FGFR tyrosine kinase inhibitors for the treatment of urothelial carcinoma

Abstract

Described herein are methods of treating urothelial carcinoma in a patient, the methods comprising evaluating a biological sample from the patient for the presence of at least two fibroblast growth factor receptor (FGFR) genetic alterations and treating the patient with an FGFR inhibitor. Also described herein are methods of treating urothelial carcinoma in a patient with at least two fibroblast growth factor receptor (FGFR) genetic alterations, the methods comprising administering an FGFR inhibitor.

Description

[Technical Field]

[0001] Disclosed herein is a method of treating urothelial carcinoma in a patient, the method comprising evaluating a biological sample from the patient for the presence of at least two fibroblast growth factor receptor (FGFR) genetic alterations, and treating the patient with an FGFR inhibitor if at least two fibroblast growth factor receptor (FGFR) genetic alterations are present in the sample. Also disclosed herein is a method of treating urothelial carcinoma in a patient with at least two fibroblast growth factor receptor (FGFR) genetic alterations, the method comprising administering an FGFR inhibitor. [Background technology]

[0002] Identifying genetic abnormalities can be useful in selecting appropriate treatments for cancer patients. This is also useful for cancer patients who have failed the primary treatment options (frontline treatments) for their cancer type, especially when there is no accepted standard treatment for second-line or later lines. Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases involved in regulating cell survival, proliferation, migration, and differentiation. FGFR alterations, including FGFR mutations and FGFR fusions or translocations, have been observed in some cancers. To date, there are no approved, effective treatments with FGFR inhibitors for patients with FGFR alterations. Summary of the Invention [Means for solving the problem]

[0003] Provided herein is a method of treating urothelial carcinoma in a patient, comprising: (a) evaluating a biological sample from the patient for the presence of at least two FGFR genetic alterations, wherein: (i) two or more of the at least two FGFR genetic alterations are FGFR2 fusions; (ii) one or more of the at least two FGFR genetic alterations are FGFR2 fusions and one or more of the at least two FGFR genetic alterations are FGFR3 fusions; (iii) two or more of the at least two FGFR genetic alterations are FGFR3 mutations; (iv) at least one of the at least two FGFR genetic alterations are FGFR3 mutations; and (b) treating the patient with an FGFR inhibitor if at least two FGFR genetic alterations are present in the sample.

[0004] Also described herein are methods of treating urothelial carcinoma in patients with at least two FGFR genetic alterations, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor to the patient, wherein (a) two or more of the at least two FGFR genetic alterations are FGFR2 fusions; (b) one or more of the at least two FGFR genetic alterations are FGFR2 fusions and one or more of the at least two FGFR genetic alterations are FGFR3 fusions; (c) two or more of the at least two FGFR genetic alterations are FGFR3 mutations; (d) one or more of the at least two FGFR genetic alterations are FGFR3 mutations and one or more of the at least two FGFR genetic alterations are FGFR2 fusions; or (e) one or more of the at least two FGFR genetic alterations are FGFR3 mutations and one or more of the at least two FGFR genetic alterations are FGFR3 fusions. In certain embodiments, the method of treating urothelial carcinoma in a patient with at least two FGFR gene alterations further comprises evaluating a biological sample from the patient for the presence of at least two FGFR gene alterations prior to administration of an FGFR inhibitor.

[0005] In certain embodiments of the methods of treating urothelial carcinoma disclosed herein, two or more of the at least two FGFR genetic alterations are FGFR2 fusions. In some embodiments, the two or more FGFR genetic alterations include FGFR2-BICC1 and FGFR2-CASP7.

[0006] In certain embodiments of the methods of treating urothelial carcinoma disclosed herein, one or more of the at least two FGFR genetic alterations is an FGFR2 fusion, and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion. In some embodiments, the two or more FGFR genetic alterations include FGFR2-CASP7 and FGFR3-BAIAP2L1; FGFR2-CASP7 and FGFR3-TACC3 V1; or FGFR2-CASP7 and FGFR3-TACC3 V3.

[0007] In certain embodiments of the methods of treating urothelial carcinoma disclosed herein, two or more of the at least two FGFR genetic alterations are FGFR3 mutations. In some embodiments, the two or more FGFR genetic alterations include FGFR3 G370C and FGFR3 S249C; FGFR3 R248C and FGFR3 Y373C; or FGFR3 S249C and FGFR3 Y373C.

[0008] In certain embodiments of the methods of treating urothelial carcinoma disclosed herein, one or more of the at least two FGFR genetic alterations are FGFR3 mutations, and one or more of the at least two FGFR genetic alterations are FGFR2 fusions. In some embodiments, the two or more FGFR genetic alterations include FGFR3 G370C / FGFR2-BICC1; or FGFR3 S249C, FGFR3 Y373C, FGFR2-CASP7, FGFR3-BAIAP2L1, FGFR3-TACC3 V1, and FGFR3_TACC3 V3.

[0009] In certain embodiments of the methods of treating urothelial carcinoma disclosed herein, one or more of the at least two FGFR genetic alterations are FGFR3 mutations, and one or more of the at least two FGFR genetic alterations are FGFR3 fusions. In some embodiments, the two or more FGFR genetic alterations are FGFR3 G370C and FGFR3-TACC3 V1; FGFR3 R248C and FGFR3-TACC3 V1; FGFR3 S249C and FGFR3-BAIAP2L1; FGFR3 R248C, FGFR3 S249, and FGFR3-TACC3 V1; or FGFR3 S249C, FGFR3 Y373C, FGFR2-CASP7, FGFR3-BAIAP2L1, FGFR3-TACC3 V1, and FGFR3-TACC3 V3.

[0010] In certain embodiments of the methods of treating urothelial cancer disclosed herein, the urothelial cancer is locally advanced or metastatic.

[0011] In further embodiments of the methods of treating urothelial carcinoma disclosed herein, the biological sample is blood, lymph, bone marrow, a solid tumor sample, or any combination thereof.

[0012] In some embodiments, the FGFR inhibitor is erdafitinib. In a further embodiment, erdafitinib is administered daily, particularly once a day. In a further embodiment, erdafitinib is orally administered. In certain embodiments, erdafitinib is orally administered in a daily administration schedule. In some embodiments, erdafitinib is orally administered in a dose of about 8 mg once a day. In some embodiments, erdafitinib is orally administered in a daily administration schedule in a dose of about 8 mg once a day. In a further embodiment, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily on days 14 to 21 after initiating treatment if (a) the patient exhibits serum phosphate (PO4) levels that are less than about 5.5 mg / dL on days 14 to 21 after initiating treatment; and (b) administration of erdafitinib at 8 mg once daily did not cause ocular disorders or (c) administration of erdafitinib at 8 mg once daily did not cause Grade 2 or higher adverse reactions.

[0013] In certain embodiments of the methods of treating urothelial carcinoma disclosed herein, erdafitinib is present in a solid dosage form. In some embodiments, the solid dosage form is a tablet.

[0014] The summary and the following detailed description will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the disclosed method, the drawings show exemplary embodiments of the method; however, the method is not limited to the particular embodiments disclosed. [Brief explanation of the drawings]

[0015] [Figure 1]

[0023] Figure 1 depicts the study scheme for a Phase 2, multicenter, open-label study to evaluate the efficacy and safety of erdafitinib in subjects with metastatic or surgically unresectable urothelial carcinoma harboring selected FGFR (fibroblast growth factor receptor) gene alterations (FGFR translocations or mutations). [Figure 2] Patient response to treatment with continuous erdafitinib 8 mg daily (regimen 3): Objective response rates (ORR) are shown among patient subgroups. [Figure 3-1] Figure 3: Figures 3A-C show waterfall plots of the reduction in sum of target lesion diameters after treatment with erdafitinib. Among all treated patients, (Figure 3A) reductions were observed in patients treated with 8 mg continuous erdafitinib per day (regimen 3), (Figure 3B) intermittent erdafitinib at 10 mg (regimen 1), and (Figure 3C) continuous erdafitinib at 6 mg per day (regimen 2). [Figure 3-2] (As mentioned above.) [Figure 3-3] (As mentioned above.) [Figure 4] Swimmer plot of response to treatment with erdafitinib among all patients treated with erdafitinib at 8 mg continuous daily dose. [Figure 5-1] Figure 5: Figures 5A-5B show progression-free survival and overall survival among patients treated with 8 mg continuous erdafitinib per day (Regimen 3). Kaplan-Meier curves for (Figure 5A) progression-free survival and (Figure 5B) overall survival after treatment with 8 mg continuous erdafitinib. [Figure 5-2] (As mentioned above.) [Figure 6-1] Figure 6: Figures 6A-6B show overall survival among patients treated with 10 mg intermittent and 6 mg continuous erdafitinib per day. (Figure 6A) Kaplan-Meier curves of overall survival after treatment with 10 mg intermittent erdafitinib (regimen 1) and (Figure 6B) 6 mg continuous erdafitinib per day (regimen 2). [Figure 6-2](As mentioned above.) DETAILED DESCRIPTION OF THE INVENTION

[0016] It should be understood that certain features of the invention, which are described herein for clarity in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless clearly incompatible or expressly excluded, each individual embodiment is considered combinable with any other embodiment, and such combinations are considered to be separate embodiments. Conversely, various features of the invention, which are described for brevity in the context of a single embodiment, may also be provided separately or in any subcombination. Finally, while an embodiment may be described as part of a series of steps or as part of a more general structure, each such step may be considered to be an independent embodiment in itself and combinable with the others.

[0017] Specific Terminology The transitional terms "comprising," "consisting essentially of," and "consisting of" are intended to include their generally accepted meanings in patent language; i.e., (i) "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended, and does not exclude additional, unrecited elements or method steps; (ii) "consisting of" excludes any element, step, or ingredient not specified in the claim; and (iii) "consisting essentially of" limits the claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristics" of the claimed invention. More specifically, the basic and novel characteristics relate to the ability of the method to provide at least one of the advantages described herein, including, but not limited to, the ability to improve the survival of a human population compared to the survival of a comparative human population described elsewhere herein. Embodiments described using the phrase "comprising" (or its equivalents) also provide, as embodiments, those independently described using the terms "consisting of" and "consisting essentially of."

[0018] When values ​​are expressed as approximations, by use of the descriptor "about," it will be understood that the particular value forms another embodiment. In general, the use of the term "about" indicates an approximation that may vary depending on the desired properties sought to be obtained by the disclosed subject matter and will be interpreted based on its function in the particular context in which it is used. Those of ordinary skill in the art will recognize this as routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the range of the term "about." In other cases, the step numbers used in a series of values ​​may be used to determine the intended range available to the term "about" for each value. Where present, all ranges are inclusive and combinable; that is, reference to values ​​stated in a range includes every value within that range.

[0019] Unless otherwise specified, the term "about" indicates a variation of ±10% of the associated value, although additional embodiments include those where the variation may be ±5%, ±15%, ±20%, ±25%, or ±50%.

[0020] Where lists are presented, unless otherwise stated, it is to be understood that each individual element of the list, and every combination of the list, is a separate embodiment. For example, a list of embodiments stated as "A, B, or C" is to be interpreted as including the embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0021] As used herein, the singular forms "a", "an" and "the" include the plural forms.

[0022] The following abbreviations are used throughout this disclosure: FGFR (fibroblast growth factor receptor); FGFR3-TACC3 v1 (a fusion between the gene encoding FGFR3 and transformed acidic coiled-coil-containing protein 3 variant 1, also referred to herein as FGFR3-TACC3 V1); FGFR3-TACC3 v3 (a fusion between the gene encoding FGFR3 and transformed acidic coiled-coil-containing protein 3 variant 3, also referred to herein as FGFR3-TACC3_V2); FGFR3-BAIAP2L1 (a fusion between the gene encoding FGFR3 and brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1); FGFR2-BICC1 (a fusion between the gene encoding FGFR2 and bicaudal C homolog 1); FGFR2-CASP7 (a fusion between the gene encoding FGFR2 and caspase 7).

[0023] As used herein, "patient" is intended to mean any animal, particularly a mammal. Thus, the methods are applicable to human and non-human animals, but most preferably humans. The terms "patient" and "subject" and "human" may be used interchangeably.

[0024] The terms "treat" and "treatment" refer to the treatment of a patient suffering from a condition, and refer to effects that alleviate the condition by killing cancerous cells, but also to effects that result in the inhibition of progression of the condition, and include slowing the rate of progression, stopping the rate of progression, ameliorating the condition, and curing the condition. Treatment as a prophylactic measure (i.e., preventing the onset of the condition) is also included.

[0025] The term "cancer," as used herein, refers to an abnormal growth of cells that tend to grow in an uncontrolled manner and, in some cases, to metastasize (spread).

[0026] As used herein, the term "co-administration" and the like is meant to encompass the administration of selected therapeutic agents to a single patient, and is also intended to include therapeutic regimens in which agents are administered by the same or different routes of administration or at the same or different times.

[0027] As used herein, the term "pharmaceutical combination" refers to the product resulting from the mixing or combination of two or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients.The term "fixed combination" means that the active ingredients, such as erdafitinib, and the auxiliary drug are both administered to patients simultaneously in the form of a single unit or a single dosage form.The term "non-fixed combination" means that the active ingredients, such as erdafitinib, and the auxiliary drug are administered to patients simultaneously, in parallel, or sequentially as separate units or separate dosage forms without any specific intervening time limit, and such administration provides the safety and effective level of the two active ingredients in the human patient's body.The latter also applies to cocktail therapy, for example, the administration of three or more active ingredients.

[0028] The term "daily dosing schedule" refers to the administration of a particular therapeutic agent without a drug holiday from that particular therapeutic agent. In some embodiments, a daily dosing schedule for a particular therapeutic agent comprises the administration of the particular therapeutic agent every day at approximately the same time each day.

[0029] The term "progression-free survival" is defined as the time from first administration to the date of documented evidence of disease progression or death, whichever occurs first.

[0030] The term "duration of response" is defined as the time from documentation of the first response to the date of documented evidence of disease progression or death.

[0031] The term "overall survival" is defined as the time from first dose to the date of death. Data for patients who are alive or have unknown status are censored at the last date the patient is known to be alive.

[0032] The term "placebo," as used herein, refers to the administration of a pharmaceutical composition that does not contain an FGFR inhibitor.

[0033] The term "randomization," when it refers to a clinical trial, refers to when a patient is identified as eligible for the clinical trial and assigned to a treatment arm.

[0034] The terms "kit" and "article of manufacture" are used synonymously.

[0035] "Biological sample" refers to any sample from a patient from which cancerous cells can be obtained and FGFR gene alterations can be detected. Suitable biological samples include, but are not limited to, blood, lymph, bone marrow, solid tumor samples, or any combination thereof. In some embodiments, the biological sample can be formalin-fixed paraffin-embedded tissue (FFPET).

[0036] FGFR gene alterations Provided herein is a method of treating urothelial carcinoma in a patient, comprising: (a) evaluating a biological sample from the patient for the presence of at least two FGFR genetic alterations, wherein (i) two or more of the at least two FGFR genetic alterations are FGFR2 fusions; (ii) one or more of the at least two FGFR genetic alterations are FGFR2 fusions and one or more of the at least two FGFR genetic alterations are FGFR3 fusions; (iii) two or more of the at least two FGFR genetic alterations are FGFR3 mutations; (iv) at least one of the at least two FGFR genetic alterations are FGFR3 mutations; and (b) treating the patient with an FGFR inhibitor if at least two FGFR genetic alterations are present in the sample.

[0037] Also described herein are methods of treating urothelial carcinoma in patients with at least two FGFR genetic alterations, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor to the patient, wherein (a) two or more of the at least two FGFR genetic alterations are FGFR2 fusions; (b) one or more of the at least two FGFR genetic alterations are FGFR2 fusions and one or more of the at least two FGFR genetic alterations are FGFR3 fusions; (c) two or more of the at least two FGFR genetic alterations are FGFR3 mutations; (d) one or more of the at least two FGFR genetic alterations are FGFR3 mutations and one or more of the at least two FGFR genetic alterations are FGFR2 fusions; or (e) one or more of the at least two FGFR genetic alterations are FGFR3 mutations and one or more of the at least two FGFR genetic alterations are FGFR3 fusions.

[0038] The fibroblast growth factor (FGF) family of protein tyrosine kinase (PTK) receptors regulates a wide variety of physiological functions, including mitogenesis, wound healing, cell differentiation and angiogenesis, and development. Both normal and malignant cell growth and proliferation are influenced by changes in the local concentration of FGFs, extracellular signaling molecules that act as autocrine and paracrine factors. Autocrine FGF signaling may be particularly important in the progression of steroid hormone-dependent cancers to hormone-independent states. FGFs and their receptors are expressed at increased levels in several tissues and cell lines, and overexpression is thought to contribute to the malignant phenotype. Furthermore, several oncogenes are homologs of genes encoding growth factor receptors, suggesting the possibility of aberrant activation of FGF-dependent signaling in human pancreatic cancer (Knights et al., Pharmacology and Therapeutics 2010 125:1(105-117); Korc M. et al., Current Cancer Drug Targets 2009 9:5(639-651)).

[0039] The two prototypic members are acidic fibroblast growth factor (aFGF or FGF1) and basic fibroblast growth factor (bFGF or FGF2), and at least 20 distinct FGF family members have been identified to date. Cellular responses to FGFs are mediated by four high-affinity transmembrane protein tyrosine kinase fibroblast growth factor receptors (FGFRs), numbered 1 to 4 (FGFR1 to FGFR4).

[0040] In certain embodiments, the urothelial carcinoma is susceptible to FGFR2 or FGFR3 gene alterations. In further embodiments, the urothelial carcinoma is susceptible to at least two FGFR gene alterations. In certain embodiments, the urothelial carcinoma is sensitive to at least two FGFR gene alterations, and (i) two or more of the at least two FGFR gene alterations are FGFR2 fusions; (ii) one or more of the at least two FGFR gene alterations are FGFR2 fusions and one or more of the at least two FGFR gene alterations are FGFR3 fusions; (iii) two or more of the at least two FGFR gene alterations are FGFR3 mutations; (iv) one or more of the at least two FGFR gene alterations are FGFR3 mutations and one or more of the at least two FGFR gene alterations are FGFR2 fusions; or (v) one or more of the at least two FGFR gene alterations are FGFR3 mutations and one or more of the at least two FGFR gene alterations are FGFR3 fusions.

[0041] As used herein, "FGFR gene alteration" refers to an alteration in a wild-type FGFR gene, including, but not limited to, an FGFR fusion gene, an FGFR mutation, an FGFR amplification, or any combination thereof. The terms "variant" and "alteration" are used interchangeably herein.

[0042] In certain embodiments, the FGFR gene alteration is an FGFR gene fusion. "FGFR fusion" or "FGFR gene fusion" refers to a gene encoding a portion of an FGFR (e.g., FGRF2 or FGFR3) and one of the fusion partners disclosed herein, or a portion thereof, resulting from a translocation between the two genes. The terms "fusion" and "translocation" are used interchangeably herein. The presence of one or more of the following FGFR fusion genes in a biological sample from a patient can be determined using the disclosed methods: FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof. In certain embodiments, the FGFR-TACC3 is FGFR-TACC3 variant 1 (FGFR-TACC3 v1) or FGFR-TACC3 variant 3 (FGFR-TACC3 v3). Table 1 provides FGFR fusion genes and the fused FGFR and fusion partner exons. The sequences of the individual FGFR fusion genes are disclosed in Table 1.

[0043] [Table 1]

[0044] FGFR genetic alterations include FGFR single nucleotide polymorphisms (SNPs). An "FGFR single nucleotide polymorphism" (SNP) refers to an FGFR2 or FGFR3 gene that differs by a single nucleotide between individuals. In certain embodiments, the FGFR2 or FGFR3 genetic alteration is an FGFR3 genetic mutation. In particular, an "FGFR single nucleotide polymorphism" (SNP) refers to an FGFR3 gene that differs by a single nucleotide between individuals. The presence of one or more of the following FGFR SNPs in a biological sample from a patient can be determined by methods known to those skilled in the art or the methods disclosed in WO 2016 / 048833 (FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, FGFR3 Y373C, or any combination thereof). The sequences of the FGFR SNPs are provided in Table 2.

[0045] [Table 2]

[0046] In certain embodiments, urothelial carcinoma is susceptible to at least two FGFR gene alterations. In some embodiments, the FGFR alterations can be one or more FGFR fusion genes. In some embodiments, the FGFR alterations can be one or more FGFR mutations. In some embodiments, the FGFR alterations can be one or more FGFR amplifications. In some embodiments, a combination of one or more FGFR alterations can be present in a biological sample from a patient.

[0047] In some embodiments, one or more of the at least two FGFR genetic alterations are FGFR mutations. In further embodiments, one or more of the at least two FGFR genetic alterations are FGFR2 mutations. In further embodiments, one or more of the at least two FGFR genetic alterations are FGFR3 mutations. In some embodiments, the FGFR3 mutation is FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, FGFR3 Y373C, or any combination thereof.

[0048] In some embodiments, one or more of the at least two FGFR genetic alterations are FGFR fusions. In further embodiments, one or more of the at least two FGFR genetic alterations are FGFR3 fusions. In further embodiments, the FGFR3 fusion is FGFR3-BAIAP2L1, FGFR3-TACC3 v1, FCFR3-TACC3 v3, or any combination thereof. In further embodiments, one or more of the at least two FGFR genetic alterations are FGFR2 fusions. In further embodiments, the FGFR2 fusion is FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

[0049] In certain embodiments, two or more of the at least two FGFR genetic alterations are FGFR2 fusions. In some embodiments, the two or more FGFR genetic alterations include FGFR2-BICC1 and FGFR2-CASP7.

[0050] In certain embodiments, one or more of the at least two FGFR genetic alterations are FGFR2 fusions and one or more of the at least two FGFR genetic alterations are FGFR3 fusions. In some embodiments, the two or more FGFR genetic alterations include FGFR2-CASP7 and FGFR3-BAIAP2L1; FGFR2-CASP7 and FGFR3-TACC3 V1; or FGFR2-CASP7 and FGFR3-TACC3 V3.

[0051] In certain embodiments, two or more of the at least two FGFR genetic alterations are FGFR3 mutations. In some embodiments, the two or more FGFR genetic alterations include FGFR3 G370C and FGFR3 S249C; FGFR3 R248C and FGFR3 Y373C; or FGFR3 S249C and FGFR3 Y373C.

[0052] In certain embodiments, one or more of the at least two FGFR genetic alterations are FGFR3 mutations and one or more of the at least two FGFR genetic alterations are FGFR2 fusions. In some embodiments, the two or more FGFR genetic alterations include FGFR3 G370C / FGFR2-BICC1; or FGFR3 S249C, FGFR3 Y373C, FGFR2-CASP7, FGFR3-BAIAP2L1, FGFR3-TACC3 V1, and FGFR3-TACC3 V3.

[0053] In certain embodiments, one or more of the at least two FGFR genetic alterations are FGFR3 mutations, and one or more of the at least two FGFR genetic alterations are FGFR3 fusions. In some embodiments, the two or more FGFR genetic alterations include FGFR3 G370C and FGFR3-TACC3 V1; FGFR3 R248C and FGFR3-TACC3 V1; FGFR3 S249C and FGFR3-BAIAP2L1; FGFR3 R248C, FGFR3 S249, and FGFR3-TACC3 V1; or FGFR3 S249C, FGFR3 Y373C, FGFR2-CASP7, FGFR3-BAIAP2L1, FGFR3-TACC3 V1, and FGFR3-TACC3 V3.

[0054] As used herein, an "FGFR mutant gene panel" comprises one or more of the FGFR mutants listed above. In some embodiments, the FGFR mutant gene panel depends on the patient's cancer type.

[0055] The FGFR variant panel used in the evaluation step of the disclosed methods is based in part on the patient's cancer type. For patients with urothelial carcinoma, a suitable FGFR variant gene panel may include FGFR3-TACC3_V1, FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, or FGFR3 Y373C, or any combination thereof.

[0056] FGFR inhibitors for use in the disclosed methods or uses Suitable FGFR inhibitors for use in the disclosed methods are provided herein.

[0057] In some embodiments, if one or more FGFR mutations are present in the sample, the urothelial carcinoma patient may be treated with an FGFR inhibitor (including any tautomeric or stereochemically isomeric forms thereof, and N-oxides thereof, pharmaceutically acceptable salts thereof, or solvates thereof) disclosed in U.S. Patent Application Publication No. 2013 / 0072457A1, which is incorporated herein by reference (suitable R groups are also disclosed in U.S. Patent Application Publication No. 2013 / 0072457A1).

[0058] In some aspects, for example, the patient may be treated with N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine (referred to herein as "JNJ-42756493" or "JNJ493," or erdafitinib), including any tautomeric form thereof, its N-oxide, its pharmaceutically acceptable salt, or its solvate. In some embodiments, the FGFR inhibitor is a compound of Formula (I): [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is an HCl salt. In preferred embodiments, erdafitinib base is used.

[0059] In some embodiments, patients with urothelial carcinoma may be treated with an FGFR inhibitor, wherein the FGFR inhibitor is N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,5-diemthylpiperazin-1-yl)benzamide (AZD4547), as described in Gavine, PR, et al., AZD4547: An Orally Bioavailable, Potent, and Selective Inhibitor of the Fibroblast Growth Factor Receptor Tyrosine Kinase Family, Cancer Res. April 15, 2012 72;2045. [ka] (including, if chemically possible, any tautomeric or stereochemically isomeric forms thereof, and an N-oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof).

[0060] In some embodiments, patients with urothelial cancer may be treated with an FGFR inhibitor, which is 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl}-methyl-urea (NVP-BGJ398), as described in WO 2006 / 000420: [ka] (including, if chemically possible, any tautomeric or stereochemically isomeric forms thereof, and an N-oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof).

[0061] In some embodiments, patients with urothelial carcinoma may be treated with an FGFR inhibitor, which is 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one (dovitinib), as described in WO 2006 / 127926: [ka] (including, if chemically possible, any tautomeric or stereochemically isomeric forms thereof, and an N-oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof).

[0062] In some embodiments, patients with urothelial carcinoma may be treated with an FGFR inhibitor, such as 6-(7-((1-aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide (AL3810) (lucitanib; E-3810), as described in Bello, E. et al., E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models, Cancer Res February 15, 2011 71(A)1396-1405 and WO 2008 / 112408: [ka] (including, if chemically possible, any tautomeric or stereochemically isomeric forms thereof, and an N-oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof).

[0063] Further suitable FGFR inhibitors include BAY1163877 (Bayer), BAY1179470 (Bayer), TAS-120 (Taiho), ARQ087 (ArQule), ASP5878 (Astellas), FF284 (Chugai), FP-1039 (GSK / FivePrime), Blueprint, LY-2874455 (Lilly), RG-7444 (Roche), or any combination thereof, including, where chemically possible, any tautomeric or stereochemically isomeric form thereof, its N-oxide, its pharmaceutically acceptable salt, or its solvate.

[0064] In some embodiments, FGFR inhibitors in general, and more particularly erdafitinib, are administered as pharmaceutically acceptable salts.In preferred embodiments, FGFR inhibitors in general are administered in base form.In some embodiments, FGFR inhibitors in general, and more particularly erdafitinib, are administered as pharmaceutically acceptable salts in an amount equivalent to 8 mg of base equivalent or 9 mg of base equivalent.In some embodiments, FGFR inhibitors in general, and more particularly erdafitinib, are administered in base form in an amount of 8 mg or 9 mg.

[0065] Salts can be prepared, for example, by reacting an FGFR inhibitor in general, and more specifically erdafitinib, with a suitable acid in a suitable solvent.

[0066] Acid addition salts can be formed with both inorganic and organic acids. Examples of acid addition salts include salts formed with acids selected from the group consisting of acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid (mesylate), ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propionic acid, butanoic acid, malonic acid, glucuronic acid, and lactobionic acid. Another group of acid addition salts includes salts formed with acetic acid, adipic acid, ascorbic acid, aspartic acid, citric acid, DL-lactic acid, fumaric acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloric acid, glutamic acid, DL-malic acid, methanesulfonic acid, sebacic acid, stearic acid, succinic acid, and tartaric acid.

[0067] In some embodiments, FGFR inhibitors in general, and more specifically erdafitinib, are administered in the form of a solvate. As used herein, the term "solvate" refers to the physical association of erdafitinib with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonds, including hydrogen bonds. In certain cases, a solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The term "solvate" is intended to encompass both 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.

[0068] Solvates are well known in pharmaceutical chemistry. They can be important for processes for the preparation of substances (e.g., in connection with their purification), for the preservation of substances (e.g., their stability), and for ease of handling, and are often formed as part of an isolation or purification step in a chemical synthesis. One skilled in the art can determine whether a hydrate or other solvate was formed by the isolation or purification conditions used to prepare a given compound using standard, well-established techniques. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g., single-crystal X-ray crystallography or X-ray powder diffraction), and solid-state NMR (SS-NMR, also known as magic-angle spinning NMR or MAS-NMR). Such techniques, along with NMR, IR, HPLC, and MS, are part of a skilled artisan's standard toolkit. Alternatively, one skilled in the art can intentionally form a solvate using crystallization conditions that include the amount of solvent required for a particular solvate. The standard methods described above can then be used to confirm whether a solvate was formed. Also included are any complexes (eg, inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals).

[0069] Additionally, the compounds may have one or more polymorphic (crystalline) or amorphous forms.

[0070] Compounds include compounds with one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of that element. For example, a reference to hydrogen includes within its scope: 1 H, 2 H(D), and 3 Similarly, references to carbon and oxygen include within their scope, respectively, 12 C. 13 C, and 14 C, and 16 O and 18The compound may contain one or more radioisotopes. The isotope may be radioactive or non-radioactive. In one embodiment, the compound does not contain a radioisotope. Such compounds are preferred for therapeutic use. However, in another embodiment, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in diagnostic terms.

[0071] Methods of Treatment / Compounds for Use Provided herein is a method of treating urothelial carcinoma in a patient, comprising: (a) evaluating a biological sample from the patient for the presence of at least two FGFR genetic alterations, wherein: (i) two or more of the at least two FGFR genetic alterations are FGFR2 fusions; (ii) one or more of the at least two FGFR genetic alterations are FGFR2 fusions and one or more of the at least two FGFR genetic alterations are FGFR3 fusions; (iii) two or more of the at least two FGFR genetic alterations are FGFR3 mutations; (iv) at least one of the at least two FGFR genetic alterations are FGFR3 mutations; and (b) treating the patient with an FGFR inhibitor if at least two FGFR genetic alterations are present in the sample.

[0072] Also provided herein is an FGFR inhibitor for use in treating urothelial carcinoma, said treatment comprising (a) evaluating a biological sample from a patient for the presence of at least two FGFR genetic alterations, wherein (i) two or more of the at least two FGFR genetic alterations are FGFR2 fusions; (ii) one or more of the at least two FGFR genetic alterations are FGFR2 fusions and one or more of the at least two FGFR genetic alterations are FGFR3 fusions; (iii) two or more of the at least two FGFR genetic alterations are FGFR3 mutations; (iv) assessing that one or more of the at least two FGFR genetic alterations are FGFR3 mutations and one or more of the at least two FGFR genetic alterations are FGFR2 fusions; or (v) assessing that one or more of the at least two FGFR genetic alterations are FGFR3 mutations and one or more of the at least two FGFR genetic alterations are FGFR3 fusions; and (b) administering an FGFR inhibitor to the patient if at least two FGFR genetic alterations are present in the sample.

[0073] Also provided is the use of an FGFR inhibitor in the manufacture of a medicament for the treatment of urothelial carcinoma, said treatment comprising (a) evaluating a biological sample from a patient for the presence of at least two FGFR genetic alterations, wherein (i) two or more of the at least two FGFR genetic alterations are FGFR2 fusions; (ii) one or more of the at least two FGFR genetic alterations are FGFR2 fusions and one or more of the at least two FGFR genetic alterations are FGFR3 fusions; or (iii) two or more of the at least two FGFR genetic alterations are FGFR3 mutations. or (iv) one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR2 fusion; or (v) one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion; and (b) if at least two FGFR genetic alterations are present in the sample, administering to the patient an FGFR inhibitor.

[0074] Also described herein are methods of treating urothelial carcinoma in patients with at least two FGFR genetic alterations, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor to the patient, wherein (a) two or more of the at least two FGFR genetic alterations are FGFR2 fusions; (b) one or more of the at least two FGFR genetic alterations are FGFR2 fusions and one or more of the at least two FGFR genetic alterations are FGFR3 fusions; (c) two or more of the at least two FGFR genetic alterations are FGFR3 mutations; (d) one or more of the at least two FGFR genetic alterations are FGFR3 mutations and one or more of the at least two FGFR genetic alterations are FGFR2 fusions; or (e) one or more of the at least two FGFR genetic alterations are FGFR3 mutations and one or more of the at least two FGFR genetic alterations are FGFR3 fusions.

[0075] Also described herein is an FGFR inhibitor for use in treating urothelial carcinoma in patients with at least two FGFR genetic alterations, wherein the treatment comprises, consists of, or consists essentially of administering the FGFR inhibitor to the patient, and wherein: (a) two or more of the at least two FGFR genetic alterations are FGFR2 fusions; (b) one or more of the at least two FGFR genetic alterations are FGFR2 fusions and one or more of the at least two FGFR genetic alterations are FGFR3 fusions; (c) two or more of the at least two FGFR genetic alterations are FGFR3 mutations; (d) one or more of the at least two FGFR genetic alterations are FGFR3 mutations and one or more of the at least two FGFR genetic alterations are FGFR2 fusions; or (e) one or more of the at least two FGFR genetic alterations are FGFR3 mutations and one or more of the at least two FGFR genetic alterations are FGFR3 fusions.

[0076] Also described herein is the use of an FGFR inhibitor in the manufacture of a medicament for the treatment of urothelial carcinoma in a patient with at least two FGFR genetic alterations, wherein the treatment comprises, consists of, or consists essentially of administering an FGFR inhibitor to the patient, and wherein (a) two or more of the at least two FGFR genetic alterations are FGFR2 fusions; (b) one or more of the at least two FGFR genetic alterations are FGFR2 fusions and one or more of the at least two FGFR genetic alterations are FGFR3 fusions; (c) two or more of the at least two FGFR genetic alterations are FGFR3 mutations; (d) one or more of the at least two FGFR genetic alterations are FGFR3 mutations and one or more of the at least two FGFR genetic alterations are FGFR2 fusions; or (e) one or more of the at least two FGFR genetic alterations are FGFR3 mutations and one or more of the at least two FGFR genetic alterations are FGFR3 fusions.

[0077] In certain embodiments, the urothelial carcinoma is locally advanced or metastatic. In certain embodiments, the patient is a high-risk patient, particularly a metastatic or surgically unresectable urothelial carcinoma, particularly a metastatic or surgically unresectable urothelial carcinoma with a selected FGFR gene alteration (FGFR translocation or mutation), particularly a high-risk patient with an FGFR gene alteration as defined above. High-risk patients are those who meet one or more of the following criteria: age 75 years or older; ECOG PS of 2; hemoglobin less than 10 g / dL; visceral metastasis, particularly to the liver, lung, and / or bone; and two or three Bellmunt risk factors. In one embodiment, hemoglobin concentration is measured in whole blood.

[0078] In certain embodiments, administration of an FGFR inhibitor provides improved anti-tumor activity as measured by response rate, progression-free survival, duration of response, or overall survival compared to patients with urothelial carcinoma who have not been treated with an FGFR inhibitor. In certain embodiments, administration of an FGFR inhibitor provides improved anti-tumor activity as measured by response rate or duration of response compared to patients with urothelial carcinoma who have not been treated with an FGFR inhibitor. In certain embodiments, administration of an FGFR inhibitor provides improved anti-tumor activity as measured by response rate compared to patients with urothelial carcinoma who have not been treated with an FGFR inhibitor. In certain embodiments, administration of an FGFR inhibitor provides improved anti-tumor activity as measured by progression-free survival compared to patients with urothelial carcinoma who have not been treated with an FGFR inhibitor. In certain embodiments, administration of an FGFR inhibitor provides improved anti-tumor activity as measured by duration of response compared to patients with urothelial carcinoma who have not been treated with an FGFR inhibitor. In certain embodiments, administration of an FGFR inhibitor provides improved anti-tumor activity as measured by overall survival compared to patients with urothelial carcinoma who are not treated with an FGFR inhibitor.

[0079] In certain embodiments, the improvement in anti-tumor activity is relative to treatment with a placebo. In certain embodiments, the improvement in anti-tumor activity is relative to no treatment. In certain embodiments, the improvement in anti-tumor activity is relative to standard of care.

[0080] To assess response rate or future progression, it is necessary to estimate overall tumor burden at baseline and use this as a comparison for subsequent measurements. Measurable disease is defined by the presence of at least one measurable lesion.

[0081] In some embodiments, administration of the FGFR inhibitor results in adverse events of grade 2 or less. In other embodiments, administration of the FGFR inhibitor results in adverse events of grade 3 or less. In some embodiments, administration of the FGFR inhibitor results in adverse events of grade 4 or less.

[0082] In certain embodiments, the method of treating or use in treating urothelial carcinoma in a patient with at least two FGFR gene alterations further comprises assessing a biological sample from the patient for the presence of at least two FGFR gene alterations prior to administration of the FGFR inhibitor.

[0083] In certain embodiments of the methods of treating or uses in treating urothelial carcinoma as disclosed herein, two or more of the at least two FGFR genetic alterations are FGFR2 fusions. In some embodiments, the two or more FGFR genetic alterations include FGFR2-BICC1 and FGFR2-CASP7.

[0084] In certain embodiments of the methods of treating or uses in treating urothelial carcinoma as disclosed herein, one or more of the at least two FGFR genetic alterations is an FGFR2 fusion, and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion. In some embodiments, the two or more FGFR genetic alterations comprise FGFR2-CASP7 and FGFR3-BAIAP2L1; FGFR2-CASP7 and FGFR3-TACC3 V1; or FGFR2-CASP7 and FGFR3-TACC3 V3.

[0085] In certain embodiments of the methods of treating or uses in treating urothelial carcinoma as disclosed herein, two or more of the at least two FGFR genetic alterations are FGFR3 mutations. In some embodiments, the two or more FGFR genetic alterations include FGFR3 G370C and FGFR3 S249C; FGFR3 R248C and FGFR3 Y373C; or FGFR3 S249C and FGFR3 Y373C.

[0086] In certain embodiments of the methods of treating or uses in treating urothelial carcinoma as disclosed herein, one or more of the at least two FGFR genetic alterations is an FGFR3 mutation, and one or more of the at least two FGFR genetic alterations is an FGFR2 fusion. In some embodiments, the two or more FGFR genetic alterations include FGFR3 G370C / FGFR2-BICC1; or FGFR3 S249C, FGFR3 Y373C, FGFR2-CASP7, FGFR3-BAIAP2L1, FGFR3-TACC3 V1, and FGFR3_TACC3 V3.

[0087] In certain embodiments of the methods of treating or uses in treating urothelial carcinoma as disclosed herein, one or more of the at least two FGFR genetic alterations are FGFR3 mutations, and one or more of the at least two FGFR genetic alterations are FGFR3 fusions. In some embodiments, the two or more FGFR genetic alterations include FGFR3 G370C and FGFR3-TACC3 V1; FGFR3 R248C and FGFR3-TACC3 V1; FGFR3 S249C and FGFR3-BAIAP2L1; FGFR3 R248C, FGFR3 S249, and FGFR3-TACC3 V1; or FGFR3 S249C, FGFR3 Y373C, FGFR2-CASP7, FGFR3-BAIAP2L1, FGFR3-TACC3 V1, and FGFR3-TACC3 V3.

[0088] In certain embodiments of the methods of treating or uses in treating urothelial carcinoma as disclosed herein, the at least two FGFR genetic alterations comprise FGFR3 G370C and FGFR3 S249C; or FGFR3 R248C and FGFR3 Y373C.

[0089] In certain embodiments of the methods of treating or uses in treating urothelial carcinoma as disclosed herein, the at least two FGFR genetic alterations comprise FGFR3 G370C and FGFR2-BICC1; FGFR3 G370C and FGFR3-TACC3 VI; FGFR3 R248C and FGFR3-TACC3 VI; or FGFR3 R248C, FGFR3 S249, and FGFR3-TACC3 VI.

[0090] In certain embodiments of the methods of treating or uses in treating urothelial carcinoma as disclosed herein, the at least two FGFR genetic alterations comprise FGFR3 G370C and FGFR3 S249C; FGFR3 R248C and FGFR3 Y373C; FGFR3 G370C and FGFR2-BICC1; FGFR3 G370C and FGFR3-TACC3 VI; FGFR3 R248C and FGFR3-TACC3 VI; or FGFR3 R248C, FGFR3 S249, and FGFR3-TACC3 VI.

[0091] Evaluation of samples for the presence of at least two FGFR gene alterations Also described herein are methods of treating urothelial carcinoma in patients with at least two FGFR genetic alterations, comprising, consisting of, or consisting essentially of administering an FGFR inhibitor to the patient, wherein (a) two or more of the at least two FGFR genetic alterations are FGFR2 fusions; (b) one or more of the at least two FGFR genetic alterations are FGFR2 fusions and one or more of the at least two FGFR genetic alterations are FGFR3 fusions; (c) two or more of the at least two FGFR genetic alterations are FGFR3 mutations; (d) one or more of the at least two FGFR genetic alterations are FGFR3 mutations and one or more of the at least two FGFR genetic alterations are FGFR2 fusions; or (e) one or more of the at least two FGFR genetic alterations are FGFR3 mutations and one or more of the at least two FGFR genetic alterations are FGFR3 fusions. In certain embodiments, the method of treating urothelial carcinoma in a patient with at least two FGFR gene alterations further comprises evaluating a biological sample from the patient for the presence of at least two FGFR gene alterations prior to administration of an FGFR inhibitor.

[0092] The following methods for assessing a biological sample for the presence of at least two FGFR gene alterations apply equally to any of the methods of treatment and use disclosed above.

[0093] The disclosed methods are suitable for treating cancer in a patient when at least two FGFR genetic alterations are present in a biological sample from the patient. In some embodiments, the FGFR genetic alterations can be one or more FGFR fusion genes. In some embodiments, the FGFR genetic alterations can be one or more FGFR mutations. In some embodiments, the FGFR genetic alterations can be one or more FGFR amplifications. In some embodiments, a combination of one or more FGFR genetic alterations can be present in a biological sample from a patient. For example, in some embodiments, the FGFR genetic alterations can be one or more FGFR fusion genes and one or more FGFR amplifications.

[0094] In some embodiments, the FGFR gene alteration may be one or more FGFR fusion genes and one or more FGFR mutations. In some embodiments, the FGFR alteration may be one or more FGFR mutations and one or more FGFR amplifications. In still other embodiments, the FGFR alteration may be one or more FGFR fusion genes, mutations, and amplifications. Exemplary FGFR fusion genes are provided in Table 1 and include, but are not limited to, FGFR2-BICC1; FGFR2-CASP7; FGFR3-BAIAP2L1; FGFR3-TACC3 V1; FGFR3-TACC3 V3; or any combination thereof. Exemplary FGFR3 mutations are provided in Table 2 and include, but are not limited to, FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, FGFR3 Y373C, or any combination thereof.

[0095] Exemplary combinations of FGFR genetic alterations are provided in Table 3.

[0096] [Table 3]

[0097] Suitable methods for assessing a biological sample for the presence of at least two FGFR genetic alterations are described in the Methods section herein and in International Publication No. 2016 / 048833, which is incorporated herein in its entirety. For example, and without intending to be limiting, assessing a biological sample for the presence of one or more FGFR variants can include any combination of the following steps: isolating RNA from the biological sample; synthesizing cDNA from the RNA; and amplifying the cDNA (pre-amplified or not). In some embodiments, assessing a biological sample for the presence of one or more FGFR variants can include amplifying cDNA from the patient with a pair of primers that bind to and amplify one or more FGFR variants; and determining whether one or more FGFR variants are present in the sample. In some aspects, the cDNA can be pre-amplified. In some aspects, the assessing step can include isolating RNA from the sample, synthesizing cDNA from the isolated RNA, and pre-amplifying the cDNA.

[0098] Suitable primer pairs for carrying out the amplification step include, but are not limited to, those disclosed in WO 2016 / 048833, as exemplified below.

[0099] [Table 4]

[0100] The presence of at least two FGFR gene alterations can be assessed at any suitable time point, including at the time of diagnosis, after tumor resection, after first-line therapy, during clinical treatment, or any combination thereof.

[0101] For example, a biological sample taken from a patient can be analyzed to determine whether a condition or disease, such as cancer, from which the patient is suffering or may be suffering is characterized by a genetic abnormality or aberrant protein expression that results in upregulation of FGFR levels or activity, or sensitization of pathways to normal FGFR activity, or upregulation of these growth factor signaling pathways, such as growth factor ligand levels or growth factor ligand activity, or upregulation of biochemical pathways downstream of FGFR activation.

[0102] Examples of such abnormalities that lead to activation or sensitization of FGFR signaling include loss or inhibition of apoptosis pathways, upregulation of receptors or ligands, or genetic alterations of receptors or ligands, such as the presence of PTK variants. Tumors with genetic alterations of FGFR1, FGFR2, FGFR3, or FGFR4, or upregulation, particularly overexpression, of FGFR1, or gain-of-function genetic alterations of FGFR2 or FGFR3 may be particularly sensitive to FGFR inhibitors.

[0103] The methods, compounds and uses may further comprise assessing the presence of at least two FGFR gene alterations in the biological sample prior to the administering step.

[0104] Diagnostic tests and examinations are typically performed on a biological sample selected from a tumor biopsy, a blood sample (isolation and enrichment of sloughed tumor cells), a stool biopsy, sputum, chromosome analysis, pleural fluid, ascites, buccal aspiration, biopsy, circulating DNA, or urine. In certain embodiments, the biological sample is blood, lymph, bone marrow, a solid tumor sample, or any combination thereof. In certain embodiments, the biological sample is a solid tumor sample.

[0105] Methods for identifying and analyzing genetic alterations and upregulation of proteins are known to those skilled in the art. Screening methods include, but are not limited to, standard methods such as reverse transcription polymerase chain reaction (RT-PCR) or in situ hybridization, such as fluorescent in situ hybridization (FISH).

[0106] Identifying individuals who carry genetic alterations may mean that the patient is particularly suitable for treatment with erdafitinib.Tumors can be preferentially screened for the presence of FGFR genetic alterations before treatment.The screening process usually involves direct sequencing, oligonucleotide microarray analysis, or mutant-specific antibodies.In addition, the diagnosis of tumors with such genetic alterations can be carried out using techniques known to those skilled in the art, such as RT-PCR and FISH, and described herein.

[0107] In addition, for example, mutant forms of FGFR can be identified by direct sequencing of tumor biopsies, for example, using PCR and the method of directly sequencing the PCR product described hereinabove. Those skilled in the art will recognize that all such well-known techniques for detecting overexpression, activation, or mutation of the aforementioned proteins are applicable to the present case.

[0108] In RT-PCR screening, the level of mRNA in tumors is evaluated by generating a cDNA copy of the mRNA and then amplifying the cDNA by PCR. PCR amplification methods, primer selection, and amplification conditions are known to those skilled in the art. Nucleic acid manipulation and PCR are carried out by standard methods described, for example, in Ausubel, FM et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc. or Innis, MA et al., eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al., (2001), 3rd Ed., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, commercially available kits for RT-PCR (such as Roche Molecular Biochemicals) can be used, or the methodology described in U.S. Patent Nos. 4,666,828; 4,683,202; 4,801,531; 5,192,659, 5,272,057, 5,882,864 and 6,218,529 (incorporated herein by reference).An example of the in situ hybridization method for evaluating mRNA expression would be fluorescence in situ hybridization (FISH) (see Angerer (1987) Meth.Enzymol.,152:649).

[0109] Generally, in situ hybridization involves the following major steps: (1) fixation of the tissue to be analyzed; (2) pre-hybridization treatment of the sample to increase the accessibility of the target nucleic acid and reduce nonspecific binding; (3) hybridization of a mixture of nucleic acids to nucleic acids in a biological structure or tissue; (4) post-hybridization washes to remove nucleic acid fragments not bound by hybridization; and (5) detection of the hybridized nucleic acid fragments. Probes used in such applications are typically labeled, for example, with radioisotopes or fluorescent reporters. Preferred probes are sufficiently long to allow specific hybridization with the target nucleic acid under stringent conditions, e.g., from about 50, 100, or 200 nucleotides to about 1000 nucleotides or more. Standard methods for performing FISH are described in Ausubel, F M et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc. and Fluorescence In Situ Hybridization: Technical Overview by John M S Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pp. 077-088; Series: Methods in Molecular Medicine.

[0110] The method for gene expression profiling is described by (DePrimo et al. (2003), BMC Cancer, 3:3). Briefly, the protocol is as follows: double-stranded cDNA is synthesized from total RNA using a (dT)24 oligomer (SEQ ID NO: 38: tttttttttt tttttttttt tttt) to prime first-strand cDNA synthesis, followed by second-strand cDNA synthesis with random hexamer primers. The double-stranded cDNA is used as a template for in vitro transcription of cRNA using biotinylated ribonucleotides. The cRNA is chemically fragmented according to the protocol described by Affymetrix (Santa Clara, CA, USA) and subsequently hybridized overnight on a Human Genome Array.

[0111] Alternatively, the protein products expressed from the mRNA may be assayed by immunohistochemistry of tumor samples, solid-phase immunoassays in microtiter plates, Western blotting, two-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry, and other methods for detecting specific proteins known in the art. Detection methods may include the use of site-specific antibodies. Those skilled in the art will recognize that all such well-known techniques for detecting FGFR and / or VEGFR upregulation or for detecting FGFR and / or VEGFR variants or mutations are applicable to the present case.

[0112] Abnormal levels of proteins such as FGFRs can be measured using standard enzyme assays, such as those described herein. Activation or overexpression can also be detected in tissue samples, such as tumor tissue, by measuring tyrosine kinase activity with assays such as those available from Chemicon International. The tyrosine kinase of interest will be immunoprecipitated from the sample lysate and its activity measured.

[0113] An alternative method for measuring overexpression or activation of FGFR, including isoforms, involves measuring microvessel density, which can be measured, for example, using the method described by Orre and Rogers (Int J Cancer (1999), 84(2)101-8). Assay methods also include the use of markers.

[0114] Thus, all of these approaches can be used to identify tumors that are particularly suitable for treatment with the compounds of the invention.

[0115] Erdafitinib is particularly useful in treating patients with at least two FGFR gene alterations.In certain embodiments, Erdafitinib is useful in treating patients with at least two FGFR gene alterations, where (a) two or more of at least two FGFR gene alterations are FGFR2 fusion; (b) one or more of at least two FGFR gene alterations are FGFR2 fusion, and one or more of at least two FGFR gene alterations are FGFR3 fusion; (c) two or more of at least two FGFR gene alterations are FGFR3 mutation; (d) one or more of at least two FGFR gene alterations are FGFR3 mutation, and one or more of at least two FGFR gene alterations are FGFR2 fusion; or (e) one or more of at least two FGFR gene alterations are FGFR3 mutation, and one or more of at least two FGFR gene alterations are FGFR3 fusion.

[0116] Pharmaceutical Compositions and Routes of Administration In view of their useful pharmacological properties, FGFR inhibitors in general, and erdafitinib in particular, can be formulated into various pharmaceutical forms for administration purposes.

[0117] In one embodiment, a pharmaceutical composition (e.g., formulation) comprises at least one active compound of the invention together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants, or other materials well known to those of skill in the art, and optionally other therapeutic or prophylactic agents.

[0118] To prepare pharmaceutical compositions, an effective amount of FGFR inhibitors, and more specifically erdafitinib, as active ingredients are generally mixed in a homogeneous mixture with a pharmaceutically acceptable carrier, and this carrier can take a variety of forms depending on the desired preparation form for administration.The pharmaceutical composition can be in any form suitable for oral, parenteral, topical, intranasal, ophthalmic, aural, rectal, intravaginal or transdermal administration.The pharmaceutical composition is preferably in a unit dosage form suitable for oral administration, rectal administration, transdermal administration or parenteral injection administration.For example, when preparing this composition into oral dosage form, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions, for example, water, glycols, oils, alcohols, etc.; or In the case of powders, pills, capsules, and tablets, any of the usual pharmaceutical media can be used, such as solid carriers, for example, starches, sugars, kaolin, lubricants, binders, disintegrating agents, and the like.

[0119] The pharmaceutical compositions of the present invention, particularly capsules and tablets, may include one or more pharmaceutically acceptable excipients (pharmaceutically acceptable carriers), such as disintegrants, diluents, fillers, binders, buffers, lubricants, glidants, thickeners, sweeteners, flavorings, coloring agents, preservatives, etc. Some excipients can serve more than one purpose.

[0120] Suitable disintegrants have a large swelling coefficient. Examples include hydrophilic, insoluble, or poorly water-soluble crosslinked polymers, such as crospovidone (crosslinked polyvinylpyrrolidone) and croscarmellose sodium (crosslinked sodium carboxymethylcellulose). The amount of disintegrant in the tablet according to the present invention can be conveniently in the range of about 2.5 to about 15% w / w, preferably in the range of about 2.5 to 7% w / w, and particularly in the range of about 2.5 to 5% w / w. Since disintegrants inherently result in sustained-release formulations when used in large amounts, it is advantageous to dilute the disintegrant with an inert substance called a diluent or filler.

[0121] Various materials may be used as diluents or fillers. Examples include lactose monohydrate, anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (e.g., microcrystalline cellulose (Avicel™), silicified microcrystalline cellulose), dihydrate or anhydrous calcium hydrogen phosphate, and others known in the art, as well as mixtures thereof (e.g., the spray-dried mixture of lactose monohydrate (75%) and microcrystalline cellulose (25%) commercially available as Microcelac™). Microcrystalline cellulose and mannitol are preferred. The total amount of diluent or filler in the pharmaceutical compositions of the present invention can conveniently range from about 20% to about 95% w / w, preferably from about 55% to about 95% w / w, or from about 70% to about 95%, or from about 80% to about 95% w / w, or from about 85% to about 95% w / w.

[0122] Lubricants and lubricants may be used in the manufacture of certain dosage forms, and are usually used when manufacturing tablets. Examples of lubricants and lubricants include hydrogenated vegetable oils, such as hydrogenated cottonseed oil, magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silica, colloidal anhydrous silica, talc, mixtures thereof, and others known in the art. Interesting lubricants are magnesium stearate and mixtures of magnesium stearate and colloidal silica, with magnesium stearate being preferred. A preferred lubricant is colloidal anhydrous silica.

[0123] When present, lubricants generally comprise 0.2 to 7.0% w / w, particularly 0.5 to 1.5% w / w, more particularly 1 to 1.5% w / w of the total composition weight.

[0124] When present, the lubricant will generally comprise 0.2 to 7.0% w / w of the total composition weight, in particular 0.2 to 2% w / w, or 0.5 to 2% w / w, or 0.5 to 1.75% w / w, or 0.5 to 1.5% w / w.

[0125] Binders can optionally be used in the pharmaceutical compositions of the present invention.Suitable binders include water-soluble polymers, such as alkylcelluloses such as methylcellulose; hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose; hydroxyalkylalkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose; carboxyalkylcelluloses such as carboxymethylcellulose; alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose; carboxyalkylalkylcelluloses such as carboxymethylethylcellulose; carboxyalkylcellulose esters; starch; pectins such as sodium carboxymethylamylopectin; chitin derivatives such as chitosan; disaccharides, oligosaccharides and polysaccharides such as trehalose, cyclodextrin and its derivatives, alginic acid, its alkali metal and ammonium salts, carrageenan, galactomannan, tragacanth, agar-agar, gum arabic, guar gum and xanthan gum; polyacrylic acid and its salts; polymethacrylic acid, its salts and esters, methacrylic acid copolymers; polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) and its copolymers, such as PVP-VA. Preferably, the water soluble polymer is a hydroxyalkyl alkyl cellulose, such as, for example, hydroxypropyl methylcellulose, eg, hydroxypropyl methylcellulose 15 cps.

[0126] Other excipients, such as colorants and pigments, may also be added to the compositions of the present invention. Colorants and pigments include titanium dioxide and food-grade dyes. Colorants or pigments are optional ingredients in the formulations of the present invention, but when used, the colorant may be present in an amount of up to 3.5% w / w based on the total composition weight.

[0127] Flavoring agents are optional in the composition and may be selected from synthetic flavor oils and flavoring aromatic compounds or natural oils, extracts from plant leaves, flowers, fruits, and the like, and combinations thereof. These may include cinnamon oil, wintergreen oil, peppermint oil, bay oil, anise oil, eucalyptus, and thyme oil. Vanilla, citrus oils such as lemon, orange, grape, lime, and grapefruit, and fruit essences such as apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, and apricot are also useful flavoring agents. The amount of flavoring agent can depend on several factors, including the desired organoleptic effect. Generally, flavoring agents will be present in an amount of about 0% to about 3% (w / w).

[0128] Formaldehyde scavengers are compounds capable of absorbing formaldehyde. They include compounds containing a nitrogen center reactive with formaldehyde, such as forming one or more reversible or irreversible bonds between the formaldehyde scavenger and formaldehyde. For example, formaldehyde scavengers contain one or more nitrogen atoms / centers reactive with formaldehyde, capable of forming a Schiff base imine and subsequently bonding with formaldehyde. For example, formaldehyde scavengers contain one or more nitrogen centers reactive with formaldehyde, forming one or more 5- to 8-membered rings. Formaldehyde scavengers preferably contain one or more amine or amide groups. For example, formaldehyde scavengers can be amino acids, amino sugars, alpha-amine compounds, or conjugates or derivatives thereof, or mixtures thereof. Formaldehyde scavengers can contain two or more amines and / or amides.

[0129] Formaldehyde scavengers include, for example, glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, aspartic acid, glutamic acid, arginine, lysine, ornithine, citrulline, taurine, pyrrolidine, meglumine, histidine, aspartame, proline, tryptophan, citrulline, pyrrolidine, asparagine, glutamine, or conjugates or mixtures thereof; or possibly pharmaceutically acceptable salts thereof.

[0130] In an embodiment of the invention, the formaldehyde scavenger is meglumine or a pharmaceutically acceptable salt thereof, in particular meglumine base.

[0131] Another object of the present invention is to provide a process for preparing a pharmaceutical composition as described herein, in particular in the form of a tablet or capsule, characterized in that it comprises mixing a formaldehyde scavenger, in particular meglumine, and erdafitinib, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular erdafitinib base, with a pharmaceutically acceptable carrier and compressing said mixture into a tablet or filling said mixture into a capsule.

[0132] Tablets and capsules are the most advantageous oral dosage unit forms due to their ease of administration, in which case solid pharmaceutical carriers are naturally employed. For parenteral compositions, the carrier usually comprises, at least in large part, sterile water, although other ingredients, for example, to aid solubility, may be included. For example, injectable solutions may be prepared in which the carrier comprises saline, glucose solution, or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents, etc. may be utilized. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and / or a suitable wetting agent, optionally in combination with minor proportions of suitable additives of any nature, provided that these additives do not cause significant adverse effects on the skin. Such additives may facilitate application to the skin and / or may be useful in formulating the desired composition. These compositions may be administered in various ways, for example, as a transdermal patch, a spot-on formulation, or an ointment. It is particularly advantageous to formulate the aforementioned pharmaceutical compositions into dosage unit forms for ease of administration and uniformity of dosage. "Unit dosage form," as used herein and in the claims, refers to physically discrete units suitable as unitary dosages, each containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, together with the necessary pharmaceutical carrier. Examples of such unit dosage forms include tablets (including scored or coated tablets), capsules, pills, packeted powders, cachets, injectable solutions or suspensions, teaspoons and tablespoons, and divided combinations thereof.

[0133] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the aforementioned pharmaceutical compositions into unit dosage forms.As used herein, unit dosage form refers to a physically discrete unit suitable as a unit dose, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect together with the necessary pharmaceutical carrier.Examples of such unit dosage forms include tablets (including scored tablets or coated tablets), capsules, pills, sachet powders, cachets, injection solutions or suspensions, teaspoons and tablespoons, and their divided combinations.Preferred forms are tablets and capsules.

[0134] In certain embodiments, the FGFR inhibitor, or in particular erdafitinib, is present in a solid unit dosage form, and is suitable for oral administration.The unit dosage form can contain about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg of FGFR inhibitor per unit dosage form, or the amount within the range defined by two of these values, particularly 3, 4 or 5 mg per unit dose.

[0135] Depending on the mode of administration, the pharmaceutical composition will preferably contain 0.05 to 99% by weight, more preferably 0.1 to 70% by weight, even more preferably 0.1 to 50% by weight of a compound of the invention, and 1 to 99.95% by weight, more preferably 30 to 99.9% by weight, even more preferably 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

[0136] The tablets or capsules of the present invention can be further film-coated to, for example, improve taste, ease of swallowing, and enhance appearance. Polymeric film-coating materials are known in the art. Preferred film coatings are aqueous-based film coatings, as opposed to solvent-based film coatings, because the latter may contain smaller amounts of aldehydes. A preferred film-coating material is the Opadry® II aqueous film coating system, e.g., Opadry® II 85F, such as Opadry® II 85F92209. Further preferred film coatings are aqueous-based film coatings that protect against environmental moisture, such as the aqueous moisture barrier film coating systems Readilycoat® (e.g., Readilycoat® D), AquaPolish® MS, Opadry® amb, and Opadry® amb II. A preferred film coating is Opadry® amb II, a high-performance moisture barrier film coating that is a PVA-based immediate-release system without polyethylene glycol.

[0137] In tablets according to the invention, the film coat preferably accounts for no more than about 4% (w / w) of the total tablet weight.

[0138] With regard to capsules according to the present invention, hypromellose (HPMC) capsules are preferred over gelatin capsules.

[0139] In one embodiment of the present invention, the pharmaceutical compositions described herein, particularly in capsule or tablet form, contain 0.5 mg to 20 mg base equivalents, or 2 mg to 20 mg base equivalents, or 0.5 mg to 12 mg base equivalents, or 2 mg to 12 mg base equivalents, or 2 mg to 10 mg base equivalents, or 2 mg to 6 mg base equivalents, or 2 mg base equivalents, 3 mg base equivalents, 4 mg base equivalents, 5 mg base equivalents, 6 mg base equivalents, 7 mg base equivalents, 8 mg base equivalents, 9 mg base equivalents, 10 mg base equivalents, 11 mg base equivalents, or 12 mg base equivalents of erdafitinib, its pharmaceutically acceptable salt, or solvate thereof. In particular, the pharmaceutical compositions described herein contain 3 mg base equivalents, 4 mg base equivalents, or 5 mg base equivalents of erdafitinib, its pharmaceutically acceptable salt, or solvate thereof.

[0140] In one aspect of the present invention, the pharmaceutical compositions described herein, particularly in capsule or tablet form, contain 0.5 mg to 20 mg, or 2 mg to 20 mg, or 0.5 mg to 12 mg, or 2 mg to 12 mg, or 2 mg to 10 mg, or 2 mg to 6 mg, or 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, or 12 mg of erdafitinib base. In particular, the pharmaceutical compositions described herein contain 3 mg, 4 mg, or 5 mg of erdafitinib base. In particular, the pharmaceutical compositions described herein contain 3 mg, 4 mg, or 5 mg of erdafitinib base and about 0.5 to about 5% w / w, about 0.5 to about 3% w / w, about 0.5 to about 2% w / w, about 0.5 to about 1.5% w / w, or about 0.5 to about 1% w / w of a formaldehyde scavenger, particularly meglumine. In particular, the pharmaceutical compositions described herein comprise 3 mg, 4 mg, or 5 mg of erdafitinib base and about 0.5 to about 1.5% w / w, or about 0.5 to about 1% w / w of a formaldehyde scavenger, in particular meglumine.

[0141] In certain aspects of the invention, two or more, eg, two, pharmaceutical compositions described herein may be administered to obtain a desired dose, eg, a daily dose.

[0142] The amount of formaldehyde scavenger, in particular meglumine, in the pharmaceutical composition according to the present invention may be in the range of about 0.1 to about 10% w / w, about 0.1 to about 5% w / w, about 0.1 to about 3% w / w, about 0.1 to about 2% w / w, about 0.1 to about 1.5% w / w, about 0.1 to about 1% w / w, about 0.5 to about 5% w / w, about 0.5 to about 3% w / w, about 0.5 to about 2% w / w, about 0.5 to about 1.5% w / w, or about 0.5 to about 1% w / w.

[0143] Studies that focus on safety are also required to identify potential adverse effects that may result from exposure to the drug. Efficacy is often measured by determining whether an active ingredient, when tested in an appropriate setting such as a rigorously controlled clinical trial, demonstrates a health benefit beyond that of a placebo or other intervention.

[0144] The term "acceptable" as used herein with respect to a formulation, composition, or ingredient means that the beneficial effects of the formulation, composition, or ingredient on the general health of the person being treated, to the extent that there are any, substantially outweigh its detrimental effects.

[0145] All formulations for oral administration are in dosage forms suitable for such administration.

[0146] Methods of Administration and Treatment Regimen Generally, FGFR inhibitors, and specifically erdafitinib, are administered in an amount sufficient to exert their antitumor activity. Those skilled in the art will be able to easily determine effective amounts from the test results presented herein below. Generally, a therapeutically effective amount is considered to be 0.005 mg / kg to 100 mg / kg body weight, particularly 0.005 mg / kg to 10 mg / kg body weight. It may be appropriate to administer the required dose as one, two, three, four, or more divided doses at appropriate intervals throughout the day. The divided doses may be formulated, for example, as unit dosage forms containing 0.5 to 500 mg, particularly 1 to 500 mg, more particularly 10 mg to 500 mg of active ingredient per unit dosage form.

[0147] In one aspect, the present disclosure provides a method or use for treating urothelial carcinoma, comprising, consisting of, or consisting essentially of administering a safe and effective amount of an FGFR inhibitor to a patient with urothelial carcinoma, wherein the FGFR inhibitor is orally administered. In some embodiments, the FGFR inhibitor, in general, and erdafitinib in particular, is administered daily, particularly once daily. In some embodiments, the FGFR inhibitor, in general, and erdafitinib in particular, is administered twice daily. In some embodiments, the FGFR inhibitor, in general, and erdafitinib in particular, is administered three times daily. In some embodiments, the FGFR inhibitor, in general, and erdafitinib in particular, is administered four times daily. In some embodiments, the FGFR inhibitor, in general, and erdafitinib in particular, is administered every other day. In some embodiments, the FGFR inhibitor, in general, and erdafitinib in particular, is administered once weekly. In some embodiments, the FGFR inhibitor in general, and erdafitinib in particular, is administered twice a week. In some embodiments, the FGFR inhibitor in general, and erdafitinib in particular, is administered every other week. In some embodiments, the FGFR inhibitor in general, and erdafitinib in particular, is orally administered on a daily dosing schedule.

[0148] In general, the dose of an FGFR inhibitor, and specifically erdafitinib, utilized in humans for the treatment of the diseases or conditions described herein typically ranges from about 1 to 20 mg per day. In some embodiments, the FGFR inhibitor, and specifically erdafitinib, is orally administered to a human at a dose of about 1 mg per day, about 2 mg per day, about 3 mg per day, about 4 mg per day, about 5 mg per day, about 6 mg per day, about 7 mg per day, about 8 mg per day, about 9 mg per day, about 10 mg per day, about 11 mg per day, about 12 mg per day, about 13 mg per day, about 14 mg per day, about 15 mg per day, about 16 mg per day, about 17 mg per day, about 18 mg per day, about 19 mg per day, or about 20 mg per day.

[0149] In certain embodiments, erdafitinib is administered orally once daily at a dose of about 6 mg.

[0150] In certain embodiments, erdafitinib is orally administered once daily at a dose of about 8 mg. In some embodiments, erdafitinib is orally administered once daily at a dose of about 8 mg on a daily schedule. In further embodiments, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily on days 14 to 21 after initiating treatment if (a) the patient exhibits a serum phosphate (PO4) level of less than about 5.5 mg / dL on days 14 to 21 after initiating treatment; and (b) administration of erdafitinib at 8 mg once daily does not cause ocular disorders; or (c) administration of erdafitinib at 8 mg once daily does not cause grade 2 or higher adverse reactions.

[0151] In certain embodiments, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily on the 14th day after starting treatment. In certain embodiments, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily on the 15th day after starting treatment. In certain embodiments, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily on the 16th day after starting treatment. In certain embodiments, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily on the 17th day after starting treatment. In certain embodiments, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily on the 18th day after starting treatment. In certain embodiments, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily on the 19th day after starting treatment. In certain embodiments, the dose of erdafitinib is increased from 8 mg once daily to 9 mg once daily on day 20 after initiating treatment.

[0152] In one embodiment, erdafitinib is administered at a dose of 10 mg. In one embodiment, erdafitinib is administered intermittently at a dose of 10 mg. In one embodiment, erdafitinib is administered at a dose of 10 mg intermittently, 7 days on / 7 days off.

[0153] In one embodiment, erdafitinib is administered at a dose of 8 mg, particularly 8 mg once daily. In one embodiment, erdafitinib is administered at a dose of 8 mg, particularly 8 mg once daily, with the option of increasing the dose to 9 mg depending on the serum phosphate level (e.g., the serum phosphate level is <5.5 mg / dL, or <7 mg / dL, or in the range of 7 mg / dL to ≦9 mg / dL, inclusive, or ≦9 mg / dL) and depending on any treatment-related adverse events observed. In one embodiment, the serum phosphate level used to determine whether to increase the dose is measured on the treatment day during the first cycle of erdafitinib treatment, particularly on day 14±2 of erdafitinib administration, more particularly on day 14.

[0154] In one embodiment, a treatment cycle as used herein is a 28-day cycle.

[0155] In one embodiment, the desired dose is conveniently provided in a single dose or in divided doses administered simultaneously (or closely spaced), or at appropriate intervals, for example, two, three, four or more times per day. In some embodiments, the FGFR inhibitor is conveniently provided in divided doses administered simultaneously (or closely spaced) once daily. In some embodiments, the FGFR inhibitor is conveniently provided in divided doses administered in equal portions twice daily. In some embodiments, the FGFR inhibitor is conveniently provided in divided doses administered in equal portions three times daily. In some embodiments, the FGFR inhibitor is conveniently provided in divided doses administered in equal portions four times daily.

[0156] In certain embodiments, the desired dose may be delivered in 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 sub-units over the course of a day, such that the total amount of FGFR inhibitor delivered by the sub-unit doses over the course of a day provides the total daily dose.

[0157] In some embodiments, the amount of FGFR inhibitor given to a human will vary depending on factors such as, but not limited to, the state and severity of the disease or condition, and the identity of the human (e.g., weight), and the particular additional therapeutic agent (if any) being administered.

[0158] In further embodiments, the patient has received at least one prior therapy for the treatment of urothelial cancer. In some embodiments, the at least one prior therapy for the treatment of urothelial cancer is a platinum-containing chemotherapy. In certain embodiments, the urothelial cancer has progressed during or after at least one line of platinum-containing chemotherapy. In further embodiments, the platinum-containing chemotherapy is neoadjuvant platinum-containing chemotherapy or adjuvant platinum-containing chemotherapy. In further embodiments, the urothelial cancer has progressed within 12 months during or after at least one line of neoadjuvant platinum-containing chemotherapy or adjuvant platinum-containing chemotherapy.

[0159] Kit / manufactured product Kits and articles of manufacture are also described herein for use in the methods of use described herein. Such kits include packaging or containers that are compartmentalized to accommodate one or more doses of the pharmaceutical compositions disclosed herein. Suitable containers include, for example, bottles. In one embodiment, the containers are made of various materials, such as glass or plastic.

[0160] The articles of manufacture provided herein contain packaging materials. Packaging materials used to package pharmaceuticals include, for example, those described in U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for the selected formulation and the intended mode of administration and treatment.

[0161] The kit typically includes a label listing the contents and / or instructions for use, as well as a package insert with instructions for use. A set of instructions will also typically be included.

[0162] In one embodiment, a label is present on or associated with a container. In one embodiment, a label is present on a container when letters, numbers, or other symbols forming the label are affixed, molded, or etched into the container itself, and a label is associated with a container (e.g., as a package insert) when present in a receptacle or carrier that also holds the container.

[0163] In one embodiment, a label is used to indicate that the contents are to be used for a particular therapeutic application. The label also indicates how to use the contents, for example, how to use the methods described herein.

[0164] In certain embodiments, pharmaceutical compositions are provided in a pack or dispenser device containing one or more unit dosage forms containing a compound provided herein. The pack contains, for example, metal or plastic foil, e.g., a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser also has a notice associated with the container in a format specified by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the drug form for human or veterinary administration. Such notice may be, for example, the labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. In one embodiment, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of a designated condition.

[0165] Nucleotide sequence of the FGFR fusion gene The nucleotide sequences for the FGFR fusion cDNAs are provided in Table 5. The underlined sequences correspond to either FGFR3 or FGFR2, the sequences in black represent the fusion partner, and the italicized sequences represent intron sequences of the FGFR3 gene.

[0166] [Table 5]

[0167] [Table 6]

[0168] [Table 7]

[0169] [Table 8]

[0170] [Table 9]

[0171] [Table 10]

[0172] [Table 11]

[0173] [Table 12]

[0174] [Table 13] [Example]

[0175] These examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

[0176] Example 1: Phase 2 Multicenter Open-Label Study (NCT02365597) A phase 2, multicenter, open-label study was conducted to evaluate the efficacy and safety of erdafitinib in subjects with metastatic or surgically unresectable urothelial carcinoma harboring selected FGFR genetic alterations (FGFR translocations or mutations).

[0177] This study will include a screening phase (molecular screening at any time before the first dose and study screening within 30 days of the first dose), a treatment phase, and a post-treatment follow-up phase. The treatment phase will span the period from the first dose to the end-of-treatment visit. The follow-up phase will extend until the subject dies, withdraws consent, is lost to follow-up, or the end of the study, whichever occurs first.

[0178] Study treatment was administered in 28-day cycles. Prior to interim analysis 1, there were two treatment regimens. Patients were randomized 1:1 to receive one of two 28-day cycles: regimen 1 (10 mg once daily intermittently (7 days on / 7 days off); regimen 2 (6 mg once daily continuously) until a regimen was selected for further study. Randomization was stratified by performance status (0-1 vs. 2), hemoglobin level (<10 vs. ≥10 g per deciliter), type of FGFR alteration (mutation vs. fusion), prior treatment status (chemoresistant vs. chemotherapy-naïve), and disease distribution (presence or absence of visceral [liver, lung, bone] metastases). Starting dose selection was based on phase 1 efficacy and tolerability.

[0179] Based on the interim analysis and pharmacokinetic-pharmacodynamic modeling of serum phosphate levels, the starting dose was increased to 8 mg per continuous day (regimen 3). Therefore, after the interim analysis, this became a single-arm trial. Dosing was further individualized with pharmacodynamically guided dose escalations to 9 mg per day in patients who did not achieve the target serum phosphate level by Day 14 (in Phase 1, a serum phosphate level of ≥ 5.5 mg per deciliter was associated with improved response rates) if no treatment-related adverse events were observed. Treatment continued until individual disease progression or unacceptable adverse events. Patients with investigator-assessed disease progression could continue erdafitinib at the discretion of the investigator and sponsor. For the Phase 2 study scheme, see Figure 1.

[0180] the purpose Main purpose: To evaluate the response rate (complete response [CR] + partial response [PR]) of selected dose regimens in subjects with metastatic or surgically unresectable urothelial carcinoma harboring specific FGFR genomic alterations. Secondary Objectives To evaluate the response rate of selected dose regimens in chemotherapy-resistant subjects To evaluate progression-free survival (PFS), duration of response, and overall survival of selected dose regimens in all and chemotherapy-resistant subjects To evaluate response rates in biomarker-specific subgroups (translocations vs. mutations) according to selected dosing regimens To evaluate the response rate, PFS, duration of response, and overall survival of other dose regimens tested To evaluate the safety and pharmacokinetics of erdafitinib across all dose regimens

[0181] patient Patients enrolled were adults with measurable urothelial carcinoma according to the Response Evaluation Criteria in Solid Tumors, version 1.1.

[0182] Patients were required to have at least one FGFR2 / FGFR3 mutation or fusion according to focused measurement of RNA from formalin-fixed, paraffin-embedded tumor samples using a custom reverse transcriptase polymerase chain reaction assay.

[0183] Patients had progressed during or after at least one line of prior systemic chemotherapy or within 12 months of receiving neoadjuvant or adjuvant chemotherapy.

[0184] Chemotherapy-naive patients who were cisplatin ineligible according to protocol criteria were admitted. Cisplatin ineligibility was defined as 1) a 24-hour urine count of 60 mL / min / 1.73 m 2 1) glomerular filtration rate less than 0.05; 2) calculated by the Cockcroft-Gault formula; or 3) grade 2 or greater peripheral neuropathy (based on renal dysfunction as defined by Common Terminology Criteria for Adverse Events [CTCAE] version 4.0 (National Cancer Institute. CTCAE v4.0. NCI, NIH, DHHS. May 29, 2009. NIH publication #09-7473:2009).

[0185] An Eastern Cooperative Oncology Group (ECOG) performance status (a 5-point scale with higher numbers reflecting greater disability) of 0 to 2 was required.

[0186] There was no limit on the number of lines of prior therapy.

[0187] Previous immunotherapy (e.g., treatment with immune checkpoint inhibitors) was tolerated.

[0188] Patients were required to have adequate bone marrow, liver, and renal (creatinine clearance ≥ 40 mL / min) function.

[0189] Patients with phosphate levels persistently above the upper limit of normal despite medical therapy, poorly controlled cardiovascular disease, brain metastases, known hepatitis B or C, or known HIV infection were excluded.

[0190] judgement Patients were assessed for efficacy according to RECIST v1.1 using computed tomography or magnetic resonance imaging scans of the chest, abdomen, and pelvis during screening, once every 6 weeks for the first 3 months, once every 12 weeks for the next 9 months, and then once every 4 to 6 months until disease progression. All objective responses required confirmation by additional investigator review within 4 to 6 weeks of the initial assessment. Disease assessments for Regimen 3 were also performed by an independent radiological review committee. Patients were contacted every 12 weeks for survival assessments. Safety was assessed based on clinical laboratory tests, physical examinations, electrocardiograms, and ophthalmologic examinations. Adverse events and abnormalities were assessed by the investigator and classified according to NCI CTCAE v.4.0.

[0191] Evaluation items The primary endpoint of this study was the response rate to the selected regimen (Regimen 3).

[0192] Secondary endpoints include progression-free survival (PFS), duration of response, overall survival, safety, response rate in biomarker-specific subgroups, and pharmacokinetics.

[0193] statistical analysis The study was designed to enroll 180 patients with specified FGFR alterations. At least 88 of these were required for the selected regimen. The primary hypothesis was an objective response rate (ORR) of ≥ 25% for regimen 3. The study had 85% power and a one-sided α of 0.025 to reject the null hypothesis of an ORR of ≤ 25%, since the true response rate was 42%. Responses were assessed by the investigators and an independent radiology review committee. Progression-free survival and overall survival were estimated using the Kaplan-Meier product limit method. Data from patients who were progression-free and alive or had unknown status were censored at the time of the last tumor assessment. The primary efficacy endpoint was analyzed at the primary analysis cutoff.

[0194] result patient A total of 2214 patients were assessed for eligibility. Of the 210 eligible / treated patients, 33 were enrolled in Regimen 1, 78 in Regimen 2, and 99 in Regimen 3, the selected phase 2 dose regimen.

[0195] Among patients treated with Regimen 3, at the cutoff date for the primary analysis, the median follow-up survival was 11.0 months (interquartile range, 0.7 ± 17.4 [95% confidence interval (CI), 9.1–12.2]) after 40 deaths. The median number of monthly cycles received was 5.0 (range, 1–18); the median treatment duration was 5.3 months. In Regimen 3, 41 of 99 patients were escalated to 9 mg of erdafitinib daily; 13 patients continued treatment for at least 4 weeks after progression, as permitted by the protocol.

[0196] Among patients treated with regimen 1 or 2, at the cutoff date for the primary analysis, the median follow-up survival was 22.9 months (interquartile range, 1.7 ± 25.3 ± [95% CI, 20.5 to 24.5]) in the group receiving regimen 1 and 18.5 months (interquartile range, 0.4 ± 21.6 ± [95% CI, 15.0 to 19.4]) in the group receiving regimen 2. The median number of cycles in regimens 1 and 2 was 5.0 (range, 1 to 25) and 4.5 (range, 1 to 22), respectively. The median treatment duration was 4.4 and 3.9 months in regimens 1 and 2, respectively.

[0197] The demographics and baseline disease characteristics of patients in regimens 1-3 are shown in Table 6.

[0198] [Table 14]

[0199] [Table 15]

[0200] Across all regimens, 184 patients received first-line platinum-based chemotherapy, 83 received second-line chemotherapy, and 24 received third-line chemotherapy before study enrollment.Across all regimens, the best ORR by investigator assessment was 35% (33 of 94) for first-line gemcitabine plus cisplatin; 25% (15 of 59) for first-line gemcitabine plus carboplatin; 23% (5 of 22) for first-line methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC); 17% (8 of 46) for second-line docetaxel, vinflunine, or paclitaxel; and 15% (3 of 20) for third-line docetaxel, vinflunine, or paclitaxel.

[0201] Primary endpoint The confirmed ORR (40.4%, 2-sided 95% CI 30.7% to 50.1%) and time to response among patients treated with Regimen 3 are shown in Table 7. Because the lower boundary of the confidence interval was >25%, the primary endpoint was achieved. An additional 39 (39%) patients had stable disease (>36 days) with a disease assessment assessment of ≥1. Two patients did not have a post-baseline disease assessment. The ORR was similar regardless of prior chemotherapy, number of prior lines of treatment, presence of visceral metastases, or baseline characteristics such as age, sex, hemoglobin level, or renal function (Table 7, Figure 2). Seventy-five (77%) of 97 patients with a post-baseline disease assessment of ≥1 had a reduction in the sum of target lesion diameters, and 48 (49%) had a maximum tumor shrinkage between 30% and 100% (Figure 3A). The ORR for regimen 3 by independent radiographic review was 34.3% (95% CI, 25% to 43.7%).

[0202] [Table 16]

[0203] [Table 17]

[0204] Among patients treated with Regimen 3 who had FGFR mutations (n ​​= 74), the ORR was 48.6% (Table 7). An additional 26 patients had stable disease for a median of 3.7 months (range, 0 + / - 13.6 months). Response was not affected by the specific mutation. Among the 25 patients on Regimen 3 who had FGFR fusions, the ORR was 16.0% (Table 7). FGFR3-TACC3 V1 was the most common fusion (n = 11; Table 6); 4 of these patients (36.4%) responded.

[0205] In Regimen 3, 22 patients received immunotherapy prior to study enrollment (Table 6); the confirmed ORR to erdafitinib was 59% among these patients. Exploratory analysis determined that only 1 of these 22 (5%) patients responded to prior immunotherapy by investigator assessment.

[0206] The ORR for regimens 1 and 2 are also shown in Table 7.

[0207] Of the 99 patients treated with Regimen 3, 87 had disease that had progressed during or after at least one prior chemotherapy regimen (chemotherapy-relapsed / refractory disease) and harbored at least one of the following genetic alterations as determined by centrally performed clinical assays: FGFR3 gene mutations (R248C, S249C, G370C, Y373C) or FGFR gene fusions (FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7) (Table 6). Among this population, the median age was 67 years (range: 36-87 years), 79% were male, and 74% were Caucasian. Most patients (92%) had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Three (3%) patients had disease progression after receiving only prior platinum-containing neoadjuvant or adjuvant therapy. 84 (97%) patients had previously received at least one of cisplatin or carboplatin. 56% of patients had previously received a cisplatin-based regimen alone, 29% had previously received a carboplatin-based regimen alone, and 10% had previously received both cisplatin and carboplatin-based regimens. 24% of patients had been treated with prior anti-PD-L1 / PD-1 therapy. 79% of patients had visceral metastases (bone, liver, or lung).

[0208] Among 87 chemotherapy-resistant patients on Regimen 3, the overall response rate as assessed by the investigator was 40.2%; results for this population of patients are shown in Table 8A. Responders included patients who had not responded to previous anti-PD-L1 / PD-1 therapy. ORR by FGFR alterations is shown in Table 9A.

[0209] [Table 18]

[0210] [Table 19]

[0211] Among 87 chemotherapy-relapsed / refractory patients on Regimen 3, the overall response rate as assessed by a blinded independent review committee was 32.2%; results for this population of patients are shown in Table 8B. Responders included patients who had not responded to previous anti-PD-L1 / PD-1 therapy. ORR by FGFR alterations is shown in Table 9B.

[0212] [Table 20]

[0213] [Table 21]

[0214] Overall response, duration of response, progression-free survival, and overall survival according to FGFR alterations / co-alterations in chemotherapy-relapsed / resistant subjects Best overall response, duration of response, progression-free survival, and overall survival separated by FGFR alteration are provided in Tables 10-13.

[0215] [Table 22]

[0216] [Table 23]

[0217] [Table 24]

[0218] [Table 25]

[0219] [Table 26]

[0220] [Table 27]

[0221] [Table 28]

[0222] [Table 29]

[0223] [Table 30]

[0224] [Table 31]

[0225] Secondary endpoints Duration of response among patients receiving Regimen 3 is shown in Table 7; approximately 30% of responses were maintained for >12 months. Among 39 patients with stable disease, 13 (33%) had disease stabilization lasting >6 months (Figure 4). Twenty-one percent of patients remained on treatment at the time of data cutoff.

[0226] The median investigator-assessed progression-free survival in patients receiving Regimen 3 at a median follow-up of 11.2 months is shown in Figure 5A. The progression-free survival rate (95% CI) at 12 months was 19% (11%-29%). The median overall survival at a median follow-up of 11.0 months is shown in Figure 5B. The survival rate at 12 months was 55% (43%-66%).

[0227] Of the 99 patients receiving regimen 3, 34 (34%) continued on subsequent therapy, 25 (25%) received one subsequent line, and 9 (9%) received two subsequent lines. As their first subsequent therapy, 19 (19%) received chemotherapy and 15 (15%) received immunotherapy. No patients had an objective response to their first subsequent chemotherapy; one patient had a partial response to their first subsequent immunotherapy.

[0228] Duration of response for patients treated with regimens 1 and 2 is also shown in Table 7. Progression-free survival and overall survival among patients receiving regimens 1 and 2 are shown in Figures 6A-6B.

[0229] The median (95% CI) investigator-assessed progression-free survival was 4.8 (2.7-5.5) months and 5.3 (4.1-5.5) months among patients receiving regimens 1 and 2, respectively. The 12-month progression-free survival rates (95% CI) for regimens 1 and 2 were 18% (7%-33%) and 11% (5%-19%), respectively. The median overall survival (95% CI) for patients receiving regimens 1 and 2 was 7.5 (6.0-10.7) months and 8.6 (6.5-9.7) months, respectively, with a median follow-up of survival of 22.9 months for regimen 1 and 18.5 months for regimen 2 (Figures 6A-6B). Overall survival rates (95% CI) at 12 months were 31% (16%-48%) and 33% (22%-44%) among patients on regimens 1 and 2, respectively.

[0230] Preventive measures Precautions were taken to minimize the risk of common adverse events associated with FGFR inhibition. A low-phosphate diet (dietary phosphate intake of 600–800 mg per day) was recommended for all patients to reduce the risk of hyperphosphatemia. Application of an alcohol-free emollient moisturizing cream and avoidance of unnecessary exposure to sunlight, soaps, scented products, and hot baths were recommended to reduce the risk of skin effects. Patients were asked to keep their fingers and toes clean and clip their nails to reduce the risk of nail effects.

[0231] Because central serious retinopathy, a retinal disorder reversible upon temporary drug discontinuation, has been reported with kinase inhibitors and FGFR inhibitors, patients were examined at baseline and monitored periodically for this ocular adverse event with in-house Amsler grid testing and ophthalmologic examinations, including fundus examination and optical coherence tomography imaging when available. Additional ophthalmologic examinations were performed if clinically indicated.

[0232] safety All patients in Regimen 3 reported treatment-emergent adverse events (Table 19); 67% were grade 3 or 4. Serious treatment-emergent adverse events were reported in 39 patients (39%) (Table 15). Disease progression was the most common reason for treatment discontinuation in 62 patients (63%). Thirteen patients (13%) discontinued due to treatment-emergent adverse events, including retinal pigment epithelial detachment, hand-foot syndrome, and dry mouth and skin / nail events (n=2 each). Fifty-five patients (56%) required dose reductions; the most common treatment-emergent adverse events leading to dose reductions were stomatitis in 16 patients (16%) and hyperphosphatemia in 9 patients (9%). The safety profile allowed successive dose escalations to 9 mg of erdafitinib per day in 41 patients who did not reach the target serum phosphate of 5.5 mg per deciliter by Day 14 on the 8 mg regimen. Of these 41 patients, 24 (59%) required a dose reduction of ≥1. A similar percentage of patients in the 8 mg per day sequentially escalated to 9 mg per day group reported grade ≥3 treatment-emergent adverse events compared with the overall study population (68% and 66%, respectively). Common treatment-emergent and treatment-related adverse events were similar across all regimens (Tables 16 and 17). One patient died as a result of an adverse event (myocardial infarction considered unrelated to treatment). Treatment-related adverse events of interest or clinical importance and their management are shown in Table 18. 76% of central serious retinopathy events resolved; all unresolved events were grade 1 or 2.

[0233] [Table 32]

[0234] [Table 33]

[0235] Table 34

[0236] Table 35

[0237] Table 36

[0238] Table 37

[0239] Table 38

[0240] Table 39

[0241] Treatment-related adverse events considered to be of interest / clinical importance were hyperphosphatemia, skin effects, nail effects, and eye disorders, including central serous retinopathy (CSR) and other non-CSR ocular events (Table 18). Treatment-related hyperphosphatemia and skin and nail effects were reported in 73%, 49%, and 52%, respectively, of patients treated with erdafitinib 8 mg per day continuously. Most events were mild to moderate. In this group, the most common treatment-related skin effects were dry skin (32%) and hand-foot syndrome (22%), and the most common treatment-related nail effects were nail dystrophy and onycholysis in 16% of patients, respectively. Overall, 63% of patients treated with erdafitinib 8 mg per day continuously and 54% of patients overall experienced some type of eye disorder, whether or not considered treatment-related. Among patients with ocular disorders (n=62), the majority (n=52, 84%) experienced grade 1 or 2 events. Twenty-one patients (21%) who received continuous erdafitinib 8 mg per day had treatment-related CSR (a preferred term that includes chorioretinopathy, retinal detachment, and retinal pigment epithelial detachment); only three of these patients (3%) had grade ≥ 3 events. Most patients with CSR events were able to continue treatment after management with dose interruption or dose reduction. CSR led to discontinuation in three patients; no patients had retinal vein or artery occlusion.

[0242] Adverse Event Management Hyperphosphatemia, the most common treatment-related adverse event (Tables 16, 14, and 16), was managed by dose interruption (23%), dose reduction (9%), and treatment with phosphate binders when medically justified. Elevated phosphate levels typically peaked 6 weeks after erdafitinib initiation and normalized by cycle 5. One patient discontinued treatment due to grade 1 hyperphosphatemia. Dry skin was managed with additional topical ointments such as ammonium lactate, salicylic acid, or zinc oxide cream. Nail involvement was managed with topical nail strengtheners, and in severe cases, antibiotics or silver nitrate were applied.

[0243] Consideration This study met its primary objective, demonstrating antitumor activity compared with currently available treatment options in patients with locally advanced and unresectable / metastatic urothelial carcinoma harboring specific FGFR gene mutations, with 40% confirmed ORR after continuous treatment with erdafitinib at 8 mg per day. Response to erdafitinib was rapid and independent of the number and type of prior therapy, the presence of visceral metastases, or tumor location.

[0244] Importantly, median progression-free and overall survival were 5.5 months (Figure 5A) and 13.8 months (Figure 5B), respectively, including patients with visceral metastases and inadequate renal function who progressed during or after multiple lines of therapy. As permitted by the protocol, 13 patients continued treatment after progression, which was either limited progression of target lesions or the appearance of small new lesions; however, patients were assessed as having ongoing clinical benefit. The safety profile tolerated continuous dosing of 8 mg per day, with dose escalation to 9 mg per day guided by serum phosphate levels. Dose escalation did not increase the severity of adverse events, as the percentage of grade ≥3 events was similar across both groups. Hyperphosphatemia, a known class effect of FGFR inhibitors, was reported in 77% (regimen 3) and was typically manageable and reversible. Ocular events, such as central serous retinopathy, are known class effects of mitogen-activated protein kinase pathway inhibitors. Ocular adverse events were common with erdafitinib treatment, but most were mild to moderate and resolved with dose interruption or reduction.

[0245] Patients with FGFR mutations or fusions may be less likely to respond to immunotherapy. In our study, only 1 of 22 (5%) patients responded to previous immunotherapy, and 59% of these patients responded to erdafitinib after immunotherapy failure. This observation was also observed in the rogaratinib study, where 9 of 10 patients (90%) had disease progression on previous immunotherapy, and 30% responded to rogaratinib.

[0246] These results demonstrate that the pan-FGFR inhibitor erdafitinib had measurable benefit in patients with advanced urothelial carcinoma harboring FGFR alterations.

[0247] Example 2: Pharmacodynamics and Pharmacokinetics Pharmacodynamics Cardiac Electrophysiology Erdafitinib did not have a significant effect on the QTc interval (ie, >20 ms), also based on evaluation of the QTc interval in an open-label dose-escalation and dose-expansion study in 187 patients with cancer.

[0248] Serum phosphate Erdafitinib increases serum phosphate levels as a result of FGFR inhibition. Erdafitinib should be increased to the highest recommended dose in early cycles with daily dosing to achieve a target serum phosphate level of 5.5–7.0 mg / dL.

[0249] In clinical trials of erdafitinib, the use of medications that can increase serum phosphate levels, such as potassium phosphate supplements, vitamin D supplements, antacids, phosphate-containing enemas or laxatives, and drugs known to have phosphate as an excipient, was prohibited unless alternatives existed. Phosphate binders were permitted to manage elevated phosphate. Avoid concomitant use of medications that may alter serum phosphate levels prior to the initial dose escalation period based on serum phosphate levels.

[0250] Pharmacokinetics After administration of 8 mg once daily, the mean steady-state maximum plasma concentration (Cmax), area under the curve (AUCtau), and minimum plasma concentration (Cmin) of erdafitinib (coefficient of variation [CV%]) were 1399 ng / mL (51%), 29268 ng·h / mL (60%), and 936 ng / mL (65%), respectively.

[0251] After single and repeated daily administration, erdafitinib exposure (maximum plasma concentration [Cmax] and area under the plasma concentration-time curve [AUC]) increased proportionally over the dose range of 0.5 to 12 mg (0.06 to 1.3 times the maximum approved recommended dose). Steady state was achieved after 2 weeks of once-daily dosing, with a mean accumulation rate of 4-fold.

[0252] absorption The median time to reach peak plasma concentration (tmax) was 2.5 hours (range: 2-6 hours).

[0253] The effects of diet No clinically relevant differences in the pharmacokinetics of erdafitinib were observed following administration of a high-fat and high-calorie meal (800 to 1,000 calories, with approximately 50% of the total caloric content of the meal coming from fat) in healthy subjects.

[0254] distribution The mean apparent volume of distribution of erdafitinib in patients was 29 L. Protein binding of erdafitinib was 99.8% in patients, primarily to alpha-1-acid glycoprotein.

[0255] Disappearance The mean total apparent clearance (CL / F) of erdafitinib was 0.362 L / h in patients.

[0256] The mean effective half-life of erdafitinib was 59 hours in patients.

[0257] metabolism Erdafitinib is primarily metabolized by CYP2C9 and CYP3A4. The contributions of CYP2C9 and CYP3A4 to the total clearance of erdafitinib are estimated to be 39% and 20%, respectively. Unchanged erdafitinib was the major drug-associated moiety in plasma, and there were no metabolites in the circulating blood.

[0258] discharge After a single oral dose of radiolabeled erdafitinib, approximately 69% of the dose was recovered in the feces (19% unchanged) and 19% in the urine (13% unchanged).

[0259] Specific populations Clinically meaningful trends in the pharmacokinetics of erdafitinib were observed across age (21-88 years), sex, race, weight (36-132 kg), and mild to moderate (eGFR [estimated glomerular filtration rate, using the Modification of Diet in Renal Disease formula] 60-89 mL / min / 1.73 m 2 ) or moderate (eGRR 30-59 mL / min / 1.73 m 2 ) Renal impairment or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1.0 to 1.5 × ULN and any AST) was not observed.

[0260] The pharmacokinetics of erdafitinib in patients with severe renal impairment, renal impairment requiring dialysis, or moderate or severe hepatic impairment are unknown.

[0261] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes will be suggested to one skilled in the art and are to be included within the spirit and scope of this application and the appended claims. The following aspects may be included. [1] A method of treating urothelial carcinoma in a patient, comprising: (a) evaluating a biological sample from said patient for the presence of at least two FGFR genetic alterations, (i) two or more of the at least two FGFR gene alterations are FGFR2 fusions; (ii) one or more of the at least two FGFR genetic alterations is an FGFR2 fusion and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion; (iii) two or more of the at least two FGFR gene alterations are FGFR3 mutations; (iv) one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR2 fusion; or (v) assessing that one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion; and (b) treating said patient with an FGFR inhibitor if said at least two FGFR genetic alterations are present in said sample. A method comprising: [2] A method of treating urothelial carcinoma in a patient with at least two FGFR genetic alterations, comprising administering to the patient an FGFR inhibitor; (a) two or more of the at least two FGFR gene alterations are FGFR2 fusions; (b) one or more of the at least two FGFR genetic alterations is an FGFR2 fusion and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion; (c) two or more of the at least two FGFR gene alterations are FGFR3 mutations; (d) one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR2 fusion; or (e) The method, wherein one or more of the at least two FGFR genetic alterations is an FGFR3 mutation, and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion. [3] The method according to [2] above, further comprising evaluating a biological sample from the patient for the presence of the at least two FGFR gene alterations prior to administration of the FGFR inhibitor. [4] The method according to [1] or [2] above, wherein two or more of the at least two FGFR gene alterations are FGFR2 fusions. [5] The method according to [4] above, wherein the two or more FGFR gene alterations include FGFR2-BICC1 and FGFR2-CASP7. [6] The method according to [1] or [2] above, wherein one or more of the at least two FGFR gene alterations is an FGFR2 fusion, and one or more of the at least two FGFR gene alterations is an FGFR3 fusion. [7] The method according to [6] above, wherein the two or more FGFR gene alterations include FGFR2-CASP7 and FGFR3-BAIAP2L1; FGFR2-CASP7 and FGFR3-TACC3 V1; or FGFR2-CASP7 and FGFR3-TACC3 V3. [8] The method according to [1] or [2] above, wherein two or more of the at least two FGFR gene alterations are FGFR3 mutations. [9] The method according to [8] above, wherein the two or more FGFR gene alterations include FGFR3 G370C and FGFR3 S249C; FGFR3 R248C and FGFR3 Y373C; or FGFR3 S249C and FGFR3 Y373C.

[10] The method according to [1] or [2] above, wherein one or more of the at least two FGFR gene alterations is an FGFR3 mutation, and one or more of the at least two FGFR gene alterations is an FGFR2 fusion.

[11] The method according to

[10] above, wherein the two or more FGFR gene alterations include FGFR3 G370C / FGFR2-BICC1; or FGFR3 S249C, FGFR3 Y373C, FGFR2-CASP7, FGFR3-BAIAP2L1, FGFR3-TACC3 V1, and FGFR3_TACC3 V3.

[12] The method according to [1] or [2] above, wherein one or more of the at least two FGFR gene alterations is an FGFR3 mutation, and one or more of the at least two FGFR gene alterations is an FGFR3 fusion.

[13] The method according to

[12] above, wherein the two or more FGFR gene alterations include FGFR3 G370C and FGFR3-TACC3 V1; FGFR3 R248C and FGFR3-TACC3 V1; FGFR3 S249C and FGFR3-BAIAP2L1; FGFR3 R248C, FGFR3 S249, and FGFR3-TACC3 V1; or FGFR3 S249C, FGFR3 Y373C, FGFR2-CASP7, FGFR3-BAIAP2L1, FGFR3-TACC3 V1, and FGFR3-TACC3 V3.

[14] The method according to any one of [1] to

[13] above, wherein the urothelial cancer is locally advanced or metastatic.

[15] The method according to [1] or [3] above, wherein the biological sample is a blood, lymph, bone marrow, solid tumor sample, or any combination thereof.

[16] The method according to any one of [1] to

[15] above, wherein the FGFR inhibitor is erdafitinib.

[17] The method according to

[16] above, wherein erdafitinib is administered daily.

[18] The method according to

[16] or

[17] above, wherein erdafitinib is administered orally.

[19] The method according to any one of

[16] to

[18] above, wherein erdafitinib is orally administered on a daily administration schedule.

[20] The method according to any one of

[16] to

[19] above, wherein erdafitinib is orally administered at a dose of about 8 mg once a day.

[21] The dose of erdafitinib is (a) the patient has a serum phosphate (PO ) of less than about 5.5 mg / dL between 14 and 21 days after initiating treatment; 4 ) level; and (b) administration of erdafitinib at 8 mg once daily did not cause ocular disorders; or (c) Administration of erdafitinib at 8 mg once daily did not cause grade 2 or higher adverse reactions. The method according to

[20] above, wherein the dose is increased from 8 mg once daily to 9 mg once daily on days 14 to 21 after initiating treatment.

[22] The method according to any one of

[16] to

[21] above, wherein erdafitinib is in a solid dosage form.

[23] The method according to

[22] above, wherein the solid dosage form is a tablet.

[24] An FGFR inhibitor for use in the treatment of urothelial carcinoma, comprising: (a) evaluating a biological sample from said patient for the presence of at least two FGFR genetic alterations, (i) two or more of the at least two FGFR gene alterations are FGFR2 fusions; (ii) one or more of the at least two FGFR genetic alterations is an FGFR2 fusion and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion; (iii) two or more of the at least two FGFR gene alterations are FGFR3 mutations; (iv) one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR2 fusion; or (v) assessing that one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion; and (b) administering an FGFR inhibitor to said patient if said at least two FGFR gene alterations are present in said sample.

[25] An FGFR inhibitor for use in treating urothelial carcinoma in a patient with at least two FGFR genetic alterations, wherein the treatment comprises administering an FGFR inhibitor to the patient; (a) two or more of the at least two FGFR gene alterations are FGFR2 fusions; (b) one or more of the at least two FGFR genetic alterations is an FGFR2 fusion and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion; (c) two or more of the at least two FGFR gene alterations are FGFR3 mutations; (d) one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR2 fusion; or (e) An FGFR inhibitor, wherein one or more of the at least two FGFR genetic alterations is an FGFR3 mutation, and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion.

[26] The FGFR inhibitor for use according to

[24] or

[25] above, wherein the at least two FGFR gene alterations include FGFR3 G370C and FGFR3 S249C; or FGFR3 R248C and FGFR3 Y373C.

[27] The FGFR inhibitor for use according to

[24] or

[25] above, wherein the at least two FGFR gene alterations include FGFR3 G370C and FGFR2-BICC1; FGFR3 G370C and FGFR3-TACC3 V1; FGFR3 R248C and FGFR3-TACC3 V1; or FGFR3 R248C, FGFR3 S249, and FGFR3-TACC3 V1.

[28] Use of an FGFR inhibitor in the manufacture of a medicament for the treatment of urothelial carcinoma, wherein the treatment comprises: (a) evaluating a biological sample from said patient for the presence of at least two FGFR genetic alterations, (i) two or more of the at least two FGFR gene alterations are FGFR2 fusions; (ii) one or more of the at least two FGFR genetic alterations is an FGFR2 fusion and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion; (iii) two or more of the at least two FGFR gene alterations are FGFR3 mutations; (iv) one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR2 fusion; or (v) assessing that one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion; and (b) administering an FGFR inhibitor to said patient if said at least two FGFR genetic alterations are present in said sample. Use including.

[29] Use of an FGFR inhibitor in the manufacture of a medicament for treating urothelial carcinoma in a patient with at least two FGFR gene alterations, wherein the treatment comprises administering an FGFR inhibitor to the patient; (a) two or more of the at least two FGFR gene alterations are FGFR2 fusions; (b) one or more of the at least two FGFR genetic alterations is an FGFR2 fusion and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion; (c) two or more of the at least two FGFR gene alterations are FGFR3 mutations; (d) one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR2 fusion; or (e) The use, wherein one or more of the at least two FGFR genetic alterations is an FGFR3 mutation, and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion.

[30] Use of an FGFR inhibitor according to

[28] or

[29] above, wherein the at least two FGFR gene alterations include FGFR3 G370C and FGFR3 S249C; or FGFR3 R248C and FGFR3 Y373C.

[31] Use of an FGFR inhibitor according to

[28] or

[29] above, wherein the at least two FGFR gene alterations include FGFR3 G370C and FGFR2-BICC1; FGFR3 G370C and FGFR3-TACC3 V1; FGFR3 R248C and FGFR3-TACC3 V1; or FGFR3 R248C, FGFR3 S249, and FGFR3-TACC3 V1.

Claims

1. 1. A pharmaceutical composition for use in a method of treating urothelial carcinoma in a patient, comprising: The pharmaceutical composition comprises erdafitinib or a pharmaceutically acceptable salt thereof, The method comprises: (a) evaluating a biological sample from said patient for the presence of at least two FGFR gene alterations, (i) one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR2 fusion; or (ii) assessing that one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion; and (b) if said at least two FGFR gene alterations are present in said sample, treating said patient with erdafitinib or a pharmaceutically acceptable salt thereof. Including, The pharmaceutical composition, wherein the FGFR3 mutation comprises FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, or FGFR3 Y373C; the FGFR2 fusion comprises FGFR2-BICC1 or FGFR2-CASP7; and the FGFR3 fusion comprises FGFR3-TACC3.

2. 1. A pharmaceutical composition for use in a method for treating urothelial carcinoma in a patient with at least two FGFR gene alterations, comprising: The pharmaceutical composition comprises erdafitinib or a pharmaceutically acceptable salt thereof, The method comprises administering erdafitinib or a pharmaceutically acceptable salt thereof to the patient; (a) one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR2 fusion; or (b) one or more of the at least two FGFR genetic alterations is an FGFR3 mutation, and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion; The pharmaceutical composition, wherein the FGFR3 mutation comprises FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, or FGFR3 Y373C; the FGFR2 fusion comprises FGFR2-BICC1 or FGFR2-CASP7; and the FGFR3 fusion comprises FGFR3-TACC3.

3. 3. The pharmaceutical composition of claim 2, wherein the method further comprises evaluating a biological sample from the patient for the presence of the at least two FGFR gene alterations prior to administration of erdafitinib or a pharmaceutically acceptable salt thereof.

4. 3. The pharmaceutical composition of claim 1, wherein one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR2 fusion.

5. 5. The pharmaceutical composition of claim 4, wherein the two or more FGFR gene alterations include FGFR3 G370C / FGFR2-BICC1; or FGFR3 S249C, FGFR3 Y373C, FGFR2-CASP7, FGFR3-BAIAP2L1, FGFR3-TACC3 V1, and FGFR3_TACC3 V3.

6. 3. The pharmaceutical composition of claim 1, wherein one or more of the at least two FGFR genetic alterations is an FGFR3 mutation, and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion.

7. 7. The pharmaceutical composition of claim 6, wherein the two or more FGFR gene alterations comprise FGFR3 G370C and FGFR3-TACC3 V1; FGFR3 R248C and FGFR3-TACC3 V1; FGFR3 R248C, FGFR3 S249, and FGFR3-TACC3 V1; or FGFR3 S249C, FGFR3 Y373C, FGFR2-CASP7, FGFR3-BAIAP2L1, FGFR3-TACC3 V1, and FGFR3-TACC3 V3.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the urothelial cancer is locally advanced or metastatic.

9. 4. The pharmaceutical composition of claim 1 or 3, wherein the biological sample is blood, lymph, bone marrow, a solid tumor sample, or any combination thereof.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the erdafitinib or a pharmaceutically acceptable salt thereof is erdafitinib.

11. The pharmaceutical composition of claim 10, wherein erdafitinib is administered daily.

12. The pharmaceutical composition of claim 10 or 11, wherein erdafitinib is administered orally.

13. The pharmaceutical composition of any one of claims 10 to 12, wherein erdafitinib is administered orally on a daily dosing schedule.

14. The pharmaceutical composition of any one of claims 10 to 13, wherein erdafitinib is orally administered at a dose of about 8 mg once daily.

15. The dose of erdafitinib is (a) the patient has a serum phosphate (PO) of less than about 5.5 mg / dL between 14 and 21 days after initiating treatment; ４ ) level; and (b) administration of erdafitinib at 8 mg once daily did not cause ocular disorders; or (c) administration of erdafitinib at 8 mg once daily did not cause Grade 2 or higher adverse reactions; 15. The pharmaceutical composition of claim 14, wherein the dose is increased from 8 mg once daily to 9 mg once daily from 14 to 21 days after initiating treatment.

16. The pharmaceutical composition of any one of claims 10 to 15, wherein erdafitinib is in a solid dosage form.

17. 17. The pharmaceutical composition of claim 16, wherein the solid dosage form is a tablet.

18. A pharmaceutical composition for use in treating urothelial carcinoma in a patient, comprising: The pharmaceutical composition comprises erdafitinib or a pharmaceutically acceptable salt thereof, wherein the treatment (a) evaluating a biological sample from said patient for the presence of at least two FGFR gene alterations, (i) one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR2 fusion; or (ii) assessing that one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion; and (b) administering erdafitinib or a pharmaceutically acceptable salt thereof to the patient if the at least two FGFR genetic alterations are present in the sample; The pharmaceutical composition, wherein the FGFR3 mutation comprises FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, or FGFR3 Y373C; the FGFR2 fusion comprises FGFR2-BICC1 or FGFR2-CASP7; and the FGFR3 fusion comprises FGFR3-TACC3.

19. 1. A pharmaceutical composition for use in the treatment of urothelial carcinoma in patients with at least two FGFR gene alterations, comprising: The pharmaceutical composition comprises erdafitinib or a pharmaceutically acceptable salt thereof, the treatment comprises administering erdafitinib or a pharmaceutically acceptable salt thereof to the patient; (a) one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR2 fusion; or (b) one or more of the at least two FGFR genetic alterations is an FGFR3 mutation, and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion; The pharmaceutical composition, wherein the FGFR3 mutation comprises FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, or FGFR3 Y373C; the FGFR2 fusion comprises FGFR2-BICC1 or FGFR2-CASP7; and the FGFR3 fusion comprises FGFR3-TACC3.

20. 20. The pharmaceutical composition of claim 18 or 19, wherein the at least two FGFR gene alterations comprise: FGFR3 G370C and FGFR2-BICC1; FGFR3 G370C and FGFR3-TACC3 V1; FGFR3 R248C and FGFR3-TACC3 V1; or FGFR3 R248C, FGFR3 S249, and FGFR3-TACC3 V1.

21. The pharmaceutical composition according to any one of claims 18 to 20, wherein the erdafitinib or a pharmaceutically acceptable salt thereof is erdafitinib.

22. The pharmaceutical composition according to any one of claims 18 to 21, wherein the urothelial cancer is locally advanced or metastatic.

23. Use of erdafitinib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of urothelial carcinoma in a patient, said treatment comprising: (a) evaluating a biological sample from said patient for the presence of at least two FGFR gene alterations, (i) one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR2 fusion; or (ii) assessing that one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion; and (b) administering erdafitinib or a pharmaceutically acceptable salt thereof to said patient if said at least two FGFR gene alterations are present in said sample. Including, The FGFR3 mutation comprises FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, or FGFR3 Y373C; the FGFR2 fusion comprises FGFR2-BICC1 or FGFR2-CASP7; and the FGFR3 fusion comprises FGFR3-TACC3.

24. 1. Use of erdafitinib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of urothelial carcinoma in a patient with at least two FGFR gene alterations, wherein said treatment comprises administering erdafitinib or a pharmaceutically acceptable salt thereof to said patient; (a) one or more of the at least two FGFR genetic alterations is an FGFR3 mutation and one or more of the at least two FGFR genetic alterations is an FGFR2 fusion; or (b) one or more of the at least two FGFR genetic alterations is an FGFR3 mutation, and one or more of the at least two FGFR genetic alterations is an FGFR3 fusion; The FGFR3 mutation comprises FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, or FGFR3 Y373C; the FGFR2 fusion comprises FGFR2-BICC1 or FGFR2-CASP7; and the FGFR3 fusion comprises FGFR3-TACC3.

25. The use of erdafitinib or a pharmaceutically acceptable salt thereof according to claim 23 or 24, wherein the at least two FGFR gene alterations comprise FGFR3 G370C and FGFR2-BICC1; FGFR3 G370C and FGFR3-TACC3 V1; FGFR3 R248C and FGFR3-TACC3 V1; or FGFR3 R248C, FGFR3 S249, and FGFR3-TACC3 V1.

26. The use of erdafitinib or a pharmaceutically acceptable salt thereof according to any one of claims 23 to 25, wherein the erdafitinib or a pharmaceutically acceptable salt thereof is erdafitinib.

27. The use of erdafitinib or a pharmaceutically acceptable salt thereof according to any one of claims 23 to 26, wherein the urothelial cancer is locally advanced or metastatic.

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