosphate-buffered saline). A dose of 5 mg / ml was added to each well. Cells were incubated at 37°C and 5% CO2 for 2 hours. The crystals were evaporated, and then the growth medium was removed. The remaining crystals were mixed with 125 μl of glycine / DMSO. The solution was dissolved in a buffer solution, and the optical density was measured at 540 nm. (Without erdafitinib) Incubated cells were used as an untreated control and defined as 100%. Table 5 As shown, the effect of erdafitinib was measured as a percentage of the control, and the dose-response effect was measured. - From fitting to IC 50 The value was calculated.

[0236] CellTiter-Glo assay In a 96-well culture plate containing 180 μl of growth medium as recommended by the provider, Cells were seeded at a density that ensured continuous logarithmic growth over a 4-day culture period. The samples were incubated for 24 hours in a humidified incubator at 37°C and 5% CO2. A range of rudafitinib concentrations was prepared in growth medium, and 20 μl was added to the cells in each well. Incubate the cells for another 4 days, then add 100 μl of CellTiter-Glo Add the reagent (Promega) to each well and shake the plate at 500 rpm for 5 minutes. The light emission was detected using the Envision plate reader (Perkin Elmer). Cells incubated without erdafitinib were used as an untreated control. This was defined as 100%. The effect of erdafitinib was compared as shown in Table 5. Measured as a percentage, and IC from dose-response curve fitting. 50 The value was calculated.

[0237] [Table 15]

[0238] conclusion Cell viability assays revealed several N1s, including FGFR3 mutations (mutations or fusions). MIBC cell lines (MGH-U3, RT4, and 97-7) were treated with low nanomolar concentrations of ELDAF. Susceptibility to itinib was demonstrated. FGFR3 was WT(T24) or Two cell lines of unknown status (EJ28) showed no response to erdafitinib. There was no receptiveness.

[0239] Example 2: Phase 2 multicenter open-label trial (NCT04172675) Having fibroblast growth factor receptor (FGFR) mutations or fusions, Calmette Guérin Participants with high-risk nonmuscle-invasive bladder cancer (NMIBC) that have relapsed after BCG therapy. For participants, the recurrence-free survival (RFS) of participants treated with erdafitinib was measured. This is a non-limiting example of a phase 2, multicenter, open-label trial evaluating the treatment in comparison to the investigator's choice.

[0240] the purpose The primary objective of this study was to study HR-19 patients with FGFR mutations or fusions who relapsed after BCG therapy. In patients with NMIBC, RFS in patients treated with erdafitinib was measured using intravesical gem. Comparison with investigator-selected treatment using cytabine / mitomycin C (MMC) / hyperthermic MMC therapy. The process involves evaluation.

[0241] method Exam Overview Eligible patients were screened for the presence of FGFR mutations or fusions in three cohorts. We will allocate it to one of these. Please refer to Figure 1 for an overview of the test design.

[0242] Cohort 1 (erdafitinib and active control agent) (n=240) included patients who had received BCG therapy. The disease has recurred, and the patient has refused or is unsuitable for cystectomy, and has only a papillary tumor (epithelium). This includes HR-NMIBC patients (without carcinomatous encephalopathy (CIS)). Patients were unresponsive to BCG. Those who have received the BCG vaccine are also welcome.

[0243] Cohort 2 (experimental) (n=20) included patients who refused or were unsuitable for cystectomy. HR- This cohort includes patients with NMIBC and those who did not respond to BCG. This cohort is exploratory. .

[0244] Cohort 3 (experimental) (n=20) includes IR-NMIB, which is shown as only a papillary disorder. This cohort includes patients with type C. Prescribed BCG or intravesical chemotherapy is not required. It is exploratory.

[0245] Patients in Cohort 1 received oral erdafitinib or intravesical gemcitabine or To receive either mitomycin C (MMC) or thermal MMC in the bladder, in a 2:1 ratio. Participants may be randomized in the following proportions. Cohort 1 will be randomized to either gemcitabine or MMC / thermal MMC. Participants who showed relapse as assessed by the principal investigator were treated with erdafitinib. There is an opportunity to cross over with other treatments. In randomization, tumor stage (Ta vs. T1) ) and the type of previous BCG therapy (BCG non-responder vs. BCG experienced) are stratified.

[0246] All patients enrolled in Cohorts 2 and 3 will receive erdafitinib treatment. In step 2, erdafitinib is discontinued if complete response (CR) is not observed within 3 months. In step 3, if a partial response (PR) or complete response (CR) is not observed within 3 months, erdafit is administered. Discontinue nib. In Cohort 2, CR is defined as at least one of the following: 1) 1) Negative cystoscopy and negative (including atypical) urine cytology; or 2) benign diagnosis by biopsy Alternatively, a positive cystoscopy and negative cytology test with low-grade NMIBC. (6 months post-coital status) The complete response (CR) rate is calculated using a two-sided 95% accurate CI. In Cohort 3, CR was achieved when the residuals were Absence of the marker lesion, no viable tumors found in histopathological examination, and disappearance of the marker lesion. The CR rate is calculated using the two-sided 95% accurate CI.

[0247] The follow-up period includes 30-day safety follow-up visits, disease evaluation follow-up, and survival follow-up. This includes an inspection.

[0248] In Cohort 1 (erdafitinib), participants started from day 1 of cycle 1. Until the completion of the two-year treatment period, the following will occur: recurrence of the disease, unacceptable toxicity, withdrawal of consent, and the principal investigator. Until the decision by the therapist to discontinue treatment, or until the end of the examination (whichever occurs first), Eldafiti Nib may be administered orally. Each cycle is 28 days. The dose is 8 mg per day. The dosage may be gradually increased to 9 mg based on the phosphate level at day 14 of the first course of treatment. Protocol After the correction, the dosage will be changed to 6 mg per day, but at the end of the treatment period of cycle 1 (cycle 2) Based on the phosphate level on day 1, there is an option to gradually increase the dose to 8 mg per day. Cohort 1 (Investigator-selected treatment) involves initiating at least four doses, followed by at least six months of treatment. During the monthly maintenance period, gemcitabine is administered once a week (2,000 mg). Cohort In 1 (investigator-selected treatment), at least four doses are administered, followed by at least six months. During the monthly maintenance period, mitomycin C is administered once a week (at a dose of 40 mg). In Cohort 2, participants will begin treatment on day 1 of cycle 1 and complete the 2-year treatment period. Up to the point of treatment is available in the event of disease recurrence, unacceptable toxicity, withdrawal of consent, or discontinuation of treatment by the principal investigator. Receive erdafitinib orally until the end of the trial period (whichever comes first). The cycle is 28 days. The dose is 8 mg per day, and the phosphate level at day 14 of cycle 1. The dose may be gradually increased to 9 mg based on salt levels. After protocol modification, the dose should be 6 mg per day. The dosage will be changed, but based on the phosphate levels at the end of the treatment period of Cycle 1 (Day 1 of Cycle 2). Subsequently, there is an option to gradually increase the dose to 8 mg per day. In Cohort 3, participants underwent cycle 1. Starting from day 1, until the completion of 2 years of treatment, disease recurrence, unacceptable toxicity, and the same Withdrawal of intent, decision by the principal investigator to discontinue treatment, or termination of the trial (whichever occurs first) Receive erdafitinib orally until (the end of the course). Each cycle is 28 days. The dose is 8mg per day. The amount is g, and it may be gradually increased to 9 mg based on the phosphate level at day 14 of cycle 1. The dosage will be changed to 6 mg per day after the protocol is modified, but at the end of the treatment period of cycle 1. Based on the phosphate level on day 1 of cycle 2, there is an option to gradually increase to 8 mg per day. ru.

[0249] Inclusion and exclusion criteria In the trial, patients were selected according to the following inclusion and exclusion criteria across 14 countries, including the United States. To include.

[0250] Inclusion Criteria 1. Must be 18 years of age or older; 2. The general status of the East Coast Cancer Clinical Group (ECOG) is 1 or less; 3. Histologically confirmed recurrent urothelial carcinoma of the bladder that is accompanied by the following: a. Cohort 1: High-grade papillary disease with Ta / T1 lesions; b. Cohort 2: CIS regardless of the presence or absence of nipple disease; c. Cohort 3: Low-grade (G1-G2) Ta / T1 marker lesions; 4. One or more specified FGFR2 or FGFR3 gene mutations (including mutations and fusions) A growing tumor. 5. Cystectomy was refused or deemed unsuitable (Cohorts 1 and 2 only); 6. On the signed informed consent form, he or she must state the purpose and necessity of the test. This demonstrates an understanding of the procedure and a willingness to participate in the exam; 7. Within 7 days prior to randomization (Cohort 1) or at the time of the first dose of the investigational drug (Cohorts 2 and 2) (3) In this case, women of childbearing age should take a pregnancy test (β-hCC [β-human chorionic gonadotropin]). The test (urine or serum) must be negative. 8. Sufficient bone marrow, liver, and kidney function; 9. Participants who were unresponsive to BCG after adequate BCG therapy, or participants who had previously received BCG.

[0251] BCG non-response: The patient has one of the following recurrent disease conditions and meets the following criteria: Received BCG vaccination: a. Single persistent or recurrent CIS within 12 months of completing sufficient BCG therapy, or associated with recurrent Ta / T1 (non-invasive papillary disease / tumor infiltrating subepithelial connective tissue) disease. Persistent or recurrent CIS (Cohort 2 only); b. Relapsed high-grade Ta / T1 disease within 6 months of completing sufficient BCG therapy; c. The initial disease assessment after the introduction of the BCG course shows that the tumor is T1 high-grade.

[0252] Sufficient BCG vaccination (minimum treatment requirement) a. At least 5 doses out of the 6 doses in the initial introductory course, plus less than 5 doses over a 6-month period. Both require one maintenance dose (2 out of 3 doses per week) (the total BCG dose is a minimum of 1 x 10⁻¹⁴). 8 Ko It must include the entire vial containing Ronnie's unit (CFU); or b. At least 5 doses out of the 6 doses in the initial introductory course, plus all doses in the second introductory course. At least two of the six dosages.

[0253] BCG survivors: Patients who have completed BCG therapy have a relapsed high-grade Ta / T1 disease within 12 months of completing BCG therapy. If the patient has the disease and their previous BCG therapy meets the minimum treatment requirements as specified below ru: d. At least 5 doses out of the 6 doses in the initial introductory course; or e. At least 5 of the 6 doses in the initial introductory course, plus less than 5 doses over a 6-month period. Maintenance is once a week (2 out of 3 doses). During maintenance, 1 / 2 dose or 1 / 3 dose. The dosage is approved.

[0254] Exclusion criteria 1. Histologically confirmed muscle-invasive (stage T2 or higher) urothelial carcinoma of the bladder: 2. Histopathological examination of the small cell component of the bladder: pure bladder adenocarcinoma, pure bladder squamous cell carcinoma. , or pure bladder squamous epithelial CIS; 3. Other active malignant tumors. The only recognized exception is: (a) complete cure (b) Skin cancer treated within the last 24 months, (b) appropriately treated small (c) A history of lobar carcinoma in situ (LCIS) and intraductal CIS, and localized breast cancer, and anti-hormone If you are receiving medication or have a history of localized prostate cancer (N0M0) and are undergoing androgen deprivation therapy, you should not be taking this medication. Receiving; 4. Prior treatment with FGFR inhibitors; 5. Major surgery within four weeks prior to day 1 of cycle 1 (C1D1); 6. The patient has not recovered from the toxicity of the previous anti-cancer therapy. 7. Central serous retinopathy or retinal pigment epithelial detachment of any grade.

[0255] Test objectives In Cohort 1, the primary objective was to identify patients with FGFR mutations or fusions who had relapsed after BCG therapy. In high-risk NMIBC patients, the RFS of patients treated with erdafitinib was... The objective is to evaluate it in comparison to the investigator's choice of treatment. A secondary objective is to evaluate other efficacy criteria. That is what it is.

[0256] In Cohort 2, the exploratory objective was to identify high-risk BCG-unresponsive NMIBC patients and FG In terms of the CR rate at 6 months in patients with FR mutations or fusions, Eldafi The objective is to evaluate the effectiveness of tinib.

[0257] In Cohort 3, the exploratory objective was to identify patients with intermediate-risk NMIBC and those with FGFR mutations or In terms of the CR rate for marker lesions in patients with fusion, erdafitinib The purpose is to evaluate effectiveness.

[0258] Primary outcome measures and exploratory outcome measures / evaluation criteria In Cohort 1, the primary endpoint is RFS over a time frame of up to 4 years. Secondary endpoints The time slots and explanations are shown in Table 6.

[0259] [Table 16]

[0260] [Table 17]

[0261] [Table 18]

[0262] In Cohort 2, the exploratory endpoint was the complete response (CR) rate at 6 months.

[0263] In Cohort 3, the exploratory endpoint is the complete response (CR) rate.

[0264] Safety evaluation Safety assessment involves a medical review of adverse event reports, as well as baseline monitoring after the final dose of the investigational drug. Vital signs measurements, 12-lead ECG, physical examination, and clinical tests for up to 30 days from the time of arrival. Based on ophthalmic examinations and other safety assessment results. All adverse events, serious adverse events, and We will report on any specially reported circumstances, regardless of whether they are serious or not.

[0265] The subject matter of the present invention will be explained in the following sections. 1. A dose of approximately 6 mg of a fibroblast growth factor receptor (FGFR) inhibitor per day is given in small amounts. High-risk individuals have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. HR - How to treat NMIBC. 2. The patient underwent Bacillus Calmette-Guérin (BCG) therapy prior to the administration of the FGFR inhibitor. The method described in item 1. 3. The method described in item 2, wherein BCG therapy is sufficient BCG therapy. 4. The method described in item 2 or 3, for patients who are unresponsive to BCG therapy. 5. The method described in item 2 or 3, provided the patient is a BCG survivor. 6. The method according to any one of items 1 to 5, wherein the patient has a papillary tumor. 7. The method according to any one of items 1 to 6, wherein the patient has carcinoma in situ. 8. The patient has not previously undergone or is ineligible for cystectomy, or any of items 1-7. The method described in item 1. 9. The administration of FGFR inhibitors compared to the HR-NMIBC patient population that received placebo. Compared to any one of the methods described in items 1 to 8, the method results in an improvement in recurrence-free survival. 10. The administration of the FGFR inhibitor is performed by administering gemcitabine intravesically, or by mitoma Compared to a group of HR-NMIBC patients who received intravesical administration of Icin C (MMC) / thermal MMC The method described in any one of paragraphs 1 to 8, which results in an improvement in recurrence-free survival. 11. The patient achieves a complete response to an FGFR inhibitor within approximately 6 months, according to any of items 1-10. The method described in item 1. 12. FGFR2 gene mutation and / or FGFR3 gene mutation, FGFR3 gene mutation One of the following, items 1-11: mutation, FGFR2 gene fusion, or FGFR3 gene fusion. The method described in item 1. 13. FGFR3 gene mutations include R248C, S249C, G370C, and Y373C. The method described in paragraph 12, or any combination thereof. 14. FGFR2 or FGFR3 gene fusion results in FGFR3-TACC3, specifically FG FR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAI AP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof The method described in item 12. 15. Prior to the administration of the FGFR inhibitor, a patient-derived biological sample was tested for FGFR2 gene mutations. This further includes evaluating the presence of at least one FGFR3 gene mutation. The method described in any one of items 1 to 14. 16. If the biological sample is blood, lymph, bone marrow, solid tumor sample, or any combination thereof A method described in item 15. 17. The FGFR inhibitor is erdafitinib, as described in any one of items 1 to 16. method. 18. The method according to item 17, wherein erdafitinib is administered daily. 19. The method according to item 17 or 18, wherein erdafitinib is administered orally. 20. Erdafitinib is administered orally on a daily schedule, as described in items 17-19. The method described in either of the above terms. 21. Erdafitinib is administered once daily at a dose of approximately 6 mg, as per items 17-19. The method described in any one of the items. 22. If the patient has a serum phosphate (PO4) level of less than approximately 5.5 mg / dL, The dose of dafitinib was increased from 6 mg per day to 8 mg per day after the start of treatment. or the method described in any one of items 17 to 19. 23. Erdafitinib is administered in a solid dosage form as described in any one of items 17-22. Method of loading. 24. The method according to item 23, wherein the solid dosage form is a tablet. 25. A method for treating high-risk nonmuscle-invasive bladder cancer (HR-NMIBC), (a) Biological samples from patients diagnosed with HR-NMIBC were subjected to the growth of one or more fibroblasts. To evaluate the presence of factor receptor (FGFR) gene mutations; and (b) If one or more FGFR gene mutations are present in the sample, the dose is approximately 6 mg per day. A method of administering fibroblast growth factor receptor (FGFR) inhibitors to patients. 26. A dose of approximately 6 mg of a fibroblast growth factor receptor (FGFR) inhibitor per day is used in small doses. Medium squirrels have at least one FGFR2 gene mutation and / or FGFR3 gene mutation. I include administering it to patients diagnosed with irradiated bladder cancer without muscle invasiveness (IR-NMIBC). How to treat R-NMIBC. 27. The method according to item 26, for a patient having a papillary tumor. 28. The method of paragraph 26 or 27, in which the patient has an incomplete transurethral resection. 29. The patient achieves a complete response to an FGFR inhibitor within approximately 3 months, or one of items 26-28. The method described in item 1. 30. FGFR2 gene mutation and / or FGFR3 gene mutation, FGFR3 gene mutation The mutation, FGFR2 gene fusion, or FGFR3 gene fusion, as specified in items 26-29. The method described in item 1. 31. FGFR3 gene mutations include R248C, S249C, G370C, and Y373C. The method described in paragraph 30, or any combination thereof. 32. FGFR2 or FGFR3 gene fusion results in FGFR3-TACC3, specifically FG FR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAI AP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof The method described in item 30. 33. The FGFR inhibitor is erdafitinib, as described in any one of items 26-32. method. 34. FGFR inhibitors should be administered at a dose of approximately 6 mg per day, at least High-risk patients with another FGFR2 gene mutation and / or FGFR3 gene mutation. Fibroblast proliferation for use in the treatment of non-muscle-invasive bladder cancer (HR-NMIBC) Factor receptor (FGFR) inhibitors. 35. FGFR inhibitors should be administered at a dose of approximately 6 mg per day, at least Intermediate-risk patients with one additional FGFR2 gene mutation and / or FGFR3 gene mutation. Fibroblast proliferation for use in the treatment of non-muscle-invasive bladder cancer (IR-NMIBC) Factor receptor (FGFR) inhibitors. 36. FGFR inhibitors should be administered at a dose of approximately 6 mg per day, at least High-risk muscle tissue also has one FGFR2 gene mutation and / or FGFR3 gene mutation. To manufacture pharmaceuticals for the treatment of patients diagnosed with non-invasive bladder cancer (HR-NMIBC) Therefore, use of fibroblast growth factor receptor (FGFR) inhibitors. 37. FGFR inhibitors should be administered at a dose of approximately 6 mg per day, at least The intermediate-risk muscle tissue also has one FGFR2 gene mutation and / or FGFR3 gene mutation. To manufacture pharmaceuticals for the treatment of patients diagnosed with non-invasive bladder cancer (IR-NMIBC) Therefore, use of fibroblast growth factor receptor (FGFR) inhibitors. 38. The patient received Bacillus Calmette-Guérin (BCG) therapy prior to the administration of the FGFR inhibitor. Fibroblast growth factor for use as described in any one of paragraphs 34-37, which is receiving Use of receptor (FGFR) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors. 39. Fibroblasts for use as described in item 38, if BCG therapy is sufficient BCG therapy. Growth factor receptor (FGFR) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors use. 40. If the patient is unresponsive to BCG therapy, use of fibroblasts as described in paragraph 38 or 39. Cell growth factor receptor (FGFR) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors Use of the agent. 41. If the patient is a BCG survivor, fibroblast growth for use as described in paragraph 38 or 39. Use of growth factor receptor (FGFR) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors For. 42. If the patient has a papillary tumor, use of the line described in any one of paragraphs 34 to 41. Fibroblast growth factor receptor (FGFR) inhibitors or fibroblast growth factor receptor (FGFR) Inhibitors were used. 43. If the patient has carcinoma in situ, the line for use described in any one of paragraphs 34 to 42. Fibroblast growth factor receptor (FGFR) inhibitors or fibroblast growth factor receptor (FGFR) Inhibitors were used. 44. The patient has not previously undergone cystectomy or is ineligible for it, according to paragraphs 34-43. A fibroblast growth factor receptor (FGFR) inhibitor for use as described in any one of the paragraphs or Use of fibroblast growth factor receptor (FGFR) inhibitors. 45. FGFR2 gene mutation and / or FGFR3 gene mutation, FGFR3 gene mutation The mutation, FGFR2 gene fusion, or FGFR3 gene fusion, as specified in items 34-44. A fibroblast growth factor receptor (FGFR) inhibitor or fibroblast for use as described in paragraph 1. Use of cell growth factor receptor (FGFR) inhibitors. 46. ​​FGFR3 gene mutations include R248C, S249C, G370C, and Y373C. Fibroblast growth factors for use, as described in item 45, or any combination thereof. Use of receptor (FGFR) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors. 47. FGFR2 or FGFR3 gene fusion results in FGFR3-TACC3, more specifically... FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-B AIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof The combination is the fibroblast growth factor receptor (FGFR) for use as described in item 45. Use of inhibitors or fibroblast growth factor receptor (FGFR) inhibitors. 48. The FGFR inhibitor is erdafitinib, as described in any one of items 34-47. , fibroblast growth factor receptor (FGFR) inhibitors or fibroblast growth factor receptors for use Use of FGFR inhibitors.

[0266] The examples and embodiments described herein are for illustrative purposes only and are intended for those skilled in the art. The various modifications or changes presented hereto the purpose and scope of this application and the attached claims. It is included within.

Claims

1. A dose of approximately 8 mg of fibroblast growth factor receptor (FGFR) inhibitor per day is used in small doses. High-risk muscle cells that both have one FGFR2 gene mutation and / or FGFR3 gene mutation. HR-NMIBC is administered to patients diagnosed with bladder cancer without invasive layer (HR-NMIBC). How to treat NMIBC.

2. The aforementioned patient received Bacillus Calmette-Guérin (BCG) therapy prior to the administration of the FGFR inhibitor. The method according to claim 1, which has been received.

3. The method according to claim 2, wherein the BCG therapy is sufficient BCG therapy.

4. The method according to claim 2 or 3, wherein the patient is unresponsive to BCG therapy.

5. The method according to claim 2 or 3, wherein the patient is a BCG recipient.

6. The method according to any one of claims 1 to 5, wherein the patient has a papillary tumor.

7. The method according to any one of claims 1 to 6, wherein the patient has carcinoma in situ.

8. The patient has not previously undergone cystectomy or is ineligible for it, according to claims 1 to 7. The method described in either of the above terms.

9. The administration of the FGFR inhibitor compared to the HR-NMIBC patient population that received a placebo. The method according to any one of claims 1 to 8, which results in an improved recurrence-free survival period. 。

10. The administration of the FGFR inhibitor is performed by intravesical administration of gemcitabine or mitoma Compared to a group of HR-NMIBC patients who received intravesical administration of Icin C (MMC) / thermal MMC The method according to any one of claims 1 to 8, which results in an improvement in recurrence-free survival.

11. The patient shows a complete response to the FGFR inhibitor in approximately six months, according to claims 1 to 10. The method described in any one of the items.

12. The aforementioned FFFR2 gene mutation and / or FFFR3 gene mutation may be a mutation in the FFFR3 gene. A mutation, an FGFR2 gene fusion, or an FGFR3 gene fusion, according to any of claims 1 to 11 The method described in any one of the items.

13. The aforementioned FGFR3 gene mutations are R248C, S249C, G370C, Y373C The method according to claim 12, or any combination thereof.

14. The aforementioned FFFR2 or FFFR3 gene fusion is FFFR3-TACC3, more specifically FG FR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAI AP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof The method according to claim 12, which is a combination of the two.

15. Prior to the administration of the FGFR inhibitor, the patient-derived biological sample was modified to alter the FGFR2 gene. Further evaluation should be conducted for the presence of at least one variant and / or FGFR3 gene mutation. The method according to any one of claims 1 to 14, including the method described herein.

16. The aforementioned biological sample is blood, lymph, bone marrow, solid tumor sample, or any combination thereof. A method according to claim 15.

17. The FGFR inhibitor is erdafitinib, as described in any one of claims 1 to 16. Method of loading.

18. The method according to claim 17, wherein erdafitinib is administered daily.

19. The method according to claim 17 or 18, wherein erdafitinib is administered orally.

20. The erdafitinib is administered orally on a daily schedule, according to claims 17 to 19. The method described in either of the above terms.

21. Erdafitinib is administered once daily at a dose of approximately 8 mg, as described in any of items 17-19. The method described in item 1.

22. The aforementioned patient had a serum phosphate level (PO) of less than approximately 5.5 mg / dL. ４ ) When indicating the level, L The dose of dafitinib was increased from 8 mg per day to 9 mg per day after the start of treatment. The method according to any one of claims 17 to 19.

23. Erdafitinib is administered in a solid dosage form, as described in any one of claims 17 to 22. Method of loading.

24. The method according to claim 23, wherein the solid dosage form is a tablet.

25. A method for treating high-risk nonmuscle-invasive bladder cancer (HR-NMIBC), (a) One or more fibroblast proliferations in biological samples from patients diagnosed with HR-NMIBC To evaluate the presence of factor receptor (FGFR) gene mutations; and (b) If one or more FGFR gene mutations are present in the sample, approximately 8 mg per day A method of administering a dose of a fibroblast growth factor receptor (FGFR) inhibitor to the patient.

26. A dose of approximately 8 mg of fibroblast growth factor receptor (FGFR) inhibitor per day is used in small doses. Intermediate-risk muscle cells that both have one FGFR2 gene mutation and / or FGFR3 gene mutation. This includes administering the drug to patients diagnosed with irradiated bladder cancer-non-invasive bladder cancer (IR-NMIBC). How to treat NMIBC.

27. The method according to claim 26, wherein the patient has a papillary tumor.

28. The method according to claim 26 or 27, wherein the patient has an incomplete transurethral resection.

29. The patient shows a complete response to the FGFR inhibitor in about three months, according to claims 26 to 28. The method described in either of the above terms.

30. The aforementioned FFFR2 gene mutation and / or FFFR3 gene mutation may be a mutation in the FFFR3 gene. The mutation, FGFR2 gene fusion, or FGFR3 gene fusion of claims 26 to 29 The method described in either of the above terms.

31. The aforementioned FGFR3 gene mutations are R248C, S249C, G370C, Y373C The method according to claim 30, or any combination thereof.

32. The aforementioned FFFR2 or FFFR3 gene fusion is FFFR3-TACC3, more specifically FG FR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAI AP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof The method according to claim 30, which is a combination of the two.

33. The FGFR inhibitor is erdafitinib, as described in any one of claims 26 to 32. Method of loading.

34. The FGFR inhibitor should be administered at a dose of approximately 8 mg per day, at least High-risk patients with an additional FGFR2 gene mutation and / or FGFR3 gene mutation. Fibroblast proliferation for use in the treatment of nonmuscle-invasive bladder cancer (HR-NMIBC) Factor receptor (FGFR) inhibitor.

35. The FGFR inhibitor should be administered at a dose of approximately 8 mg per day, at least Intermediate-risk patients with one additional FGFR2 gene mutation and / or FGFR3 gene mutation. Fibroblast proliferation for use in the treatment of non-muscle-invasive bladder cancer (IR-NMIBC) Factor receptor (FGFR) inhibitor.

36. The FGFR inhibitor should be administered at a dose of approximately 8 mg per day, at least High-risk muscle tissue also has one FGFR2 gene mutation and / or FGFR3 gene mutation. To manufacture medicines for the treatment of patients diagnosed with bladder cancer in non-invasive situ (HR-NMIBC) Therefore, use of fibroblast growth factor receptor (FGFR) inhibitors.

37. The FGFR inhibitor should be administered at a dose of approximately 8 mg per day, at least The intermediate-risk muscle tissue also has one FGFR2 gene mutation and / or FGFR3 gene mutation. To manufacture medicines for the treatment of patients diagnosed with non-invasive bladder cancer (IR-NMIBC) Therefore, use of fibroblast growth factor receptor (FGFR) inhibitors.

38. The aforementioned patient received Bacillus Calmette-Guérin (BCG) therapy prior to the administration of the FGFR inhibitor. Fibroblast proliferation for use according to any one of claims 34 to 37, which has been received Use of factor receptor (FGFR) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors 。

39. The fibroblast for use according to claim 38, wherein the BCG therapy is sufficient BCG therapy. Cell growth factor receptor (FGFR) inhibitor or fibroblast growth factor receptor (FGFR) inhibitor Use of the agent.

40. The patient is unresponsive to BCG therapy, the line for use according to claim 38 or 39 Fibroblast growth factor receptor (FGFR) inhibitor or Fibroblast growth factor receptor (FGFR) Inhibitors were used.

41. The patient is a BCG recipient, and the fibroblast for use according to claim 38 or 39 Fibroid growth factor receptor (FGFR) inhibitor or fibroblast growth factor receptor (FGFR) inhibitor Use.

42. The patient has a papillary tumor, for use according to any one of claims 34 to 41 Fibroblast growth factor receptor (FGFR) inhibitors or fibroblast growth factor receptor (FGF R) Use of inhibitors.

43. The patient has carcinoma in situ, for use according to any one of claims 34 to 42 Fibroblast growth factor receptor (FGFR) inhibitors or fibroblast growth factor receptor (FGF R) Use of inhibitors.

44. Claims 34-4, the patient has not previously undergone cystectomy or is ineligible for it. A fibroblast growth factor receptor (FGFR) inhibitor for use as described in any one of paragraphs 3. Alternatively, use of fibroblast growth factor receptor (FGFR) inhibitors.

45. The aforementioned FFFR2 gene mutation and / or FFFR3 gene mutation may be a mutation in the FFFR3 gene. The mutation, FGFR2 gene fusion, or FGFR3 gene fusion of claims 34 to 44 Any of the fibroblast growth factor receptor (FGFR) inhibitors or fibroblast inhibitors described in item 1 for use Use of fibroblast growth factor receptor (FGFR) inhibitors.

46. The aforementioned FGFR3 gene mutations are R248C, S249C, G370C, Y373C , or any combination thereof, fibroblast proliferation for use according to claim 45 Use of factor receptor (FGFR) inhibitors or fibroblast growth factor receptor (FGFR) inhibitors 。

47. The aforementioned FGFR2 or FGFR3 gene fusion is FGFR3-TACC3, more specifically FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-B AIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any of the above. The combination is the fibroblast growth factor receptor (FG) for use according to claim 45. Use of FR inhibitors or fibroblast growth factor receptor (FGFR) inhibitors.

48. The FGFR inhibitor is erdafitinib, as described in any one of claims 34 to 47. The listed fibroblast growth factor receptor (FGFR) inhibitors or fibroblast growth factors for use Use of fibroreceptor (FGFR) inhibitors.

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