Treatment of locally advanced or metastatic urothelial carcinoma with erdafitinib

Abstract

The present invention relates to the treatment of locally advanced or metastatic urothelial carcinoma with erdafitinib in patients with FGFR-changing urothelial carcinoma (mUC) that has progressed during or after one or more prior treatments including checkpoint inhibitors, particularly anti-PD-(L)1 agents.

Description

Technical Field

[0001] The present invention relates, inter alia, to the treatment of locally advanced urothelial cancer or metastatic urothelial cancer with erdafitinib in patients with FGFR-altered urothelial cancer (mUC) that has progressed during or after one or more prior treatments, including checkpoint inhibitors, particularly anti-PD-(L)1 agents.

Background Art

[0002] For patients with metastatic urothelial cancer, or mUC, first-line systemic therapy includes platinum-based chemotherapy with or without maintenance avelumab for platinum-eligible populations. Platinum-ineligible patients may receive anti-PD-1 or anti-PD-L1 therapy if approved, or, if approved, a combination of pembrolizumab and enfortumab vedotin. Second-line systemic therapy includes checkpoint inhibitors for the checkpoint inhibitor-naive population. In patients who have previously received checkpoint inhibitor therapy, second-line systemic therapy includes single-agent chemotherapy (taxanes, vinflunine), or, if approved, enfortumab vedotin, sacituzumab govitecan, and erdafitinib.

[0003] Thus, checkpoint inhibitors are used in both first-line and second-line settings for the treatment of mUC, but only approximately 30% of patients with mUC respond to immune checkpoint inhibitor therapy. Treatment options after progression on checkpoint inhibitors are limited. In the actual situation, only approximately 30% of patients receive subsequent anti-cancer treatment after interruption of checkpoint inhibitors. There is a clearly unmet need to expand treatment options for patients after anti-PD-1 therapy or anti-PD-L1 therapy.

[0004] WO2011 / 135376 describes quinoxaline derivative compounds for the treatment of cancer.

[0005] WO2016 / 161239 describes FGFR / PD-1 combination therapy for cancer treatment.

[0006] WO2018 / 141921 describes the treatment of cancer with erdafitinib.

[0007] WO2021 / 058798 describes the use of FGFR inhibitors in FGFR gene-modified cancers to enhance the patient response to immune checkpoint inhibitors in a sequential treatment setting.

[0008] (Disclosure of the invention) This application is written in several sections for readability. However, this does not mean that each section should be read in isolation. On the contrary, unless otherwise specified, each section should be read in cross-referencing with the other sections, that is, the entire application should be interpreted as a whole. Unless explicitly stated, no artificial separation of embodiments is intended.

[0009] Accordingly, all embodiments described herein with respect to one aspect of the present invention are equally applicable to, i.e., disclosed with respect to / in combination with respect to other aspects described herein.

[0010] Specific terms The transitional phrases “comprising,” “consisting essentially of,” and “consisting” are intended to imply the meanings generally accepted in patent terminology. Specifically, (i) “comprising” is synonymous with “including,” “containing,” or “characterizing,” and is comprehensive or non-restrictive, not excluding other unlisted elements or process steps; (ii) “consisting” excludes any elements, processes, or components not specified in the claims or embodiments; and (iii) “consisting essentially of” limits the scope of the claims or embodiments to specified materials or processes, and “not substantially affecting the basic and novel features” of the claimed invention or embodiment. More specifically, the basic and novel features relate to the ability of the Method to provide at least one of the benefits described herein, including, but not limited to, the ability to improve the survivability of a human population compared to the survivability of a comparative human population, as described elsewhere in this Spec. Embodiments described in the term "comprising" (or its equivalent) also provide embodiments that are independently described in the terms "consisting of" and "essentially consisting of."

[0011] When a value is expressed as an approximation by the use of the descriptive term “approximately,” it is understood that the particular value may form another embodiment. Unless otherwise specified, the term “approximately” means a variation of ±10% of the value in question, but further embodiments include those where the variation may be ±5%, ±15%, ±20%, ±25%, or ±50%, and more specifically, the term “approximately” means a variation of ±5% or ±10% of the value in question, more specifically ±5%.

[0012] Where a list is presented, please understand that, unless otherwise stated, each individual element of that list and all combinations of that list are distinct embodiments. For example, a list of embodiments presented as "A, B, or C" should be interpreted as including embodiments "A", "B", "C", "A or B", "A or C", "B or C", or "A, B, or C".

[0013] As used herein, the singular forms "a," "an," and "the" are to be interpreted as including the plural form.

[0014] The following abbreviations will be used throughout this disclosure: FGFR (fibroblast growth factor receptor); FGFR3-TACC3 V1 (a fusion of the gene encoding FGFR3 and the gene encoding transformed acid-coiled-coil-containing protein 3 variant 1); FGFR3-TACC3 V3 (a fusion of the gene encoding FGFR3 and the gene encoding transformed acid-coiled-coil-containing protein 3 variant 3); FGFR3-BAIAP2L1 (a fusion of the gene encoding FGFR3 and the gene encoding brain-specific angiogenesis inhibitor 1-related protein 2-like protein 1); FGFR2-BICC1 (a fusion of the gene encoding FGFR2 and the gene encoding twin-tailed C homolog 1); FGFR2-CASP7 (a fusion of the gene encoding FGFR2 and the gene encoding caspase 7).

[0015] As used herein, “patient” means any animal, specifically a mammal. Therefore, the method and its use are applicable to humans and non-human animals, but are most preferably applicable to humans. The terms “patient,” “subject,” “human,” and “subject requiring treatment” may be used interchangeably. “Adult patient” means a patient aged 18 years or older. In preferred embodiments, the subject or patient requiring treatment is the human subject or human patient requiring treatment. It will be understood by those skilled in the art that “patient” may also mean a population of patients. Those skilled in the art will understand that, for example, when referring to median endpoints such as median overall survival or median progression-free survival, “patient” means a population of patients.

[0016] The terms "to treat" and "treatment" refer to the treatment of a patient affected by a disease, encompassing not only the action of alleviating the disease by killing cancer cells, but also the action of inhibiting the progression of the disease, including a decrease in the rate of progression, a cessation of the rate of progression, remission of the disease, and a cure of the disease. Treatment as a preventive measure (i.e., preventive measures) is also included. In one embodiment, treatment does not include preventive measures.

[0017] The "therapeutic dose" refers to the effective amount required to obtain the desired therapeutic outcome in the necessary dosage and duration. The therapeutic dose may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the drug or combination of drugs to induce the desired response in the individual. An example of an effective drug or combination of drugs is, for example, the patient's improved health.

[0018] The term "gradually increasing the dose" means increasing the dose.

[0019] "Dosage" refers to information regarding the amount of medication administered to a patient and the frequency of administration of that medication.

[0020] The term "dosage" refers to the amount or quantity of medication taken each time.

[0021] As used herein, the term "cancer" refers to the abnormal proliferation of cells that tend to grow uncontrollably and, in some cases, tend to invade (spread).

[0022] The term "continuous daily dosing schedule" refers to the administration of a particular drug without any rest days for that drug. In some embodiments, a continuous daily dosing schedule for a particular drug includes administering the drug daily at approximately the same time each day.

[0023] The term "objective response rate" (ORR) is defined as the percentage of patients who achieve a complete or partial response, as assessed by the principal investigator in accordance with RECIST V1.1.

[0024] The term "definitive objective response rate as assessed by the principal investigator" is defined as the ORR assessment by the principal investigator in two or more consecutive instances.

[0025] The term "disease control rate" (DCR) is defined as the percentage of participants who achieved SD and confirmed CR and PR, as well as those who did not.

[0026] The term "adverse event" refers to any undesirable medical event that occurs in a subject administered with the study drug, and does not necessarily refer only to events that have a clear causal relationship with the study drug in question.

[0027] The term "complete response" (CR) is defined in the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as the disappearance of all target lesions, the absence of residual tissue, and the absence of surviving tumors on histopathological examination.

[0028] The term "partial response" (PR) is defined in RECIST Version 1.1 as a reduction of at least 30% in the sum of diameters of the target lesions, relative to the baseline sum of diameters.

[0029] The term "stable disease" (SD) is defined in RECIST Version 1.1 as follows: based on the minimum sum of diameters during the trial, there is neither sufficient contraction to qualify for partial reduction (PR) nor sufficient increase to qualify for progressive reduction (PD).

[0030] The term "progressive disease" (PD) is defined in RECIST Version 1.1 as an increase of at least 20% in the sum of diameters of target lesions, relative to the minimum sum of diameters during the trial (which includes the baseline sum, if it is the minimum during the trial). In addition to a relative 20% increase, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

[0031] The term "Time to Response" (TTR) is defined as the time from the date of randomization to the date of the first documented response (CR or PR).

[0032] The term "overall survival" (OS) is defined as the time from the date of randomization to the date of death of the subject. If the subject is alive or their life status is unknown, the OS is calculated from the date the subject's survival was last confirmed.

[0033] The term "progression-free survival" (PFS) is defined as the number of days from the date of randomization to the date on which the first reported disease progression (assessed by the principal investigator in accordance with RECIST V1.1) or relapse from complete response (CR) or death occurs. For subjects who are alive and have not experienced disease progression, and for subjects with unknown disease progression or unknown survival status at the clinical cutoff date, PFS is censored on the date of the last appropriate disease assessment. If there is no post-baseline tumor assessment for a subject, PFS is censored on the date of randomization. An appropriate disease assessment is defined as one that has sufficient evidence to accurately indicate whether or not progression has occurred.

[0034] The term "DOR" (Duration of Response) is defined for responders as the period of days from the date of initial documentation of response to the date of first documented evidence of progressive disease (or relapse for subjects experiencing a complete response during the study) or death. Censorship is the same as for PFS.

[0035] The term "safety" refers to the collection of adverse events, clinical laboratory values, electrocardiograms, vital signs, ophthalmological assessments, and physical examination data.

[0036] Patient-reported changes from baseline in health status, and physical function scales such as Functional Assessment of Cancer Therapy-Bladder Cancer (FACT-Bl), Time Until Symptom Deterioration (a subset of FACT-Bl items), Patient-Global Impression of Severity (PGIS), as well as the usefulness and visual analog scales of the European Quality of Life-5 Dimensions-5 Levels Questionnaire (EQ-5D-5L).

[0037] When referring to clinical trials, the term "randomization" refers to the point in time when a patient is confirmed to be eligible for the trial and assigned to a treatment group.

[0038] The term "NCI CTCAE" refers to the National Cancer Institute Common Terminology Criteria for Adverse Events.

[0039] The terms "kit" and "manufactured item" are used synonymously.

[0040] The term "biological sample" refers to any patient-derived sample from which cancer 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 may be formalin-fixed paraffin-embedded tissue (FFPET).

[0041] The term "anti-programmed cell death (ligand) 1 agent (anti-PD-(L)1 agent)" refers to an anti-PD-1 antibody that, for example, specifically binds to PD-1, thereby blocking the interaction between PD-1 and PD-L1 and suppressing at least one biological activity mediated by the PD-1 ligand PD-L1 or PD-L2. An anti-PD-1 antibody is an antagonist if at least one biological activity mediated by PD-L1 or PD-L2 is suppressed by at least approximately 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more than in the absence of an antagonist (e.g., negative control), or if the suppression is statistically significant compared to the suppression in the absence of an antagonist. The typical biological activity mediated by the binding of PD-L1 or PD-L2 to PD-1 is the inhibition of antigen-specific CD4+ and / or CD8+ T cells. Therefore, antagonist antibodies reduce PD-L1-mediated suppression, leading to an enhanced immune response.

[0042] As used herein, “interaction blocking” refers to the ability of an anti-PD-1 antibody to inhibit or reduce the binding of PD-L1 to PD-1 such that PD-1-mediated signaling / function is disabled or attenuated.

[0043] The terms "specifically bind," "specifically bind," or "bind" refer to an antibody binding to an antigen (e.g., PD-1) or an epitope within an antigen with a higher affinity than it does to other antigens. Typically, an antibody binds to approximately 1 × 10⁻¹⁶ antibodies. -8 Less than M, for example, approximately 1 × 10 -9 M or less, approximately 1×10 -10 M or less, approximately 1×10 -11 M or less, or approximately 1 × 10 -12 Antibodies bind to an antigen or an epitope within an antigen with an equilibrium dissociation constant (KD) of M or less, and typically, the KD is at least 1 / 100th smaller than the KD for binding to nonspecific antigens (e.g., BSA, casein). The KD can be measured using standard procedures. However, antibodies that specifically bind to an antigen or an epitope within that antigen may exhibit cross-reactivity to the same antigen (homolog) from other related antigens, such as humans or monkeys, e.g., Macaca fascicularis (cynomolgus monkey, cyno), Pan troglodytes (chimpanzee, chimp), or Callisrix jacchus (common marmoset, marmoset).

[0044] The term "PD-1" refers to human programmed cell death protein 1, PD-1. PD-1 is also known as CD279 or PDCD1. The amino acid sequence (without signal sequence) of mature human PD-1 is shown in SEQ ID NO: 1. The extracellular domain is located at residues 1-150 of SEQ ID NO: 1, the transmembrane domain is located at residues 151-171 of SEQ ID NO: 1, and the cytoplasmic domain is located at residues 172-268 of SEQ ID NO: 1 (Table 1A).

[0045] As used herein, the “intended treatment” or “ITT” population refers to all randomized subjects in a given cohort.

[0046] [Table 1]

[0047] The term "antibody" has a broad meaning and includes immunoglobulin molecules belonging to any class, IgA, IgD, IgE, IgG, and IgM, or subclasses IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4, and containing either a kappa (κ) light chain or a lambda (λ) light chain. Antibodies include monoclonal antibodies, full-length antibodies, antigen-binding fragments, bispecific or multispecific antibodies, dimers, tetramers, or multimers, single-chain antibodies, domain antibodies, and any other modified configurations of immunoglobulin molecules, including antigen-binding fragments of the required specificity. A "full-length antibody" consists of two heavy chains (HC) and two light chains (LC) interconnected by disulfide bonds. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (composed of domains CH1, hinge, CH2, and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL may be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), which are interspersed with framework regions (FRs). Each VH and VL consists of three CDR segments and four FR segments arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Antibodies include antibodies produced using various techniques, including antibodies generated from immunized mice or rats, or antibodies identified from phage or mammalian display libraries described herein.

[0048] The "complementarity-determining region (CDR)" is the region of the antibody that binds to the antigen. There are three CDRs in the VH (Very High) antibody (HCDR1, HCDR2, HCDR3) and three CDRs in the VL (Very Low) antibody (LCDR1, LCDR2, LCDR3). CDR can be defined using various descriptions, such as Kabat (Wu et al. (1970) J Exp Med 132:211-50) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al. (1987) J Mol Biol 196:901-17), IMGT (Lefranc et al. (2003) Dev Comp Immunol 27:55-77), and AbM (Martin and Thornton (1996) J Bmol Biol 263:800-15). Correspondence between various descriptions and variable region numbering is provided (see, for example, Lefranc et al. (2003) Dev Comp Immunol 27:55-77; Honegger and Pluckthun, (2001) J Mol Biol 309:657-70; International ImMunoGeneTics (IMGT) database; web resource, see http: / / www_imgt_org). CDRs can be described using available programs such as abYsis by UCL Business PLC. As used herein, the terms “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2”, and “LCDR3”, include CDRs defined by any of the Kabat, Chothia, IMGT, or AbM methods described above, unless otherwise expressly stated herein.

[0049] An "antigen-binding fragment" refers to a portion of an immunoglobulin molecule that retains the antigen-binding properties of a parent full-length antibody. Exemplary antigen-binding fragments include heavy chain complementarity-determining regions (HCDRs) 1, 2 and / or 3, light chain complementarity-determining regions (LCDRs) 1, 2 and / or 3, VH, VL, VH and VL, Fab, F(ab')2, Fd, and Fv fragments, and domain antibodies (dAb) consisting of either one VH domain or one VL domain. The VH and VL domains can be linked to each other via synthetic linkers to form various types of single-chain antibody designs that form monovalent antigen-binding sites or diabodies, such as single-chain Fv (scFv), by pairing the VH / VL domains intramolecularly or intermolecularly if the VH and VL domains are expressed on separate chains. This is described, for example, in International Publication Nos. 1998 / 44001, 1988 / 01649, 1994 / 13804, and 1992 / 01047.

[0050] A "humanized antibody" refers to an antibody in which the CDR sequence is derived from a non-human species and the framework is derived from a human immunoglobulin sequence. Because humanized antibodies may contain substitutions within their framework, the framework may not be an exact copy of the expressed human immunoglobulin or human immunoglobulin germline gene sequence. A humanized antibody is one in which at least one CDR is derived from a non-human species and at least one framework is derived from a human immunoglobulin sequence. Because humanized antibodies can contain substitutions in their framework, the framework may not be an exact copy of the expressed human immunoglobulin or human immunoglobulin germline gene sequence.

[0051] A "human antibody" refers to an antibody optimized to produce the minimum possible immune response when administered to a human subject. The variable region of a human antibody is derived from a human germline immunoglobulin sequence. If the antibody contains a constant region or a portion of a constant region, the constant region is also derived from a human germline immunoglobulin sequence.

[0052] When the variable region of an antibody is obtained from a system using human germline immunoglobulin genes, the human antibody contains a heavy chain or light chain variable region "derived from" a human germline immunoglobulin sequence. Exemplary such systems include human immunoglobulin gene libraries displayed on phages or mammalian cells, and transgenic non-human animals such as mice, rats, or chickens possessing human immunoglobulin loci. "Human antibody" typically involves amino acid differences compared to immunoglobulins expressed in humans, due to differences between the antibody and the systems used to obtain the human immunoglobulin loci, the introduction of naturally occurring somatic mutations, substitutions, or intentional introduction into the framework or CDR. "Human antibodies" are typically approximately 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by the human germline immunoglobulin sequence. In some cases, "human antibodies" may contain, for example, a consensus framework sequence derived from human framework sequence analysis described in (Knappik et al. (2000) J Mol Biol 296:57-86), or synthetic HCDR3 incorporated into a phage-displayed human immunoglobulin gene library described in, for example, (Shi et al. (2010) J Mol Biol 397:385-96) and International Publication No. 2009 / 085462. Antibodies derived from non-human species are not included in the definition of "human antibodies."

[0053] A "monoclonal antibody" refers to a population of antibodies in which each antibody chain has a single amino acid composition, except for possible known modifications such as the removal of C-terminal lysine from the antibody heavy chain, or post-translational modifications of amino acids, such as methionine oxidation or deamidation of asparagine or glutamine. Monoclonal antibodies usually bind specifically to one antigenic epitope, but bispecific or multispecific monoclonal antibodies bind specifically to two or more different antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibodies can be monospecific or multispecific, and monovalent, bivalent, or polyvalent. Bispecific antibodies are included in the term monoclonal antibody.

[0054] "Isolated" refers to a homogeneous population of molecules (e.g., synthetic polynucleotides or proteins such as antibodies) that has been substantially separated and / or purified from other components involved in the system in which the molecules are produced, such as recombinant cells, in addition to proteins that have undergone at least one purification or isolation step. "Isolated antibody" refers to an antibody that is substantially free of other cellular material and / or chemicals, and includes antibodies isolated to higher purities, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0055] As used herein, “FGFR gene alteration” refers to alterations of the wild-type FGFR gene and includes FGFR fusion genes, FGFR mutations, or any combination thereof. The terms “variant” and “alteration” are used interchangeably herein.

[0056] In certain embodiments, the FGFR2 or FGFR3 gene alteration is an FGFR gene fusion. “FGFR fusion” or “FGFR gene fusion” means a gene that encodes a portion of FGFR (e.g., FGFR2 or FGFR3) and one or a portion of one of the fusion partners disclosed herein, 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 patient's biological sample—FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof—can be determined using the disclosed methods or uses, or by methods well known to those skilled in the art. In certain embodiments, FGFR3-TACC3 is FGFR3-TACC3 variant 1 (FGFR3-TACC3 V1) or FGFR3-TACC3 variant 3 (FGFR3-TACC3 V3). Table 2A provides FGFR fusion genes, as well as the exons of the fused FGFR and fusion partner. The nucleotide sequences of individual FGFR fusion genes are disclosed in Table 3A. Underlined sequences correspond to either FGFR3 or FGFR2, and sequences shown in black represent the fusion partner.

[0057] [Table 2]

[0058] [Table 3-1]

[0059] [Table 3-2]

[0060] [Table 3-3]

[0061] Table 3-4

[0062] Table 3-5

[0063] Table 3-6

[0064] Table 3-7

[0065] Table 3-8

[0066] Table 3-9

[0067] Table 3-10

[0068] Table 3-11

[0069] Table 3-12

[0070] FGFR gene variations include single nucleotide polymorphisms (SNPs) of FGFR. An "FGFR single nucleotide polymorphism" (SNP) refers to a single nucleotide that differs between individuals in the FGFR2 or FGFR3 gene. In certain embodiments, an FGFR2 or FGFR3 gene variation is an FGFR3 gene variation. In particular, an "FGFR single nucleotide polymorphism" (SNP) refers to a single nucleotide that differs between individuals in the FGFR3 gene. The presence of one or more of the following FGFR SNPs in a patient's biological sample, namely FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, FGFR3 Y373C, or any combination thereof, can be determined by methods known to those skilled in the art or by the methods disclosed in International Publication No. 2016 / 048833. The sequences of FGFR SNPs are provided in Table 4A.

[0071] [Table 4] The sequence corresponds to nucleotides 920-1510 of FGFR3 (Genebank identification number NM_000142.4). The nucleotides in bold and underlined represent SNPs. * In some literature, it is mistakenly referred to as Y375C.

[0072] As used herein, "FGFR gene alteration gene panel" includes one or more of the FGFR gene alterations listed above.

[0073] The gene panel of FGFR gene alterations used in the step of evaluating the method of this disclosure for patients with urothelial carcinoma, particularly locally advanced UC or metastatic UC, includes 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.

[0074] In one embodiment, one or more FGFR gene mutations described herein 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. In one embodiment, one or more of these FGFR gene mutations are considered to be susceptible to FGFR gene mutations.

[0075] In one embodiment, one or more FGFR gene alterations described herein include FGFR3 gene alterations, and in particular, one or more FGFR gene alterations include FGFR3-TACC3 V1, FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, or FGFR3 Y373C, or any combination thereof. In one embodiment, these one or more FGFR gene alterations are considered to be susceptible to FGFR gene alterations.

[0076] In one embodiment, one or more FGFR gene mutations described herein include FGFR3-TACC3 V1, FGFR3-TACC3 V3, or any combination thereof. In one embodiment, these one or more FGFR gene mutations are considered to be susceptible to FGFR gene mutations.

[0077] In one embodiment, one or more FGFR gene mutations described herein include FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, or FGFR3 Y373C, or any combination thereof. In one embodiment, these one or more FGFR gene mutations are considered to be susceptible to FGFR gene mutations.

[0078] Provided herein is a method for treating a subject having advanced urothelial carcinoma with one or more FGFR changes (either advanced or urothelial carcinoma with one or more FGFR changes that has progressed after one or two prior treatments, at least one of which included an antiprogrammed cell death-[ligand]1 (PD-[L]1) agent), comprising administering to the subject a therapeutically effective dose of erdafitinib, the method providing an improved treatment for the subject compared to chemotherapy. [Overview of the Initiative] [Means for solving the problem]

[0079] In one embodiment, a method is provided for treating locally advanced urothelial carcinoma or metastatic urothelial carcinoma having one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering a therapeutically effective dose of erdafitinib to a subject in need of treatment, particularly a patient having locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly an adult patient having locally advanced urothelial carcinoma or metastatic urothelial carcinoma, wherein the subject, particularly the patient, and more particularly the adult patient, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic urothelial carcinoma. In a particular embodiment, locally advanced UC (urothelial carcinoma) or metastatic UC is suprasulourinary tract ulcers.

[0080] In one embodiment, a method is provided for treating locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering a therapeutically effective dose of erdafitinib to a subject in need of treatment, particularly a patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly an adult patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, wherein the subject, particularly the patient, and more particularly the adult patient, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent. In a particular embodiment, locally advanced UC or metastatic UC is suprasulourinary tract ulcers.

[0081] In one embodiment, a method is provided for treating locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more FGFR gene mutations, comprising administering a therapeutically effective dose of erdafitinib to a subject in need of treatment, particularly a patient having locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly an adult patient having locally advanced urothelial carcinoma or metastatic urothelial carcinoma, wherein the subject, particularly the patient, and more particularly the adult patient, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months. In a particular embodiment, locally advanced UC or metastatic UC is suprasulourinary tract ulcers.

[0082] In one embodiment, a method is provided for treating locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more FGFR gene mutations, comprising administering a therapeutically effective dose of erdafitinib to a subject in need of treatment, particularly a patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly an adult patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, wherein the locally advanced urothelial carcinoma or metastatic urothelial carcinoma or the subject, particularly the patient, and more particularly the adult patient, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent in a neoadjuvant or adjuvant setting. In a particular embodiment, locally advanced UC or metastatic UC is suprasulourinary tract ulcers.

[0083] In one embodiment, a method is provided for the treatment of a subject in need of treatment, particularly a patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly an adult patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, having a tumor having one or more fibroblast growth factor receptor (FGFR) gene alterations and having received at least one line of systemic therapy containing an anti-PD-(L)1 agent in a locally advanced or metastatic treatment setting, comprising administering a therapeutically effective dose of erdafitinib to the subject, particularly the patient, and more particularly the adult patient. In a particular embodiment, locally advanced UC or metastatic UC is suprasulent UC.

[0084] In one embodiment, a method is provided for the treatment of a subject, particularly a patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly an adult patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, who has a tumor having one or more fibroblast growth factor receptor (FGFR) gene mutations and whose condition has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, comprising administering a therapeutically effective dose of erdafitinib to the subject, particularly the patient, and more particularly the adult patient. In a particular embodiment, locally advanced UC or metastatic UC is suprasulent ulcerative colitis.

[0085] In one embodiment, a method for treating patients in need of treatment who have one or more FGFR gene mutations and whose disease has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, A method is provided comprising administering a therapeutically effective dose of erdafitinib to a subject, particularly a patient, and more particularly to an adult patient. In certain embodiments, locally progressive UC or metastatic UC is suprasulent ulcerative colitis.

[0086] In one embodiment, a method for treating locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), (a) Evaluating biological samples from subjects in need of treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the subjects, particularly patients, and more particularly adult patients, have received at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the subject, in particular the patient, and especially to the adult patient. A method is provided which includes the following: In a particular embodiment, locally progressive UC or metastatic UC is suprasulent ulcerative colitis.

[0087] In one embodiment, a method for treating subjects requiring treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from subjects, particularly patients, and more particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein subjects, particularly patients, and more particularly adult patients, have progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the subject, in particular the patient, and especially to the adult patient. A method is provided which includes the following: In a particular embodiment, locally progressive UC or metastatic UC is suprasulent ulcerative colitis.

[0088] In one embodiment, the use of erdafitinib for the manufacture of a medicament for the treatment of locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations in subjects requiring treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, wherein erdafitinib is administered or planned to be administered in a therapeutically effective dose, and the subjects, particularly patients, and more particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic UC. In certain embodiments, locally advanced UC or metastatic UC is suprasulent ulcerative ulcer.

[0089] In one embodiment, the use of erdafitinib for the manufacture of a medicament for the treatment of locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations in subjects requiring treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, wherein erdafitinib is administered or planned to be administered in a therapeutically effective dose, and the subject, particularly patients, and more particularly adult patients, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent. In certain embodiments, locally advanced UC or metastatic UC is suprasulourinary tract ulcers.

[0090] In one embodiment, the use of erdafitinib for the manufacture of a medicament for the treatment of locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations in subjects requiring treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, wherein erdafitinib is administered or planned to be administered in a therapeutically effective dose, and the subject, particularly patients, and more particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months. In certain embodiments, locally advanced UC or metastatic UC is suprasulent ulcerative colitis.

[0091] In one embodiment, the use of erdafitinib for the manufacture of a medicament for the treatment of locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations in subjects requiring treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, is provided, wherein erdafitinib is administered or planned to be administered in a therapeutically effective dose, and the locally advanced urothelial carcinoma or metastatic urothelial carcinoma, or subject, particularly patients, and more particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent in a neoadjuvant or adjuvant setting. In certain embodiments, locally advanced UC or metastatic UC is suprasulent ulcerative colitis.

[0092] In one embodiment, a use of erdafitinib is provided for the manufacture of a medicament for the treatment of a patient in need of treatment, particularly a patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly an adult patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, having a tumor having one or more fibroblast growth factor receptor (FGFR) gene alterations and having received at least one line of systemic therapy containing an anti-PD-(L)1 agent in a locally advanced or metastatic treatment setting, wherein erdafitinib is administered or to be administered in a therapeutically effective dose. In a particular embodiment, locally advanced UC or metastatic UC is suprasulent ulcerative colitis.

[0093] In one embodiment, the use of erdafitinib for the manufacture of a medicament for the treatment of subjects in need of treatment who have a tumor having one or more fibroblast growth factor receptor (FGFR) gene alterations and whose disease has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, is provided, wherein erdafitinib is administered or will be administered in a therapeutically effective dose. In certain embodiments, locally advanced UC or metastatic UC is suprasulent ulcerative colitis.

[0094] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product for the treatment of patients in need of treatment who have one or more FGFR gene mutations and whose disease has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, A use is provided in which erdafitinib is administered or will be administered in a therapeutically effective dose. In certain embodiments, locally progressive UC or metastatic UC is suprasulent ulcerative colitis.

[0095] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product for the treatment of locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations in subjects requiring treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluating biological samples from subjects, particularly patients, and more particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein subjects, particularly patients, and more particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the subject, in particular the patient, and especially to the adult patient. Uses are provided, including the following. In certain embodiments, locally progressive UC or metastatic UC is suprasulent ulcerative colitis.

[0096] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product for the treatment of locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations in subjects requiring treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from subjects, particularly patients, and more particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein subjects, particularly patients, and more particularly adult patients, have progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the subject, in particular the patient, and especially to the adult patient. Uses are provided, including the following. In certain embodiments, locally progressive UC or metastatic UC is suprasulent ulcerative colitis.

[0097] In one embodiment, erdafitinib is provided for use in the treatment of locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations in subjects requiring treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, which is administered or planned to be administered in a therapeutically effective dose, wherein the subjects, particularly patients, and more particularly adult patients are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic urothelial carcinoma. In a particular embodiment, locally advanced UC or metastatic UC is suprasulourinary tract ulcers.

[0098] In one embodiment, erdafitinib is provided for use in the treatment of locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations in subjects requiring treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, administered or planned to be administered in a therapeutically effective dose, wherein the subjects, particularly patients, and more particularly adult patients, have progressed during or after one or more prior treatments including an anti-PD-(L)1 agent. In a particular embodiment, locally advanced UC or metastatic UC is suprasulourinary tract ulcers.

[0099] In one embodiment, erdafitinib is provided for use in the treatment of locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations in subjects requiring treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, administered or planned to be administered in a therapeutically effective dose, wherein the subject, particularly patients, and more particularly adult patients, have progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months. In a particular embodiment, locally advanced UC or metastatic UC is suprasulourinary tract ulcer.

[0100] In one embodiment, erdafitinib is provided for use in the treatment of locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations in subjects requiring treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, which is administered or planned to be administered in a therapeutically effective dose, wherein the locally advanced urothelial carcinoma or metastatic urothelial carcinoma, or subjects, particularly patients, and more particularly adult patients, have progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent in a neoadjuvant or adjuvant setting. In a particular embodiment, locally advanced UC or metastatic UC is suprasulourinary tract ulcer.

[0101] In one embodiment, erdafitinib is provided for use in the treatment of patients in need of treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, who have a tumor having one or more fibroblast growth factor receptor (FGFR) gene mutations and are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in a locally advanced or metastatic treatment setting, and which is administered or will be administered in a therapeutically effective dose. In a particular embodiment, locally advanced UC or metastatic UC is suprasulent UC.

[0102] In one embodiment, erdafitinib is provided for use in the treatment of patients in need of treatment who have a tumor having one or more fibroblast growth factor receptor (FGFR) gene alterations and whose disease has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, provided that erdafitinib is administered or will be administered in a therapeutically effective dose. In a particular embodiment, locally advanced UC or metastatic UC is suprasulent UC.

[0103] In one embodiment, erdafitinib for use in the treatment of patients in need of treatment who have one or more FGFR gene mutations and whose disease has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, Erdafitinib is provided, administered or to be administered in a therapeutically effective dose. In certain embodiments, locally progressive UC or metastatic UC is suprasulent UC.

[0104] In one embodiment, erdafitinib for use in the treatment of locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations in patients requiring treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluating biological samples from subjects, particularly patients, and more particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein subjects, particularly patients, and more particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the subject, in particular the patient, and especially to the adult patient. Erdafitinib is provided, which includes [a specific component]. In certain embodiments, locally progressive UC or metastatic UC is suprasulent UC.

[0105] In one embodiment, erdafitinib for use in the treatment of locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations in patients requiring treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from subjects, particularly patients, and more particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein subjects, particularly patients, and more particularly adult patients, have progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the subject, in particular the patient, and especially to the adult patient. Erdafitinib is provided, which includes [a specific component]. In certain embodiments, locally progressive UC or metastatic UC is suprasulent UC.

[0106] In one embodiment, a method is provided for improving overall survival, particularly median overall survival, in patients having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in adult patients having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly the adult patient, wherein the patient, particularly the adult patient, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease.

[0107] In one embodiment, a method is provided for improving overall survival, particularly median overall survival, in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly the adult patient, wherein the patient, particularly the adult patient, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent.

[0108] In one embodiment, a method is provided for improving overall survival, particularly median overall survival, in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly the adult patient, wherein the patient, particularly the adult patient, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, for 12 months or less.

[0109] In one embodiment, a method for improving overall survival, particularly median overall survival, in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), especially in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. A method is provided that includes this.

[0110] In one embodiment, a method for improving overall survival, particularly median overall survival, in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), especially in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. A method is provided that includes this.

[0111] In one embodiment, the use of erdafitinib for the manufacture of a pharmacopoeia to improve overall survival, particularly median overall survival, in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, is receiving at least one line of systemic therapy including an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease, and erdafitinib is being administered or will be administered in a therapeutically effective dose.

[0112] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical to improve overall survival, particularly median overall survival, in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly in adult patients, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, and erdafitinib is administered or will be administered in a therapeutically effective dose.

[0113] In one embodiment, the use of erdafitinib for the manufacture of a medicament to improve overall survival, particularly median overall survival, in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly in adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months, and erdafitinib is being administered or will be administered in a therapeutically effective dose.

[0114] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product to improve overall survival, particularly median overall survival, in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Uses including the following are provided.

[0115] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product to improve overall survival, particularly median overall survival, in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Uses including the following are provided.

[0116] In one embodiment, erdafitinib is provided for use in improving overall survival, particularly median overall survival, in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, is receiving or will receive at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic urothelial carcinoma, and is being administered or will be administered at a therapeutically effective dose.

[0117] In one embodiment, erdafitinib is provided for use in improving overall survival, particularly median overall survival, in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma having one or more fibroblast growth factor receptor (FGFR) gene mutations, wherein the patient, particularly the adult patient, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, and is or will be administered an effective therapeutic dose of erdafitinib.

[0118] In one embodiment, erdafitinib is provided for use in improving overall survival, particularly median overall survival, in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months, and is or will be administered at a therapeutically effective dose.

[0119] In one embodiment, erdafitinib for use in improving overall survival, particularly median overall survival, in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Erdafitinib, which includes this, is offered.

[0120] In one embodiment, erdafitinib for use in improving overall survival, particularly median overall survival, in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Erdafitinib, which includes this, is offered.

[0121] In one embodiment, a method is provided for reducing the risk of death in patients having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in adult patients having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly in adult patients, wherein the patient, particularly in adult patients, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic urothelial carcinoma.

[0122] In one embodiment, a method is provided for reducing the risk of death in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly in adult patients, wherein the patient, particularly in adult patients, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent.

[0123] In one embodiment, a method is provided for reducing the risk of death in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly in adult patients, wherein the patient, particularly in adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months.

[0124] In one embodiment, a method for reducing the risk of death in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. A method is provided that includes this.

[0125] In one embodiment, a method for reducing the risk of death in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. A method is provided that includes this.

[0126] In one embodiment, the use of erdafitinib for the manufacture of a medicament to reduce the risk of death in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic urothelial carcinoma, and erdafitinib is being administered or will be administered in a therapeutically effective dose.

[0127] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical to reduce the risk of death in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly in adult patients, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, and erdafitinib has been or will be administered in a therapeutically effective dose.

[0128] In one embodiment, the use of erdafitinib for the manufacture of a medicament to reduce the risk of death in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly in adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months, and erdafitinib is being administered or will be administered in a therapeutically effective dose.

[0129] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product to reduce the risk of death in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Uses including the following are provided.

[0130] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product to reduce the risk of death in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Uses including the following are provided.

[0131] In one embodiment, erdafitinib is provided for use in reducing the risk of death in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, is receiving or will receive at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic urothelial carcinoma, and is being administered in a therapeutically effective dose.

[0132] In one embodiment, erdafitinib is provided for use in reducing the risk of death in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma having one or more fibroblast growth factor receptor (FGFR) gene mutations, wherein the patient, particularly the adult patient, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, and is or will be administered an effective therapeutic dose of erdafitinib.

[0133] In one embodiment, erdafitinib is provided for use in reducing the risk of death in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months, and is or will be administered at a therapeutically effective dose.

[0134] In one embodiment, erdafitinib for use in reducing the risk of death in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Erdafitinib, which includes this, is offered.

[0135] In one embodiment, erdafitinib for use in reducing the risk of death in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Erdafitinib, which includes this, is offered.

[0136] In one embodiment, a method is provided for improving the median PFS in a patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in an adult patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly the adult patient, wherein the patient, particularly the adult patient, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease.

[0137] In one embodiment, a method is provided for improving the median PFS in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly the adult patient, wherein the patient, particularly the adult patient, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent.

[0138] In one embodiment, a method is provided for improving the median PFS in a patient having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in an adult patient having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly the adult patient, wherein the patient, particularly the adult patient, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months.

[0139] In one embodiment, a method for improving the median PFS in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. A method is provided that includes this.

[0140] In one embodiment, a method for improving the median PFS in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. A method is provided that includes this.

[0141] In one embodiment, the use of erdafitinib for the manufacture of a pharmacopoeia for improving median PFS in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease, and erdafitinib is being administered or will be administered in a therapeutically effective dose.

[0142] In one embodiment, the use of erdafitinib for the manufacture of a pharmacopoeia to improve median PFS in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly in adult patients, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, and erdafitinib is administered or will be administered in a therapeutically effective dose.

[0143] In one embodiment, the use of erdafitinib for the manufacture of a medicament to improve median PFS in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly in adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months, and erdafitinib is being administered or will be administered in a therapeutically effective dose.

[0144] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product for improving the median PFS in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Uses including the following are provided.

[0145] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product for improving the median PFS in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Uses including the following are provided.

[0146] In one embodiment, erdafitinib is provided for use in improving the median PFS in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, is receiving or will receive at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic urothelial carcinoma, and is being administered at a therapeutically effective dose.

[0147] In one embodiment, erdafitinib is provided for use in improving the median PFS in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma having one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, and is or will be administered an effective therapeutic dose of erdafitinib.

[0148] In one embodiment, erdafitinib is provided for use in improving median PFS in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma having one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months, and is or will be administered at a therapeutically effective dose.

[0149] In one embodiment, erdafitinib for use in improving the median PFS in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Erdafitinib, which includes this, is offered.

[0150] In one embodiment, erdafitinib for use in improving the median PFS in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Erdafitinib, which includes this, is offered.

[0151] In one embodiment, a method is provided for reducing the risk of progression or death in a patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in an adult patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly the adult patient, wherein the patient, particularly the adult patient, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease.

[0152] In one embodiment, a method is provided for reducing the risk of progression or death in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly in adult patients, wherein the patient, particularly in adult patients, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent.

[0153] In one embodiment, a method is provided for reducing the risk of progression or death in a patient having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly in adult patients, wherein the patient, particularly in adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months.

[0154] In one embodiment, a method for reducing the risk of progression or death in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. A method is provided that includes this.

[0155] In one embodiment, a method for reducing the risk of progression or death in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. A method is provided that includes this.

[0156] In one embodiment, the use of erdafitinib for the manufacture of a medicament to reduce the risk of progression or death in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease, and erdafitinib is being administered or will be administered in a therapeutically effective dose.

[0157] In one embodiment, the use of erdafitinib for the manufacture of a medicament to reduce the risk of progression or death in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly in adult patients, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, and erdafitinib is administered or will be administered in a therapeutically effective dose.

[0158] In one embodiment, the use of erdafitinib for the manufacture of a medicament to reduce the risk of progression or death in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly in adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months, and erdafitinib is being administered or will be administered in a therapeutically effective dose.

[0159] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product to reduce the risk of progression or death in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Uses including the following are provided.

[0160] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product to reduce the risk of progression or death in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Uses including the following are provided.

[0161] In one embodiment, erdafitinib is provided for use in reducing the risk of progression or death in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, is receiving or will receive at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic urothelial carcinoma, and is being administered in a therapeutically effective dose.

[0162] In one embodiment, erdafitinib is provided for use in reducing the risk of progression or death in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, and is or will be administered an effective therapeutic dose of erdafitinib.

[0163] In one embodiment, erdafitinib is provided for use in reducing the risk of progression or death in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months, and is being administered or will be administered at a therapeutically effective dose.

[0164] In one embodiment, erdafitinib for use in reducing the risk of progression or death in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Erdafitinib, which includes this, is offered.

[0165] In one embodiment, erdafitinib for use in reducing the risk of progression or death in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Erdafitinib, which includes this, is offered.

[0166] In one embodiment, a method is provided for improving the ORR in a patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in an adult patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly the adult patient, wherein the patient, particularly the adult patient, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease. In a particular embodiment, the ORR is a confirmed ORR as assessed by the principal investigator.

[0167] In one embodiment, a method is provided for improving the objective risk reduction (ORR) in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma having one or more fibroblast growth factor receptor (FGFR) gene alterations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly the adult patient, wherein the patient, particularly the adult patient, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent. In certain embodiments, the ORR is a confirmed ORR as assessed by the principal investigator.

[0168] In one embodiment, a method is provided for improving the ORR in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly in adult patients, wherein the patient, particularly in adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months. In certain embodiments, the ORR is a confirmed ORR as assessed by the principal investigator.

[0169] In one embodiment, a method for improving ORR in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. A method is provided that includes the following: In a particular embodiment, the ORR is a determined ORR as assessed by the principal investigator.

[0170] In one embodiment, a method for improving ORR in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. A method is provided that includes the following: In a particular embodiment, the ORR is a determined ORR as assessed by the principal investigator.

[0171] In one embodiment, the use of erdafitinib for the manufacture of a medicament to improve the ORR in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease, and erdafitinib is being administered or will be administered in a therapeutically effective dose. In certain embodiments, the ORR is a confirmed ORR as assessed by the principal investigator.

[0172] In one embodiment, the use of erdafitinib for the manufacture of a medicament to improve the ORR in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma having one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly in adult patients, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, and erdafitinib is administered or will be administered in a therapeutically effective dose. In certain embodiments, the ORR is a confirmed ORR as assessed by the principal investigator.

[0173] In one embodiment, the use of erdafitinib for the manufacture of a medicament to improve the ORR in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma having one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly in adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months, and erdafitinib is administered or will be administered at a therapeutically effective dose. In certain embodiments, the ORR is a confirmed ORR as assessed by the principal investigator.

[0174] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product for improving ORR in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. A method is provided that includes the following: In a particular embodiment, the ORR is a determined ORR as assessed by the principal investigator.

[0175] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product for improving ORR in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. A method is provided that includes the following: In a particular embodiment, the ORR is a determined ORR as assessed by the principal investigator.

[0176] In one embodiment, erdafitinib is provided for use in improving the objective response rate (ORR) in patients with locally advanced or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients with locally advanced or metastatic urothelial carcinoma having one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, is receiving or will receive at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease, and is administered at or will be administered at a therapeutically effective dose. In a particular embodiment, the ORR is a confirmed ORR as assessed by the principal investigator.

[0177] In one embodiment, erdafitinib is provided for use in improving the objective response rate (ORR) in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma having one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, and is or will be administered at a therapeutically effective dose. In certain embodiments, the ORR is a confirmed ORR as assessed by the principal investigator.

[0178] In one embodiment, erdafitinib is provided for use in improving the objective response rate (ORR) in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma having one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months, and is or will be administered at a therapeutically effective dose. In certain embodiments, the ORR is a confirmed ORR as assessed by the principal investigator.

[0179] In one embodiment, erdafitinib for use in improving ORR in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Erdafitinib is provided, which includes [a specific compound]. In certain embodiments, the ORR is a confirmed ORR as determined by the investigator's assessment.

[0180] In one embodiment, erdafitinib for use in improving ORR in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Erdafitinib is provided, which includes [a specific compound]. In certain embodiments, the ORR is a confirmed ORR as determined by the investigator's assessment.

[0181] In one embodiment, a method is provided for improving disease control rates in patients having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly in adult patients, wherein the patient, particularly in adult patients, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease.

[0182] In one embodiment, a method is provided for improving disease control rates in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly the adult patient, wherein the patient, particularly the adult patient, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent.

[0183] In one embodiment, a method is provided for improving disease control rates in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, comprising administering a therapeutically effective dose of erdafitinib to the patient, particularly in adult patients, wherein the patient, particularly in adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months.

[0184] In one embodiment, a method for improving disease control rates in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. A method is provided that includes this.

[0185] In one embodiment, a method for improving disease control rates in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. A method is provided that includes this.

[0186] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product to improve disease control rates in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease, and erdafitinib is being administered or will be administered in a therapeutically effective dose.

[0187] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product to improve disease control rates in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly in adult patients, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, and erdafitinib is administered or will be administered in a therapeutically effective dose.

[0188] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product to improve disease control rates in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly in adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months, and erdafitinib is being administered or will be administered in a therapeutically effective dose.

[0189] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product to improve disease control rates in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Uses including the following are provided.

[0190] In one embodiment, the use of erdafitinib for the manufacture of a pharmaceutical product to improve disease control rates in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Uses including the following are provided.

[0191] In one embodiment, erdafitinib is provided for use in improving disease control rates in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, is receiving or will receive at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease, and is being administered at a therapeutically effective dose.

[0192] In one embodiment, erdafitinib is provided for use in improving disease control rates in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma having one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, and is or will be administered an effective therapeutic dose of erdafitinib.

[0193] In one embodiment, erdafitinib is provided for use in improving disease control rates in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma having one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months, and is or will be administered at a therapeutically effective dose.

[0194] In one embodiment, erdafitinib for use in improving disease control rates in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Erdafitinib, which includes this, is offered.

[0195] In one embodiment, erdafitinib for use in improving disease control rates in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the patient, especially the adult patient. Erdafitinib, which includes this, is offered.

[0196] In any of the embodiments described above, the improvement may be for a reference population of patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, particularly a reference population of adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, the reference population of which has been administered chemotherapy. In a particular embodiment, the chemotherapy is docetaxel administered intravenously over 1 hour at a dose of 75 mg per square meter once every three weeks. In a particular embodiment, the chemotherapy is vinflunin administered intravenously over 20 minutes at a dose of 320 mg per square meter once every three weeks.

[0197] In one embodiment, a method is provided for achieving a favorable tolerability profile in a patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in an adult patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has received at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease, and the method comprises administering a therapeutically effective dose of erdafitinib to the patient, particularly the adult patient, wherein the favorable tolerability profile is compared to the tolerability profile of chemotherapy, particularly monotherapy.

[0198] In one embodiment, a method is provided for achieving a favorable tolerability profile in a patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in an adult patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, and the patient, particularly the adult patient, is administered a therapeutically effective dose of erdafitinib, the favorable tolerability profile being compared to the tolerability profile of chemotherapy, particularly monotherapy.

[0199] In one embodiment, a method is provided for achieving a favorable tolerability profile in a patient having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in an adult patient having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months, and the patient, particularly the adult patient, is administered a therapeutically effective dose of erdafitinib, wherein the favorable tolerability profile is compared to the tolerability profile of chemotherapy, particularly monotherapy.

[0200] In one embodiment, a method for achieving a favorable tolerability profile in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, the patient, particularly the adult patient, is administered a therapeutically effective dose of erdafitinib, wherein the preferred tolerability profile is compared to that of chemotherapy, particularly monotherapy. A method is provided.

[0201] In one embodiment, a method for achieving a favorable tolerability profile in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, the patient, particularly the adult patient, is administered a therapeutically effective dose of erdafitinib, wherein the preferred tolerability profile is compared to that of chemotherapy, particularly monotherapy. A method is provided.

[0202] In one embodiment, the use of erdafitinib for the manufacture of a medicament to achieve a favorable tolerability profile in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease, and erdafitinib is administered or scheduled to be administered in a therapeutically effective dose, and the favorable tolerability profile is compared to the tolerability profile of chemotherapy, particularly monotherapy.

[0203] In one aspect, the use of erdafitinib for the manufacture of a medicament for achieving a favorable tolerability profile in patients having locally advanced urothelial cancer or metastatic urothelial cancer (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly adult patients having locally advanced urothelial cancer or metastatic urothelial cancer having one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has progressed during or after one or more prior treatments comprising an anti-PD-(L)1 agent, and erdafitinib is administered or is to be administered in a therapeutically effective amount, and the favorable tolerability profile is compared to the tolerability profile of chemotherapy, particularly single-agent chemotherapy, is provided.

[0204] In one aspect, the use of erdafitinib for the manufacture of a medicament for achieving a favorable tolerability profile in patients having locally advanced urothelial cancer or metastatic urothelial cancer (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly adult patients having locally advanced urothelial cancer or metastatic urothelial cancer having one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, which includes neoadjuvant therapy or adjuvant therapy within 12 months, and erdafitinib is administered or is to be administered in a therapeutically effective amount, and the favorable tolerability profile is compared to the tolerability profile of chemotherapy, particularly single-agent chemotherapy, is provided.

[0205] In one aspect, the use of erdafitinib for the manufacture of a medicament for achieving a favorable tolerability profile in patients having locally advanced urothelial cancer or metastatic urothelial cancer (mUC), particularly adult patients having locally advanced urothelial cancer or metastatic urothelial cancer, (a) Evaluating a biological sample from a patient, particularly an adult patient, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly an adult patient, has received at least one line of systemic treatment containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) When one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administering an therapeutically effective amount of erdafitinib to the patient, particularly the adult patient, wherein the favorable tolerability profile is compared to the tolerability profile of chemotherapy, particularly single-agent chemotherapy. Use is provided.

[0206] In one aspect, use of erdafitinib for the manufacture of a medicament for achieving a favorable tolerability profile in a patient having locally advanced urothelial cancer or metastatic urothelial cancer (mUC), particularly an adult patient having locally advanced urothelial cancer or metastatic urothelial cancer, (a) Evaluating a biological sample from a patient, particularly an adult patient, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly an adult patient, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months; and (b) When one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administering an therapeutically effective amount of erdafitinib to the patient, particularly the adult patient, wherein the favorable tolerability profile is compared to the tolerability profile of chemotherapy, particularly single-agent chemotherapy. Use is provided.

[0207] In one embodiment, erdafitinib is provided for use in achieving a favorable tolerability profile in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has received at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease, and erdafitinib is administered or scheduled to be administered in a therapeutically effective dose, and the favorable tolerability profile is compared to the tolerability profile of chemotherapy, particularly monotherapy.

[0208] In one embodiment, erdafitinib is provided for use in achieving a favorable tolerability profile in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly an adult patient, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, and erdafitinib is administered or scheduled to be administered in a therapeutically effective dose, and the favorable tolerability profile is compared to the tolerability profile of chemotherapy, particularly monotherapy.

[0209] In one embodiment, erdafitinib is provided for use in achieving a favorable tolerability profile in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly an adult patient, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy within 12 months, and erdafitinib is administered or scheduled to be administered in a therapeutically effective dose, and the favorable tolerability profile is compared to the tolerability profile of chemotherapy, particularly monotherapy.

[0210] In one embodiment, erdafitinib for use in achieving a favorable tolerability profile in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patients, particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, the patient, particularly the adult patient, is administered a therapeutically effective dose of erdafitinib, wherein the preferred tolerability profile is compared to that of chemotherapy, particularly monotherapy. Erdafitinib will be offered.

[0211] In one embodiment, erdafitinib for use in achieving a favorable tolerability profile in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from patients, particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, the patient, particularly the adult patient, is administered a therapeutically effective dose of erdafitinib, wherein the preferred tolerability profile is compared to that of chemotherapy, particularly monotherapy. Erdafitinib will be offered.

[0212] In any of the embodiments disclosed herein that refer to an improvement or reduction, the improvement or reduction may be compared to a reference patient or population of reference patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma, in particular to a reference adult patient or population of reference adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma, the reference patient or population being administered chemotherapy instead of erdafitinib. In certain embodiments, the chemotherapy is docetaxel or vinflunin.

[0213] "Reference patient" or "reference patient population" refers to a subject or population of subjects having locally advanced or metastatic urothelial carcinoma and being treated with chemotherapy, such as docetaxel or vinflunin, instead of erdafitinib. The reference subject or reference population of subjects is substantially the same as the subject or population of subjects before treatment with chemotherapy or erdafitinib. Exemplary reference subjects or reference populations of subjects are those described in Example 1 or Example 2 of this specification. In some embodiments, the population of subjects and the reference population of subjects include at least two subjects. In some embodiments, the population of subjects and the reference population of subjects include several subjects that enable a statistically significant analysis of improvements in safety and / or efficacy.

[0214] In any embodiment disclosed herein that refers to progression, it should be understood that references to progression in a patient or adult patient are interchangeable with references to progression of cancer in a patient or adult patient. For example, the phrase "the patient, in particular the adult patient, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent" is interchangeable with "the disease has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent," in particular "urothelial carcinoma that has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent," and even more particularly "locally advanced urothelial carcinoma or metastatic urothelial carcinoma that has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent."

[0215] In any of the aforementioned embodiments in which locally advanced urothelial carcinoma or metastatic urothelial carcinoma, or a patient or population of patients, particularly adult patients or populations of adult patients, is described as having progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including a neoadjuvant or adjuvant setting, it should be understood that the pre-progression disease state includes, for example, non-metastatic diseases such as non-metastatic urothelial carcinoma. [Brief explanation of the drawing]

[0216] The present invention will be described with reference to the attached figures for illustrative purposes only. [Figure 1] Study design for Phase 3 trial NCT03390504 (Trial 42756493-BLC3001). Cohort 1 had a planned enrollment of 280 participants. [Figure 2] Kaplan-Meier plot of overall survival; ITT analysis set for Cohort 1 (Trial 42756493-BLC3001) [Figure 3] Kaplan-Meier plots of progression-free survival; ITT analysis set for Cohort 1 (Trial 42756493-BLC3001) [Figure 4] Objective response rate to erdafitinib treatment and chemotherapy (Trial 42756493-BLC3001). [Figure 5A] This is a CONSORT diagram showing the screening patient flow for THOR (trial 42756493 - BLC3001). [Figure 5B] Shows the THOR trial design. Draw a red box around THOR cohort 1. [Figure 5C] This is a CONSORT diagram showing the patient flow of THOR cohort 1. Three patients who did not receive prior anti - PD-(L)1 agents were misassigned to cohort 1 (erlotinib, n = 1; chemotherapy, n = 2). Due to the worldwide shortage of vinflunine during the trial from June to December 2022, new patients assigned to the chemotherapy group could only receive docetaxel. Patients who received treatment with vinflunine in this trial continued to receive vinflunine. Paclitaxel was not included in the choice of the treating physicians for the chemotherapy options in the trial because at the time this trial was planned, docetaxel and vinflunine were the most commonly prescribed chemotherapy agents in the participating countries. [Figure 5D] This is a graph showing baseline FGFR changes. Footnotes for Figures 5D and 5E: *Intention - to - treat population (2 patients were false positives for FGFR changes [erlotinib group, n = 1; chemotherapy group, n = 1] †Patients with only FGFR mutations; ‡Patients with only FGFR fusions. §FGFR mutations and fusions (erlotinib group, n = 2; chemotherapy group, n = 3) are shown in Table 17. [Figure 5E] This is a graph showing baseline FGFR changes. Footnotes for Figures 5D and 5E: *Intention - to - treat population (2 patients were false positives for FGFR changes [erlotinib group, n = 1; chemotherapy group, n = 1] †Patients with only FGFR mutations; ‡Patients with only FGFR fusions. §FGFR mutations and fusions (erlotinib group, n = 2; chemotherapy group, n = 3) are shown in Table 17. [Figure 6A]Overall survival is shown. Figure 6A shows Kaplan-Meier estimates of overall survival by treatment group. Figure 6B shows overall survival by important subgroups. The vertical dotted line represents the hazard ratio (HR) for the entire population for comparison. CI, confidence interval; CPS, composite positivity score; ECOG PS, US East Coast Cancer Clinical Trials Group Performance Status; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1. [Figure 6B] Overall survival is shown. Figure 6A shows Kaplan-Meier estimates of overall survival by treatment group. Figure 6B shows overall survival by important subgroups. The vertical dotted line represents the hazard ratio (HR) for the entire population for comparison. CI, confidence interval; CPS, composite positivity score; ECOG PS, US East Coast Cancer Clinical Trials Group Performance Status; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1. [Figure 7A] These graphs show the primary secondary endpoints. Figure 7A shows the Kaplan-Meier estimates of progression-free survival by treatment group. Figure 7B is a graph showing progression-free survival. [Figure 7B] These graphs show the primary secondary endpoints. Figure 7A shows the Kaplan-Meier estimates of progression-free survival by treatment group. Figure 7B is a graph showing progression-free survival. [Figure 7C] This graph shows the objective response rates for key subgroups. CI (Confidence Interval); CPS (Composite Positive Score); CR (Complete Response); ECOG PS (East Coast Cancer Clinical Trials Group Performance Status); PD-1 (Programmed Cell Death Protein 1); PD-L1 (Programmed Cell Death Ligand 1); PR (Partial Response). [Figure 8] Forest plot of overall survival - showing subgroup analysis; ITT analysis set for Cohort 1 (Trial 42756493-BLC3001) [Figure 9] Forest plot of overall survival - showing subgroup analysis; ITT analysis set for Cohort 1 (Trial 42756493-BLC3001) [Figure 10]The Kaplan-Meier plot of overall survival is shown (Cohort 1 of the BLC3001 trial). [Figure 11] The Kaplan-Meier plot of progression-free survival is shown (Cohort 1 of the BLC3001 trial). [Modes for carrying out the invention]

[0217] Erdafitinib, or N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine, is a panfibroblast growth factor receptor (FGFR 1,2,3,4) tyrosine kinase inhibitor.

[0218] The chemical structure of erdafitinib is,

[0219] [ka] That is the case.

[0220] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma. In one embodiment, the cancer described herein is suprasulourothelial carcinoma.

[0221] In one embodiment, locally advanced urothelial carcinoma or metastatic urothelial carcinoma as referred to herein is locally advanced unresectable urothelial carcinoma or metastatic urothelial carcinoma (mUC).

[0222] In one embodiment, in the aspects of the present invention, one or more FGFR gene alterations are FGFR fusions and / or mutations, in particular FGFR fusions and / or mutations that are sensitive to erdafitinib. In one embodiment, the FGFR fusions and / or mutations are FGFR3 mutations and / or FGFR2 and 3 fusions. In one embodiment, one or more FGFR gene alterations are selected from FGFR3-TACC3, in particular FGFR3-TACC3 V1 and FGFR3-TACC3 v3; FGFR3-BAIAP2L1; FGFR2-BICC1; FGFR2-CASP7; FGFR3 R248C; FGFR3 S249C; FGFR3 G370C; and FGFR3 Y373C. In one embodiment, one or more FGFR gene alterations are FGFR3 mutations and / or FGFR3 fusions. In one embodiment, one or more FGFR gene mutations are selected from FGFR3-TACC3, particularly FGFR3-TACC3 V1 and FGFR3-TACC3 v3; FGFR3-BAIAP2L1; FGFR3 R248C; FGFR3 S249C; FGFR3 G370C; and FGFR3 Y373C.

[0223] In one embodiment, one or more FGFR gene mutations are FGFR3 S249C.

[0224] In one embodiment, one or more FGFR gene mutations are FGFR3 Y373C.

[0225] In one embodiment, one or more FGFR gene mutations are FGFR3 G370C.

[0226] In one embodiment, one or more FGFR gene mutations are FGFR3 R248C.

[0227] In one embodiment, one or more FGFR gene mutations are FGFR3-TACC3 V1.

[0228] In one embodiment, one or more FGFR gene mutations are FGFR3-TACC3 v3.

[0229] In one embodiment, one or more FGFR gene mutations are FGFR3-BAIAP2L1.

[0230] In one embodiment, one or more FGFR gene mutations are FGFR2-BICC1.

[0231] In one embodiment, one or more FGFR gene mutations are FGFR2-CASP7.

[0232] In one embodiment, one or more FGFR gene mutations are FGFR3 R248C and FGFR3 Y373C.

[0233] In one embodiment, one or more FGFR gene mutations are FGFR3 S249C and FGFR3 Y373C.

[0234] In one embodiment, one or more FGFR gene mutations are FGFR3 G370C and FGFR3 Y373C.

[0235] In one embodiment, one or more FGFR gene mutations are FGFR3 R248C and FGFR3 S249C.

[0236] In one embodiment, one or more FGFR gene mutations are FGFR3 G370C, FGFR3 S249C, and FGFR3 Y373C.

[0237] In one embodiment, one or more FGFR gene mutations are FGFR3 R248C, FGFR3 S249C, and FGFR3 Y373C.

[0238] In one embodiment, one or more FGFR gene mutations are FGFR3-BAIAP2L1 and FGFR3-TACC3_V1.

[0239] In one embodiment, one or more FGFR gene mutations are FGFR3-TACC3_V1 and FGFR3-TACC3_V3.

[0240] In one embodiment, one or more FGFR gene mutations are FGFR3 S249C and FGFR3-TACC3_V1.

[0241] In one embodiment, one or more FGFR gene mutations are FGFR3 S249C and FGFR3-TACC3_V3.

[0242] In one embodiment, one or more FGFR gene mutations are FGFR3 Y373C and FGFR3-TACC3_V1.

[0243] In one embodiment, one or more FGFR gene mutations are FGFR3 R248C and FGFR3-TACC3_V1.

[0244] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3 S249C.

[0245] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3 Y373C.

[0246] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3 G370C.

[0247] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3 R248C.

[0248] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3-TACC3 V1.

[0249] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3-TACC3 v3.

[0250] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3-BAIAP2L1.

[0251] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR2-BICC1.

[0252] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR2-CASP7.

[0253] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3 R248C and FGFR3 Y373C.

[0254] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3 S249C and FGFR3 Y373C.

[0255] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3 G370C and FGFR3 Y373C.

[0256] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3 R248C and FGFR3 S249C.

[0257] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3 G370C, FGFR3 S249C, and FGFR3 Y373C.

[0258] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3 R248C, FGFR3 S249C, and FGFR3 Y373C.

[0259] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3-BAIAP2L1 and FGFR3-TACC3_V1.

[0260] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3-TACC3_V1 and FGFR3-TACC3_V3.

[0261] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3 S249C and FGFR3-TACC3_V1.

[0262] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3 S249C and FGFR3-TACC3_V3.

[0263] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3 Y373C and FGFR3-TACC3_V1.

[0264] In one embodiment, the cancer described herein is locally advanced urothelial carcinoma or metastatic urothelial carcinoma having FGFR3 R248C and FGFR3-TACC3_V1.

[0265] In one embodiment, in an aspect of the present invention, patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) are positive for PD-(L)1 expression. In one embodiment, patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) have one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly one or more FGFR3 gene alterations, and are positive for PD-(L)1 expression. In a particular embodiment, PD-(L)1 expression is low, and in particular, PD-(L)1 expression has a composite positive score of less than 10 in the PD-L1 immunohistochemistry 22C3 assay.

[0266] In one embodiment, in an aspect of the present invention, patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) are negative for PD-(L)1 expression. In one embodiment, patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) have one or more fibroblast growth factor receptor (FGFR) gene alterations, particularly one or more FGFR3 gene alterations, and are negative for PD-(L)1 expression.

[0267] In one embodiment, in aspects of the present invention, the methods, uses, or devices for use described herein result in an improvement in OS, particularly median OS, and more particularly, OS is significantly prolonged compared to chemotherapy. In one embodiment, the methods, uses, or devices for use described herein result in a median OS of about 12.1 months. In one embodiment, the methods, uses, or devices for use described herein result in a median OS of about 12.1 months compared to a median OS of about 7.8 months for chemotherapy (HR=0.64; 95%CI:0.47, 0.88; p=0.0050). In one embodiment, the chemotherapy is docetaxel or vinflunin, particularly docetaxel 75 mg / m2 every three weeks or vinflunin 320 mg / m2 every three weeks.

[0268] In one embodiment, the methods, uses, or devices for use described herein result in a reduction in the risk of death, particularly the risk of death from chemotherapy. In one embodiment, the methods, uses, or devices for use described herein reduced the risk of death from chemotherapy by about 36%. In one embodiment, the chemotherapy is docetaxel or vinflunin, in particular docetaxel 75 mg / m2 once every three weeks or vinflunin 320 mg / m2 once every three weeks.

[0269] In one embodiment, in aspects of the present invention, the methods, uses or for use described herein provide an improvement in median PFS, and in particular, PFS is significantly prolonged compared to chemotherapy. In one embodiment, the methods, uses or for use described herein result in a median PFS of about 5.6 months. In one embodiment, the methods, uses or for use described herein result in a median PFS of about 5.6 months compared to a median PFS of about 2.7 months for chemotherapy (HR, 0.58 (95% CI, 0.44~0.78; p=0.0002)). In one embodiment, the chemotherapy is docetaxel or vinflunin, in particular docetaxel 75 mg / m2 once every three weeks or vinflunin 320 mg / m2 once every three weeks.

[0270] In one embodiment, the methods, uses, or purposes for use described herein result in a reduction in the risk of progression or death, particularly a reduction in the risk of progression or death compared to chemotherapy. In one embodiment, the methods, uses, or purposes for use described herein reduced the risk of progression or death by about 42% compared to chemotherapy. In one embodiment, the chemotherapy is docetaxel or vinflunin, particularly docetaxel 75 mg / m2 once every three weeks or vinflunin 320 mg / m2 once every three weeks.

[0271] In one embodiment, the methods, uses, or devices for use described herein result in an improvement in ORR, particularly a significantly higher ORR compared to chemotherapy. In one embodiment, the methods, uses, or devices for use described herein result in an ORR of approximately 45.6% (CR 6.6%; PR 39.0%), as determined particularly by the investigator's assessment. In one embodiment, the methods, uses, or devices for use described herein result in an ORR (CR+PR) of approximately 45.6% compared to approximately 11.5% ORR (CR+PR) (CR<0.8%; PR 10.8%) for chemotherapy, as determined particularly by the investigator's assessment (relative risk, 3.94 (95% CI, 2.37~6.57), p<0.001). In one embodiment, the methods, uses, or devices for use described herein result in a confirmed ORR (CR+PR; two or more consecutive evaluations) of approximately 35.3% (CR 5.1%; PR 30.1%), as determined particularly by the investigator's assessment. In one embodiment, the methods, uses, or uses described herein result in a confirmed ORR (CR+PR; two or more consecutive evaluations) of approximately 35.3% compared to approximately 8.5% (CR 0.8%; PR 7.7%) for chemotherapy, as determined particularly by the investigator's assessment (relative risk, 3.94 (95% CI, 2.37~6.57), p<0.001). In one embodiment, the chemotherapy is docetaxel or vinflunin, in particular docetaxel 75 mg / m2 once every three weeks or vinflunin 320 mg / m2 once every three weeks. In one embodiment, the ORR is determined by the investigator's assessment. In one embodiment, the ORR is confirmed by the investigator's assessment. In one embodiment, the methods, uses, or uses described herein result in a confirmed objective response rate of approximately 35.3% compared to approximately 8.5% for chemotherapy, as determined by the investigator's assessment.

[0272] In one embodiment, the methods, uses, or devices for use described herein result in improved disease control rates, particularly improved disease control rates compared to chemotherapy. In one embodiment, the methods, uses, or devices for use described herein improve disease control rates by about 39% compared to chemotherapy. In one embodiment, the methods, uses, or devices for use described herein provide a disease control rate of about 82.4%. Chemotherapy results in a disease control rate of about 43.1%. In one embodiment, the chemotherapy is docetaxel or vinflunin, particularly docetaxel 75 mg / m2 once every three weeks or vinflunin 320 mg / m2 once every three weeks.

[0273] In one embodiment, in aspects of the present invention, the methods, uses, or uses described herein provide a favorable tolerability profile, particularly a favorable tolerability profile rate, for chemotherapy, in particular for a single chemotherapy line. In one embodiment, the chemotherapy is docetaxel or vinflunin, in particular docetaxel 75 mg / m2 once every three weeks or vinflunin 320 mg / m2 once every three weeks.

[0274] In one embodiment, the methods, uses, or uses described herein result in a median DOR of approximately 4.9 months. Chemotherapy results in a median DOR of approximately 5.6 months.

[0275] In one embodiment, the methods, uses, or devices for use described herein result in a reduction in discontinuation due to treatment-related adverse events, particularly with respect to chemotherapy. In one embodiment, the methods, uses, or devices for use described herein reduce discontinuation due to treatment-related adverse events by about 5.3% compared to chemotherapy. In one embodiment, the methods, uses, or devices for use described herein result in discontinuation due to treatment-related adverse events of about 8.1%. Chemotherapy results in discontinuation due to treatment-related adverse events of about 13.4%. In one embodiment, chemotherapy is docetaxel or vinflunin, particularly docetaxel 75 mg / m2 once every three weeks or vinflunin 320 mg / m2 once every three weeks.

[0276] In one embodiment, in the aspects of the present invention, the therapeutically effective dose of erdafitinib is 8 mg per day, particularly 8 mg once daily.

[0277] In one embodiment, in the aspects of the present invention, the therapeutically effective dose of erdafitinib is 9 mg per day, particularly 9 mg once daily.

[0278] In one embodiment, in an aspect of the present invention, the starting dose of erdafitinib is 8 mg per day, particularly once daily, and may be increased up to 9 mg per day, particularly once daily, based on measured serum phosphate levels, particularly serum phosphate levels assessed on any of days 14 to 21 after the start of erdafitinib treatment. In one embodiment, serum phosphate levels are assessed on day 14 of erdafitinib treatment to determine whether to increase the dose of erdafitinib from 8 mg once daily to 9 mg once daily. In one embodiment, serum phosphate levels are assessed on day 15 of erdafitinib treatment to determine whether to increase the dose of erdafitinib from 8 mg once daily to 9 mg once daily. In one embodiment, serum phosphate levels are assessed on day 16 of erdafitinib treatment to determine whether to increase the dose of erdafitinib from 8 mg once daily to 9 mg once daily. In one embodiment, serum phosphate levels are assessed on day 17 of erdafitinib treatment to determine whether to gradually increase the dose of erdafitinib from 8 mg once daily to 9 mg once daily. In one embodiment, serum phosphate levels are assessed on day 18 of erdafitinib treatment to determine whether to gradually increase the dose of erdafitinib from 8 mg once daily to 9 mg once daily. In one embodiment, serum phosphate levels are assessed on day 19 of erdafitinib treatment to determine whether to gradually increase the dose of erdafitinib from 8 mg once daily to 9 mg once daily. In one embodiment, serum phosphate levels are assessed on day 20 of erdafitinib treatment to determine whether to gradually increase the dose of erdafitinib from 8 mg once daily to 9 mg once daily. In one embodiment, serum phosphate levels are assessed on day 21 of erdafitinib treatment to determine whether to escalate the erdafitinib dose from 8 mg once daily to 9 mg once daily. In another embodiment, serum phosphate levels are assessed between 14 and 21 days after the start of erdafitinib treatment to determine whether to escalate the erdafitinib dose from 8 mg once daily to 9 mg once daily.In one embodiment, serum phosphate levels are assessed on any one day between day 14 and day 21 (including day 21) after initiation of erdafitinib treatment to determine whether to escalate the erdafitinib dose from 8 mg once daily to 9 mg once daily. In one embodiment, if the serum phosphate level is less than 5.5 mg / dL, the erdafitinib dose is escalated per day, in particular to 9 mg once daily. In one embodiment, if the serum phosphate level is less than 7 mg / dL, the erdafitinib dose is escalated per day, in particular to 9 mg once daily. In one embodiment, if the serum phosphate level is less than 9 mg / dL, the erdafitinib dose is escalated per day, in particular to 9 mg once daily. In one embodiment, if the serum phosphate level is in the range of 7.00 mg / dL to 8.99 mg / dL while simultaneously initiating treatment with a phosphate binder such as sevelamer, the erdafitinib dose is gradually increased to 9 mg per day, particularly once daily.

[0279] In one embodiment, in an aspect of the present invention, if the serum phosphate level assessed on any one day between day 14 and day 21 (including day 21) after initiation of erdafitinib treatment is less than 5.5 mg / dL, the starting dose of erdafitinib is 8 mg per day, particularly once daily, and is gradually increased to 9 mg per day, particularly once daily.

[0280] In one embodiment, according to the present invention, if the serum phosphate level assessed on any one day between day 14 and day 21 (including day 21) after initiation of erdafitinib treatment is less than 5.5 mg / dL and there is no drug-related toxicity, the starting dose of erdafitinib is 8 mg per day, particularly once daily, and is gradually increased to 9 mg per day, particularly once daily.

[0281] In one embodiment, according to the present invention, if the serum phosphate level assessed on any one day between day 14 and day 21 (including day 21) after initiation of erdafitinib treatment is less than 5.5 mg / dL and there are no eye disorders or adverse reactions of grade 2 or higher, the starting dose of erdafitinib is 8 mg per day, particularly once daily, and is gradually increased to 9 mg per day, particularly once daily.

[0282] In one embodiment, in an aspect of the present invention, if the serum phosphate level assessed on any one day between day 14 and day 21 (including day 21) after initiation of erdafitinib treatment is less than 7.0 mg / dL, the starting dose of erdafitinib is 8 mg per day, particularly once daily, and is gradually increased to 9 mg per day, particularly once daily.

[0283] In one embodiment, according to the present invention, if the serum phosphate level assessed on any one day between day 14 and day 21 (including day 21) after initiation of erdafitinib treatment is less than 7.0 mg / dL and there is no drug-related toxicity, the starting dose of erdafitinib is 8 mg per day, particularly once daily, and is gradually increased to 9 mg per day, particularly once daily.

[0284] In one embodiment, according to the present invention, if the serum phosphate level assessed on any one day between day 14 and day 21 (including day 21) after initiation of erdafitinib treatment is less than 7.0 mg / dL and there are no eye disorders or adverse reactions of grade 2 or higher, the starting dose of erdafitinib is 8 mg per day, particularly once daily, and is gradually increased to 9 mg per day, particularly once daily.

[0285] In one embodiment, in an aspect of the present invention, if the serum phosphate level assessed on any one day between day 14 and day 21 (including day 21) after the start of erdafitinib treatment is less than 9.0 mg / dL, the starting dose of erdafitinib is 8 mg per day, particularly once daily, and is gradually increased up to 9 mg per day, particularly once daily. In another embodiment, if the serum phosphate level assessed on any one day between day 14 and day 21 (including day 21) after the start of erdafitinib treatment is in the range of 7.00 mg / dL or more and 8.99 mg / dL or less, while simultaneously initiating treatment with a phosphate binder such as sevelamer, the starting dose of erdafitinib is 8 mg per day, particularly once daily, and is gradually increased up to 9 mg per day, particularly once daily.

[0286] In one embodiment, in an aspect of the present invention, if the serum phosphate level assessed on any one day between day 14 and day 21 (including day 21) after the start of erdafitinib treatment is less than 9.0 mg / dL and there is no drug-related toxicity, the starting dose of erdafitinib is 8 mg per day, particularly once daily, and is gradually increased up to 9 mg per day, particularly once daily. In another embodiment, if the serum phosphate level assessed on any one day between day 14 and day 21 (including day 21) after the start of erdafitinib treatment is in the range of 7.00 mg / dL or more and 8.99 mg / dL or less, and there is no drug-related toxicity, while simultaneously initiating treatment with a phosphate binder such as sevelamer, the starting dose of erdafitinib is 8 mg per day, particularly once daily, and is gradually increased up to 9 mg per day, particularly once daily.

[0287] In one embodiment, in an aspect of the present invention, if the serum phosphate level assessed on any one day between day 14 and day 21 (including day 21) after the start of erdafitinib treatment is less than 9.0 mg / dL and there are no ocular disorders or adverse reactions of grade 2 or higher, the starting dose of erdafitinib is 8 mg per day, particularly once daily, and is gradually increased up to 9 mg per day, particularly once daily. In another embodiment, if the serum phosphate level assessed on any one day between day 14 and day 21 (including day 21) after the start of erdafitinib treatment is in the range of 7.00 mg / dL or more and 8.99 mg / dL or less, and there are no ocular disorders or adverse reactions of grade 2 or higher, while simultaneously initiating treatment with a phosphate binder such as sevelamer, the starting dose of erdafitinib is 8 mg per day, particularly once daily, and is gradually increased up to 9 mg per day, particularly once daily.

[0288] In one embodiment, an 8 mg dose of erdafitinib is administered or given as two formulations, particularly two tablets, each containing 4 mg of erdafitinib. In another embodiment, an 8 mg dose of erdafitinib is administered or given as two formulations, particularly two tablets, one containing 3 mg of erdafitinib and the other containing 5 mg of erdafitinib. In a preferred embodiment, an 8 mg dose of erdafitinib is administered or given as two formulations, particularly two tablets, each containing 4 mg of erdafitinib.

[0289] In one embodiment, a 9 mg dose of erdafitinib can be administered as three formulations, particularly three tablets, each containing 3 mg of erdafitinib. In one embodiment, a 9 mg dose of erdafitinib is administered or is administered as two formulations, particularly two tablets, one containing 4 mg of erdafitinib and the other containing 5 mg of erdafitinib. In a preferred embodiment, a 9 mg dose of erdafitinib is administered or is administered as three formulations, particularly three tablets, each containing 3 mg of erdafitinib.

[0290] It should be understood that serum phosphate levels may be further monitored during erdafitinib treatment, especially when measured as a pharmacodynamic marker to determine whether to escalate the starting dose of 8 mg of erdafitinib, particularly on any one day between day 14 and day 21 of erdafitinib administration, or especially on any one day between day 14 and day 14 ± 2 of erdafitinib administration. In one embodiment, clinical management of serum phosphate levels is carried out as shown in Table 5A.

[0291] [Table 5]

[0292] Table 6A lists the recommended dose changes for adverse reactions, including hyperphosphatemia.

[0293] [Table 6]

[0294] [Table 7]

[0295] In one embodiment, the use, use for treatment, or method for treatment of a subject in need of treatment, particularly locally advanced or metastatic urothelial carcinoma in cancer patients, as referred herein, is a use for or treatment of a subject or patient having luminal cluster I subtype urothelial carcinoma.

[0296] In one embodiment, erdafitinib is administered as a pharmaceutically acceptable salt. In one embodiment, erdafitinib is administered as a pharmaceutically acceptable salt in an amount equivalent to 8 mg base equivalent or 9 mg base equivalent.

[0297] In a preferred embodiment, erdafitinib (in its base form) is administered.

[0298] In one embodiment, erdafitinib is administered as a pharmaceutically acceptable salt in an amount equivalent to 8 mg base equivalent or 9 mg base equivalent.

[0299] In one embodiment, erdafitinib is administered in the form of 8 mg of erdafitinib itself (erdafitinib base) or 9 mg of erdafitinib itself (erdafitinib base).

[0300] These salts can be prepared, for example, by reacting erdafitinib with a suitable acid in a suitable solvent.

[0301] Acid addition salts may be formed with both inorganic and organic acids. Examples of acid addition salts include salts formed with acids selected from the group consisting of acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid (mesylate), ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propanoic acid, butanoic acid, malonic acid, glucuronic acid, and lactobionic acid. Another group of acid addition salts includes salts formed from 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.

[0302] In one embodiment, erdafitinib is administered in the form of a solvate. As used herein, the term “solvate” means the physical association of erdafitinib with one or more solvent molecules. This physical association involves changes in the degree of ionic and covalent bonding, such as hydrogen bonding. In certain cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate becomes separable. The term “solvate” shall encompass both solution-phase solvates and separable solvates. Non-limiting examples of solvents that can form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

[0303] Solvates are well known in pharmaceutical chemistry. Solvates can be important in the process of preparing substances (e.g., in relation to their purification), for the storage of substances (e.g., their stability), and for the ease of handling of substances, and are often formed as part of the isolation or purification steps in chemical synthesis. Those skilled in the art can determine, by standard and long-used techniques, whether a hydrate or other solvate has been formed by the isolation or purification conditions used to prepare a given compound. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g., single-crystal X-ray crystallography or X-ray powder diffraction), and solid-state NMR (also known as SS-NMR, Magic Angle Spinning NMR, or MAS-NMR). Such techniques, along with NMR, IR, HPLC, and MS, are part of the standard analytical toolkit of a skilled chemist. Alternatively, those skilled in the art can intentionally form a solvate using crystallization conditions containing the required amount of solvent for a particular solvate. Then, the standard methods described above can be used to confirm whether the solvate has been formed. Furthermore, any complex (for example, an inclusion complex or inclusion complex with a compound such as cyclodextrin, or a complex with a metal) is also included.

[0304] All references cited herein are incorporated herein by reference in their entirety. [Examples]

[0305] Example 1: Phase 3, multicenter, open-label trial (NCT03390504) NCT03390504 is a randomized, open-label, multicenter, combined phase 3 trial comparing erdafitinib versus standard treatment, consisting of chemotherapy (docetaxel or vinflunin) or the anti-PD-(L)1 agent pembrolizumab, in patients with advanced urothelial carcinoma and selected FGFR abnormalities who have progressed during or after one or two prior treatments (cohort 1) or one prior treatment (cohort 2).

[0306] Participants will be assigned to either Cohort 1 or Cohort 2 based on their prior treatment with anti-PD-(L)1 agents. In Cohort 1, participants who have previously received anti-PD-(L)1 agents will be randomized to erdafitinib versus chemotherapy (approximately 280 participants planned for enrollment). In Cohort 2, participants who have not previously received anti-PD-(L)1 agents will be randomized to erdafitinib versus pembrolizumab. Cohorts 1 and 2 will be evaluated independently.

[0307] An independent data monitoring committee (IDMC) will be appointed for this trial. For each cohort, the IDMC will review safety data after at least 60 participants have been enrolled in the cohort, and then every six months thereafter. The IDMC will also review one designated interim analysis for each cohort, with respect to both safety and efficacy data.

[0308] The screening phase begins with molecular screening, which is performed by a central laboratory or by reviewing past local test results submitted to the sponsor for molecular eligibility assessment. Full trial screening is performed after completion of prior treatment and disease progression documentation for subjects meeting the molecular screening criteria. The treatment phase continues from randomization until disease progression, unacceptable toxicity, withdrawal of consent, or the investigator's decision to discontinue treatment. Post-treatment follow-up continues from the final visit at the end of treatment until the subject dies, withdraws consent, becomes unable to follow up, or the trial is completed (i.e., the end of data collection is achieved for each cohort), whichever comes first.

[0309] A diagram of the research design is provided in Figure 1.

[0310] The following explanation pertains to Cohort 1.

[0311] Administration Erdafitinib is provided as an oral tablet, and patients are instructed to take 8 mg orally once daily for 21 days in 21-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, or a decision by the principal investigator to discontinue treatment. Based on phosphate levels measured on day 14 of cycle 1, and considering the toxicity observed up to that day, treatment may be escalated up to 9 mg, maintained at 8 mg, or withheld.

[0312] Target group Screening for molecular eligibility may be performed at any point before randomization. A complete trial screening for molecularly eligible subjects will be performed within 30 days prior to administration of the investigational drug.

[0313] Inclusion Criteria Each potential participant must meet all of the following criteria in order to be enrolled in this study: 1. The person must be 18 years of age or older (or the legal age of consent in the jurisdiction where the test is being conducted). 2. Histological demonstration of transitional cell carcinoma of the urothelium. Minor components of mutant histology (less than 50% overall), such as glandular or squamous cell differentiation, or evolution to more invasive phenotypes, such as sarcomatoid or micropapillary changes, are acceptable. 3. Metastatic urothelial carcinoma or unresectable urothelial carcinoma 4. A documented disease progression, defined as any progression requiring a change in treatment prior to randomization. 5. Prior treatment with anti-PD-(L)1 agents as monotherapy or in combination therapy; prior systemic treatment of two lines or less. Prior treatment with anti-PD-(L)1 agents may have been given as neoadjuvant, adjuvant, or as frontline or maintenance therapy in metastatic treatment lines, as follows: □ Used in conjunction with chemotherapy or as maintenance therapy □In the case of metastasis, chemotherapy is used in conjunction with □ For superficial cancer (early stage / non-muscle-invasive bladder cancer), or in the setting of neoadjuvant or adjuvant therapy: If these subjects do not recur within one year of the last dose of anti-PD-(L)1, this is not counted as a prior systemic treatment line. However, these subjects are still eligible for Cohort 1 only. Note: Patients who received neoadjuvant chemotherapy, adjuvant chemotherapy, or immunotherapy and showed disease progression within 12 months of their last dose are considered to have received systemic therapy in a metastatic state. 6. Subjects must meet appropriate molecular eligibility criteria, such as those determined by central laboratory screening or by past local test results (from tissue or blood) performed in a Clinical Laboratory Improvement Amendments (CLIA) accredited or equivalent local laboratory using the following methods: local next-generation sequencing (NGS), direct digital counting, or Qiagen Therascreen FGFR Rotor-Gene Q (RGQ) reverse transcription polymerase chain reaction (RT-PCR) testing. Local testing in the THOR test is entirely NGS-based (either tumor or blood). The tumor must have at least one of the following translocations: FGFR2-BICC1, FGFR2-CASP7, FGFR3-TACC3, FGFR3-BAIAP2L1, in particular FGFR2-BICC1, FGFR2-CASP7, FGFR3-TACC3_V1, FGFR-TACC3_V2, FGFR3-BAIAP2L1; or one of the following FGFR3 gene mutations: R248C, S249C, G370C, Y373C. 7. ECOG Performance Status Grade 0, 1, or 2 8. Appropriate bone marrow, liver, and kidney function: a. Bone marrow function (without cytokine or erythropoiesis-stimulating support in the past two weeks): Absolute neutrophil count (ANC) exceeds 1,500 / mm3 Platelet count exceeding 75,000 / mm3 (100,000 / mm3 or higher in Cohort 1 of facilities that selected vinflunin chemotherapy) Hemoglobin level above 8.0 g / dL (no transfusion, or stable; i.e., no significant decrease in hemoglobin 2 weeks after transfusion) b. Liver function: Total bilirubin is 1.5 × the upper limit of the institutional standard (ULN) or less, or direct bilirubin is 1.5 × ULN or less for subjects whose total bilirubin exceeds 1.5 × ULN [1 × ULN or less for subjects in Cohort 1 of facilities that select docetaxel chemotherapy]. For subjects with liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are ≤2.5 × institutional ULN or ≤5 × institutional ULN. (In Cohort 1 of facilities that have chosen docetaxel chemotherapy, both ALT and AST levels must be ≤1.5×ULN simultaneously with alkaline phosphatase levels ≤2.5×ULN.) c. Renal function: Creatinine clearance (CrCl) of 30 mL / min, either measured directly via a 24-hour urine collection or calculated using the Cockcroft-Gault formula. d. Criteria are removed with each protocol modification. e. Phosphate: Less than ULN within 14 days of treatment and before day 1 of cycle 1 (when medical management is permitted). 9. Each individual must sign an Informed Consent Form (ICF) indicating that they understand the nature, importance, purpose, procedures and results of the examination and are willing to take the examination (or their legally authorized representative must sign it). 10. Women who may be pregnant must have a negative pregnancy test (beta-human chorionic gonadotropin [βhCG]) at the time of screening (urine or serum). 11. The use of contraceptives by men or women must comply with local regulations regarding the use of contraception for the subjects participating in the clinical trial. A woman of childbearing potential (defined as a woman of childbearing age, from menarche until menopause, unless permanently infertile). Methods of permanent sterilization include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Use a highly effective method of contraception (less than 1% failure rate per year when used consistently and correctly). I agree to continue using a highly effective method of contraception during the trial and for at least six months after the last dose of the study drug. I agree not to donate eggs (oocytes, oocytes) for assisted reproductive purposes during the trial and for at least six months after the last dose of the study drug. You must not breastfeed and have no plans to become pregnant during the study or for at least six months after the last dose of the study drug. For women of childbearing potential and sexually active men: I agree to use condoms containing spermicidal foam / gel / film / cream / suppositories. I agree not to provide sperm during the trial and for at least six months after the last dose of the study drug. You do not plan to have children during the trial or within six months of the last dose of the study drug.

[0314] Exclusion criteria for all targets Individuals who may meet any of the following criteria will be excluded from participation in the study: 1. Participation in any other investigational drug treatment or another clinical trial for therapeutic purposes within 30 days prior to randomization. 2. Active malignant disease (i.e., requiring a change in treatment within the past 24 months). The only acceptable exception is as follows: Urothelial carcinoma. Skin cancer treated within the past 24 months that is considered to be completely cured. Focal prostate with a Gleason score of 6 (treated within the past 24 months, or untreated and under surveillance). Focal prostate with a Gleason score of 3+4, treated more than 6 months prior to complete trial screening, and considered to have a very low risk of recurrence. 3. Symptomatic central nervous system metastases. 4. The patient has received prior treatment with an FGFR inhibitor. 5. Known allergies, hypersensitivity, or intolerances to erdafitinib or its excipients. 6. Currently, you have central serous retinopathy (CSR) or retinal pigment epithelial detachment of any grade. 7. A history of uncontrolled cardiovascular disease, including the following: a. Unstable angina, myocardial infarction, ventricular fibrillation, polymorphic ventricular tachycardia, cardiac arrest, or known congestive heart failure class III-V within the past three months; cerebrovascular event or transient ischemic attack within the past three months. b. QTc prolongation (Fridericia; QTc exceeding 480 milliseconds) confirmed by triple evaluation during screening. c. Pulmonary embolism or other venous thromboembolism (VTE) within the past two months. 8. Known active AIDS (human immunodeficiency virus (HIV) infection), except in cases where the subject has not received a stable antiretroviral therapy regimen for the past six months or more, has not had an opportunistic infection in the past six months, and has a CD4 count greater than 350. 9. Known active hepatitis B or C infection (unless polymerase chain reaction [PCR] negative [by local laboratory range] in all available tests over the past 6 months). 10. Failure to recover from reversible toxicity of prior anticancer therapy (excluding clinically insignificant toxicity such as alopecia, skin discoloration, neuropathy, and hearing loss). 11. Impairment of wound healing ability as defined as skin / pressure ulcers, chronic lower leg ulcers, known gastric ulcers, or unhealed incisions. 12. Major surgery performed within 4 weeks prior to randomization. 13. Any condition, in the opinion of the principal investigator, that would not be in the best interests of the participant (e.g., would be detrimental to their health) or that would interfere with, limit, or interfere with the assessments specified in the protocol. Examples include an ongoing active infection requiring systemic treatment and an ongoing, uncontrolled medical condition. In addition to the exclusion criteria above, Cohort 1 subjects who may meet the following criteria will be excluded from participation in the study: 14. For individuals participating in facilities using docetaxel: A history of severe hypersensitivity reactions (e.g., generalized rash / erythema, hypotension, bronchospasm, angioedema, or anaphylaxis) to docetaxel or any other medication prescribed with polysorbate and paclitaxel. In facilities using docetaxel, individuals with evidence of interstitial lung disease or active non-infectious pneumonia are excluded.

[0315] Treatment allocation This trial will utilize central randomization. Participants will be assigned to either Cohort 1 or Cohort 2 based on their prior treatment with anti-PD-(L)1 agents. Within each cohort, participants will be randomly assigned to one of two treatment groups based on a computer-generated randomization schedule. Randomization will be balanced using randomly rearranged blocks and stratified by region (North America vs. EU vs. the rest of the world), Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs. 2), and disease distribution (presence or absence of visceral metastases: lung, liver, or bone).

[0316] Dosage and administration 1. Erdafitinib Erdafitinib is provided as an oral tablet. Participants randomized to Arm 1A (see Figure 1) will be instructed to orally take erdafitinib once daily at an initial dose of 8 mg for 21 days in 21-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, or a decision by the principal investigator to discontinue treatment. Each dose should be taken at approximately the same time each day, with or without food. The study drug is to be taken with approximately 240 mL (8 ounces) of water. The tablets should be swallowed whole, and participants should not attempt to dissolve them in water, nor should they be crushed or chewed. Participants should avoid consuming grapefruit or Seville oranges due to CYP450 3A4 / 5 inhibition.

[0317] Weight Gain Guidelines All participants will begin treatment with erdafitinib 8 mg once daily from day 1 to day 14 of cycle 1. A blood sample will be taken on day 14 of cycle 1 to determine serum phosphate levels. Patients with serum phosphate concentrations exceeding 9.00 mg / dL (exceeding 2.91 mmol / L) should initiate treatment with a phosphate binder such as sevelamer, while monitoring serum phosphate concentrations at least once a week. Erdafitinib treatment should be withheld until serum phosphate concentrations return to less than 7.00 mg / dL (less than 2.25 mmol / L). Patients with serum phosphate levels of 7.00–8.99 mg / dL (2.25 mmol / L–2.90 mmol / L) should have their erdafitinib dose increased to 9 mg once daily while simultaneously initiating treatment with a phosphate binder such as sevelamer. For patients with serum phosphate levels less than 7.00 mg / dL (less than 2.25 mmol / L), the erdafitinib dose should be increased to 9 mg once daily. Concomitant therapy is not necessary for these patients.

[0318] If medication is missed, it can be taken up to 6 hours after the scheduled time. The patient may return to the normal schedule the following day. If more than 6 hours have passed since the missed dose, the dose must be skipped, and the patient must continue treatment at the scheduled time the following day. If vomiting occurs after drug administration, the supplemental dose should not be taken, and such events occurring within 4 hours of dose administration must be recorded in the electronic case report form (eCRF).

[0319] [Table 8] a For phosphate concentrations exceeding 5.5 mg / dL, phosphate intake should be limited to 600-800 mg / day.

[0320] Table 6C lists the recommended dose changes for adverse reactions, including hyperphosphatemia.

[0321] [Table 9]

[0322] 2. Vinflunin or docetaxel In Arm 1B (see Figure 1), subjects randomized to chemotherapy will receive either vinflunine 320 mg / m2 as a 20-minute intravenous infusion every three weeks, or docetaxel 75 mg / m2 as a 1-hour intravenous infusion every three weeks. Treatment with either drug will continue until disease progression, unacceptable toxicity, withdrawal of consent, or a decision by the principal investigator to discontinue treatment.

[0323] The choice of which chemotherapy regimen to use at each facility is determined by the principal investigator.

[0324] If toxicity does not recover to grade 0-1 within two weeks of the last infusion of vinflunine or four weeks of the last infusion of docetaxel, the study treatment should be discontinued after consultation with the sponsor. With the agreement of the principal investigator and the sponsor, subjects who still have a grade 2 laboratory adverse event after four weeks may continue the study only if they are asymptomatic and stable.

[0325] 2.1. Binflunin Vinflunine, 320 mg / m2, should be administered after all procedures and assessments for the day have been completed. Body surface area (BSA) (in m2 units) should be calculated according to local facility practices. Refer to the Vinflunine Summary of Product Characteristics for instructions on the preparation and administration of Vinflunine infusion, as well as recommendations for concomitant administration (i.e., laxatives and dietary means, including oral hydration, are recommended from day 1 to day 7 after each Vinflunine administration).

[0326] 2.1.1. Change in Vinflunin Dosage If the WHO / ECOG performance status (PS) is 1 or greater, or if the PS is 0 and pelvic irradiation has not yet occurred, vinflunin therapy should be initiated at a dose of 280 mg / m2. If no hematological toxicity occurs during the first cycle that would cause a delay in treatment or a reduction in dose, the dose should be increased to 320 mg / m2 every three weeks for subsequent cycles.

[0327] For patients with moderate renal impairment (40 mL / min ≤ CrCl ≤ 60 mL / min), the recommended dose is 280 mg / m2 administered once every three weeks. For patients with severe renal impairment (20 mL / min ≤ CrCl < 40 mL / min), the recommended dose is 250 mg / m2 administered once every three weeks.

[0328] The recommended dose of vinflunin is 250 mg / m2 administered once every three weeks for patients with mild hepatic impairment (Child-Pugh grade A), or those with a prothrombin time of 60% or higher and 1.5 × ULN < bilirubin ≤ 3 × ULN, and who meet at least one of the following criteria: Transaminase > ULN or gamma-glutamyltransferase > 5×ULN.

[0329] The recommended dose of vinflunin is 200 mg / m2 administered once every three weeks in patients with moderate hepatic impairment (Child-Pugh grade B), or in patients with prothrombin time ≥ 50% of normal and bilirubin > 3 × ULN, transaminase > ULN, and gamma-glutamyltransferase > ULN.

[0330] The recommended dosage for individuals aged 75 and over is as follows: □For subjects aged at least 75 years but under 80 years, the appropriate dose of vinflunin to be administered is 280 mg / m2 every three weeks. □For patients aged 80 and over, the appropriate dose of vinflunin to be administered is 250 mg / m2 every three weeks.

[0331] In patients who are initiated with vinflunine at 280 mg / m2 and experience an adverse event (AE) requiring a dose change, the dose should be reduced to 250 mg / m2 after the first occurrence and resolution, and discontinued after the second occurrence. In patients who are initiated with vinflunine at 250 mg / m2 and experience an AE requiring a dose change, the dose should be reduced to 225 mg / m2 after the first occurrence and resolution, and discontinued after the second occurrence.

[0332] Cases of posterior reversible encephalopathy syndrome (PRES) have been observed after administration of vinflunin. Typical clinical symptoms include neurological (headache, confusion, seizures, visual disturbances), systemic (hypertension), and gastrointestinal (nausea, vomiting). Radiographic signs include white matter abnormalities in the posterior brain region. Vinflunin should be discontinued in patients who develop neurological signs of PRES.

[0333] For all grades of neutropenia lasting 7 days or less, vinflunine administration should be maintained until neutrophil counts recover to over 1500 cells / mm3. For grades 1, 2, and 3 of thrombocytopenia, vinflunine should be maintained until platelet counts recover to over 100,000 cells / mm3. For grades 1, 2, and 3 of anemia, vinflunine should be maintained until it resolves to grade 1 or baseline. Specific dose adjustments for those receiving vinflunine are recommended in Table 7A below. Dose adjustments for vinflunine should also be considered according to the local product label.

[0334] [Table 10]

[0335] 2.2. Docetaxel Docetaxel, 75 mg / m2, should be administered after all procedures and assessments for the day have been completed. Body surface area (BSA) (in m2 units) should be calculated according to local facility practice. All subjects should be premedicated with an oral corticosteroid, such as dexamethasone 16 mg per day (e.g., 8 mg twice daily), for 3 days, starting one day prior to docetaxel administration, to reduce the incidence and severity of fluid retention and hypersensitivity reactions. The appropriate premedication regimen may be determined by the principal investigator.

[0336] Cystic macular edema has been reported in patients treated with docetaxel. Patients with visual impairment should undergo a prompt and complete ophthalmological examination. If cystic macular edema is diagnosed, docetaxel treatment should be discontinued and appropriate treatment should be initiated.

[0337] I will consult docetaxel prescribing information regarding instructions for preparing and administering docetaxel infusion solution, as well as recommendations for simultaneous administration.

[0338] 2.2.1. Changes in docetaxel dosage Docetaxel should not be administered to patients with bilirubin levels exceeding 1 × ULN, or AST or ALT levels exceeding 1.5 × ULN, and alkaline phosphatase levels exceeding 2.5 × ULN. Patients with elevated bilirubin or transaminase abnormalities simultaneously with alkaline phosphatase are at high risk of developing grade 4 neutropenia, febrile neutropenia, infection, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Docetaxel should also not be administered to patients with neutrophil counts less than 1500 cells / mm3. Severe fluid retention has been reported after docetaxel therapy. Patients should be premedicated with oral corticosteroids before each docetaxel administration to reduce the incidence and severity of fluid retention. Patients with pre-existing exudation should be closely monitored from the first dose for the possibility of exacerbation. Patients developing peripheral edema can be treated with standard measures, such as salt restriction and oral diuretics.

[0339] For all grades of neutropenia lasting 7 days or less, continue docetaxel until neutrophil count recovers to >1500 cells / mm3. For grades 1, 2, and 3 of thrombocytopenia, continue docetaxel until platelet count recovers to 100,000 cells / mm3. For grades 1, 2, and 3 of anemia, continue docetaxel until it resolves to grade 1 or baseline. Dose changes for patients receiving docetaxel are recommended in Table 8A below.

[0340] Dosage adjustments for docetaxel should also be considered in accordance with local product labeling.

[0341] [Table 11]

[0342] Effectiveness analysis Primary endpoint The primary endpoint is overall survival (OS). The primary efficacy analysis is based on an intention-to-treat (ITT) population that includes all randomized subjects in each cohort. The distribution of OS is estimated for each treatment group within each cohort using the Kaplan-Meier method. Survival curves for OS are compared between two treatment groups using a stratified log-rank test. The stratification factors used in the analysis are: region (North America vs. EU vs. the rest of the world), ECOG performance status (0 or 1 vs. 2), and disease distribution (presence or absence of visceral metastases: lung, liver, or bone). If some strata have too few OS events, a pre-specified stratification join is performed.

[0343] Furthermore, the hazard ratios for erdafitinib relative to the control and its associated 95% CI are calculated based on the Cox proportional hazards model.

[0344] Secondary efficacy endpoints Secondary efficacy endpoints are PFS, ORR (objective response), and safety. Secondary endpoints also include DOR and changes from baseline in patient-reported outcomes (Functional Assessment of Cancer Therapy - Bladder Cancer, Patient - Global Impression of Severity, and the European Quality of Life - 5 Dimensions - 5 Levels). PFS is analyzed similarly to OS. The distribution of DOR is estimated using the Kaplan-Meier method. ORR is analyzed by the Cochran-Mantel-Haenszel chi-square test for randomized subjects with measurable disease at baseline. Analysis of secondary efficacy endpoints includes all randomized subjects (ITT subjects) unless otherwise specified. Family-wise type 1 error is strongly controlled at 5% (two-sided) for secondary efficacy endpoints.

[0345] Subgroup analysis Primary and secondary efficacy endpoints will be analyzed by subgroup.

[0346] Evaluation (Cohort 1) The response to solid tumors was assessed by the principal investigator according to RECIST V1.1, every six weeks for the first six months, then every twelve weeks for the following six months and thereafter. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Baseline ophthalmological examinations included Amsler grid scans, optical coherence tomography (OCT) scans, and ophthalmological assessments. Amsler grid scans were performed in each cycle. Repeated OCTs were performed as clinically indicated based on Amsler grid scans or clinical assessments.

[0347] Safety analysis Adverse events The verbatim terminology used by the principal investigator to identify adverse events in case report forms (CRFs) is coded using the Medical Dictionary for Regulatory Activities (MedDRA). Adverse events occurring under treatment are those that occur during the treatment phase or those that result from a pre-existing condition that worsened from baseline. All reported adverse events are included in the analysis. For each adverse event, the percentage of subjects experiencing at least one occurrence of the given event is summarized by treatment group. Further comparisons between treatment groups are provided where appropriate.

[0348] Adverse events will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03. The severity of an adverse event is a clinical determination of its intensity. Severity assessment of adverse or serious adverse events should be completed using NCI-CTCAE, Version 4.03. Any adverse or serious adverse events not listed in NCI-CTCAE, Version 4.03 will be graded according to the clinical judgment of the principal investigator using the following standard grades. Grade 1: Mild; asymptomatic or mild; clinical or diagnostic observation only; no intervention recommended. Grade 2: Moderate; minimal intervention, local intervention, or non-invasive intervention recommended; age-appropriate instrumental activities of daily living restricted. Grade 3: Severe or medically significant, but not immediately life-threatening; hospitalization or extension of hospitalization recommended; causing disability; limiting independent activities of daily living. Grade 4: Life-threatening consequences; order for emergency intervention. Grade 5: Death related to an adverse event.

[0349] The principal investigator must use clinical judgment when assessing the severity of events that the subject did not directly experience (e.g., laboratory anomalies).

[0350] Statistical analysis (Cohort 1) The trial was designed to have at least 85% output to detect a hazard ratio of 0.65, corresponding to a 53% increase in median overall survival in the erdafitinib group compared to the chemotherapy group, with a two-sided type I error level of 0.05; one interim analysis for both efficacy and futility was planned with approximately 65% ​​information fraction (approximately 136 deaths out of a total of 208). Enrollment of approximately 280 patients was determined to be sufficient to provide the required statistical power. The O'Brien-Fleming boundary was applied and performed by the Lan-DeMets consumption function for a total type I error of 0.05. Early termination for efficacy was guaranteed if the two-sided p-value in the interim analysis was less than 0.019 based on the measured 75% information fraction at the clinical cutoff date (i.e., 155 deaths). Considering the entire data, termination for futility was possible if the hazard ratio in the interim analysis was greater than 1.0.

[0351] A key secondary endpoint was part of the hierarchical trial strategy to strongly control the overall family-wise type I error rate at 0.05 (two-sided). Descriptive subgroup analyses were performed without adjustment for multiplicity. 95% confidence intervals are provided but should not be used as a substitute for hypothesis testing. Efficacy analyses used the intention-to-treat population, including all randomized patients. Safety analyses used the safety population, including all patients who received at least one study treatment. Distributions of overall survival and progression-free survival for each treatment group were summarized using the Kaplan-Meier method and compared to the log-rank test. Estimated hazard ratios with 95% confidence intervals summarizing the magnitude of the benefit of erdafitinib over chemotherapy were derived from a Cox proportional hazards model using treatment as the sole independent variable. Distributions of objective responses between treatment groups, including estimates of relative risk in 95% confidence intervals, were compared using the Cochrane-Mantel-Henzel method.

[0352] Results: Part 1

[0353] [Table 12] a One patient in the erdafitinib group had received 3 lines of prior systemic therapy. b For PD-L1 status, the percentages are based on patients with available data (n = 96 for erdafitinib and n = 79 for chemotherapy). c All registered patients had an FGFR3 alteration. Two patients were subsequently identified as false positives; they were included in the ITT population. CPS, composite positive score.

[0354] Patient baseline characteristics were generally balanced across treatment groups. Most patients had a PD-L1 low-expression status. 33% of patients in the erdafitinib group and 25% of patients in the chemotherapy group had received 1 line of prior systemic therapy. 66% and 75% had received 2 lines of prior therapy, respectively.

[0355]

Table 13

[0356] 1 line of treatment: ○ Erda: 33 patients (24.3%) received both chemotherapy and anti-PD-(L)1 ○ Chemo: 16 patients (12.3%) received anti-PD-(L)1 without chemotherapy; 15 patients (11.5%) received both chemotherapy and anti-PD-(L)1 2 lines of treatment: ○ First line: ■ Erda: 77 patients (56.6%) received chemotherapy without anti-PD-(L)1 ■ Chemo: 76 patients (58.5%) are receiving chemotherapy without anti-PD-(L)1. ○ Second line: ■ Erda: 76 patients (55.9%) are receiving anti-PD-(L)1 without chemotherapy. ■ Chemo: 78 patients (60.0%) received anti-PD-(L)1 without chemotherapy.

[0357] For patients who have received one line of prior treatment: ■ There was a mixed group of patients who received checkpoint inhibitors (anti-PD-(L)1) alone (without chemotherapy) and patients who received checkpoint inhibitors (anti-PD-(L)1) as maintenance therapy or in combination with chemotherapy.

[0358] For patients who have received two lines of prior treatment: ■ Most patients receive chemotherapy as their first-line treatment and checkpoint inhibitors (anti-PD-(L)1) as their second-line treatment.

[0359] [Table 14]

[0360] Primary efficacy endpoint: Overall survival (OS), defined as the time from randomization to death from any cause, is the primary efficacy endpoint. ●In Cohort 1, after approximately 65% ​​of the information fraction had been achieved, an intermedication (IA) was pre-planned to assess both efficacy and futility. The IA occurred in approximately 75% of the information fraction, and the significance level was determined using the O'Brien-Fleming (OBF) alpha consumption function to control for type I error at a significance level of 0.05 (two-sided). The efficacy boundary p-value was determined to be 0.019 (two-sided). Based on these interim results demonstrating the superiority of erdafitinib over chemotherapy, the Independent Data Monitoring Committee (IDMC) recommended stopping the trial, deblinding the trial, and allowing crossover to erdafitinib for patients randomized to the chemotherapy group.

[0361] At the clinical cutoff (CCO) date, a total of 266 subjects (136 for erdafitinib; 130 for chemotherapy) were randomized. Of the randomized subjects, 247 (135 for erdafitinib; 112 for chemotherapy) received at least one dose of the study drug. Subjects who were randomized but not treated were discontinued from the study, most commonly due to subject withdrawal (10 subjects) and death (9 subjects). At the data cut, 208 of the 247 treated subjects (106 for erdafitinib; 102 for chemotherapy) had discontinued treatment. The median follow-up was 15.9 months.

[0362] The analysis was unstratified for OS and PFS. The ORR analysis was stratified by ECOG Performance Status (PS) according to a pooling algorithm.

[0363] [Table 15] Note: All reported p-values ​​are two-sided; CI = confidence interval

[0364] A total of 155 OS events (erdafitinib: 77; chemotherapy: 78) occurred in the ITT population at the data cut, which corresponds to approximately 75% of the information fraction in the interim analysis (IA). The Kaplan-Meier (KM) estimates for median OS were 12.1 months (95% CI: 10.3, 16.4) for erdafitinib and 7.8 months (95% CI: 6.5, 11.1) for chemotherapy. A hazard ratio (HR) of 0.64 (95% CI: 0.47, 0.88) was observed based on the (unstratified) Cox proportional hazards model, representing a 36.0% reduction in the risk of death for the erdafitinib group (two-sided log-rank test p-value = 0.0050). The superiority of erdafitinib over chemotherapy for OS was established by the crossover of a predetermined two-sided efficacy boundary p-value of 0.019 based on the OBF alpha consumption function. Figure 2 shows the K-MOS curves for the two treatment groups. The results are generally consistent across clinically significant subgroups, including age, FGFR change, baseline ECOG PS, presence / absence of visceral metastases, and PD-L1 status.

[0365] Forest plot of overall survival - subgroup analysis; ITT analysis set for Cohort 1 (Trial 42756493-BLC3001)

[0366] [Table 16]

[0367] Forest plot of overall survival - subgroup analysis; ITT analysis set for Cohort 1 (Trial 42756493-BLC3001)

[0368] [Table 17]

[0369] Important secondary efficacy endpoints Progression-free survival A total of 191 progression-free survival (PFS) events (erdafitinib: 101; chemotherapy: 90) occurred at the data cut-off time. The KM estimates for median PFS were 5.6 months (95% CI: 4.4, 5.7) for erdafitinib and 2.7 months (95% CI: 1.8, 3.7) for chemotherapy. A HR of 0.58 (95% CI: 0.44, 0.78) was observed based on an (unstratified) Cox proportional hazards model, representing a 42.0% reduction in the risk of progression or death in the erdafitinib group (two-sided log-rank test p-value = 0.0002). The superiority of erdafitinib over chemotherapy in terms of PFS was established by the crossover of a predetermined two-sided efficacy boundary p-value of 0.019. Figure 3 shows the KM PFS curves for the two treatment groups.

[0370] Objective response rate In the ITT population, the objective response rate (ORR), defined as the proportion of subjects with the best response (partial or complete response), was 45.6% (62 / 136) (95% CI: 37.0%, 54.3%) and 11.5% (15 / 130) (95% CI: 6.6%, 18.3%) for erdafitinib and chemotherapy, respectively. Based on the Cochrane-Mantel-Henzel (CMH) test, this represented an observed relative risk of 3.94 (95% CI: 2.37, 6.57), indicating that the probability of achieving an objective response was approximately four times higher in the erdafitinib group (two-sided p-value < 0.001) compared to the chemotherapy group (Table 13). The superiority of erdafitinib over chemotherapy in terms of ORR was established by the crossover of a predetermined two-sided efficacy boundary p-value of 0.019 based on the OBF alpha consumption function. The median duration of response (DOR) was 4.9 (95% CI: 3.8, 7.5) for erdafitinib and 5.6 (95% CI: 2.1, 6.0) months for chemotherapy, respectively.

[0371] [Table 18]

[0372] Cohort 1 Safety Overview ●Of the 247 subjects in the safety analysis set, 133 (98.5%) in the erdafitinib group and 109 (97.3%) in the chemotherapy group experienced a specialized adverse event (TEAE) that occurred under at least one treatment. ● Grade 3-4 TEAEs were reported in 85 patients (63.0%) in the erdafitinib group and 72 patients (64.3%) in the chemotherapy group. ●Serious TEAEs were reported in 56 patients (41.5%) in the erdafitinib group and 47 patients (42.0%) in the chemotherapy group. ● In the erdafitinib group, 19 patients (14.1%) discontinued treatment due to TEAE, while in the chemotherapy group, 20 patients (17.9%) discontinued treatment due to TEAE. ● In the erdafitinib group, 19 patients (14.1%) discontinued treatment due to adverse events of any cause, while in the chemotherapy group, 20 patients (17.9%) discontinued treatment due to adverse events of any cause. ● Fatal TEAEs were reported in 6 patients (4.4%) in the erdafitinib group and 7 patients (6.2%) in the chemotherapy group. Clinically significant TEAEs (Triple Emergency Events) with erdafitinib were reported in 125 patients (92.6%) in the erdafitinib group: hyperphosphatemia (108 patients, 80.0%), stomatitis (65 patients, 48.1%), dry mouth (53 patients, 39.3%), onycholysis (31 patients, 23.0%), dry skin (31 patients, 23.0%), palmar-plantar erythema paresthesia (41 patients, 30.4%), and dry eye (23 patients, 17.0%). Fewer patients in the chemotherapy group reported these events.

[0373] Central serous retinopathy (CSR), a known class effect of FGFR inhibitors, is a particularly interesting adverse event. TEAEs of CSR were reported in 23 patients (17.0%) in the erdafitinib group. No CSR events were reported in patients in the chemotherapy group.

[0374] In the erdafitinib group: Eighteen patients (13.3%) had serious treatment-related adverse events (AEs). One treatment-related death occurred. c Émergencies associated with erdafitinib were mostly manageable with dose adjustments and supportive care.

[0375] In the chemotherapy group: Twenty-seven patients (24.1%) had serious treatment-related adverse events (AEs). Six treatment-related deaths occurred. f

[0376] [Table 19] Adverse events (AEs); PPE (personal protective equipment), palmar-plantar redness and numbness. a If an event of any grade occurs in 30% or more of patients in the erdafitinib group, or if a grade 3-4 event occurs in 5% or more of patients, the adverse events (AEs) will be listed using preferred terminology. b The most frequent treatment-related adverse events leading to discontinuation of erdafitinib included eye disorders (3 patients) and skin and subcutaneous disorders (3 patients). c Treatment-related adverse events leading to death were reported as sudden death. d If an event of any grade occurs in 20% or more of patients in the chemotherapy group, or if a grade 3-4 event occurs in 5% or more of patients, list the adverse events using preferred terminology. e The most frequent treatment-related adverse events leading to discontinuation of chemotherapy included blood and lymphatic disorders (5 patients) and infections and extrinsic infections (3 patients). f In the chemotherapy group, fatal treatment-related adverse events included febrile myelopathy (2 patients), febrile neutropenia (1 patient), septic shock (2 patients), and atypical pneumonia (1 patient).

[0377] [Table 20] a Nail disorders: Nail bed hemorrhage, nail discoloration, nail disorders, onycholysis, perinail elevation, onychotoxicity, nail pain, onycholysis, onycholysis, perinatal inflammation, onycholysis. b Skin disorders: blisters, dry skin, erythema, hyperkeratosis, palmar erythema, palmoplantar erythematous dysesthesia syndrome, plantar erythema, rash, erythematous rash, generalized rash, maculopapular rash, maculopapular rash, skin atrophy, skin exfoliation, skin fissures, skin disorders, skin ulcers, toxic skin rash, xerosis. c Eye disorders (excluding central serous retinopathy): blepharitis, cataracts, subcapsular cataracts, conjunctival hemorrhage, conjunctival hyperemia, conjunctival irritation, corneal erosion, corneal infiltrates, dry eye, ocular inflammation, eye irritation, eye pain, foreign body sensation in the eye, keratitis, increased tearing, night blindness, conjunctival hyperemia, photophobia, blurred vision, decreased visual acuity, visual impairment, xanthopsia, macular inflammation, chorioretinitis, conjunctivitis, ulcerative keratitis. d Central serous retinopathy: retinal detachment, vitreous detachment, retinal edema, retinopathy, chorioretinopathy, retinal pigment epithelium detachment, macular retinal pigment epithelium detachment, macular detachment, serous retinal detachment, subretinal fluid, retinal thickening, chorioretinitis, serous retinopathy, macular dystrophy, choroidal exudation

[0378] conclusion The results above demonstrate that the primary objective of the Cohort 1 trial was met: Erdafitinib significantly extended or extended overall survival (OS) compared to chemotherapy in patients with progressive / muC with FGFR changes following prior anti-PD-(L)1 treatment (i.e., median OS of 12.1 months vs. 7.8 months; HR=0.64; p=0.0050). Erdafitinib resulted in a 36% reduction in the risk of death compared to chemotherapy. The OS benefit of erdafitinib was consistent across clinically relevant subgroups. Erdafitinib also significantly extended progression-free survival (PFS of 5.5 months vs. 2.7 months; HR=0.58; p=0.0002). ORR was also significantly greater for erdafitinib, while DOR was similar. The treatment groups were balanced in terms of demographic and baseline disease characteristics. The safety results were consistent with the known safety profiles for erdafitinib and chemotherapy in this patient population.

[0379] The Phase 3 trial supports the clinical efficacy of erdafitinib as a standard of care option for mUC patients with FGFR changes after anti-PD-(L)1 treatment.

[0380] Results: Part 2 patient In the THOR trial, of a total of 8,733 patients (Cohorts 1 and 2) centrally screened for molecular eligibility, 8,396 had tumor samples available with any laboratory results, and 7,293 had valid central laboratory results; of the patients with validated central laboratory results, 1,212 had FGFR changes (positive rate, 16.6%; Figures 5A and 5B). Of the 1,324 patients with any laboratory results, FGFR changes were detected, 1,212 based on central laboratory results, 108 based on local laboratory results (patients with local results may also have central results), and 64 transferred from other studies (ANNAR [NCT03955913] and NORSE [NCT03473743]). In Cohort 1, 266 patients were randomized, with 136 assigned to the erdafitinib group and 130 to the chemotherapy group (Figure 5C). A disparity in the number of untreated patients was observed between the groups, primarily due to 12 patients refusing treatment in the chemotherapy group (1 in the erdafitinib group and 18 in the chemotherapy group). 99.2% of patients in Cohort 1 had altered FGFR (two patients had altered FGFR on central laboratory tests, which were later identified as false positives after randomization due to a problem with the FGFR test kit at a specific central laboratory identified by the kit manufacturer; these two patients had not undergone repeated central or pre-random local testing). In Cohort 1, 197 (74.2%) of the 264 patients with altered FGFR were enrolled based on central laboratory results; 67 patients were enrolled by local testing (tissue, n=60; blood, n=6; unspecified, n=1). 80.8% had FGFR mutations, 16.5% had FGFR fusions, and 1.9% had both FGFR mutations and fusions (Figures 5D, 5E, 7B, and 7C, and Table 17). No patients had FGFR2 alterations; the most frequent FGFR alteration was FGFR3S249C mutation (46.6%), followed by FGFR3Y373C mutation (16.9%), and FGFR3-TACC3_V1 fusion (9.8%). Baseline demographic and clinical characteristics of patients were well-balanced across the erdafitinib and chemotherapy treatment groups (Tables 16 and 18).Only one patient was identified as Black; this was primarily due to the small number of registrations in the United States and restrictions on reporting race due to local regulations regarding clinical practice (e.g., France). Most patients with PD-L1 results (89.7%) had low PD-L1 expression (composite positive score <10 [Dako PD-L1 IHC 22C3 assay, Labcorp]), and baseline PD-L1 expression was not reported for some patients due to insufficient tumor availability.

[0381] With the exception of three patients who were misassigned, all patients had received prior treatment with anti-PD-(L)1 therapy (Table 19). More than half of the patients in both treatment groups received anti-PD-(L)1 as monotherapy in the second-line setting (erdafitinib, 55.9%; chemotherapy, 58.5%). One-third (33.1%) of the patients in the erdafitinib group and one-quarter (25.4%) of the patients in the chemotherapy group had received one line of prior systemic therapy. Although not required by the study protocol, the vast majority of patients (89.1%) had received at least one line of prior chemotherapy (50.8% had prior cisplatin; 29.3% had prior carboplatin).

[0382] Effectiveness The median survival follow-up was 15.9 months (18.0 months and 14.9 months in the erdafitinib group and chemotherapy group, respectively). In the interim analysis, a total of 155 patients died (approximately 75% of the information fraction; two-sided alpha 0.019) (77 and 78 patients in the erdafitinib group and chemotherapy group, respectively). The median overall survival was 12.1 months (95% confidence interval [CI], 10.3–16.4) in the erdafitinib group and 7.8 months (95% CI, 6.5–11.1) in the chemotherapy group, with an estimated hazard ratio of 0.64 (95% CI, 0.47–0.88; P=0.005). (Figure 6A). The estimated percentages of patients surviving at 6 months and 12 months were 66% (95% CI, 56–74) and 38% (95% CI, 28–47), respectively, in the chemotherapy group, compared to 85% (95% CI, 77–90) and 51% (95% CI, 41–60), respectively, in the erdafitinib group. The efficacy of erdafitinib was generally consistent across subgroups (Figure 6B). Following the interim analysis, the independent data monitoring committee recommended halting the trial, deblinding the data, and allowing crossover from chemotherapy to erdafitinib.

[0383] The median progression-free survival was 5.6 months (95% CI, 4.4–5.7) and 2.7 months (95% CI, 1.8–3.7) in the erdafitinib group and the chemotherapy group, respectively, with an estimated hazard ratio of 0.58 (95% CI, 0.44–0.78; P<0.001) (Figure 7A). Differences in progression-free survival and objective response rates were generally consistent across the evaluated subgroups (Figures 7B and 7C). Disease control rates were also higher in the erdafitinib group (82.4%) than in the chemotherapy group (43.1%) (RR, 1.9; 95% CI 1.6–2.4). The confirmed objective response rate, as assessed by the principal investigator (with two or more consecutive assessments), was 35.3% (27.3, 43.9) in the erdafitinib group and 8.5% (4.3, 14.6) in the chemotherapy group (relative risk (RR), 4.2; 95% CI, 2.3–7.6; p-value <0.001. The p-value was estimated using the Cochrane-Haenzel (CMH) test with ECOG performance status (0 or 1 vs. 2) as a stratification factor). The median duration of response was 4.9 months (95% CI, 3.8–7.5) in the erdafitinib group and 5.6 months (95% CI, 2.1–6.0) in the chemotherapy group.

[0384] Of the patients, 92 (34.6%) received subsequent anti-cancer therapy, with 44 (32.4%) in the erdafitinib group and 48 (36.9%) in the chemotherapy group (Table 20).

[0385] safety A total of 135 patients in the erdafitinib group and 112 patients in the chemotherapy group received at least one dose of the study treatment. The median exposure time was longer with erdafitinib compared with chemotherapy (4.8 months [range, 0.2–38.2] vs. 1.4 months [range, 0.03–27.0]). In the erdafitinib group, 104 patients (77%) had dose escalations to 8–9 mg, and 66 patients (48.9%) maintained a dose of 8 mg or higher without dose reduction.

[0386] As shown in Table 21, adverse events of some cause occurred in 98.5% of patients in the erdafitinib group and 97.3% of patients in the chemotherapy group (overall safety is shown in Table 23). Grade 3-4 treatment-related adverse events occurred in 45.9% of the erdafitinib group and 46.4% of the chemotherapy group. The most common (over 5%) grade 3 or higher treatment-related adverse events were palmar-plantar erythrodyssesmus (9.6%), stomatitis (8.1%), and onycholysis (5.9%) in the erdafitinib group, and neutropenia (13.4%) and anemia (6.3%) in the chemotherapy group (Table 24).

[0387] Six patients (4.4%) in the erdafitinib group and seven patients (6.3%) in the chemotherapy group experienced fatal treatment-related adverse events (Table 25). The erdafitinib group (0.7% [n=1]; sudden death [n=1]) had fewer fatal, investigator-assessed treatment-related adverse events than the chemotherapy group (5.4% [n=6]; atypical pneumonia [n=1], febrile myeloplasmosis [n=2], febrile neutropenia [n=1], septic shock [n=2]).

[0388] Serious adverse events occurred in 18 patients (13.3%) and 27 patients (24.1%) in the erdafitinib group and the chemotherapy group, respectively (Table 23; Serious adverse events occurring during treatment in Table 26).

[0389] Adverse events of any cause led to treatment discontinuation in 19 patients (14.1%) and 20 patients (17.9%) in the erdafitinib group and chemotherapy group, respectively (Table 27). In the erdafitinib group, treatment discontinuation was due to fewer treatment-related adverse events (8.1% vs. 13.4%).

[0390] Based on the known safety profile of erdafitinib, the target grade 3–4 adverse events included nail disorders (11.1%), skin disorders (11.9%), and central serous retinopathy (2.2%) (Table 28). In 16 of 23 patients (70%) with central serous retinopathy of any grade, the event resolved by the clinical cutoff date; and in 5 of 7 patients (71%) with ongoing events, it was grade 1.

[0391] conclusion 8,733 patients were screened for molecular eligibility in this trial; of 7,293 patients, 1,212 had FGFR changes assessed via central screening (16.6% positive rate). 266 patients were randomized in a pre-specified interim analysis; 136 received erdafitinib and 130 received chemotherapy. The median follow-up was 15.9 months. Overall survival was significantly longer with erdafitinib than with chemotherapy (median overall survival, 12.1 months vs. 7.8 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.47–0.88; P=0.005). Progression-free survival was also extended with erdafitinib (median progression-free survival, 5.6 months vs. 2.7 months; hazard ratio for progression or death, 0.58; 95% CI, 0.44-0.78; P<0.001). The incidence of grade 3-4 treatment-related adverse events was similar in both groups (45.9% in the erdafitinib group and 46.4% in the chemotherapy group). Less fatal treatment-related adverse events were reported with erdafitinib than with chemotherapy (0.7% vs. 5.4%).

[0392] In conclusion, in patients with mUC and FGFR alt prior to anti-PD-(L)1 treatment, erdafitinib significantly extended median overall survival compared to chemotherapy, with a median overall survival of approximately 1 year (HR=0.64).

[0393] [Table 21] * Visceral metastases in the lungs, liver, and bones. † The Eastern Cooperative Oncology Group (ECOG) scale score ranges from 0 (no disability) to 5 (death). ‡ Based on patients for whom data is available.

[0394] [Table 22] Table 17. Summary of FGFR changes. * Two patients were randomized based on central laboratory results, which were later identified as false positives. FGFR results were transferred from other trials based on central laboratory results, local laboratory results (patients with local results may also have had central results) (ANNAR [NCT03955913] and NORSE [NCT03473743]). Local tests used were next-generation sequencing (NGS), direct digital counting, or Qiagen Therascreen FGFR Rotor-Gene Q (RGQ) reverse transcription polymerase chain reaction (RT-PCR) testing.

[0395] [Table 23] * The TNM classification was not available for one patient in the chemotherapy group.

[0396] [Table 24] * With the exception of three patients who were mistakenly assigned to Cohort 1 due to an incorrect assignment flow in the interactive web response system during randomization, all enrolled patients had received prior anti-PD-(L)1 treatment (erdafitinib group, n=1; chemotherapy group, n=2). † One patient in the erdafitinib group had received three prior lines of systemic therapy. ‡This includes patients who received chemotherapy + anti-PD-(L)1 in addition to other therapies. § This includes patients who received other therapies in addition to anti-PD-(L)1. PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1.

[0397] [Table 25]

[0398] FGFR, fibroblast growth factor receptor.

[0399] [Table 26] * List the adverse events that occurred under treatment for any cause, reported in more than 15% of patients in either treatment group, using preferred terminology and worst toxicity grade.

[0400] [Table 27] SEER, The Surveillance, Epidemiology, and End Results Program.

[0401] [Table 28]

[0402] [Table 29] * List the treatment-induced adverse events reported in more than 15% of patients in either treatment group, using preferred terminology and worst toxicity grade.

[0403] [Table 30]

[0404] [Table 31] * List all adverse events of any cause reported in more than 2% of patients, using preferred terminology and worst toxicity grade.

[0405] [Table 32]

[0406] [Table 33] * List all adverse events of any cause reported in more than 2% of patients, using preferred terminology and worst toxicity grade. †Nail disorders: Nail bed hemorrhage, nail discoloration, nail disorders, onycholysis, perinail elevation, onychotoxicity, nail pain, onycholysis, onycholysis, perinatal inflammation, onycholysis. ‡Skin disorders: Blisters, dry skin, erythema, hyperkeratosis, palmar erythema, palmar-plantar erythematous dysphoric syndrome, plantar erythema, rash, erythematous rash, generalized rash, maculopapular rash, maculopapular rash, skin atrophy, skin exfoliation, skin fissures, skin disorders, skin ulcers, toxic skin rash, xerosis. § Eye disorders (excluding central serous retinopathy): Blepharitis, cataracts, subcapsular cataracts, conjunctival hemorrhage, conjunctival hyperemia, conjunctival irritation, corneal erosion, corneal infiltrates, dry eye, ocular inflammation, eye irritation, eye pain, foreign body sensation in the eye, keratitis, increased tearing, night blindness, conjunctival hyperemia, photophobia, blurred vision, decreased visual acuity, visual impairment, xanthopsia, macular inflammation, chorioretinitis, conjunctivitis, ulcerative keratitis.

[0407] Example 2: FDA-approved drug label On January 19, 2024, the FDA approved the following drug label for BALVERSA (erdafitinib), a listed drug for erdafitinib.

[0408] BALVERSA - Erdafitinib tablets, film coated Janssen Products LP Main part of prescription information These main sections do not contain all the information necessary for the safe and effective use of BALVERSA. Please refer to the complete prescribing information for BALVERSA.

[0409] BALVERSA® (erdafitinib) tablets for oral use First US approval: 2019 Recent major changes Instructions and Usage (1) 01 / 2024 Dosage and administration (2.2), (2.3) 01 / 2024 Warnings and Precautions (5.1), (5.2) 01 / 2024

[0410] Indications and Dosage BALVERSA is a kinase inhibitor indicated for the treatment of adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) susceptible to FGFR3 gene mutations, where the disease has progressed during or after at least one line of prior systemic therapy.

[0411] Based on the FDA-approved companion diagnostic for BALVERSA, patients for treatment will be selected. (1, 2.1)

[0412] Usage restrictions BALVERSA is not recommended for the treatment of patients who are eligible for PD-1 or PD-L1 inhibitor therapy but have not received prior PD-1 or PD-L1 inhibitor therapy. (1, 14.1)

[0413] Dosage and administration Before initiating treatment with BALVERSA, confirm the presence of FGFR3 gene alterations in tumor specimens. (2.1) Recommended initial dose: 8 mg orally once daily, increasing the dose up to 9 mg per day if criteria are met. (2.2) Swallow the whole thing with or without food. (2.2)

[0414] Dosage form and content Tablets: 3 mg, 4 mg, and 5 mg. (3)

[0415] contraindication None. (4)

[0416] Warnings and Precautions for Use Ocular complications: BALVERSA may cause central serous retinopathy / retinal pigment epithelial detachment (CSR / RPED). Ophthalmic examinations should be performed monthly for the first four months of treatment, and every three months thereafter, whenever there are visual symptoms. If CSR / RPED occurs, BALVERSA should be withheld and permanently discontinued if it does not resolve within four weeks or if the severity is grade 4. (2.3, 5.1) Hyperphosphatemia: Increased phosphate levels are a pharmacodynamic effect of BALVERSA. Monitor hyperphosphatemia and adjust the dose if necessary. (2.3, 5.2) Embryo-fetal toxicity: May harm the fetus. Advise patients of the potential risk to the fetus and the use of effective contraception (5.3, 8.1, 8.3).

[0417] Adverse reactions The most common (≥20%) adverse reactions, including laboratory abnormalities, were elevated phosphate, nail disorders, stomatitis, diarrhea, elevated creatinine, elevated alkaline phosphatase, elevated alanine aminotransferase, decreased hemoglobin, decreased sodium, elevated aspartate aminotransferase, fatigue, dry mouth, dry skin, decreased phosphate, decreased appetite, dysgeusia, constipation, elevated calcium, dry eyes, palmar-plantar erythrodyssesmus, elevated potassium, alopecia, and central serous retinopathy. (6.1)

[0418] To report suspected adverse reactions, contact Janssen Products, LP at 1-800-526-7736 (1-800-JANSSEN and www.BALVERSA.com) or the FDA at 1-800-FDA-1088 or www.fda.gov / medwatch.

[0419] Drug interactions ● Moderate CYP2C9 or potent CYP3A4 inhibitors: Consider alternative medications or closely monitor for adverse reactions. (7.1) ● Avoid concomitant use with the potent CYP3A4 inducer: BALVERSA. (7.1) ● Moderate CYP3A4 inducer: Administer BALVERSA at a dose of 9 mg (7.1) ● Serum phosphate level altering agents: Avoid concomitant use with drugs that can alter serum phosphate levels before the initial dose change period. (2.3, 7.1) ● P-gp substrates: BALVERSA administration should be isolated at least 6 hours before or after administration of P-gp substrates with a narrow therapeutic index. (7.2)

[0420] Use in specific groups Breastfeeding: Advise against breastfeeding. (8.2) For patient consultation information and FDA-approved patient information inserts, please refer to section 17. Revised: 1 / 2024

[0421] Complete prescription information: Table of Contents * 1. Indications and Dosage 2. Dosage and Administration 2.1 Patient Selection 2.2 Recommended dosage and schedule 2.3 Dose changes due to adverse reactions 3. Dosage Form and Strength 4 Contraindications 5. Warnings and Precautions for Use 5.1 Eye disorders 5.2 Hyperphosphatemia and soft tissue calcification 5.3 Embryo-fetal toxicity 6. Adverse reactions 6.1 Experience in clinical trials 7. Drug Interactions 7.1 Effects of other drugs on BALVERSA 7.2 Effects of BALVERSA on other drugs 8. Use in a specific population 8.1 Pregnancy 8.2 Breastfeeding 8.3 Reproductively capable women and men 8.4 Use in children 8.5 Use by the elderly 8.6 CYP2C9 poor metabolizer 11 Properties 12. Clinical Pharmacology 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacological Genomics 13 Nonclinical Toxicology 13.1 Carcinogenicity, mutagenicity, and fertility disorders 14 Clinical Trials 14.1 Urothelial carcinoma with susceptibility FGFR3 gene mutations 16. Supply / Storage / Handling Methods 17. Patient consultation information * Sections or subsections omitted from the complete prescription information are not included.

[0422] Full prescription information 1. Indications and Dosage BALVERSA is indicated for the treatment of adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) susceptible to FGFR3 gene mutations, where the disease has progressed during or after at least one line of prior systemic therapy.

[0423] Based on the FDA-approved companion diagnostic for BALVERSA, patients for treatment should be selected [see Dosage and Administration (2.1) and Clinical Trials (14.1)].

[0424] Usage restrictions BALVERSA is not recommended for the treatment of patients who are eligible for PD-1 or PD-L1 inhibitor therapy but have not received prior PD-1 or PD-L1 inhibitor therapy [see Clinical Trials (14.1)].

[0425] 2. Dosage and Administration 2.1 Patient Selection Patients are selected for treatment of locally advanced or metastatic urothelial carcinoma with BALVERSA based on the presence of susceptible FGFR3 gene alterations in tumor specimens detected by an FDA-approved companion diagnostic [see Clinical Trials (14.1)].

[0426] Information on FDA-approved tests for detecting FGFR3 gene alterations in urothelial carcinoma is available at http: / / www.fda.gov / CompanionDiagnostics.

[0427] 2.2 Recommended dosage and schedule The recommended starting dose of BALVERSA is 8 mg (two 4 mg tablets) orally once daily, and the dose should be increased to 9 mg (three 3 mg tablets) once daily between days 14 and 21, based on tolerability, including hyperphosphatemia [see Dosage and Administration (2.3)].

[0428] Swallow the entire tablet with or without food. If vomiting occurs at any point after taking BALVERSA, the next dose should be taken the following day. Treatment should be continued until disease progression or unacceptable toxicity occurs.

[0429] If you miss a dose of BALVERSA, you can take it as soon as possible on the same day. The next day, resume your usual daily dose schedule for BALVERSA. You should not take any extra tablets to make up for the missed dose.

[0430] Dose increase based on serum phosphate levels Serum phosphate levels should be assessed 14 to 21 days after the start of treatment. If serum phosphate levels are less than 9.0 mg / dL and there are no eye disturbances or grade 2 or higher adverse reactions, the dose of BALVERSA should be increased to 9 mg once daily. Phosphate levels should be monitored monthly for hyperphosphatemia [see pharmacodynamics (12.2)].

[0431] 2.3 Dose changes due to adverse reactions Table 1 lists the modifications to the recommended dosage for adverse reactions.

[0432] [Table 34]

[0433] Table 2 summarizes the recommendations for interrupting, reducing, or discontinuing BALVERSA in the management of specific adverse reactions.

[0434] [Table 35]

[0435] 3. Dosage Form and Strength tablet: ● 3mg: Yellow, round, biconvex, film coated, with "3" embossed on one side and "EF" on the other. ● 4mg: Orange, round, biconvex, film coated, with "4" embossed on one side and "EF" on the other. ● 5mg: Brown, circular, biconvex, film coated, with "5" embossed on one side and "EF" on the other.

[0436] 4 Contraindications none.

[0437] 5. Warnings and Precautions for Use 5.1 Eye Disorders BALVERSA can cause ocular disorders, including central serous retinopathy / retinal pigment epithelial detachment (CSR / RPED), which can lead to visual field defects.

[0438] In the pooled safety population [see Adverse Reactions (6)], CSR / RPED occurred in 22% of patients treated with BALVERSA, with a median time to first onset of 46 days. Of the 104 patients with CSR, 40% required drug discontinuation and 56% required dose reduction; 2.9% of BALVERSA-treated patients required permanent discontinuation due to CSR. Of the 24 patients who resumed BALVERSA after discontinuation, with or without dose reduction, 67% experienced a recurrence and / or exacerbation of CSR after resumption. CSR was ongoing in 41% of the 104 patients at the time of final evaluation.

[0439] Dry eye symptoms occurred in 26% of patients treated with BALVERSA. All patients should receive dry eye prevention with eye lubricants as needed.

[0440] For the first four months of treatment, ophthalmological examinations for visual symptoms should be performed monthly, then every three months thereafter, and whenever necessary in an emergency. The ophthalmological examination should include assessment of visual acuity, slit-lamp examination, fundus examination, and optical coherence tomography.

[0441] Based on the severity and / or ophthalmological findings, BALVERSA should be withheld or permanently discontinued [see Dosage and Administration (2.3)].

[0442] 5.2 Hyperphosphatemia and soft tissue calcification BALVERSA can cause hyperphosphatemia, leading to soft tissue calcification, cutaneous calcification, non-uremic calciphylaxis, and vascular calcification. Increased phosphate levels are a pharmacodynamic effect of BALVERSA [see pharmacodynamics (12.2)].

[0443] In the pooled safety population [see Adverse Reactions (6)], elevated phosphate levels occurred in 73% of patients treated with BALVERSA. The median time to onset of elevated phosphate levels was 16 days (range: 8–421) after the start of BALVERSA. 24 percent of patients received phosphate binders during treatment with BALVERSA. Vascular calcification was observed in 0.2% of patients treated with BALVERSA.

[0444] Monitor hyperphosphatemia during treatment. Limit dietary phosphate intake (600-800 mg per day) and avoid concomitant use of medications that may increase serum phosphate levels.

[0445] If serum phosphate levels exceed 7.0 mg / dL, consider adding an oral phosphate binder until serum phosphate levels return to below 7.0 mg / dL. Based on the duration and severity of hyperphosphatemia, BALVERSA should be withheld, the dose reduced, or permanently discontinued according to Table 2 [see Dosage and Administration (2.3)].

[0446] 5.3 Embryo-fetal toxicity Based on its mechanism of action and findings from animal studies, BALVERSA may be harmful to the fetus if administered to pregnant women. In embryo-fetal toxicity studies, oral administration of erdafitinib to pregnant rats during organogenesis caused malformations and embryo-fetal death at lower maternal exposure levels than human exposure at the maximum recommended human dose, based on the area under the curve (AUC). Inform pregnant women of the potential risks to the fetus. Advise female patients to use effective contraception during treatment with BALVERSA and for one month after the last dose. Advise male patients with fertile female partners to use effective contraception during treatment with BALVERSA and for one month after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

[0447] 6. Adverse reactions The following serious adverse reactions are also described elsewhere on the label: ● Eye irritation [See Warnings and Precautions for Use (5.1)]. ● Hyperphosphatemia [See Warnings and Precautions for Use (5.2)].

[0448] 6.1 Experience in clinical trials Because clinical trials are conducted under a wide range of varying conditions, the adverse reaction rates observed in a clinical trial of a drug cannot be directly compared to rates in a clinical trial of another drug and may not reflect the rates actually observed.

[0449] The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to BALVERSA as monotherapy at the recommended dose (8–9 mg orally per day) in 479 patients with advanced urothelial carcinoma, as well as changes in FGFR in 42756493BLC3001 (NCT03390504), 42756493BLC2001 (NCT02365597), 42756493BLC2002 (NCT 03473743), and 42756493EDI1001 (NCT01703481). Among the 479 patients who received BALVERSA, the median treatment duration was 4.8 months (range: 0.1–43 months). In this pooled safety population, the most common (over 20%) adverse reactions, including laboratory abnormalities, were elevated phosphate, nail disorders, stomatitis, diarrhea, elevated creatinine, elevated alkaline phosphatase, elevated alanine aminotransferase, decreased hemoglobin, decreased sodium, elevated aspartate aminotransferase, fatigue, dry mouth, dry skin, decreased phosphate, decreased appetite, dysgeusia, constipation, elevated calcium, dry eyes, palmar-plantar erythrodyssesmus, elevated potassium, alopecia, and central serous retinopathy.

[0450] BLC3001 The safety of BALVERSA was evaluated in Cohort 1 of the BLC3001 trial, which included patients with locally advanced unresectable or metastatic urothelial carcinoma who were susceptible to FGFR3 gene mutations and had been previously treated with PD-1 or PD-L1 inhibitors [see Clinical Trials (14.1)]. Patients received BALVERSA (8 mg orally once daily, escalated individually to 9 mg) (n=135) or chemotherapy (docetaxel 75 mg / m²). 2 This is administered once every three weeks, or vinflunine 320 mg / m². 2 They received one of the following treatments (once every three weeks) (n=112). Among patients who received BALVERSA, the median treatment duration was 4.8 months (range: 0.2–38 months).

[0451] Serious adverse reactions occurred in 41% of patients who received BALVERSA. Serious reactions in more than 2% of patients included urinary tract infection (4.4%), hematuria (3.7%), hyponatremia (2.2%), and acute kidney injury (2.2%). Fatal adverse reactions occurred in 4.4% of patients who received BALVERSA, including sudden death (1.5%), pneumonia (1.5%), renal failure (0.7%), and cardiac and respiratory arrest (0.7%).

[0452] Permanent discontinuation of BALVERSA due to adverse reactions occurred in 14% of patients. Adverse reactions that led to permanent discontinuation of BALVERSA in more than 2% of patients included nail disorders (3%) and eye disorders (2.2%).

[0453] Discontinuation of BALVERSA due to side effects occurred in 72% of patients. Adverse reactions requiring discontinuation in more than 4% of patients included nail disorders (22%), stomatitis (19%), eye disorders (16%), palmar-plantar erythrodysphoric dysphoria syndrome (15%), diarrhea (10%), hyperphosphatemia (7%), increased aspartate aminotransferase (6%), and increased alanine aminotransferase (5%).

[0454] Dose reduction of BALVERSA due to side effects occurred in 69% of patients. Adverse reactions requiring dose reduction in more than 4% of patients included nail disorders (27%), stomatitis (19%), eye disorders (17%), palmar-plantar erythrodysphoria syndrome (12%), diarrhea (7%), dry mouth (4.4%), and hyperphosphatemia (4.4%).

[0455] Table 3 shows adverse reactions reported in 15% or more of patients treated with 8 mg or 9 mg of BALVERSA once daily versus the chemotherapy agent.

[0456] [Table 36]

[0457] Clinically relevant adverse reactions in less than 15% of patients who received BALVERSA included nausea (15%), fever (15%), nosebleed (13%), vomiting (10%), and arthralgia (10%).

[0458] Table 4 shows laboratory abnormalities reported in 15% or more of patients treated with BALVERSA once daily at 8 or 9 mg versus chemotherapy.

[0459] [Table 37]

[0460] BLC2001 The safety of BALVERSA was evaluated in the BLC2001 trial, which included 87 patients with sensitive FGFR3 and other FGFR changes and locally advanced or metastatic urothelial carcinoma that had progressed during or after at least one prior chemotherapy line, including neoadjuvant or adjuvant chemotherapy, within 12 months [see Clinical Trials (14.1)]. Patients were treated with 8 mg of BALVERSA orally once daily; the dose was increased to 9 mg on day 14 of cycle 1 in patients with phosphate levels <5.5 mg / dL. The median duration of treatment was 5.3 months (ranging from 0 to 17 months).

[0461] Serious adverse reactions occurred in 41% of patients. The most frequent (over 3%) serious adverse reactions were central serous retinopathy (4.6%), urinary tract infection (3.4%), and deterioration of overall physical health (3.4%).

[0462] Fatal adverse reactions, including acute myocardial infarction (1.1%), occurred in 8% of patients.

[0463] Permanent discontinuation of BALVERSA due to adverse reactions occurred in 21% of patients. The most frequent reasons for permanent discontinuation (≥2%) included central serous retinopathy (4.6%), deterioration of general physical health (3.4%), palmar-plantar erythrodysesthesia syndrome (2.3%), acute kidney injury (2.3%), and fatigue (2.3%).

[0464] Discontinuation of BALVERSA occurred in 68% of patients. The most frequent (≥5%) adverse reactions requiring discontinuation included hyperphosphatemia (24%), stomatitis (17%), nail disorders (16%), central serous retinopathy (9%), palmar-plantar erythrodysesthesia syndrome (8%), and fatigue (8%).

[0465] Dose reduction of BALVERSA occurred in 53% of patients. The most frequent (≥5%) adverse reactions associated with dose reduction included nail disorders (21%), stomatitis (15%), central serous retinopathy (14%), hyperphosphatemia (7%), palmar-plantar erythrodysesthesia syndrome (7%), fatigue (6%), and blurred vision (6%).

[0466] Table 5 shows adverse reactions reported in 15% or more of patients treated with 8 mg or 9 mg of BALVERSA once daily.

[0467] [Table 38]

[0468] Clinically relevant adverse reactions in less than 15% of patients who received BALVERSA included fever (14%), limb pain (13%), vomiting (13%), and peripheral edema (10%).

[0469] Table 6 shows laboratory abnormalities reported in 15% or more of patients treated with BALVERSA at 8 mg or 9 mg once daily.

[0470] [Table 39]

[0471] 7. Drug Interactions 7.1 Effects of other drugs on BALVERSA Table 7 summarizes drug interactions that affect BALVERSA exposure or serum phosphate levels and their clinical management.

[0472] [Table 40]

[0473] 7.2 Effects of BALVERSA on other drugs Table 8 summarizes the effects of BALVERSA on other drugs and their clinical management.

[0474] [Table 41]

[0475] 8. Use in a specific population 8.1 Pregnancy Risk Overview Based on its mechanism of action and findings from animal studies, BALVERSA may be harmful to the fetus if administered to pregnant women [see Clinical Pharmacology (12.1)]. There is no available data to inform pregnant women about drug-related risks of BALVERSA use. Oral administration of erdafitinib to pregnant rats during organogenesis caused malformations and embryo-fetal death at lower maternal exposures than human exposures at the maximum recommended human dose based on AUC (see data). Pregnant women and women of childbearing potential should be advised of the potential risks to the fetus.

[0476] The estimated background risks for major birth defects and miscarriage in the adapted population are unknown. All pregnant women have a background risk of birth defects, miscarriage, or other adverse outcomes. In the general U.S. population, the estimated background risks for major birth defects and miscarriage in clinically recognized pregnant women are 2–4% and 15–20%, respectively.

[0477] data Animal data In embryo-fetal toxicity studies, erdafitinib was orally administered to pregnant rats during organogenesis. Doses of 4 mg / kg / day or higher (with total maternal exposure less than 0.1% of total human exposure at the maximum recommended human dose based on AUC) resulted in increased incidence of embryo-fetal death, major vascular malformations and other vascular abnormalities, limb malformations (finger deficiencies, long bone deficiencies or malformations), skeletal abnormalities in multiple bones (vertebrae, sternum, ribs), and decreased fetal weight.

[0478] 8.2 Breastfeeding Risk Overview There is no data on the presence of erdafitinib in human milk, or on the effects of erdafitinib on breastfeeding or milk production. Due to the potential for serious adverse reactions from erdafitinib in lactating children, lactating women should be advised not to breastfeed during treatment with BALVERSA and for one month after the last dose.

[0479] 8.3 Reproductively capable women and men BALVERSA may harm the fetus if administered to pregnant women [see Use in specific populations (8.1)].

[0480] Pregnancy test Before starting treatment with BALVERSA, confirm the pregnancy status of fertile women.

[0481] contraception woman Women should be advised to use effective contraception during treatment with BALVERSA and for one month after their last dose.

[0482] male Male patients with female partners should be advised to use effective contraception during treatment with BALVERSA and for one month after the last dose.

[0483] infertility woman Based on findings from animal studies, BALVERSA may impair fertility in fertile women [see Nonclinical Toxicology (13.1)].

[0484] 8.4 Use in children The safety and efficacy of BALVERSA in infant patients have not been established.

[0485] In 4-week and 13-week repeated-dose toxicity studies in rats and dogs, toxicity in bone and teeth was observed at exposures below the human exposure (AUC) at the maximum recommended human dose. Chondroid dysplasia / metaplasia was reported in multiple bones in both species, and dental abnormalities included abnormal / irregular dentin formation in rats and dogs, as well as discoloration and degeneration of odontoblasts in rats.

[0486] 8.5 Use by the elderly In the clinical trial, of the 479 patients treated with BALVERSA, 40% were under 65 years old, 40% were between 65 and 74 years old, and 20% were 75 years or older.

[0487] Patients aged 65 and older treated with BALVERSA experienced a higher incidence of adverse reactions requiring discontinuation of treatment compared to younger patients. In clinical trials, the incidence of BALVERSA treatment discontinuation due to adverse reactions was 10% in patients under 65 years of age, 20% in patients aged 65-74 years, and 35% in patients aged 75 years and older.

[0488] No overall difference in efficacy was observed between these patients and younger patients [see clinical trials (14.1)].

[0489] 8.6 CYP2C9 poor metabolizer CYP2C9 * 3 / * 3 genotypes: Erdafitinib plasma concentration is measured by CYP2C9 * 3 / * It is predicted to be higher in patients with three genotypes. CYP2C9 * 3 / *Monitor for increased adverse reactions in patients known or suspected to have all three genotypes [see Pharmacological Genomics (12.5)].

[0490] 11 Properties The active ingredient in BALVERSA, erdafitinib, is a kinase inhibitor. Its chemical name is (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine. Erdafitinib is a yellow powder. It is substantially insoluble or freely soluble from insoluble in organic solvents, and slightly soluble to substantially insoluble or insoluble in aqueous media over a wide range of pH values. Its molecular formula is C 25 H 30 It is N6O2, and its molecular weight is 446.56.

[0491] The chemical structure of erdafitinib is as follows:

[0492] [ka]

[0493] BALVERSA® erdafitinib tablets are supplied as 3 mg, 4 mg, or 5 mg film-coated tablets for oral administration and contain the following inactive ingredients: Tablet core: Croscarmellose sodium, magnesium stearate (from a plant source), mannitol, meglumine, and microcrystalline cellulose. Film coating (Opadry amb II): Glycerol monocaprylocate type I, polyvinyl alcohol - partially hydrolyzed, sodium lauryl sulfate, talc, titanium dioxide, yellow iron oxide, red iron oxide (orange and brown tablets only), triiron tetroxide / black iron oxide (brown tablets only).

[0494] 12. Clinical Pharmacology 12.1 Mechanism of Action Erdafitinib is a kinase inhibitor that, based on in vitro data, binds to and inhibits the enzymatic activity of FGFR1, FGFR2, FGFR3, and FGFR4. Erdafitinib has been found to inhibit FGFR phosphorylation and signaling, reducing cell viability in cell lines expressing FGFR gene alterations, including point mutations, amplifications, and fusions. Erdafitinib demonstrated antitumor activity in FGFR-expressing cell lines and in xenograft models derived from tumor types, including bladder cancer.

[0495] 12.2 Pharmacodynamics Cardiac electrophysiology Based on evaluations of the QTc interval in open-label, escalation- and dose-expansion trials in 187 cancer patients, erdafitinib did not have a significant effect on the QTc interval (i.e., greater than 20 ms).

[0496] Serum phosphate BALVERSA inhibits FGFR levels, which increases serum phosphate levels [see Dosage and Administration (2.3) and Drug Interactions (7.1)].

[0497] 12.3 Pharmacokinetics After administering BALVERSA 8 mg once daily, the mean (coefficient of variation [CV%]) of the peak steady-state plasma concentration (C) of erdafitinib was measured. max ), area under the curve (AUC tau ), and minimum plasma concentration (C min The concentrations were 1,399 ng / mL (51%), 29,268 ng·h / mL (60%), and 936 ng / mL (65%), respectively.

[0498] After single and repeated once-daily administration of BALVERSA, exposure to erdafitinib (C max The saturation point and AUC increased proportionally over the dose range of 0.5–12 mg (0.06–1.3 times the maximum approved recommended dose). Steady state was reached after 2 weeks with once-daily administration, and the mean accumulation ratio was 4-fold.

[0499] absorption Peak plasma concentration (t max The median time to reach ) was 2.5 hours (range: 2-6 hours).

[0500] The effects of food No clinically significant difference in erdafitinib exposure was observed after administration of BALVERSA, which included a high-fat, high-calorie diet (800-1,000 calories, with approximately 50% of the total calories from fat).

[0501] distribution The mean apparent distribution volume of erdafitinib was 29 L.

[0502] Erdafitinib protein binding was 99.7% in patients, primarily to α-1-acid glycoprotein.

[0503] Withdrawal The mean total apparent clearance (CL / F) of erdafitinib was 0.362 L / hour.

[0504] The average effective half-life of erdafitinib was 59 hours.

[0505] 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 primary drug-related portion in plasma, with no circulating metabolites.

[0506] excretion After a single oral dose of radiolabeled erdafitinib, approximately 69% of the dose was recovered in the feces (19% unchanged), and 19% was recovered in the urine (13% unchanged).

[0507] A specific population Age (21-92 years), sex, race (Caucasian, Hispanic, or Asian), weight (36-166 kg), mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, or mild to moderate renal impairment (eGFR 30-89 mL / min / 1.73 m²). 2 Based on the above, no clinically significant effects of erdafitinib exposure were observed. Limited data are available in patients with severe (Child-Pugh C) hepatic impairment and severe renal impairment. The pharmacokinetics of erdafitinib in patients with renal impairment requiring dialysis are unknown.

[0508] Drug interaction testing Clinical trials Effects of other drugs on erdafitinib Moderate CYP2C9 inhibitor C max and AUC inf The mean ratios of erdafitinib were 121% and 148% when BALVERSA was administered co-administered with fluconazole, a moderate CYP2C9 and CYP3A4 inhibitor, compared to BALVERSA administered alone.

[0509] A potent CYP3A4 inhibitor C max and AUC inf The mean erdafitinib ratios for BALVERSA were 105% and 134% when BALVERSA was administered co-administered with itraconazole (a potent CYP3A4 inhibitor and P-gp inhibitor), compared to BALVERSA alone.

[0510] CYP3A4 / 2C9 inducer C max and AUC inf The mean erdafitinib ratios were 78% and 45% when BALVERSA was administered co-administered with carbamazepine (a potent CYP3A4 and weak CYP2C9 inducer), compared to BALVERSA alone.

[0511] Effects of erdafitinib on other drugs CYP3A4 substrate: No clinically significant effects of exposure to midazolam (CYP3A4 substrate) were observed after co-administration with BALVERSA.

[0512] OCT2 substrate: No clinically significant effect on metformin (OCT2 substrate) exposure was observed after co-administration with BALVERSA.

[0513] In vitro testing CYP substrate Erdafitinib is a time-dependent inhibitor and inducer of CYP3A4. Erdafitinib is not an inhibitor of other major CYP isozymes at clinically relevant concentrations.

[0514] Transporter Erdafitinib is a substrate and inhibitor of P-gp. P-gp inhibitors are not expected to affect erdafitinib exposure to a clinically relevant degree. Erdafitinib is an inhibitor of OCT2.

[0515] Erdafitinib does not inhibit BCRP, OATP1B, OATP1B3, OAT1, OAT3, OCT1, MATE-1, or MATE-2K at clinically relevant concentrations.

[0516] Acid-reducing agents Erdafitinib has adequate solubility over a pH range of 1 to 7.4. Antacids (including H2 antagonists and proton pump inhibitors) are not expected to affect the bioavailability of erdafitinib.

[0517] 12.5 Pharmacological Genomics CYP2C9 activity is CYP2C9 * 2 and CYP2C9 * It is reduced in individuals with genetic variations such as the 3 polymorphism. Erdafitinib exposure reduces CYP2C9* 1 / * Compared to a subject with one genotype (wild type), CYP2C9 * 1 / * 2 and * 1 / * The same was true for subjects with three genotypes. Other genotypes (for example, * 2 / * 2. * 2 / * 3. * 3 / * 3) No data is available for the subjects characterized by this. The simulation is performed using CYP2C9. * 2 / * 2 and * 2 / * The study suggested no clinically significant difference in erdafitinib exposure among subjects with three genotypes. Erdafitinib exposure was associated with CYP2C9 * 3 / * In subjects with all three genotypes, the incidence is predicted to be 50% higher, and it is estimated to be present in 0.4% to 3% of populations across various ethnic groups.

[0518] 13 Nonclinical Toxicology 13.1 Carcinogenicity, mutagenicity, and fertility disorders No carcinogenicity studies have been conducted using erdafitinib.

[0519] Erdafitinib was not mutagenic in bacterial reverse mutation (Ames) assays and was not chromosomal aberration-inducing in in vitro micronucleus or in vivo rat bone marrow micronucleus assays.

[0520] Animal studies on fertilization ability have not been conducted using erdafitinib. In a 3-month repeated-dose toxicity study, erdafitinib showed efficacy against female reproductive organs (necrosis of the ovarian corpus luteum) in rats at exposure levels lower than the human exposure (AUC) at the maximum recommended human dose.

[0521] 14 Clinical Trials 14.1 Urothelial carcinoma with susceptibility FGFR3 gene mutations The efficacy of BALVERSA was evaluated in the trial BLC3001 (NCT03390504). Cohort 1 consisted of 266 patients with advanced urothelial carcinoma and selected FGFR3 changes, randomized in a 1:1 ratio to receive either BALVERSA (8 mg, with a maximum dose of 9 mg) or chemotherapy (docetaxel 75 mg / m²) until unacceptable toxicity or progression. 2 or vinflunine 320 mg / m² once every three weeks 2 This was a randomized, open-label, multicenter trial in which the drug was administered once every three weeks. Randomization was stratified by region (North America vs. Europe vs. the rest of the world), Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs. 2), and visceral or bone metastases (with vs. without). All patients had to have disease progression after one or two prior treatments, at least one of which included a PD-1 or PD-L1 inhibitor. FGFR3 gene alterations were identified in 75% of patients from tumor tissue in a central laboratory using the QIAGEN therascreen® FGFRRGQ RT-Polymerase Chain Reaction (PCR) kit, while the remainder (25%) were identified by local next-generation sequencing (NGS) assays.

[0522] The primary efficacy endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), as assessed by the investigator using RECIST (Response Evaluation Criteria in Solid Tumors) Version 1.1.

[0523] The median age was 67 years (ranging from 32 to 86 years), 71% were male, 54% were Caucasian, 29% Asian, 0.4% Black, 0.4% multiracial, 16% unreported, and 2% Hispanic / Latino; baseline ECOG performance status was 0 (43%), 1 (48%), or 2 (9%). 81 percent of patients had FGFR3 mutations, 17% had fusions, and 2% had both mutations and fusions. 95 percent of patients had pure transitional cell carcinoma (TCC), and 5% had TCC with other histological mutations. The primary tumor location was in the suprasuli for 33% of the subjects and in the subsulci for 67%. 74% of patients had visceral or bone metastases. 88 percent of patients had previously received platinum-containing chemotherapy. PD-1 or PD-L1 inhibitor therapy was received only in a neoadjuvant or adjuvant setting in 7% of patients.

[0524] Statistically significant improvements in OS, PFS, and ORR were demonstrated with BALVERSA compared to chemotherapy.

[0525] Table 9 and Figures 1 and 2 summarize the efficacy results for BLC3001 Cohort 1.

[0526] [Table 42]

[0527] [Table 43]

[0528] [Table 44]

[0529] Cohort 2 of the BLC3001 trial Cohort 2 of the BLC3001 trial (NCT03390504) was a multicenter, open-label, randomized trial in 351 patients with locally advanced or metastatic urothelial carcinoma with selected FGFR3 changes who had received one line of prior systemic therapy and no prior PD-1 or PD-L1 inhibitors. Patients were randomized 1:1 to receive either BALVERSA (8 mg, up to 9 mg) or pembrolizumab 200 mg every three weeks. This trial did not meet the primary efficacy endpoint criterion for overall survival (OS) superiority in the pre-specified final analysis. The OS hazard ratio (HR) was 1.18 (95% CI: 0.92, 1.51; p=0.18), with a median of 10.9 months (95% CI: 9.2, 12.6) for BALVERSA and 11.1 months (95% CI: 9.7, 13.6) for pembrolizumab [see Indications and Dosage (1)].

[0530] Test BLC2001 Study BLC2001 (NCT02365597) was a multicenter, open-label, single-arm study to evaluate the efficacy and safety of BALVERSA in patients with locally advanced or metastatic urothelial carcinoma (mUC). FGFR mutation status for patient screening and enrollment was determined by clinical trial assays (CTAs). The efficacy population consisted of a cohort of 87 patients enrolled in the study who had disease that had progressed at least once prior chemotherapy or thereafter and who had at least one of the following genetic alterations: FGFR3 gene mutations (R248C, S249C, G370C, Y373C) or FGFR gene fusions (FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7), as determined by CTAs performed in a central laboratory. Tumor samples from 69 patients were retrospectively examined using the QIAGEN CeraScreen® FGFRRGQ RT-PCR kit, which is an FDA-approved study for the selection of patients with mUC for BALVERSA.

[0531] Patients received an initial dose of 8 mg of BALVERSA once daily, and those whose serum phosphate levels fell below the target of 5.5 mg / dL between days 14 and 17 received a dose increase to 9 mg once daily. Dose increases occurred in 41% of patients. BALVERSA was administered until disease progression or unacceptable toxicity occurred. The primary efficacy endpoints were objective response rate (ORR) and duration of response (DoR), as determined by a blinded independent review committee (BIRC) in accordance with RECIST V1.1.

[0532] 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. 66 percent of patients had visceral metastases. 84 patients (97%) had previously received at least one of either cisplatin or carboplatin. 56 percent of patients had received only cisplatin-based regimens prior to treatment, 29% had received only carboplatin-based regimens prior to treatment, and 10% had received both cisplatin and carboplatin-based regimens. Three patients (3%) experienced disease progression after prior platinum-containing neoadjuvant therapy or adjuvant therapy alone. 24 percent of patients had been treated with prior anti-PD-L1 / PD-1 therapy.

[0533] The efficacy results are summarized in Tables 10 and 11. The ORR was 32.2%. Respondents included patients who had not previously responded to anti-PD-L1 / PD-1 therapy.

[0534] [Table 45]

[0535] [Table 46]

[0536] 16. Supply / Storage / Handling Methods BALVERSA® (erdafitinib) tablets are available in the following strengths and packaging: ● 3mg tablets: Yellow, circular, biconvex, film coated, with "3" embossed on one side and "EF" on the other. - A bottle of 56 tablets with a child-proof closure (NDC 59676-030-56). - A bottle containing 84 tablets with a child-proof closure (NDC 59676-030-84). ● 4mg tablet: Orange, circular, biconvex, film coated, with "4" embossed on one side and "EF" on the other. - A bottle of 28 tablets with a child-proof closure (NDC 59676-040-28). - A bottle of 56 tablets with a child-proof closure (NDC 59676-040-56). ● 5mg tablets: Brown, round, biconvex, film coated, with "5" embossed on one side and "EF" on the other. - A bottle of 28 tablets with a child-proof closure (NDC 59676-050-28).

[0537] Store at 20°C to 25°C (68°F to 77°F); the permissible temperature range is 15°C to 30°C (59°F to 86°F) [see USP Room Temperature Control].

[0538] 17. Patient consultation information Advise patients to read the FDA-approved prescribing information (patient information).

[0539] FGFR gene disorder Patients should be advised that evidence of a susceptible FGFR3 mutation or gene fusion in the tumor specimen is required to identify patients for whom treatment is prescribed [Dosage and Administration (2.1)].

[0540] Eye disorders If the patient experiences any visual changes, advise them to contact their healthcare provider [see Warnings and Precautions (5.1)]. To prevent or treat dry eye, advise the patient to use an artificial tear substitute, hydrating or lubricating eye gel or ointment frequently, at least every two hours during waking hours [see Dosage and Administration (2.3)].

[0541] Disorders of the skin, mucous membranes, or nails If a patient experiences progressive or unacceptable skin, mucous membrane, or nail disturbance, advise them to contact their healthcare provider [see Adverse Reactions (6.1)].

[0542] Hyperphosphatemia and soft tissue calcification Inform patients that BALVERSA may cause hyperphosphatemia and soft tissue calcification. Advise patients to immediately inform their healthcare provider of any painful skin lesions or any symptoms associated with acute changes in phosphate levels, such as muscle spasms, paralysis, or tingling around the mouth [see Warnings and Precautions (5.2)].

[0543] Advise patients that their serum phosphate levels be assessed between 14 and 21 days of treatment initiation and that the dose be adjusted as necessary [see Warnings and Precautions (5.2)]. Advise patients to limit their phosphate intake to 600–800 mg per day. Advise patients to avoid concomitant use with medications that may alter serum phosphate levels during this initial phosphate assessment period. After the initial phosphate assessment period, advise patients that they should undergo monthly phosphate level monitoring for hyperphosphatemia during treatment with BALVERSA [see Drug Interactions (7.1)].

[0544] Drug interactions Advise patients to inform their healthcare provider of all concomitant medications, including prescription drugs, over-the-counter medications, and herbal products [see Drug Interactions (7.1, 7.2)].

[0545] Medication instructions Instruct the patient to swallow the tablet whole once daily, with or without food. If vomiting occurs at any point after taking BALVERSA, advise the patient to take the next dose the following day [see Dosage and Administration (2.2)].

[0546] Dose that was omitted If a dose is missed, advise the patient to take the missed dose as soon as possible. The following day, resume the usual daily dose schedule for BALVERSA. Extra tablets should not be taken to make up for the missed dose [see Dosage and Administration (2.3)].

[0547] Embryo-fetal toxicity Advise pregnant women and women of childbearing potential about potential risks to the fetus. Advise women to inform their healthcare provider of known or suspected pregnancies [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].

[0548] Advise female patients to use effective contraception during treatment and for one month after the last dose of BALVERSA. Advise male patients with fertile female partners to use effective contraception during treatment and for one month after the last dose of BALVERSA [see Use in Specific Populations 8.3)].

[0549] breastfeeding Women should be advised not to breastfeed during treatment with BALVERSA and for one month after the last dose [see Use in specific populations (8.2)].

[0550] infertility See Use in Specific Populations (8.3) where fertile females are advised that BALVERSA may impair fertility.

[0551] Swiss products Client: Janssen Products, LP Horsham, PA 19044, USA Under license from Astex Therapeutics Limited.

[0552] Patent information: www.janssenpatents.com (Copyright) 2019 Janssen Pharmaceutical Companies

[0553] PATIENT INFORMATION BALVERSA (registered trademark) (bal-VER-sah) (erdafitinib) tablets What is BALVERSA? BALVERSA is a prescription drug used to treat adults with bladder cancer (urothelial carcinoma) that has spread or cannot be removed by surgery. ● Possessing certain abnormal FGFR genes, ● Individuals who have tried at least one other medication, either orally or by injection (systemic therapy), but it has been ineffective or is no longer effective.

[0554] Your healthcare provider will test for cancers with specific types of abnormal FGFR genes to confirm that BALVERSA is right for you.

[0555] BALVERSA is not recommended for the treatment of individuals who are eligible for PD-1 or PD-L1 inhibitor therapy but have not received prior PD-1 or PD-L1 inhibitor therapy.

[0556] It is unclear whether BALVERSA is safe and effective in children.

[0557] Before taking BALVERSA, tell your healthcare provider about all your medical conditions, including the following: ● If you have vision or eye problems. ● If you are pregnant or planning to become pregnant: BALVERSA may harm the fetus. You should not become pregnant while undergoing treatment with BALVERSA.

[0558] Women of childbearing potential: ○ Healthcare providers may perform a pregnancy test before initiating treatment with BALVERSA. ○ Effective contraception should be used during treatment and for one month after the last dose of BALVERSA. Consult your healthcare provider about contraception methods that may be suitable for you. ○ If you become pregnant, or suspect you may be pregnant, immediately inform your healthcare provider.

[0559] Men with a female partner capable of becoming pregnant: ○ If a patient is sexually active during treatment with BALVERSA and for one month after the last dose, effective fertility control should be used. ● If you are currently breastfeeding or plan to breastfeed, do not breastfeed during treatment and for one month after the last dose of BALVERSA.

[0560] Inform your healthcare provider about all medications you are currently taking, including prescription drugs, over-the-counter medications, vitamins, and herbal supplements.

[0561] Have you taken BALVERSA? ● Take BALVERSA exactly as instructed by your healthcare provider. ● Take BALVERSA once daily. ● Swallow the entire BALVERSA with or without food. ● Healthcare providers may change the dosage of BALVERSA, temporarily discontinue treatment, or discontinue it completely if certain side effects occur. ● If you forget to take BALVERSA, take the usual dose as soon as possible on the same day. Take the prescribed dose of BALVERSA the following day. Do not take more BALVERSA than prescribed to make up for the missed dose. ● If you vomit after taking BALVERSA, do not take another BALVERSA tablet. Take the prescribed dose of BALVERSA the following day.

[0562] What are some possible side effects of BALVERSA? BALVERSA may cause serious side effects, including: Eye problems. Eye problems are common in BALVERSA, but can also be serious. Eye problems include dry or inflamed eyes, inflammation of the cornea (the front of the eye), and damage to the retina (the inside of the eye). If you experience blurred vision, vision loss, or other visual changes, inform your healthcare provider immediately. To help prevent dry eyes, you should use an artificial tear substitute, hydrating or lubricating eye gel or ointment at least every two hours while awake. Your healthcare provider will ask you to see an ophthalmologist while undergoing treatment with BALVERSA.

[0563] High levels of phosphate in the blood (hyperphosphatemia). Hyperphosphatemia is common with BALVERSA, but can also be serious. High levels of phosphate in the blood can lead to the accumulation of minerals such as calcium in various tissues in the body. Healthcare providers will check blood phosphate levels 14 to 21 days after starting BALVERSA treatment, and then monthly thereafter. ○ Healthcare providers may prescribe changes to diet or phosphate-lowering therapy, or, if necessary, modify or discontinue treatment with BALVERSA. ○ If you experience painful skin lesions, muscle spasms, or numbness or tingling around your mouth, immediately inform your healthcare provider.

[0564] The most common side effects of BALVERSA include: ● The nail peels away from the base coat, or the nail is poorly formed. ● Sores on the mouth Diarrhea ● Increased blood creatinine levels ● Increased blood alkaline phosphatase levels ● Changes in liver function ● Decreased red blood cells (anemia) ● Decreased blood salt (sodium) levels ● Fatigue ● Dry mouth ● Dry skin ● Decreased blood phosphate levels ● Loss of appetite ● Changes in taste ● Constipation ● Increased blood calcium levels ● Dry eyes ● Redness, swelling, peeling, or tenderness, mainly of the hands or feet (hand-foot syndrome) ● Increased blood potassium levels ● Hair Removal ● Fluid accumulates behind the retina of the eye.

[0565] If you develop any nail or skin problem, including separation of the nail from the nail bed, nail pain, nail bleeding, nail breakage, changes in the color or texture of the nail, infected skin around the nail, itchy skin rash, dry skin, or cracked skin, immediately inform your healthcare provider.

[0566] BALVERSA may affect the fertility of women who are able to become pregnant. If you have any concerns, please inform your healthcare provider.

[0567] These are not all possible side effects of BALVERSA. Call your healthcare provider for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

[0568] How should I store BALVERSA? Store BALVERSA at room temperature, 68°F to 77°F (20°C to 25°C).

[0569] Keep BALVERSA and all other medications out of the reach of children.

[0570] General information regarding the safe and effective use of BALVERSA.

[0571] Medications may be prescribed for purposes other than those described in the patient information manual. Do not use BALVERSA when it has not been prescribed. Do not give BALVERSA to others, even if they have the same symptoms. BALVERSA may be harmful to them. Consult your healthcare provider for more information. You can ask your pharmacist or healthcare provider for information about BALVERSA written for healthcare providers.

[0572] What are the ingredients of BALVERSA? Active ingredient: Erdafitinib Inactive ingredients: Tablet core: Croscarmellose sodium, magnesium stearate (from a plant source), mannitol, meglumine, and microcrystalline cellulose.

[0573] Film coating (Opadry amb II): Glycerol monocaprylocate type I, partially hydrolyzed polyvinyl alcohol, sodium lauryl sulfate, talc, titanium dioxide, yellow iron oxide, red iron oxide (orange and brown tablets only), triiron tetroxide / black iron oxide (brown tablets only).

[0574] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes are presented to those skilled in the art and are included within the spirit and scope of this application and the appended claims.

[0575] Next, the present invention will be described with reference to the following numbered sections. To avoid misunderstanding, these embodiments do not limit the scope of the present invention. Modifications can be made within the scope and spirit of the present invention. 1. A method for treating locally advanced or metastatic urothelial carcinoma having one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering a therapeutically effective dose of erdafitinib to a subject in need of treatment, particularly a patient with locally advanced or metastatic urothelial carcinoma, and more particularly an adult patient with locally advanced or metastatic urothelial carcinoma, wherein the subject, particularly the patient, and more particularly the adult patient, has received at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic urothelial carcinoma. 2. A method for treating locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering a therapeutically effective dose of erdafitinib to a subject in need of treatment, particularly a patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly an adult patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, wherein the subject, particularly the patient, and more particularly the adult patient, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent. 3. A method for treating locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more FGFR gene mutations, comprising administering a therapeutically effective dose of erdafitinib to a subject in need of treatment, particularly a patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly an adult patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, wherein the subject, particularly the patient, and more particularly the adult patient, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months. 4. A method for treating a subject in need of treatment, particularly a patient with locally advanced or metastatic urothelial carcinoma, and more particularly an adult patient with locally advanced or metastatic urothelial carcinoma, who has a tumor having one or more fibroblast growth factor receptor (FGFR) gene alterations and has received at least one line of systemic therapy containing an anti-PD-(L)1 agent in a locally advanced or metastatic treatment setting, comprising administering a therapeutically effective dose of erdafitinib to the subject, particularly the patient, and more particularly an adult patient. 5. A method for treating subjects, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, who have a tumor having one or more fibroblast growth factor receptor (FGFR) gene alterations and whose disease has progressed, progressed, or requires treatment during or after one or more prior treatments including an anti-PD-(L)1 agent, comprising administering a therapeutically effective dose of erdafitinib to the subject, particularly the patient, and more particularly adult patients. 6. A method for treating patients in need of treatment, particularly those with locally advanced or metastatic urothelial carcinoma, and especially adult patients with locally advanced or metastatic urothelial carcinoma, who have one or more FGFR gene mutations and whose urothelial carcinoma, particularly locally advanced or metastatic urothelial carcinoma, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months. A method comprising administering a therapeutically effective dose of erdafitinib to a subject, particularly a patient, and more particularly to an adult patient. 7. A method for treating locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC), (a) Evaluating biological samples from subjects in need of treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the subjects, particularly patients, and more particularly adult patients, have received at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the subject, in particular the patient, and especially to the adult patient. Methods that include... 8. A method for treating patients in need of treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from subjects, particularly patients, and more particularly adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein subjects, particularly patients, and more particularly adult patients, have progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib to the subject, in particular the patient, and especially to the adult patient. Methods that include... 9. Use of erdafitinib for the manufacture of a pharmaceutical product for the treatment of locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) having one or more fibroblast growth factor receptor (FGFR) gene alterations in subjects requiring treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, wherein erdafitinib is administered or planned to be administered in a therapeutically effective dose, and subjects, particularly patients, and more particularly adult patients, are receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic urothelial carcinoma. 10. Use of erdafitinib for the manufacture of a pharmaceutical product for the treatment of locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations in subjects requiring treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, wherein erdafitinib is administered or planned to be administered in a therapeutically effective dose, and the subject, particularly patients, and more particularly adult patients, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent. 11. Use of erdafitinib for the manufacture of a pharmaceutical product for the treatment of locally advanced urothelial carcinoma or metastatic urothelial carcinoma (mUC) with one or more fibroblast growth factor receptor (FGFR) gene alterations in subjects requiring treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, wherein erdafitinib is administered or planned to be administered in a therapeutically effective dose, and the subject, particularly patients, and more particularly adult patients, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months. 12. Use of erdafitinib for the manufacture of a pharmaceutical product for the treatment of patients in need of treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, wherein erdafitinib is administered or will be administered in a therapeutically effective dose. 13. Use of erdafitinib for the manufacture of a pharmaceutical product for the treatment of patients in need of treatment who have a tumor with one or more fibroblast growth factor receptor (FGFR) gene alterations and whose disease has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, wherein erdaf...

Claims

1. A method for treating locally advanced or metastatic urothelial carcinoma having one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof to a subject in need of treatment, particularly a patient having locally advanced or metastatic urothelial carcinoma, and more particularly an adult patient having locally advanced or metastatic urothelial carcinoma, wherein the subject, particularly the patient, and more particularly the adult patient has received at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic urothelial carcinoma.

2. A method for treating locally advanced urothelial carcinoma or metastatic urothelial carcinoma having one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof to a subject in need of treatment, particularly a patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly an adult patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, wherein the urothelial carcinoma, particularly the locally advanced urothelial carcinoma or metastatic urothelial carcinoma, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent.

3. A method for treating locally advanced urothelial carcinoma or metastatic urothelial carcinoma having one or more FGFR gene mutations, comprising administering a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof to a subject in need of treatment, particularly a patient having locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly an adult patient having locally advanced urothelial carcinoma or metastatic urothelial carcinoma, wherein the urothelial carcinoma, particularly the locally advanced urothelial carcinoma or metastatic urothelial carcinoma, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months.

4. A method for treating a subject in need of treatment, particularly a patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly an adult patient with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, who has a tumor having one or more fibroblast growth factor receptor (FGFR) gene mutations and has received at least one line of systemic therapy containing an anti-PD-(L)1 agent in a locally advanced or metastatic treatment setting, comprising administering a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof to the subject, particularly the patient, and more particularly the adult patient.

5. A method for treating a patient in need of treatment, particularly a patient with locally advanced or metastatic urothelial carcinoma, and more particularly an adult patient with locally advanced or metastatic urothelial carcinoma, who has a tumor having one or more fibroblast growth factor receptor (FGFR) gene mutations and whose urothelial carcinoma, particularly locally advanced or metastatic urothelial carcinoma, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent, comprising administering a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof to the patient, particularly the adult patient.

6. A method for treating patients in need of treatment, particularly those with locally advanced or metastatic urothelial carcinoma, and especially adult patients with locally advanced or metastatic urothelial carcinoma, who have one or more FGFR gene mutations and whose urothelial carcinoma, particularly locally advanced or metastatic urothelial carcinoma, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months, and who require treatment, A method comprising administering a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof to the subject, particularly the patient, and more particularly the adult patient.

7. A method for treating locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluating biological samples from subjects in need of treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the subjects, particularly the patients, and more particularly the adult patients have received at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof to the subject, in particular the patient, and more particularly the adult patient. Methods that include...

8. A method for treating subjects requiring treatment, particularly patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, and more particularly adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from the subjects, particularly the patients, and more particularly the adult patients, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein urothelial carcinoma, particularly locally advanced or metastatic urothelial carcinoma, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent including neoadjuvant therapy or adjuvant therapy within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof to the subject, in particular the patient, and more particularly the adult patient. Methods that include...

9. A method for improving overall survival in patients having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in adult patients having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering to the patient, particularly the adult patient, a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof, wherein the patient, particularly the adult patient, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease.

10. A method for improving overall survival in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering to the patient, particularly the adult patient, a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof, wherein the urothelial carcinoma, particularly the locally advanced urothelial carcinoma or metastatic urothelial carcinoma, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent.

11. A method for improving overall survival in patients having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in adult patients having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering to the patient, particularly the adult patient, a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof, wherein the urothelial carcinoma, particularly the locally advanced or metastatic urothelial carcinoma, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, for 12 months or less.

12. A method for improving overall survival in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluating biological samples from the patient, particularly the adult patient, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has received at least one line of systemic treatment containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof to the patient, particularly the adult patient. Methods that include...

13. A method for improving overall survival in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from the patient, particularly the adult patient, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein urothelial carcinoma, particularly the locally advanced or metastatic urothelial carcinoma, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof to the patient, particularly the adult patient. Methods that include...

14. A method for reducing the risk of death in patients having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in adult patients having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering to the patient, particularly the adult patient, a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof, wherein the patient, particularly the adult patient, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic urothelial carcinoma.

15. A method for reducing the risk of death in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering to the patient, particularly the adult patient, a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof, wherein the urothelial carcinoma, particularly the locally advanced urothelial carcinoma or metastatic urothelial carcinoma, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent.

16. A method for reducing the risk of death in a patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in an adult patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering to the patient, particularly the adult patient, a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof, wherein the urothelial carcinoma, particularly the locally advanced or metastatic urothelial carcinoma, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months.

17. A method for reducing the risk of death in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluating biological samples from the patient, particularly the adult patient, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has received at least one line of systemic treatment containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) A method comprising administering a therapeutically effective amount of erdafitinib or a pharmaceutically acceptable salt thereof to the patient, particularly the adult patient, if one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample.

18. A method for reducing the risk of death in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma. (a) Evaluate biological samples from the patient, particularly the adult patient, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein urothelial carcinoma, particularly the locally advanced or metastatic urothelial carcinoma, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof to the patient, particularly the adult patient. Methods that include...

19. A method for improving the median PFS in a patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in an adult patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering to the patient, particularly the adult patient, a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof, wherein the patient, particularly the adult patient, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease.

20. A method for improving the median PFS in a patient having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in an adult patient having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering to the patient, particularly the adult patient, a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof, wherein the urothelial carcinoma, particularly the locally advanced urothelial carcinoma or metastatic urothelial carcinoma, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent.

21. A method for improving the median PFS in a patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in an adult patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering to the patient, particularly the adult patient, a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof, wherein the urothelial carcinoma, particularly the locally advanced or metastatic urothelial carcinoma, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months.

22. A method for improving the median PFS in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluating biological samples from the patient, particularly the adult patient, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has received at least one systemic treatment line containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof to the patient, particularly the adult patient. Methods that include...

23. A method for improving the median PFS in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from the patient, particularly the adult patient, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein urothelial carcinoma, particularly the locally advanced or metastatic urothelial carcinoma, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof to the patient, particularly the adult patient. Methods that include...

24. A method for reducing the risk of progression or death in a patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in an adult patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering to the patient, particularly the adult patient, a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof, wherein the patient, particularly the adult patient, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease.

25. A method for reducing the risk of progression or death in a patient having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in an adult patient having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering to the patient, particularly the adult patient, a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof, wherein the urothelial carcinoma, particularly the locally advanced urothelial carcinoma or metastatic urothelial carcinoma, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent.

26. A method for reducing the risk of progression or death in a patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in an adult patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering to the patient, particularly the adult patient, a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof, wherein the urothelial carcinoma, particularly the locally advanced or metastatic urothelial carcinoma, has progressed during or after at least one prior line of treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months.

27. A method for reducing the risk of progression or death in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluating biological samples from the patient, particularly the adult patient, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has received at least one systemic treatment line containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof to the patient, particularly the adult patient. Methods that include...

28. A method for reducing the risk of progression or death in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from the patient, particularly the adult patient, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein urothelial carcinoma, particularly the locally advanced or metastatic urothelial carcinoma, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof to the patient, particularly the adult patient. Methods that include...

29. A method for improving ORR in a patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in an adult patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering to the patient, particularly the adult patient, a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof, wherein the patient, particularly the adult patient, is receiving at least one line of systemic therapy containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease.

30. A method for improving ORR in patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in adult patients having locally advanced urothelial carcinoma or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering to the patient, particularly the adult patient, a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof, wherein the urothelial carcinoma, particularly the locally advanced urothelial carcinoma or metastatic urothelial carcinoma, has progressed during or after one or more prior treatments including an anti-PD-(L)1 agent.

31. A method for improving ORR in a patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, particularly in an adult patient having locally advanced or metastatic urothelial carcinoma with one or more fibroblast growth factor receptor (FGFR) gene mutations, comprising administering to the patient, particularly the adult patient, a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof, wherein the patient, particularly the adult patient, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, for 12 months or less.

32. A method for improving ORR in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluating biological samples from the patient, particularly the adult patient, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein the patient, particularly the adult patient, has received at least one line of systemic treatment containing an anti-PD-(L)1 agent in the treatment of locally advanced or metastatic disease; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof to the patient, particularly the adult patient. Methods that include...

33. A method for improving ORR in patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, particularly in adult patients with locally advanced urothelial carcinoma or metastatic urothelial carcinoma, (a) Evaluate biological samples from the patient, particularly the adult patient, for the presence of one or more fibroblast growth factor receptor (FGFR) gene alterations, wherein urothelial carcinoma, particularly the locally advanced or metastatic urothelial carcinoma, has progressed during or after at least one line of prior treatment with an anti-PD-(L)1 agent, including neoadjuvant therapy or adjuvant therapy, within 12 months; and (b) If one or more fibroblast growth factor receptor (FGFR) gene alterations are present in the sample, administer a therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof to the patient, particularly the adult patient. Methods that include...

34. The method according to any one of claims 9 to 13, wherein the improvement in overall survival is approximately 12.1 months to the median overall survival.

35. The method according to any one of claims 9 to 13, wherein the improvement in overall survival is due to chemotherapy.

36. The method according to any one of claims 9 to 13, wherein the improvement in overall survival is approximately 12.1 months of overall survival compared to approximately 7.8 months of overall survival for chemotherapy.

37. The method according to claim 35 or 36, wherein the chemotherapy is docetaxel or vinflunin.

38. The method according to any one of claims 14 to 18, wherein the reduction in the risk of death is a reduction of approximately 36% of the risk of death.

39. The method according to any one of claims 14 to 18, wherein the reduction in the risk of death is due to chemotherapy.

40. The method according to any one of claims 14 to 18, wherein the reduction in mortality risk is approximately a 36% reduction in mortality risk compared to chemotherapy.

41. The method according to claim 39 or 40, wherein the chemotherapy is docetaxel or vinflunin.

42. The method according to any one of claims 19 to 23, wherein the improvement in PFS is a median PFS over approximately 5.6 months.

43. The method according to any one of claims 19 to 23, wherein the improvement of PFS is due to chemotherapy.

44. The method according to any one of claims 19 to 23, wherein the improvement in PFS is approximately 5.6 months of PFS compared to approximately 2.7 months of PFS for chemotherapy.

45. The method according to claim 43 or 44, wherein the chemotherapy is docetaxel or vinflunin.

46. The method according to any one of claims 24 to 28, wherein the reduction in the risk of progression or death is a reduction of approximately 42% of the risk of progression or death.

47. The method according to any one of claims 24 to 28, wherein the reduction in the risk of progression or death is due to chemotherapy.

48. The method according to any one of claims 24 to 28, wherein the reduction in the risk of progression or death is approximately a 42% reduction in the risk of progression or death compared to chemotherapy.

49. The method according to claim 47 or 48, wherein the chemotherapy is docetaxel or vinflunin.

50. The method according to any one of claims 29 to 33, wherein the improvement in ORR is approximately 35.3% confirmed ORR.

51. The method according to any one of claims 29 to 33, wherein the improvement in ORR is due to chemotherapy.

52. The method according to any one of claims 29 to 33, wherein the improvement in ORR is approximately 35.3% confirmed ORR compared to 8.5% confirmed ORR for chemotherapy.

53. The method according to claim 51 or 52, wherein the chemotherapy is docetaxel or vinflunin.

54. The method according to any one of claims 1 to 53, wherein one or more FGFR gene changes are selected from FGFR fusions and / or mutations.

55. The method according to any one of claims 1 to 54, wherein one or more FGFR gene mutations are selected from FGFR3 mutations and / or FGFR2 fusions and / or FGFR3 fusions.

56. The method according to any one of claims 1 to 55, wherein the one or more FGFR gene mutations are selected from FGFR3-TACC3, particularly FGFR3-TACC3 V1 and FGFR3-TACC3 v3; FGFR3-BAIAP2L1; FGFR2:BICC1; FGFR2:CASP7; FGFR3 R248C; FGFR3 S249C; FGFR3 G370C; and FGFR3 Y373C.

57. The method according to any one of claims 1 to 53, wherein one or more FGFR gene changes are selected from FGFR3 mutations and / or FGFR3 fusions.

58. The method according to claim 57, wherein the one or more FGFR gene mutations are selected from FGFR3-TACC3, particularly FGFR3-TACC3 V1 and FGFR3-TACC3 v3; FGFR3-BAIAP2L1; FGFR3 R248C; FGFR3 S249C; FGFR3 G370C; and FGFR3 Y373C.

59. The method according to any one of claims 1 to 53, wherein the one or more FGFR gene mutations include or consist of FGFR3 S249C.

60. The method according to any one of claims 1 to 53, wherein the one or more FGFR gene mutations include or consist of FGFR3 Y373C.

61. The method according to any one of claims 1 to 53, wherein the one or more FGFR gene mutations include or consist of FGFR3 G370C.

62. The method according to any one of claims 1 to 53, wherein the one or more FGFR gene mutations include or consist of FGFR3 R248C.

63. The method according to any one of claims 1 to 53, wherein the one or more FGFR gene mutations include or consist of FGFR3-TACC3 V1.

64. The method according to any one of claims 1 to 53, wherein the one or more FGFR gene mutations include or consist of FGFR3-TACC3 v3.

65. The method according to any one of claims 1 to 53, wherein the one or more FGFR gene mutations include or consist of FGFR3-BAIAP2L1.

66. The method according to any one of claims 1 to 53, wherein the one or more FGFR gene mutations include or consist of FGFR2:BICC1.

67. The method according to any one of claims 1 to 53, wherein the one or more FGFR gene mutations include or consist of FGFR2:CASP7.

68. The method according to any one of claims 1 to 67, wherein the therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof is 8 mg base equivalent per day, particularly 8 mg base equivalent once daily.

69. The method according to any one of claims 1 to 67, wherein the therapeutically effective dose of erdafitinib or a pharmaceutically acceptable salt thereof is 9 mg base equivalent per day, particularly 9 mg base equivalent once daily.

70. The method according to any one of claims 1 to 67, wherein the starting dose of erdafitinib or a pharmaceutically acceptable salt thereof is 8 mg base equivalents per day, particularly once daily, and may be increased up to 9 mg base equivalents per day, particularly once daily, based on measured serum phosphate levels, particularly on any day between 14 and 21 after the start of erdafitinib treatment.

71. The method according to any one of claims 1 to 67, wherein the starting dose of erdafitinib or a pharmaceutically acceptable salt thereof is 8 mg base equivalents per day, particularly once daily, and there is a possibility of escalation up to 9 mg base equivalents per day based on measured serum phosphate levels assessed on day 14 of erdafitinib treatment.

72. The method according to any one of claims 1 to 67, wherein the starting dose of erdafitinib or a pharmaceutically acceptable salt thereof is 8 mg base equivalents per day, particularly once daily, and there is a possibility of escalation up to 9 mg base equivalents per day, particularly once daily, based on measured serum phosphate levels assessed on day 15 of erdafitinib treatment.

73. The method according to any one of claims 1 to 67, wherein the starting dose of erdafitinib or a pharmaceutically acceptable salt thereof is 8 mg base equivalents per day, particularly once daily, and there is a possibility of escalation up to 9 mg base equivalents per day, particularly once daily, based on measured serum phosphate levels assessed on day 16 of erdafitinib treatment.

74. The method according to any one of claims 1 to 67, wherein the starting dose of erdafitinib or a pharmaceutically acceptable salt thereof is 8 mg base equivalents per day, particularly once daily, and there is a possibility of escalation up to 9 mg base equivalents per day, particularly once daily, based on measured serum phosphate levels assessed on day 17 of erdafitinib treatment.

75. The method according to any one of claims 1 to 67, wherein the starting dose of erdafitinib or a pharmaceutically acceptable salt thereof is 8 mg base equivalents per day, particularly once daily, and there is a possibility of escalation up to 9 mg base equivalents per day, particularly once daily, based on measured serum phosphate levels assessed on day 18 of erdafitinib treatment.

76. The method according to any one of claims 1 to 67, wherein the starting dose of erdafitinib or a pharmaceutically acceptable salt thereof is 8 mg base equivalents per day, particularly once daily, and there is a possibility of escalation up to 9 mg base equivalents per day, particularly once daily, based on measured serum phosphate levels assessed on day 19 of erdafitinib treatment.

77. The method according to any one of claims 1 to 67, wherein the starting dose of erdafitinib or a pharmaceutically acceptable salt thereof is 8 mg base equivalents per day, particularly once daily, and there is a possibility of escalation up to 9 mg base equivalents per day, particularly once daily, based on measured serum phosphate levels assessed on day 20 of erdafitinib treatment.

78. The method according to any one of claims 1 to 67, wherein the starting dose of erdafitinib or a pharmaceutically acceptable salt thereof is 8 mg base equivalents per day, particularly once daily, and there is a possibility of escalation up to 9 mg base equivalents per day, particularly once daily, based on measured serum phosphate levels assessed on day 21 of erdafitinib treatment.

79. The method according to any one of claims 70 to 78, wherein if the serum phosphate level is less than 5.5 mg / dL, the erdafitinib dose is gradually increased to 9 mg base equivalent per day, particularly once daily.

80. The method according to any one of claims 70 to 78, wherein if the serum phosphate level is less than 7 mg / dL, the erdafitinib dose is gradually increased to 9 mg base equivalent per day, particularly once daily.

81. The method according to any one of claims 70 to 78, wherein if the serum phosphate level is less than 9 mg / dL, the erdafitinib dose is gradually increased to 9 mg base equivalent per day, particularly once daily.

82. The method according to any one of claims 70 to 78, wherein if the serum phosphate level is less than 9 mg / dL, and in particular if the serum phosphate level evaluated 14 to 21 days after the initiation of erdafitinib treatment is in the range of 7.00 mg / dL to 8.99 mg / dL, while simultaneously initiating treatment with a phosphate binder such as sevelamer, the dose of erdafitinib is gradually increased to 9 mg base equivalent per day, particularly once daily.

83. The method according to any one of claims 70 to 82, wherein, in the absence of drug-related toxicity, the erdafitinib dose is gradually increased to 9 mg base equivalent per day, particularly once daily.

84. The method according to any one of claims 70 to 82, wherein, in the absence of ocular impairment or a grade 2 or higher adverse reaction, the erdafitinib dose is gradually increased to 9 mg base equivalent per day, particularly once daily.

85. The method according to any one of claims 68, 70 to 84, wherein the erdafitinib dose of 8 mg base equivalent is administered as two formulations, particularly two tablets, each containing 4 mg of erdafitinib base equivalent.

86. The method according to any one of claims 68, 70 to 84, wherein the erdafitinib dose of 8 mg base equivalent is administered as two formulations, particularly two tablets, one containing 3 mg of erdafitinib base equivalent and the other containing 5 mg of erdafitinib base equivalent.

87. The method according to any one of claims 69 to 84, wherein the 9 mg base equivalent dose of erdafitinib is administered or is administered as three formulations, particularly three tablets, each containing 3 mg of erdafitinib base equivalent.

88. The method according to any one of claims 69 to 84, wherein the 9 mg base equivalent dose of erdafitinib is administered or is administered as two formulations, particularly two tablets, one containing a 4 mg base equivalent of erdafitinib and the other containing a 5 mg base equivalent of erdafitinib.

89. The method according to any one of claims 1 to 88, wherein erdafitinib or a pharmaceutically acceptable salt thereof is erdafitinib.

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