WO2025059602A1

WO2025059602A1 - Methods of treating bladder cancer using intravesical administration of erdafitinib

Info

Publication number: WO2025059602A1
Application number: PCT/US2024/046807
Authority: WO
Inventors: Sabine BROOKMAN-MAY; Josh LAURING; Carrye COST; Mark Lewis; Wei Zhu; Neil BEEHARRY
Original assignee: Taris Biomedical LLC
Current assignee: Taris Biomedical LLC
Priority date: 2023-09-14
Filing date: 2024-09-13
Publication date: 2025-03-20
Anticipated expiration: 2026-03-14
Also published as: TW202529765A

Abstract

Provided herein are methods of treatment comprising administering erdafitinib and drug delivery systems comprising erdafitinib for use in the treatment of bladder cancer.

Description

METHODS OF TREATING BLADDER CANCER USING INTRAVESICAL ADMINISTRATION OF ERDAFITINIB

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application Nos. 63/582,833, filed September 14, 2023; 63/582,835, filed September 14, 2023;

63/583,820, filed September 19, 2023; 63/590,367, filed October 13, 2023; 63/590,368, filed October 13, 2023; 63/590,370, filed October 13, 2023; 63/590,376, filed October 13, 2023; 63/623,192, filed January 19, 2024; 63/561,725, filed March 5, 2024; 63/566,181, filed March 15, 2024; 63/640,816, filed April 30, 2024; and 63/691,878, filed September 6, 2024, the contents of each of which are incorporated herein in their entirety.

REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (761662002540seqlist.xml; Size: 53,246 bytes; and Date of Creation: August 28, 2024) is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0003] The present disclosure is generally in the field of methods of treatment for bladder cancer.

BACKGROUND

[0004] The present disclosure is generally in the field of pharmaceutical formulations and drug-device combination products, and more particularly relates to erdafitinib based formulations and systems for intravesical administration of such formulations.

[0005] Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl-lH- pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) is a potent pan FGFR kinase inhibitor that binds to and inhibits enzymatic activity of FGFR1, FGFR2, FGFR3 and FGFR4. The synthetic preparation of erdafitinib has been described in WO2011/135376. Erdafitinib has been found to inhibit FGFR phosphorylation and signaling and decrease cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. Erdafitinib has demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer. [0006] Currently, Erdafitinib (BAL VERSA®) is available as film-coated tablets for oral administration, and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma that has susceptible fibroblast growth factor receptor (FGFR)3 or FGFR2 genetic alterations and progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

[0007] Individuals with high-risk NMIBC are often initially treated with BCG, however up to 50% of patients experience recurrence. A subset of patients may receive a radical cystectomy, however the utility of radical cystectomy is limited due to high morbidity and decreased quality of life.

BRIEF SUMMARY

[0008] Provided herein are methods of treating recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) comprising administering erdafitinib locally to the bladder of a patient. Also provided herein are methods of treating recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising administering erdafitinib locally to the bladder of a patient.

[0009] In some aspects, a drug delivery system is provided herein, comprising: a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 2.5 mg/day to about 3.5 mg/day, and wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure. [0010] In some aspects, a drug delivery system is provided herein, comprising: a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 3 mg/day and wherein the two interface edges are disposed at an arc angle of about 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The detailed description is set forth with reference to the accompanying drawings. The use of the same reference numerals may indicate similar or identical items. Various embodiments may utilize elements and/or components other than those illustrated in the drawings, and some elements and/or components may not be present in various embodiments. Elements and/or components in the figures are not necessarily drawn to scale.

[0012] FIG. 1 is a longitudinal cross-sectional view of one embodiment of a drug delivery system in a coiled retention shape, in accordance with the present disclosure.

[0013] FIG. 2 is a transverse cross-sectional view of one embodiment of a drug delivery system, in accordance with the present disclosure.

[0014] FIG. 3 is a transverse cross-sectional view of one embodiment of a drug delivery system, in accordance with the present disclosure.

[0015] FIG. 4 is a photograph of one embodiment of a drug delivery system loaded with erdafitinib drug tablets, in accordance with the present disclosure.

[0016] FIG. 5 is a longitudinal cross-sectional view of one embodiment of a drug delivery system having an elastic retention frame and prior to loading with drug tablets, in a coiled retention shape, in accordance with the present disclosure. [0017] FIG. 6A is a longitudinal cross-sectional view of one embodiment of an elastic retention frame in a coiled retention shape, in accordance with the present disclosure.

[0018] FIG. 6B is a partial magnified view of one end of the retention frame of FIG. 6A.

[0019] FIG. 7A is a perspective view of one embodiment of a drug delivery system, without drug disposed therein or an elastic retention frame, in a relatively straightened shape, in accordance with the present disclosure.

[0020] FIG. 7B is a longitudinal cross-sectional view of the drug delivery system shown in FIG. 7A, taken along line 7B-7B.

[0021] FIG. 7C is a transverse cross-sectional view of the drug delivery system shown in FIG. 7A, taken along line 7C-7C.

[0022] FIG. 8 is a photograph showing the cross-section of the drug reservoir lumen of a drug delivery system without drug disposed therein, in accordance with the present disclosure.

[0023] FIG. 9A shows the two doses for erdafitinib treatment (TAR-210-B, about 2mg/day; TAR-210-D, about 4 mg/day) and the two cohorts of participants treated in the clinical study described herein in Example 1.

[0024] FIG. 9B depicts a clinical protocol for administration of erdafitinib. TURBT, transurethral resection of the bladder tumor as described herein in Example 1.

[0025] FIG. 10 shows a summary of demographics for the 43 patients in Cohorts 1 and 3 treated in the clinical study (16 patients from Cohort 1 and 27 patients from Cohort 3) described herein in Example 1, Part A.

[0026] FIGS. 11A-11B shows a summary of baseline disease characteristics for the 43 patients treated in the clinical study described herein in Example 1, Part A.

[0027] FIG. 12A is a swim lane plot for treatment duration and response of patients in Cohort 1 of the clinical study described herein in Example 1, Part A, treated with TAR-210-B (about 2 mg/day erdafitinib; diagonally striped) or TAR-210-D (about 4 mg/day erdafitinib; dotted). A key describing patient treatment status and milestones is included. Non-CR, noncomplete response; non-PD, non-progressive disease.

[0028] FIG. 12B is a swim lane plot for treatment duration and response of patients in Cohort 3 of the clinical study described herein in Example 1, Part A, treated with TAR-210-B (about 2 mg/day erdafitinib; diagonally striped) or TAR-210-D (about 4 mg/day erdafitinib; dotted). A key describing patient treatment status and milestones is included. Non-CR, noncomplete response; non-PD, non-progressive disease. [0029] FIG. 13 shows a summary of recurrence-free survival for the 16 patients treated in Cohort 1 of the clinical study of Example 1, Part A.

[0030] FIG. 14 shows a summary of complete response for the 15 patients treated and showing treatment efficacy in Cohort 3 of the clinical study of Example 1, Part A.

[0031] FIG. 15 shows a summary of the duration of response for the 13 patients achieving complete response in Cohort 3 of the clinical study of Example 1, Part A. [0032] FIG. 16 shows a summary of treatment disposition for the 43 patients treated in Cohorts 1 and 3 of the described clinical study of Example 1, Part A, including ongoing study treatment, completed study treatment, and discontinued study treatment.

[0033] FIG. 17 shows a summary of treatment-emergent adverse effects for 43 patients treated in Cohorts 1 and 3 of the described clinical study in Example 1, Part A.

[0034] FIG. 18 shows the quantified urine concentration of erdafitinib (left) and the quantified plasma concentration of erdafitinib (right) from patient samples after TAR-210-B (dashed line) or TAR-210-D (solid line) administration in Example 1, Part A.

[0035] FIG. 19A is a schematic overview of a clinical study related to the safety and efficacy of an intravesical drug delivery system (TAR-210) in the treatment of patients with intermediate risk (IR) non-muscle invasive bladder cancer (NMIBC), described in Example 2. SOC, standard of care; LG, low-grade; MMC, mitomycin C; Gem, gemcitabine.

[0036] FIG. 19B is a schematic overview of the treatment phase of the clinical study described in Example 2. Patients are randomized 1 : 1 and treated as described in Group A with either the intravesical drug delivery system (TAR-210) or Group B with gemcitabine or MMC for up to 1 year. TURBT, transurethral resection of bladder tumor; CT, computed tomography; IV, intravenous; MRI, magnetic resonance imaging; EOT, end of treatment. [0037] FIG. 20 is a schematic overview of the tissue assay and urine assay concordance study using paired samples from bladder cancer patients from the Bladder BRIDGister clinical trial in Germany.

[0038] FIG. 21 is a heat map of identified genetic alterations from matched urine NGS and FFPE tissue RT-PCR samples (bladder cancer patients from the Bladder BRIDGister clinical trial in Germany).

[0039] FIG. 22A is a scatter plot for the variant allele frequency (VAF) between matched urine NGS (X-axis) and tissue (“FFPE”) RT-PCR (Y-axis) variants for all identified genetic alterations including somatic and germline variants. [0040] FIG. 22B is a scatter plot for the variant allele frequency (VAF) between matched urine NGS (X-axis) and tissue (“FFPE”) RT-PCR (Y-axis) variants for somatic FGFR3 alterations.

[0041] FIG. 23 shows a flow chart comparing urine test and tissue test performance from all screened patients with NMIBC (N=178) at cut-off date. Patients are from the first in human study as described in Example 1.

[0042] FIG. 24A is a swim lane plot showing clinical efficacy data (treatment duration and response) for disease-evaluable HR-NMIBC patients in Cohort 1, screened by urine sample assay and/or tumor tissue sample assay and treated with the intravesical drug delivery system TAR-210-B (about 2 mg/day erdafitinib; circle pattern) or TAR-210-D (about 4 mg/day erdafitinib; dash pattern). Patients are from the first in human study as described in Example 1. A key depicting patient enrollment (“Enrolled by”; left in the Figure) by tumor tissue sample assay (left in the key) or urine sample assay (right in the key) is included with associated check marks. Another key describing patient treatment status and milestones is included (right in the Figure).

[0043] FIG. 24B is a swim lane plot showing clinical efficacy data (treatment duration and response) for disease-evaluable IR-NMIBC patients in Cohort 3, screened by urine sample assay and/or tumor tissue sample assay and treated with the intravesical drug delivery system TAR-210-B (about 2 mg/day erdafitinib; circle pattern) or TAR-210-D (about 4 mg/day erdafitinib; dash pattern). Patients are from the first in human study as described in Example 1. A key depicting patient enrollment (“Enrolled by”; left in the Figure) by tumor tissue sample assay (left in the key) or urine sample assay (right in the key) is included with associated check marks. Another key describing patient treatment status and milestones is included (right in the Figure).

[0044] FIG. 25 depicts the landscape of pathogenic somatic variants for the 15 most prevalent genes detected in urine from all evaluable samples. Del = deletion; UTR = untranslated region; Ins = insertion; CNV = copy number variation.

[0045] FIGS. 26A-26D show an updated protocol for the Phase I clinical trial of intravesical administration of erdafitinib of Example 1.

[0046] FIG. 27A is a top, schematic view of an embodiment of a drug delivery system according to the present disclosure, shown in a coiled retention shape. In FIG. 27A, the portion of the housing bounding the drug reservoir lumen is shown as being translucent, revealing the erdafitinib minitablets contained therein. [0047] FIG. 27B is a bottom, schematic view of the drug delivery system of FIG. 27A, shown in a coiled retention shape. In FIG. 27B, the portion of the housing bounding the drug reservoir lumen is shown as being translucent, revealing the erdafitinib minitablets contained therein.

[0048] FIG. 28 is a transverse cross-sectional view of the drug delivery system of FIG. 27A, taken along lines A-A of FIG. 27A.

[0049] FIG. 29A is a side, schematic view of the drug delivery system of FIG. 27A, shown in a relatively straightened insertion shape. In FIG. 29A, the portion of the housing bounding the drug reservoir lumen is shown as being translucent, revealing the erdafitinib minitablets contained therein.

[0050] FIG. 29B is a side cross-sectional view of a portion of the drug delivery system of FIG. 27A, shown in a relatively straightened insertion shape. In FIG. 29B, the housing is shown in cross section to reveal the erdafitinib minitablets located in the drug reservoir lumen and the retention frame located in the retention frame lumen; the ends of the drug delivery system are truncated.

[0051] FIG. 30A shows a summary of demographics for the 64 patients in Cohorts 1 and 3 treated in the clinical study (21 patients from Cohort 1 and 43 patients from Cohort 3) described herein in Example 1, Part C.

[0052] FIG. 30B shows a summary of baseline disease characteristics for the 64 patients treated in the clinical study (21 patients from Cohort 1 and 43 patients from Cohort 3) described herein in Example 1, Part C.

[0053] FIG. 31A is a swim lane plot for treatment duration and response of patients in Cohort 1 of the clinical study described herein in Example 1, Part C, treated with TAR-210-B (about 2 mg/day erdafitinib; circle pattern) or TAR-210-D (about 4 mg/day erdafitinib; dash pattern). A key describing patient treatment status and milestones is included. RFS, recurrence-free survival.

[0054] FIG. 31B is a swim lane plot for treatment duration and response of patients in Cohort 3 of the clinical study described herein in Example 1, Part C, treated with TAR-210-B (about 2 mg/day erdafitinib; circle pattern) or TAR-210-D (about 4 mg/day erdafitinib; dotted pattern). A key describing patient treatment status and milestones is included. DOR, duration of response; CR, complete response; Non-CR, non-complete response; non-PD, nonprogressive disease.

[0055] FIG. 32A shows the urine concentration of erdafitinib from patient samples after TAR-210-B or TAR-210-D administration in Example 1, Part C. [0056] FIG. 32B shows the plasma concentration of erdafitinib from patient samples after TAR-210-B or TAR-210-D administration in Example 1, Part C.

[0057] FIG. 33 shows pie charts demonstrating the proportion of efficacy evaluable patients enrolled by urine and tissue sample for Cohort 1 (HR-NMIBC) and Cohort 3 (IR- NMIBC) patients in Example 4, Part B.

[0058] FIG. 34A shows a diagram illustrating the proportion of Cohort 1 patients with HR-NMIBC who were recurrence-free by enrolled sample type in Example 4, Part B.

[0059] FIG. 34B shows a diagram illustrating the proportion of Cohort 3 patients with IR-NMIBC with a complete response at 3 -month evaluation by enrolled sample type in Example 4, Part B.

[0060] FIG. 35 shows a summary of demographics and baseline disease characteristics for the 21 HR-NMIBC (Cohort 1) patients and 49 IR-NMIBC (Cohort 3) patients treated in the clinical study described herein in Example 1, Part D.

[0061] FIG. 36A is a swim lane plot for treatment duration and response of HR-NMIBC (Cohort 1) patients of the clinical study described herein in Example 1, Part D, treated with TAR-210-B (about 2 mg/day erdafitinib; diagonally striped) or TAR-210-D (about 4 mg/day erdafitinib; dotted). A key describing patient treatment status and milestones is included.

[0062] FIG. 36B is a swim lane plot for treatment duration and response of IR-NMIBC (Cohort 3) patients of the clinical study described herein in Example 1, Part D, treated with TAR-210-B (about 2 mg/day erdafitinib; diagonally striped) or TAR-210-D (about 4 mg/day erdafitinib; dotted). A key describing patient treatment status and milestones is included.

[0063] FIG. 37A shows the quantified urine concentration of erdafitinib from patient samples after TAR-210-B (dashed line) or TAR-210-D (solid line) administration in Example 1, Part D.

[0064] FIG. 37B shows the quantified plasma concentration of erdafitinib from patient samples after TAR-210-B (dashed line) or TAR-210-D (solid line) administration in Example 1, Part D.

DETAILED DESCRIPTION

[0065] With limited available therapies and poor outcomes, provided herein are methods of treating non-muscle invasive bladder cancer (NMIBC), in particular high risk (HR) NMIBC such as for example recurrent HR-NMIBC, and intermediate risk (IR) NMIBC such as for example recurrent IR-NMIBC in multiple cohorts of patients. Intravesical delivery of erdafitinib provides for localized bladder cancer treatment while avoiding systemic toxicities, providing a much-needed therapeutic option for NMIBC. As demonstrated herein, methods of treating HR-NMIBC, in particular recurrent bacillus Calmette-Guerin (BCG)-experienced high risk NMIBC comprising administering about 2 mg/day erdafitinib to about 4 mg/day erdafitinib for about 90 days locally to the bladder of the patient result in a recurrence-free (RF) rate of at least 85% in a population of patients receiving 2 mg/day erdafitinib and a RF rate of at least 80% in a population of patients receiving 4 mg/day erdafitinib. Further, methods of treating IR-NMIBC, in particular recurrent intermediate-risk NMIBC are presented, comprising administering about 2 mg/day to about 4 mg/day erdafitinib for about 90 days locally to the bladder of the patient results in a complete response (CR) rate of at least 75% in a population of patients receiving 2 mg/day erdafitinib and a CR rate of at least 90% in a population of patients receiving 4 mg/day erdafitinib. Methods of the instant application demonstrate excellent RF and CR rates for each cohort of treated patients, respectively. Further, the methods provided herein showed limited treatment-emergent adverse effects (TEAEs) and very few serious TEAEs, suggesting a safe and well-tolerated treatment.

[0066] In further aspects, local and continuous administration of erdafitinib to the bladder according to the methods presented herein demonstrated improved rates of event free survival and duration of response (DOR). Patients who received such treatment and achieved efficacious response were likely to experience 6 months of event free survival or DOR.

[0067] The unexpected improvement in RF and CR rates of the methods disclosed herein provides the added benefit of delaying invasive alternative treatments such as surgical removal of the bladder (radical cystectomy), which results in significant impacts to an individual’s quality of life. Such quality-of-life impacts include incontinence, sexual disfunction, infertility, and bowel function complications. Moreover, local administration of erdafitinib to the bladder according to the methods presented herein results in reduced side effects as compared to systemic chemotherapy. Together, these clinical improvements yield a safe and effective treatment method for individuals with NMIBC such as recurrent high- and intermediate-risk NMIBC.

[0068] Also described herein are erdafitinib formulations and release systems that are tailored for intravesical drug delivery, to take advantage of this route of administration, for treating NMIBC in a patient. Further provided are systems capable of delivering erdafitinib at effective release rates for the local treatment of bladder cancer. [0069] Erdafitinib exhibits pH-dependent solubility over the normal urine pH range of 5.5 to 7. In some embodiments, the formulations and release systems are tailored to minimize the effect of urine pH and composition on system release rate.

Certain Terminology

[0070] Disease-free survival (DFS) is defined as the time from randomization to the date of the first documented recurrence of non-muscle invasive bladder cancer (NMIBC) of any grade, disease progression, or death due to any cause, whichever occurs first (i.e., up to 5 years).

[0071] Recurrence is defined as reappearance of NMIBC independent of grade based on pathological assessment.

[0072] Recurrence-Free Survival (RFS) is defined as the time from randomization to the first detection of high-grade Ta or T1 bladder cancer or positive urine cytology.

[0073] Recurrence-free survival (RFS) rate is defined as the proportion of patients having RFS, from initiation of the study treatment to detection of high-grade Ta or T1 bladder cancer or positive urine cytology, wherein the proportion is assessed initially at about 3 months or about 90 days of the erdafitinib treatment, then again every 3 months while on study (year 1) and during follow-up (every 3 months to end of year 2, and every 6 months in year 3).

[0074] Recurrence-free rate is defined as the proportion of patients with at least one disease assessment who are free of recurrence, wherein the proportion is assessed initially at about 3 months or about 90 days of the erdafitinib treatment, then again every 3 months while on study (year 1) and during follow-up (every 3 months to end of year 2, and every 6 months in year 3).

[0075] High-grade recurrence rate is defined as the proportion of patients having a detection of high-grade Ta or T1 bladder cancer or positive urine cytology for HG urothelial carcinoma (HGUC or repeat sample showing suspicious for HGUC), wherein the proportion is assessed initially at about 3 months or about 90 days of the erdafitinib treatment, then again every 3 months while on study (year 1) and during follow-up (every 3 months to end of year 2, and every 6 months in year 3).

[0076] Low-grade recurrence rate is defined as the proportion of patients having a detection of low-grade Ta or T1 bladder cancer or positive urine cytology for LG urothelial carcinoma, wherein the proportion is assessed initially at about 3 months or about 90 days of the erdafitinib treatment, then again every 3 months while on study (year 1) and during follow-up (every 3 months to end of year 2, and every 6 months in year 3). [0077] Progressive disease rate is defined as the proportion of patients that progress to muscle invasive bladder cancer (MIBC) (stage T2 or higher), wherein the proportion is assessed initially at about 3 months or about 90 days of the erdafitinib treatment, then again every 3 months while on study (year 1) and during follow-up (every 3 months to end of year 2, and every 6 months in year 3).

[0078] Non-complete response (non-CR) or non-progressive disease (non-PD) is defined as no new tumors or larger tumors identified on cystoscopy.

[0079] Disease progression is defined as having post-baseline assessments of > T2 disease or positive lymph nodes or metastases.

[0080] Complete Response (CR) is defined as the absence of urothelial carcinoma by cystoscopy, confirmed pathologically at first assessment, and negative urine cytology.

[0081] Complete response (CR) rate is defined as the proportion of patients with an absence of urothelial carcinoma by cystoscopy, confirmed pathologically at first assessment, and negative urine cytology.

[0082] Duration of CR is defined as the time from first documentation of CR until the date of documented recurrence or progression, or death, whichever comes first.

[0083] Pathological Complete Response (pCR) Rate is defined as percentage of participants with no pathologic evidence of intravesical disease (pTO) and no pathologic evidence of nodal involvement (pNO).

[0084] No Pathologic Evidence of Intravesical Disease (pTO) rate is defined as percentage of participants with no Pathologic Evidence of Intravesical Disease.

[0085] BCG-experienced describes an individual that experiences recurrent high-grade Ta/Tl disease within 18 months of completion of prior BCG Therapy. The minimum treatment requirements for a prior BCG therapy is at least 5 of 6 full doses of an initial induction course of BCG (with or without maintenance therapy). Full dose BCG is defined as 1 full vial containing a minimum of 1 X 10⁸ colony forming units.

[0086] Rate of downstaging to less than (<) pT2 is defined as percentage of participants with pT stage <2.

[0087] When used herein wt% in relation to drug or excipient(s) refers to weight % based on the total weight of the formulation concerned, unless otherwise indicated.

[0088] The present application contemplates all combinations of any of the embodiments disclosed herein.

[0089] Embodiments described herein for methods of treatment are also applicable for use in treating, or for use in a method for treating or for the manufacture of a medicament for the treatment of. For example, disclosure of a method of treating recurrent bacillus Calmette- Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient by administering erdafitinib as described herein can also be worded as erdafitinib for use in treating recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient as described herein, or erdafitinib for use in a method for treating recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient as described herein, or erdafitinib for the manufacture of a medicament for treating recurrent bacillus Calmette- Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient as described herein, or use of erdafitinib for the manufacture of a medicament for the treatment of recurrent bacillus Calmette Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient as described herein.

[0090] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

Erdafitinib Formulation & Tablets

[0091] In one aspect, this disclosure provides erdafitinib formulations, in particular erdafitinib tablets suitable for use in the disclosed intravesical drug delivery system. In particular, drug tablets comprising erdafitinib free base (N-(3,5-dimethoxyphenyl)-N’-(l- methylethyl)-N-[3-(l-methyl-U/-pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) are provided. As another example, drug tablets comprising erdafitinib HC1 salt are provided. After the drug delivery system is inserted intravesically, the drug is released from the system into the bladder. In an aspect for example, the drug delivery system may operate by diffusion, which produces a continuous release of the drug into the bladder over an extended period as the drug is released from the tablets in the system.

[0092] In order to increase or maximize the amount of drug that can be stored in and released from the disclosed drug delivery system, the drug tablets can have a relatively high erdafitinib content by weight. This relatively high weight fraction of erdafitinib in the drug tablet is attended by a reduced or low weight fraction of excipients which may be required for tablet manufacturing and system assembly and drug use considerations. For the purposes of this disclosure, terms such as “weight fraction,” “weight percentage,” and “percentage by weight” with reference to any drug or API (active pharmaceutical ingredient) refers to the drug or API in the form employed, whether in free base form, free acid form, salt form, or hydrate form. For example, a drug tablet that has 90% by weight (90 wt%) of a drug or excipient in salt form may include less than 90% by weight of that drug in free base form. Unless otherwise specified, weight percentages are relative to the entire solid pharmaceutical composition.

[0093] The erdafitinib drug tablet of this disclosure includes an erdafitinib content and an excipient content. The drug content can include one form or more than one form of erdafitinib, such as free base or salt form, and the excipient content can include one or more excipients. Particular embodiments include erdafitinib free base API, and the example formulations presented herein comprise the erdafitinib free base API. The term “excipient” is known in the art, and representative examples of excipients useful in the disclosed drug tablets may include but are not limited to ingredients such as binders, lubricants, glidants, disintegrants, solubilizers, colorants, fillers or diluents, wetting agents, stabilizers, formaldehyde scavengers, coatings, and preservatives, or any combination thereof, as well as other ingredients to facilitate manufacturing, storing, or administering the drug tablet.

[0094] Another aspect of this disclosure provides a process for making a solid pharmaceutical composition, in which the process can comprise: (a) preparing an intragranular solid composition comprising or consisting essentially of (i) erdafitinib free base and (ii) at least one intragranular pharmaceutical excipient; (b) combining the intragranular solid composition with at least one extragranular pharmaceutical excipient to form a blend; and (c) tableting the blend to form the solid pharmaceutical composition. In embodiments, the erdafitinib free base can be present in a concentration of at least 45 wt% of the solid pharmaceutical composition. The at least one intragranular pharmaceutical excipient and at least one extragranular pharmaceutical excipient can comprise or can be selected from at least one common (mutually occurring) pharmaceutical excipient, or there can be no common (mutually occurring) pharmaceutical excipient between the intragranular excipients and the extragranular pharmaceutical excipients. The solid pharmaceutical composition can be made by a process that includes an intragranular solid composition prepared by a roller compaction process or by a fluid bed granulation process. In some embodiments, the step of (a) preparing an intragranular solid composition comprises: (1) preparing a pre-blend comprising the erdafitinib free base and one or more excipients; (2) preparing a binder solution; and (3) preparing the intragranular solid composition by combining the pre-blend and the binder solution. In some embodiments, the step of (a) preparing an intragranular solid composition comprises: (1) preparing a pre-blend comprising the erdafitinib free base and one or more excipients; (2) preparing a binder solution; and (3) preparing the intragranular solid composition by combining the pre-blend and the binder solution by a fluid bed granulation process. In some embodiments, the step of (a) preparing an intragranular solid composition comprises: (1) preparing a pre-blend comprising the erdafitinib free base with a stabilizer, a solubilizer, and a filler; (2) preparing a binder solution comprising a binder and a solvent; and (3) preparing the intragranular solid composition by combining the pre-blend and the binder solution by a fluid bed granulation process. In some embodiments, the step of (a) preparing an intragranular solid composition comprises: (1) preparing a pre-blend comprising the erdafitinib free base, meglumine, hydroxypropyl-beta-cyclodextrin, and microcrystalline cellulose; (2) preparing a binder solution comprising hydroxypropyl methylcellulose and purified water; and (3) preparing the intragranular solid composition by combining the pre-blend and the binder solution by a fluid bed granulation process. In some embodiments, the step of (a) preparing an intragranular solid composition comprises: (1) preparing a pre-blend comprising the erdafitinib free base with a solubilizer and a filler; (2) preparing a binder solution comprising a binder and a solvent; and (3) preparing the intragranular solid composition by combining the pre-blend and the binder solution by a fluid bed granulation process. In some embodiments, the step of (a) preparing an intragranular solid composition comprises: (1) preparing a pre-blend of the erdafitinib free base, hydroxypropyl-beta-cyclodextrin, and microcrystalline cellulose; (2) preparing a binder solution comprising hydroxypropyl methylcellulose and purified water; and (3) preparing the intragranular solid composition by combining the pre-blend and the binder solution by a fluid bed granulation process.

[0095] Another aspect of this disclosure provides a process for making a solid pharmaceutical composition, in which the process can comprise: (a) preparing an intragranular solid composition comprising or consisting essentially of (i) erdafitinib HC1 salt form and (ii) at least one intragranular pharmaceutical excipient; (b) combining the intragranular solid composition with at least one extragranular pharmaceutical excipient to form a blend; and (c) tableting the blend to form the solid pharmaceutical composition. In embodiments, the erdafitinib HC1 salt form can be present in a concentration of at least 45 wt% of the solid pharmaceutical composition. The at least one intragranular pharmaceutical excipient and at least one extragranular pharmaceutical excipient can comprise or can be selected from at least one common (mutually occurring) pharmaceutical excipient, or there can be no common (mutually occurring) pharmaceutical excipient between the intragranular excipients and the extragranular pharmaceutical excipients. The solid pharmaceutical composition can be made by a process that includes an intragranular solid composition prepared by a roller compaction process or by a fluid bed granulation process. [0096] In embodiments, the erdafitinib drug tablets includes erdafitinib in its free base form. Other embodiments of the erdafitinib drug tablets can include erdafitinib in a salt form. In one aspect, erdafitinib drug tablets can include greater than or equal to 40 wt% erdafitinib free base, with the remainder of the weight comprising excipients, such as lubricants, binders, and stabilizers that facilitate making and using the drug tablet. Alternatively, the erdafitinib drug tablets can include greater than or equal to 45 wt%, greater than or equal to 50 wt%, greater than or equal to 55 wt%, or greater than or equal to 60 wt% erdafitinib free base. In each of these weight percentage embodiments, the practical upper limit of erdafitinib free base in the tablet formulation is about 65 wt%, or 70 wt%. Therefore, in an aspect, the drug tablets can include from 40 wt% to 60 wt% of erdafitinib in its free base form, or from 45 wt% to 55 wt% of erdafitinib in its free base form. In some embodiments of the foregoing, the drug tablets can include between about 5% and about 15% by weight of hydroxypropyl -P- cyclodextrin (HP-P-CD). In some embodiments of the foregoing, the drug tablets can include about 10% by weight of hydroxypropyl-P-cyclodextrin (HP-P-CD). In embodiments, the drug tablets can include 50% by weight of erdafitinib in its free base form, based on the total weight of the tablet. In embodiments, the drug tablets can include 50% by weight of erdafitinib in its free base form, and between about 5% and about 15% by weight of hydroxypropyl-P-cyclodextrin (HP-P-CD) based on the total weight of the tablet. In embodiments, the drug tablets can include 50% by weight of erdafitinib in its free base form, and 10% by weight of hydroxypropyl-P-cyclodextrin (HP-P-CD) based on the total weight of the tablet.

[0097] In embodiments, the erdafitinib drug tablets includes erdafitinib in its HC1 salt form. In one aspect, erdafitinib drug tablets can include greater than or equal to 40 wt% erdafitinib HC1 salt form, with the remainder of the weight comprising excipients, such as lubricants, binders, and stabilizers that facilitate making and using the drug tablet. Alternatively, the erdafitinib drug tablets can include greater than or equal to 45 wt%, greater than or equal to 50 wt%, greater than or equal to 55 wt%, or greater than or equal to 60 wt% erdafitinib HC1 salt form. In each of these weight percentage embodiments, the practical upper limit of erdafitinib salt form in the tablet formulation is about 65 wt%, or 70 wt%. Therefore, in an aspect, the drug tablets can include from 40 wt% to 60 wt% of erdafitinib in its HC1 salt form, or from 45 wt% to 55 wt% of erdafitinib in its HC1 salt form. In embodiments, the drug tablets can include 50% by weight of erdafitinib in its HC1 salt form, based on the total weight of the tablet. [0098] In one embodiment, the erdafitinib drug and excipients are selected and the tablet is formulated to permit release of the drug from the tablet. In some embodiments, the erdafitinib drug and excipients are selected and the tablet is formulated to permit solubilization of the drug from the tablet. In embodiments, the erdafitinib is formulated in a pharmaceutical composition to be sterilizable, either within or outside of the drug delivery system, without resulting in substantial or detrimental changes to the chemical or physical composition of the drug tablets which would otherwise make them unsuitable for delivering the erdafitinib as described herein. In an aspect, the erdafitinib drug and excipients are selected for their suitability for sterilization processes. In an embodiment, the drug delivery system comprising the drug tablets is sterilized as a whole. In particular, the drug delivery system comprising the drug tablets is sterilized by gamma irradiation.

[0099] In an aspect, the erdafitinib drug tablets may be sized and shaped for use with an implantable drug delivery system including the intravesical drug delivery system disclosed herein. For example, the erdafitinib drug tablets may be “mini-tablets” that are generally smaller in size than conventional tablets, which may permit inserting the system-housed drug tablets through a lumen such as the urethra into a cavity such as the bladder. The erdafitinib tablets may be coated or uncoated. In particular, uncoated tablets formulated according to this disclosure have been found to work well in combination with the system. As disclosed herein, “minitablets” and “tablets” are used interchangeably, to mean a tablet which may permit inserting the system-housed drug tablets through a lumen such as the urethra into a cavity such as the bladder.

[0100] In embodiments, the drug tablet for intravesical insertion or other in vivo implantation can be in the form of a solid cylinder having a cylindrical axis, a cylindrical side face, circular end faces perpendicular to the cylindrical axis, a diameter across the circular end faces, and a length along the cylindrical side face. In cylindrical form, each mini-tablet can have a length (L) exceeding its diameter (D) so that the mini-tablet has an aspect ratio (L:D) of greater than 1 : 1. For example, the aspect ratio (L:D) of each mini-tablet can be 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, or range in values between these aspect ratios. Embodiments of the mini-tablet can have a cylindrical diameter of from 1.0 mm to 3.2 mm, or from 1.5 mm to 3.1 mm, or from 2.0 mm to 2.7 mm, or from 2.5 mm to 2.7 mm. In some aspects, the mini-tablet can have a length of from 1.7 mm to 4.8 mm, or from 2.0 mm to 4.5 mm, or from 2.8 mm to 4 mm, or from 3 mm to 3.5 mm.

[0101] The API used in the solid tablet formulations can be erdafitinib, which is N-(3,5- dimethoxyphenyl)-N’-(l-methylethyl)-N-[3-(l-methyl-17/-pyrazol-4-yl)quinoxalin-6- yl]ethane-l,2-diamine, and the chemical structure of which is illustrated below. Erdafitinib tablets for use in the disclosed intravesical system can be formulated using the erdafitinib free base or a salt thereof. In an aspect, the erdafitinib tablets for use in the disclosed intravesical system can include erdafitinib free base. In an aspect, the erdafitinib tablets for use in the disclosed intravesical system can include erdafitinib HC1 salt, particularly erdafitinib HC1 salt which is in a crystalline form. In some embodiments of the foregoing, the erdafitinib tablets for use in the disclosed intravesical system can include erdafitinib free base which is in a crystalline form. As described herein, including certain stabilizers, solubilizers, and excipients in the erdafitinib free base formulation can provide advantageous stabilizing and dissolution properties for effective use of the free base formulation in the disclosed intravesical system.

[0102] In embodiments, the erdafitinib drug tablet can incorporate various excipients which include, but are not limited to, at least one solubilizer, at least one binder, at least one wetting agent, at least one disintegrant, at least one stabilizer, at least one diluent, at least one glidant, at least one lubricant, and the like, or any combination thereof. Any excipient or any combination of the excipients can be present in the intragranular solid composition, the extragranular solid composition, or both the intragranular and the extragranular solid composition. In an aspect, at least one intragranular pharmaceutical excipient and at least one extragranular pharmaceutical excipient can be the same, that is, can be selected from at least one common (mutually occurring) pharmaceutical excipient. In a further aspect, the intragranular pharmaceutical excipients and the extragranular pharmaceutical excipients do not comprise a common (mutually occurring) pharmaceutical excipient, such that the intragranular and the extragranular excipients are mutually exclusive. In embodiments, the erdafitinib drug tablet, in particular the erdafitinib drug tablet comprising from 40 wt% to 70 wt%, or from 40 wt% to 60 wt% , or from 45 wt% to 55 wt%, for example, 50 wt% of erdafitinib, includes at least one solubilizer, at least one binder, at least one stabilizer, at least one diluent, at least one glidant, at least one lubricant, and the like, or any combination thereof. In embodiments, the erdafitinib drug tablet, in particular the erdafitinib drug tablet comprising from 40 wt% to 70 wt%, or from 40 wt% to 60 wt% , or from 45 wt% to 55 wt%, for example, 50 wt% of erdafitinib, includes at least one solubilizer, at least one binder, at least one diluent, at least one glidant, at least one lubricant, and the like, or any combination thereof.

[0103] It will be appreciated that these functional descriptions of various excipients are used generally as follows. A solubilizer can improve or enhance the solubility of the API such as erdafitinib free base within the drug lumen of the disclosed system or within a body cavity such as the bladder once the API is released from the system. A binder can hold the solid particles of the composition together for physical stability. A wetting agent can lower the surface tension between the drug and the medium in which it occurs and help maintain the solubility of the drug. A disintegrant can aid in the minitablet disintegration when contacting water to release the drug substance. A stabilizer can improve the chemical stability such as the thermal stability of the formulation, including the API, or protects the API against degradation. A diluent can function as a bulking agent to increase the volume or weight of the composition which may aid in providing tablet of the desired size or which may aid in tabletability of the API-excipient blend. A glidant may improve the flow properties of the (granulated) particles of tablet components or of the powder blend to be tableted. A lubricant can prevent particles of the composition from adhering to components of the manufacturing apparatus, such as dies and punches of a tablet press. In an aspect, an excipient can be water soluble. In another aspect, an excipient can be colloidal in water. According to another aspect, an excipient can be soluble under the conditions of its deployment in the patient, such as in a bladder. These and other excipients are described in more detail below.

Stabilizers such as Formaldehyde Scavengers

[0104] In an aspect, erdafitinib API may be sensitive to degradation under certain conditions when incorporated into a solid formulation. For example, erdafitinib can degrade or transform in the presence of formaldehyde, to form the cyclization product 6,8-dimethoxy- 4-(l-methylethyl)-l -[3-(l -methyl- 17/-pyrazol-4-yl)quinoxalin-6-yl]-2, 3,4, 5 -tetrahydro- 1JT- 1,4-benzodiazepine. Formaldehyde can come into contact with the erdafitinib from a variety of sources in the environment, such as from packaging materials or as a contaminant in excipients or other components of the formulation.

[0105] Accordingly, in one aspect, the erdafitinib pharmaceutical formulation can include a formaldehyde scavenger to improve the stability or shelf life of the formulation. Various formaldehyde scavengers can be employed which can prevent, slow down, diminish, or postpone the formation of degradation products when erdafitinib contacts formaldehyde. Therefore, the erdafitinib pharmaceutical formulation stability such as its chemical stability can be increased in the presence of a formaldehyde scavenger as compared to a erdafitinib pharmaceutical formulations absent a formaldehyde scavenger. In an aspect, the formaldehyde scavenger can be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular solid composition. In an aspect, the formaldehyde scavenger, in particular meglumine, is present in the solid pharmaceutical composition as a component of the intragranular solid composition.

[0106] Formaldehyde scavengers can include or can be selected from compounds comprising a reactive nitrogen center, such as compounds containing amine or amide groups. Without being bound by theory, it is thought that these compounds can react with formaldehyde to form a Schiff base imine (R¹R²C=NR³, where R³ is not hydrogen), which itself can bind formaldehyde. Examples of such formaldehyde scavengers include but are not limited to amino acids, amino sugars, alpha-(a-)amine compounds, conjugates and derivatives thereof, and mixtures thereof. Such formaldehyde scavenger compounds can include two or more amine and/or amide moieties which can scavenge formaldehyde.

[0107] In an aspect, formaldehyde scavengers can include or can be selected from, for example, meglumine, glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, aspartic acid, glutamic acid, arginine, lysine, ornithine, taurine, histidine, aspartame, proline, tryptophan, citrulline, pyrrolysine, asparagine, glutamine, tris(hydroxymethyl)aminomethane, conjugates thereof, pharmaceutically acceptable salts thereof, or any combination thereof. According to an aspect, the formaldehyde scavenger can include or can be selected from meglumine or a pharmaceutically acceptable salt thereof, in particular meglumine base.

[0108] Therefore, an aspect of this disclosure is the use of a formaldehyde scavenger, in particular meglumine, in an erdafitinib pharmaceutical formulation such as a drug tablet formulation, to increase the stability of erdafitinib in any of its forms, including erdafitinib free base, a salt thereof, or a solvate thereof. The chemical stability of the erdafitinib pharmaceutical formulation is increased as compared to an erdafitinib pharmaceutical formulation or composition containing no formaldehyde scavenger. An aspect of the disclosure is a method of preventing, slowing down, diminishing, or postponing the formation of degradation products such as the following compound, which can form from erdafitinib in the presence of formaldehyde:

In an aspect, degradation products such as the above can occur in a solid tablet composition such as a mini-tablet formulation, in particular in a mini-tablet as disclosed herein.

[0109] When present in the erdafitinib solid pharmaceutical composition, the formaldehyde scavenger can be present in the solid pharmaceutical composition in a concentration of from 0.01 wt% to 5 wt%, from 0.05 wt% to 3 wt%, from 0.1 wt% to 2 wt%, from 0.5 wt% to 1.5 wt%, or about 1 wt%. In some embodiments, when present in the erdafitinib solid pharmaceutical composition, the formaldehyde scavenger can be present at a concentration of about 1 wt%. When present in the erdafitinib solid pharmaceutical composition, the formaldehyde scavenger can be present in the solid pharmaceutical composition in a concentration of, for example, from 5 wt% to 10 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt% or about 10 wt%. In some embodiments, the erdafitinib solid pharmaceutical composition contains erdafitinib free base, and the formaldehyde scavenger is present. In some embodiments, the erdafitinib solid pharmaceutical composition contains erdafitinib free base, and the formaldehyde scavenger is present in the solid pharmaceutical composition in a concentration of from 0.01 wt% to 5 wt%, from 0.05 wt% to 3 wt%, from 0.1 wt% to 2 wt%, from 0.5 wt% to 1.5 wt%, or about 1 wt%. In some embodiments, the erdafitinib solid pharmaceutical composition contains erdafitinib free base, and the formaldehyde scavenger is present in the solid pharmaceutical composition in a concentration of about 1 wt% . In some embodiments of any of the foregoing, the formaldehyde scavenger is meglumine.

[0110] In some embodiments, the pharmaceutical compositions as described herein, in particular the erdafitinib drug tablets, do not contain a stabilizer or formaldehyde scavenger.

Solubilizers

[OHl] In an aspect, the erdafitinib formulation can include a solubilizer. The solubilizer can be in the intragranular component, the extragranular component, or both the intragranular and extragranular component of the formulation. In embodiments, the solubilizer can comprise or can be selected from, for example (a) a cyclic oligosaccharide, (b) a cellulose which is functionalized with methoxy-, 2-hydroxypropoxy-, acetyl-, or succinoyl- moieties or a combination thereof, or (c) a salt thereof. In an embodiment, the solubilizer is present in the intragranular component.

[0112] In embodiments, solubilizers for the erdafitinib tablet formulation can comprise or can be selected from an oligosaccharide. In embodiments, the solubilizer can comprise or can be selected from a cyclic oligosaccharide such as a cyclodextrin. Suitable cyclodextrin solubilizers for the erdafitinib tablet formulation include, but are not limited to, hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether-beta- cyclodextrin sodium salt, or any combination thereof. In other embodiments, the solubilizer can comprise or can be hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HPMC-E5), or a combination thereof.

[0113] Oligosaccharide solubilizers can be present in erdafitinib tablet formulation, for example a erdafitinib free base formulation, in a concentration of from 1 wt% to 20 wt%, alternatively from 3 wt% to 18 wt%, alternatively from 5 wt% to 15 wt%, alternatively from 7 wt% to 12 wt%, or alternatively 10 wt% or about 10 wt%. The cyclodextrin solubilizer can be present in an erdafitinib tablet formulation, for example an erdafitinib free base formulation, in a concentration of 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, or 20 wt%, or any range between any of these weight percentages.

[0114] In an aspect, a solubilizer for the erdafitinib tablet formulation disclosed herein can comprise or can be hydroxypropyl-beta-cyclodextrin (HP-P-CD). One embodiment of an erdafitinib free base formulation includes a hydroxypropyl-beta-cyclodextrin solubilizer, in particular an erdafitinib free base formulation including hydroxypropyl-beta-cyclodextrin in from 8 wt% to 12 wt%, or alternatively, 10 wt% or about 10 wt% concentration. In some embodiments, the formulation comprises hydroxypropyl-beta-cyclodextrin at about 10 wt% concentration. In this formulation, the erdafitinib free base API can be present in a concentration of from 40 wt% to 70 wt%, or from 40 wt% to 60 wt%, or from 45 wt% to 55 wt%, for example, 50 wt%. In an embodiment, the hydroxypropyl-beta-cyclodextrin is present in the intragranular solid composition. In embodiments, the drug tablets can include 50% by weight of erdafitinib in its free base form, 1% by weight of meglumine, and hydroxypropyl-beta-cyclodextrin in from 8 wt% to 12 wt%, or alternatively, 10 wt% or about 10 wt% concentration. In embodiments, the drug tablets can include 50% by weight of erdafitinib in its free base form, 10% by weight of hydroxypropyl-P-cyclodextrin (HP-P-CD), and 1% by weight of meglumine based on the total weight of the tablet. In embodiments, the drug tablets can include at least about 45% by weight of erdafitinib in its free base form, 10% by weight of hydroxypropyl -P-cyclodextrin (HP-P-CD), and 0% by weight of meglumine based on the total weight of the tablet. In embodiments, the drug tablets can include 50% by weight of erdafitinib in its free base form, 10% by weight of hydroxypropyl-P-cyclodextrin (HP-P-CD), and 0% by weight of meglumine based on the total weight of the tablet.

Binders

[0115] Pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more binders. The one or more binders can be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular solid composition. Suitable binders can be water soluble, water insoluble, or slightly water soluble or combinations of these. In an aspect, binders can include polymeric binders such as water soluble polymeric binders, slightly water soluble polymeric binders, water insoluble polymeric binders, or any combination thereof. Polymeric binders can include non-ionic polymers.

[0116] It will be appreciated by the person of ordinary skill that binders may also function as a diluent (also termed filler) in a pharmaceutical composition. Accordingly, binders provided in this disclosure may also be used for their diluent function as appropriate and unless otherwise indicated.

[0117] In an aspect, suitable binders can include or can be selected from polyvinylpyrrolidone (PVP, also termed polyvidone, povidone, or poly(l -vinyl-2 - pyrrolidinone)), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO, also termed poly(ethylene glycol) or PEG), polypropylene oxide (PPO, also termed polypropylene glycol) or PPG), an ethylene glycol -propylene glycol copolymer, a poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, silicified microcrystalline cellulose, or combinations thereof. In an aspect, suitable binders can include or can be selected from polyvinylpyrrolidone (PVP, also termed polyvidone, povidone, or poly(l -vinyl-2 - pyrrolidinone)), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO, also termed poly(ethylene glycol) or PEG), polypropylene oxide (PPO, also termed polypropylene glycol) or PPG), an ethylene glycol -propylene glycol copolymer, a poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, or combinations thereof. In an aspect, suitable binders can include or can be selected from hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, vinylpyrrolidone-vinyl acetate copolymer, or combinations thereof. In an aspect, suitable binders can include or can be selected from hydroxypropyl methylcellulose (HPMC), vinylpyrrolidone-vinyl acetate copolymer (copovidone), or combinations thereof. In some embodiments, the binder may be hydroxypropyl methylcellulose (HPMC). In some embodiments, the binder may be hydroxypropyl methylcellulose (HPMC) at a concentration of about 1.5 wt% of the solid composition. In some embodiments, the binder may be hydroxypropyl methylcellulose (HPMC) at 1.5 wt% of the solid composition, and is present in the intragranular solid composition.

[0118] In further aspects, suitable binders can include or can be selected from polymers of or copolymers of vinylpyrrolidone (VP, also l-vinyl-2-pyrrolidinone) and vinyl acetate (VA). Such copolymers of VP and VA may also be referred to as “copovidones”. Suitable binders also may include or may be selected from polymers of or copolymers of ethylene oxide (EO) and propylene oxide (PO). Again, these binders can be used in combinations with other binders such as in combination with microcrystalline cellulose, hydroxypropyl cellulose (HPC), or hydroxypropyl methylcellulose (HPMC).

[0119] In an aspect, the total concentration of the at least one binder in the solid pharmaceutical composition can be from 1 wt% to 30 wt%, from 2 wt% to 30 wt%, from 5 wt% to 30 wt%, from 5 wt% to 25 wt%, from 10 wt% to 25 wt%, from 10 wt% to 22 wt%, from 12 wt% to 22 wt%, from 14 wt% to 19 wt%, or from 12 wt% to 19 wt%.

[0120] According to another aspect, suitable polymeric binders can include or can be selected from a copolymer of vinylpyrrolidone and vinyl acetate, which can be termed poly(vinylpyrrolidone-co-vinyl acetate) or poly(VP-co-VA). Examples of suitable poly(vinylpyrrolidone-co-vinyl acetate) binders include Kollidon® VA64 and Kollidon® VA64 Fine (BASF, Ludwigshafen am Rhein, Germany), having a molecular weight (Mw) range of from 45,000 g/mol to 70,000 g/mol based on measuring the light scatter of a solution. Another suitable binder is Kollidon® K30.

[0121] In embodiments, the polymeric binders such as the vinylpyrrolidone-vinyl acetate copolymer can be present in the disclosed erdafitinib tablet formulation in a concentration of from 2 wt% to 15 wt%, alternatively from 4 wt% to 12 wt%, alternatively from 6 wt% to 10 wt%, or alternatively, 8 wt% or about 8 wt%. For example, the vinylpyrrolidone-vinyl acetate copolymer binder can be present in erdafitinib tablet formulation, for example a erdafitinib free base formulation, in a concentration of 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt% or any range between any of these weight percentages e.g., 7.5 wt%. In an aspect, the vinylpyrrolidone- vinyl acetate copolymer is present at a concentration of 8 wt% of the solid composition. In an aspect, the vinylpyrrolidone-vinyl acetate copolymer is present in the intragranular solid composition. In an aspect, the vinylpyrrolidone-vinyl acetate copolymer is present in the intragranular solid composition and said intragranular solid composition is prepared by roller compaction. In an aspect, the vinylpyrrolidone-vinyl acetate copolymer is present in the intragranular solid composition and said intragranular solid composition is prepared by fluid bed granulation. In an aspect, the vinylpyrrolidone-vinyl acetate copolymer is present in the extragranular solid composition. In an aspect, the vinylpyrrolidone-vinyl acetate copolymer is present at a concentration of about 7.5 wt% of the solid composition. In an aspect, the vinylpyrrolidone-vinyl acetate copolymer is present at a concentration of about 7.5 wt% of the solid composition, and is in the extragranular solid composition.

[0122] In an aspect, the binder can comprise or can be microcrystalline cellulose. For example, the microcrystalline cellulose can be present in the solid pharmaceutical composition in a concentration of from 5 wt% to 30 wt%, from 10 wt% to 20 wt%, from 5 wt% to 20 wt%, from 6 wt% to 15 wt%, or from 7 wt% to 12 wt%. For example, the microcrystalline cellulose can be present in the solid pharmaceutical composition as a filler and/or as a binder at a concentration of about 17.5 wt%. For example, the microcrystalline cellulose can be present in the solid pharmaceutical composition at a concentration of about 17.5% wt% of the solid composition and is present in the intragranular solid composition and extragranular solid composition. For example, the microcrystalline cellulose can be present in the solid pharmaceutical composition as a filler in the intragranular composition, at a concentration of about 10 wt% of the solid composition, and can be present in the solid pharmaceutical composition as a binder in the extragranular composition, at a concentration of about 7.5 wt% of the solid composition.

[0123] According to another aspect, the binder can comprise or can be silicified microcrystalline cellulose. For example, the silicified microcrystalline cellulose can be present in the solid pharmaceutical composition in a concentration of from 3 wt% to 18 wt%, from 4 wt% to 15 wt%, or from 5 wt% to 12 wt%.

[0124] In a further aspect, the binder can comprise or can be hydroxypropyl methylcellulose (HPMC). For example, the hydroxypropyl methylcellulose (HPMC) can be present in the solid pharmaceutical composition in a concentration of from 0.25 wt% to 5 wt%, from 0.5 wt% to 4 wt%, or from 0.75 wt% to 3 wt%. In an aspect, the HPMC binder can be present in the solid pharmaceutical composition in the intragranular solid composition. Wetting Agents

[0125] Pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more wetting agents. The one or more wetting agents can be present in the solid pharmaceutical composition in the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular solid compositions. In exemplary embodiments, the wetting agent can comprise or can be selected independently from an anionic surfactant or a non-ionic surfactant, in particular an anionic surfactant. For example, the wetting agent can comprise or can be selected independently from sodium lauryl sulfate, sodium stearyl fumarate, a polysorbate, e.g., polysorbate 80, docusate sodium, or any combination thereof. In embodiments, the total concentration of the wetting agent in the solid pharmaceutical composition can be from 0.01 wt% to 2.5 wt%, from 0.05 wt% to 1.0 wt%, or from 0.1 wt% to 0.5 wt%. In an embodiment, the wetting agent is present in the intragranular solid composition. In an embodiment, the wetting agent is sodium lauryl sulfate.

[0126] In an embodiment, the erdafitinib solid pharmaceutical composition does not include one or more wetting agents.

Disintegrants

[0127] Pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more disintegrants. The one or more disintegrants can be present in the solid pharmaceutical composition in the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular solid composition. In an embodiment, the disintegrant is present in the intragranular solid composition. In an embodiment, the disintegrant is present in the intragranular solid composition and said intragranular solid composition is prepared by roller compaction.

[0128] In exemplary embodiments, the disintegrant can comprise or can be selected independently from a functionalized polysaccharide or a crosslinked polymer. For example, in an aspect, the disintegrant can comprise or can be selected from, for example (a) a cellulose which is functionalized with methoxy-, 2-hydroxypropoxy-, or carboxymethoxy- moieties, a salt thereof, or a combination thereof, (b) a carboxymethylated starch, or (c) a crosslinked polymer.

[0129] In embodiments, the disintegrant can comprise or can be selected independently from hydroxypropyl methylcellulose, low- substituted hydroxypropylcellulose, crospovidone (crosslinked polyvinylpyrrolidone), croscarmellose sodium (cross-linked sodium carboxymethylcellulose), sodium starch glycolate, or any combination thereof. [0130] When present, the disintegrant can be present in a range of concentrations. In embodiments, the total concentration of the disintegrant in the solid pharmaceutical composition can be from 0.1 wt% to 3 wt%, from 0.5 wt% to 2.5 wt%, from 1 wt% to 2 wt%, or about 1.5 wt%.

[0131] In an embodiment, the erdafitinib solid pharmaceutical composition does not include one or more disintegrants.

Diluents or Fillers

[0132] Pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more diluents. The one or more diluents can be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular solid composition.

[0133] In exemplary embodiments, diluents can comprise or can be selected from a sugar, starch, microcrystalline cellulose, a sugar alcohol, a hydrogen phosphate salt, a dihydrogen phosphate salt, a carbonate salt, or combinations thereof. In an aspect, diluents can comprise or can be selected from lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, anhydrous dibasic calcium phosphate, calcium carbonate, sucrose, or any combination thereof.

[0134] In embodiments, the total concentration of the diluent in the solid pharmaceutical composition can be from 10 wt% to 60 wt%, from 10 wt% to 50 wt%, from 10 wt% to 40 wt%, from 12 wt% to 30 wt%, from 15 wt% to 25 wt%, or from 18 wt% to 22 wt%, or from 20 wt% to 40 wt%, or from 20 wt% to 30 wt%, or from 25 wt% to 30 wt%. For example, in some aspects, the diluent can comprise or can be selected from microcrystalline cellulose in a concentration of from 15 wt% to 25 wt%, or from 20 wt% to 22 wt%, or from 15 wt% to 20 wt%. In a further aspect, the diluent can comprise or can be selected from anhydrous dibasic calcium phosphate in a concentration of from 18 wt% to 20 wt%. In a further aspect, the diluent can comprise or can be anhydrous dibasic calcium phosphate in a concentration of about 19 wt%. In a further aspect, the diluent can comprise or can be anhydrous dibasic calcium phosphate in a concentration of about 19 wt%, which is present in the extragranular solid composition. In a further aspect, the diluent can comprise or can be selected from silicified microcrystalline cellulose in a concentration of from 10 wt% to 20 wt%, or from 10 wt% to 15 wt%, or from 10 wt% to 12 wt%. For example, the diluent can comprise silicified microcrystalline cellulose in a concentration of about 10.75 wt% or 11.75 wt% of the solid composition. For example, the diluent can comprise silicified microcrystalline cellulose in a concentration of about 10.75 wt% or 11.75 wt% of the solid composition and is present in the extragranular composition. For example, the diluent can comprise silicified microcrystalline cellulose in a concentration of about 10.75 wt% of the solid composition and is present in the extragranular composition. For example, the diluent can comprise silicified microcrystalline cellulose in a concentration of about 11.75 wt% of the solid composition and is present in the extragranular composition. In a further aspect, the diluent does not include silicified microcrystalline cellulose. In a further aspect, the diluent may comprise microcrystalline cellulose and silicified microcrystalline cellulose. In a further aspect, the diluent may comprise microcrystalline cellulose or silicified microcrystalline cellulose. In a further aspect, the diluent may comprise microcrystalline cellulose in a concentration of about 10 wt%. In a further aspect, the diluent may comprise microcrystalline cellulose in a concentration of about 10 wt%, which is present in the intragranular composition. For example, the microcrystalline cellulose can be present in the solid pharmaceutical composition as a filler and/or as a binder at a concentration of about 17.5 wt%. For example, the microcrystalline cellulose can be present in the solid pharmaceutical composition at a concentration of about 17.5% wt% of the solid composition and is present in the intragranular solid composition and extragranular solid composition. For example, the microcrystalline cellulose can be present in the solid pharmaceutical composition as a filler in the intragranular composition, at a concentration of about 10 wt% of the solid composition, and can be present in the solid pharmaceutical composition as a binder in the extragranular composition, at a concentration of about 7.5 wt% of the solid composition.

[0135] It will be appreciated by the person of ordinary skill that some of the diluents/fillers disclosed herein may also function as binders in the pharmaceutical composition. Accordingly, some compounds or materials may be described herein as providing a binder function and providing a diluent/filler function.

Glidants

[0136] Pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more glidants. The one or more glidants can be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular solid composition. In an aspect, the glidant is present in the extragranular solid composition. As used in this disclosure, a glidant refers to a pharmaceutical excipient which improves or optimizes the particle flow properties of the granulated or powdered tablet components in particle form by decreasing the interaction, attraction, cohesion, or friction between particles. Pharmaceutically acceptable glidants are non-toxic and pharmacologically inactive substances. Further, the glidants can be water soluble or water insoluble.

[0137] In an aspect, glidants can include or can be selected from colloidal silicon dioxide, colloidal anhydrous silicon dioxide, talc, or any combination thereof. In embodiments, the total concentration of the glidant in the solid pharmaceutical composition can be from 0.01 wt% to 5 wt%, 0.05 wt% to 3 wt%, 0.1 wt% to 1 wt%, or about 0.2 wt%, or about 0.25 wt%, or about 0.3 wt%, about 0.35 wt%, or about 0.4 wt%, or about 0.45 wt% or about 0.5 wt%. In an embodiment, the glidant is colloidal silicon dioxide. In some embodiments, the glidant is colloidal silicon dioxide at about 0.5 wt% of the solid composition. In some embodiments, the glidant is colloidal silicon dioxide at about 0.5 wt% of the solid composition, and is present in the extragranular composition. In some embodiments, the glidant is colloidal silicon dioxide at about 0.25 wt% of the solid composition. In some embodiments, the glidant is colloidal silicon dioxide at about 0.25 wt% of the solid composition, and is present in the extragranular composition.

Lubricants

[0138] Pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more lubricants. The one or more lubricants can be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular solid composition. In an aspect, the lubricant is present in the extragranular solid composition. In an aspect, the lubricant is present in the intragranular solid composition, and said intragranular solid composition is prepared by roller compaction. As used in this disclosure, a lubricant refers to a pharmaceutical excipient added to a tablet formulation which reduces friction at the tablet’s surface. In embodiments, the lubricant can reduce friction between a tablet’s surface and processing equipment, e.g., between a tablet’s surface and the wall of a die cavity in which a tablet is formed. Therefore, a lubricant can reduce friction between a die wall and the granules of the formulation as the tablet is formed and ejected.

Pharmaceutically acceptable lubricants are non-toxic and pharmacologically inactive substances. Further, the lubricants can be water soluble or water insoluble.

[0139] In an aspect, the lubricant can comprise or can be selected from, for example, a fatty acid, a fatty acid salt, a fatty acid ester, talc, a glyceride ester, a metal silicate, or any combination thereof. In embodiments, the lubricant can comprise or can be selected from magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactate, sodium stearoyl fumarate, titanium dioxide, or combinations thereof. Examples of lubricants include but are not limited to leucine, sodium lauryl sulfate, sucrose stearate, boric acid, sodium acetate, sodium oleate, sodium stearyl fumarate, and PEG. In another aspect, the total concentration of the lubricant in the solid pharmaceutical composition can be from 0.05 wt% to 5 wt%, 0.1 wt% to 3 wt%, 1 wt% to 2 wt%, or about 1.5 wt%. In an embodiment, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate, and is present in the intragranular composition or the extragranular composition. In some embodiments, the lubricant is magnesium stearate, and is present in the intragranular composition and the extragranular composition. In some embodiments, the lubricant is magnesium stearate at about 1.5 wt% of the solid composition. In some embodiments, the lubricant is magnesium stearate at about 1.5 wt% of the solid composition, and is present in the intragranular composition. In some embodiments, the lubricant is magnesium stearate at about 1.5 wt% of the solid composition, and is present in the extragranular composition. In some embodiments, the lubricant is magnesium stearate at about 1.5 wt% of the solid composition, and is present in the intragranular composition and the extragranular composition.

Formulation Development

[0140] Provided herein are erdafitinib formulations, in particular erdafitinib tablets, that (a) comprise a high erdafitinib drug load, such as ranging from 40 wt% to 70 wt%, or from 40 wt% to 60 wt% , or from 45wt% to 55 wt%, or about 50 wt%, or ranging from 45wt% to 55 wt%, or about 50 wt%, (b) provide for an acceptable chemical stability of erdafitinib, (c) support high production speeds for tablet production, e.g., on an industrial scale, in particular tablets having a length (L) that exceeds its diameter (D) so that the tablet has an aspect ratio (L:D) of greater than 1 : 1, in particular such tablets having a cylindrical diameter of from 1.0 mm to 3.2 mm, or from 1.5 mm to 3.1 mm or from 2.0 mm to 2.7 mm or from 2.5 mm to 2.7 mm, in particular on an industrial scale, in particular for minitablets, (d) provide a tablet that is sufficiently robust physically, in particular is suitable for being included in a drug delivery system as described herein, in particular a permeation system, and/or (e) exhibits desired disintegration and/or dissolution properties.

[0141] Erdafitinib formulations with a range of excipient combinations, both intragranular and extragranular, are provided in Table 1 which sets out Formula 4A, Formula 4B, Formula 4C, and Formula 4D. Further erdafitinib formulations with a range of excipient combinations, are provided in Table 2 which set forth formulations 3.2, 3.3, 3.4, and 4.1.

Table 1. Exemplary erdafitinib minitablet formulations

particular 11,5 mg, of erdafitinib. In an embodiment, the above erdafitinib minitablet formulations are about 23 mg tablets, in particular 23 mg tablets.

In an embodiment, the above erdafitinib minitablet formulations contain about 11.5 mg, in particular 11,5 mg, of erdafitinib, and are about 23 mg tablets, in particular 23 mg tablets.

Table 2. Examples of erdafitinib formulations

In an embodiment, the above erdafitinib minitablet formulations contain about 11.5 mg, in particular 11,5 mg, of erdafitinib. In an embodiment, the above erdafitinib minitablet formulations are about 23 mg tablets, in particular 23 mg tablets.

[0142] Provided herein are erdafitinib solid formulations, in particular erdafitinib minitablets, in particular with a high erdafitinib drug load, such as ranging from 40 wt% to 70 wt%, or from 40 wt% to 60 wt%, or from 45wt% to 55 wt%, or about 50 wt%, or ranging from 45wt% to 55 wt%, or about 50 wt%. In an embodiment the tablets are obtainable by a process that comprises fluid bed granulation. In an embodiment the tablets are obtainable by a process that comprises roller compaction. In an embodiment the intragranular solid composition comprises a cyclodextrin, in particular hydroxypropyl-beta-cyclodextrin. In an embodiment the formulation does not comprise mannitol in the intragranular solid composition. In an embodiment, the intragranular solid composition does not comprise a water soluble filler. In an embodiment, the formulation comprises a water insoluble filler, such as for example microcrystalline cellulose. [0143] In an embodiment, there is provided a fluid bed granulation process for making granules comprising erdafitinib and hydroxypropyl-beta-cyclodextrin. In an aspect, the process does not comprise using a water soluble filler such as mannitol.

[0144] Provided herein are erdafitinib solid formulations, in particular erdafitinib minitablets, in particular with a high erdafitinib drug load, such as ranging from 45wt% to 55 wt%, or about 50 wt% comprising vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose, in particular in a weight ratio ranging from 1 :99 to 99: 1, or from 5:95 to 95:5, or from 10:90 to 90: 10, or from 20:80 to 80:20, or from 30:70 to 70:30, or from 40:60 to 60: 40 or 50:50. It was unexpectedly found that ejection forces during tableting, in particular tableting of mini-tablets, such as those described herein, were reduced in the presence of this mixture. It was found that a powder formulation comprising such a mixture had good flow properties. In an aspect the formulation further comprises hydroxypropyl-beta- cyclodextrin. In an aspect the formulation does not comprise mannitol.

[0145] In an embodiment, a process is provided for making tablets, in particular minitablets as described herein, wherein the powder blend to be tableted comprises vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose, in particular in a weight ratio ranging from 1 :99 to 99: 1, or from 5:95 to 95:5, or from 10:90 to 90: 10, or from 20:80 to 80:20, or from 30:70 to 70:30, or from 40:60 to 60: 40 or 50:50. In an aspect, there is provided a process for making tablets, in particular minitablets as described herein, wherein the powder blend to be tableted comprises erdafitinib, vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose, in particular wherein the weight ratio of vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose ranges from 1 :99 to 99:1, or from 5:95 to 95:5, or from 10:90 to 90: 10, or from 20:80 to 80:20, or from 30:70 to 70:30, or from 40:60 to 60: 40 or 50:50. In an aspect, the powder blend to be tableted further comprises hydroxypropyl-beta-cyclodextrin. In an aspect, the powder blend to be tableted does not comprise mannitol.

[0146] Provided herein are erdafitinib solid formulations, in particular erdafitinib powder formulations or erdafitinib minitablets, in particular with a high erdafitinib drug load, such as ranging from 40 wt% to 70 wt%, or from 40 wt% to 60 wt% , or from 45wt% to 55 wt%, or about 50 wt%, or ranging from 45wt% to 55 wt%, or about 50 wt% having a low content of fine particles, such as for example a content of fine particles below 20%, or below 10 %, or below 5 %, or about or below 3 %, or about or below 2%. Fine particles can increase the ejection forces during tableting, especially during tableting of minitablets as described herein, in particular when tableting at a high speed, such as for example 2500 tablets/minute. [0147] In an embodiment, provided herein is a formulation, in particular a tablet or minitablet, comprising erdafitinib, in particular with a high erdafitinib drug load, such as ranging from 40 wt% to 70 wt%, or from 40 wt% to 60 wt% , or from 45wt% to 55 wt%, or about 50 wt%, or ranging from 45wt% to 55 wt%, or about 50 wt%, hydroxypropyl-beta- cyclodextrin, vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose. In an aspect, the formulation further comprises meglumine. In an aspect, the formulation does not comprise mannitol. In an aspect the formulation further comprises at least one or all of a glidant, such as for example colloidal silica, a lubricant, such as for example magnesium stearate, a binder such as for example a cellulose derivative, such as hydroxypropyl methylcellulose, a filler, such as for example silicified microcrystalline cellulose.

[0148] In an embodiment, provided herein is a formulation, in particular a tablet or minitablet, comprising erdafitinib, in particular with a high erdafitinib drug load, such as ranging from 40 wt% to 70 wt%, or from 40 wt% to 60 wt% , or from 45wt% to 55 wt%, or about 50 wt%, or ranging from 45wt% to 55 wt%, or about 50 wt%, hydroxypropyl-beta- cyclodextrin, vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose. In an aspect, the formulation further comprises at least one or all of a glidant, such as for example colloidal silica, a lubricant, such as for example magnesium stearate, a binder such as for example a cellulose derivative, such as hydroxypropyl methylcellulose, a filler, such as for example silicified microcrystalline cellulose. In an aspect, the formulation does not comprise a stabilizer, such as meglumine. In an aspect, the formulation does not comprise mannitol.

[0149] In an embodiment, the formulation is Formula 4A. In an embodiment, the formulation is Formula 4B. In an embodiment, the formulation is Formula 4C. In an embodiment, the formulation is Formula 4D.

[0150] Accordingly, Formula 4D formulation is encompassed by this disclosure, in which the solid pharmaceutical composition includes: (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 17.5 wt% microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidonevinyl acetate copolymer; (g) 0.25 wt% colloidal silicon dioxide; (h) 1.5 wt% hydroxypropyl methylcellulose; and (i) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In an aspect, this formulation can be prepared by a process comprising (a) preparing an intragranular solid composition by a fluid bed granulation process, the intragranular solid composition consisting essentially of: (i) erdafitinib free base in a concentration of 50 wt% of the solid pharmaceutical composition; (ii) hydroxypropyl -beta-cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition; (iii) meglumine in a concentration of 1 wt% of the solid pharmaceutical composition; (iv) microcrystalline cellulose in a concentration of 10 wt% of the solid pharmaceutical composition; and (v) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the solid pharmaceutical composition; (b) combining the intragranular solid composition with extragranular components to form a blend, wherein the extragranular components consist essentially of: (i) microcrystalline cellulose in a concentration of 7.5 wt% of the solid pharmaceutical composition; and (ii) vinylpyrrolidonevinyl acetate copolymer in a concentration of 7.5 wt% of the solid pharmaceutical composition; (iii) silicified microcrystalline cellulose in a concentration of 10.75 wt% of the solid pharmaceutical composition; (iv) colloidal silicon dioxide in a concentration of 0.25 wt% of the solid pharmaceutical composition; and (iv) magnesium stearate in a concentration of 1.5 wt% of the solid pharmaceutical composition; and (c) tableting the blend to form of a solid pharmaceutical composition in the form of mini-tablets. In an embodiment, the tablet comprises 11.5 mg of erdafitinib. In an embodiment, the tablet is a 23 mg tablet.

[0151] Accordingly, Formula 4C formulation is encompassed by this disclosure, in which the solid pharmaceutical composition includes: (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 1.5 wt% hydroxypropyl methylcellulose; (e) 21.0 wt% mannitol; (f) 0.25 wt% sodium lauryl sulfate; (g) 7.25 wt% microcrystalline cellulose; (h) 7.25 wt% vinylpyrrolidone-vinyl acetate copolymer; (i) 0.25 wt% colloidal silicon dioxide; and (j) 1.50 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In an aspect, this formulation may be prepared by a process comprising (a) preparing an intragranular solid composition by a fluid bed granulation process; (b) combining the intragranular solid composition with extragranular components to form a blend; and (c) tableting the blend to form a solid pharmaceutical composition in the form of mini-tablets, in which the intragranular and the extragranular components are set out in the Examples in Table 1. In an embodiment, the tablet comprises 11.5 mg of erdafitinib. In an embodiment, the tablet is a 23 mg tablet.

[0152] Accordingly, Formula 4B formulation is encompassed by this disclosure, in which the solid pharmaceutical composition includes (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 24.5 wt% microcrystalline cellulose; (e) 6.0 wt% silicified microcrystalline cellulose; (f) 6.0 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 2.0 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In an aspect, this formulation may be prepared by a process comprising (a) preparing an intragranular solid composition by a fluid bed granulation process; (b) combining the intragranular solid composition with extragranular components to form a blend; and (c) tableting the blend to form of a solid pharmaceutical composition in the form of mini-tablets, in which the intragranular and the extragranular components are set out in the Examples in Table 1. In an aspect, this formulation may be prepared by a process comprising (a) preparing an intragranular solid composition by a roller compaction process; (b) combining the intragranular solid composition with extragranular components to form a blend; and (c) tableting the blend to form of a solid pharmaceutical composition in the form of mini-tablets, in which the intragranular and the extragranular components are set out in the Examples in Table 1. In an embodiment, the tablet comprises 11.5 mg of erdafitinib. In an embodiment, the tablet is a 23 mg tablet.

[0153] Accordingly, Formula 4A formulation is encompassed by this disclosure, in which the solid pharmaceutical composition includes (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 10 wt% microcrystalline cellulose; (e) 19 wt% anhydrous dibasic calcium phosphate; (f) 8 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 1.50 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In an aspect, this formulation may be prepared by a process comprising (a) preparing an intragranular solid composition by a fluid bed granulation process; (b) combining the intragranular solid composition with extragranular components to form a blend; and (c) tableting the blend to form a solid pharmaceutical composition in the form of mini-tablets, in which the intragranular and the extragranular components are set out in the Examples in Table 1. In an aspect, this formulation may be prepared by a process comprising (a) preparing an intragranular solid composition by a roller compaction process; (b) combining the intragranular solid composition with extragranular components to form a blend; and (c) tableting the blend to form a solid pharmaceutical composition in the form of mini-tablets, in which the intragranular and the extragranular components are set out in the Examples in Table 1. In an embodiment, the tablet comprises 11.5 mg of erdafitinib. In an embodiment, the tablet is a 23 mg tablet.

[0154] Accordingly, Formulation 4.1 is encompassed by the disclosure, in which the solid pharmaceutical composition includes: (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In an aspect, this formulation can be prepared by a process comprising (a) preparing an intragranular solid composition by a fluid bed granulation process, the intragranular solid composition consisting essentially of (i) erdafitinib free base in a concentration of 50 wt% of the solid pharmaceutical composition; (ii) hydroxypropyl- beta-cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition; (iii) microcrystalline cellulose in a concentration of 10 wt% of the solid pharmaceutical composition; and (iv) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the solid pharmaceutical composition; (b) combining the intragranular solid composition with extragranular components to form a blend, wherein the extragranular components consist essentially of (i) microcrystalline cellulose in a concentration of 7.5 wt% of the solid pharmaceutical composition; and (ii) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.5 wt% of the solid pharmaceutical composition; (iii) silicified microcrystalline cellulose in a concentration of 11.75 wt% of the solid pharmaceutical composition; (iv) colloidal silicon dioxide in a concentration of 0.25 wt% of the solid pharmaceutical composition; and (iv) magnesium stearate in a concentration of 1.5 wt% of the solid pharmaceutical composition; and (c) tableting the blend to form of a solid pharmaceutical composition in the form of mini-tablets. In an embodiment, the tablet comprises 11.5 mg of erdafitinib. In an embodiment, the tablet is a 23 mg tablet.

[0155] Accordingly, Formulation 3.4 is encompassed by the disclosure, in which the solid pharmaceutical composition includes: (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 17.5 wt% microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidonevinyl acetate copolymer; (g) 0.25 wt% colloidal silicon dioxide; (h) 1.5 wt% hydroxypropyl methylcellulose; and (i) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition.

[0156] In an aspect, this formulation can be prepared by a process comprising (a) preparing an intragranular solid composition by a fluid bed granulation process, the intragranular solid composition consisting essentially of (i) erdafitinib free base in a concentration of 50 wt% of the solid pharmaceutical composition; (ii) hydroxypropyl-beta- cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition; (iii) meglumine in a concentration of 1 wt% of the solid pharmaceutical composition; (iv) microcrystalline cellulose in a concentration of 10 wt% of the solid pharmaceutical composition; and (v) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the solid pharmaceutical composition; (b) combining the intragranular solid composition with extragranular components to form a blend, wherein the extragranular components consist essentially of: (i) microcrystalline cellulose in a concentration of 7.5 wt% of the solid pharmaceutical composition; and (ii) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.5 wt% of the solid pharmaceutical composition; (iii) silicified microcrystalline cellulose in a concentration of 10.75 wt% of the solid pharmaceutical composition; (iv) colloidal silicon dioxide in a concentration of 0.25 wt% of the solid pharmaceutical composition; and (iv) magnesium stearate in a concentration of 1.5 wt% of the solid pharmaceutical composition; and (c) tableting the blend to form of a solid pharmaceutical composition in the form of mini-tablets. In an embodiment, the tablet comprises 11.5 mg of erdafitinib. In an embodiment, the tablet is a 23 mg tablet.

Diffusion-Based Drug Delivery Systems

[0157] Drug delivery systems particularly suitable for the effective release of drug formulations containing erdafitinib, such as those described in detail above or hereinafter, are described herein. These particular systems have been developed wherein, instead of an osmotic drug release mechanism, drug release is controlled by drug diffusion through a drug- permeable polymer component defining part of the system housing.

[0158] In certain embodiments, the system includes a drug-permeable polymer component or portion that forms a portion of the housing. For example, the drug-permeable component or portion of the system may be a portion of the housing formed of a material distinct from the remaining portion of housing (e.g., a strip or multiple strips of material extending along at least a portion of the length of the housing), such that the size, shape (e.g., arc angle), thickness, and material properties of the drug-permeable wall structure may be selected to achieve the desired drug release rate. In certain embodiments, the drug permeable portion, the drug impermeable portion, or both the drug permeable and impermeable portions are formed of thermoplastic polyurethane compositions, to provide (i) controlled diffusion of the drug from the system, (ii) desired mechanical properties (e.g., able to be straightened for insertion/removal, soft enough to be well-tolerated while indwelling, tubing remains intact with small compressions/extensions, elastic deformability in response to detrusor muscle contraction (compliancy)), (iii) a system that may be thermally shape set to have a desired retention shape, and/or (iv) a system which may be manufactured in a coextrusion process. [0159] In some embodiments, the drug permeable portion is permeable to erdafitinib free base. In some embodiments, the drug permeable portion is permeable to erdafitinib free base and erdafitinib free base formulated with HP-P-CD. In some embodiments, the drug permeable portion is permeable to erdafitinib free base, erdafitinib HC1 salt, and erdafitinib free base formulated with HP-P-CD. In some embodiments of any of the foregoing, the material of the drug permeable portion is an aliphatic polyether-based TPU. In some embodiments of the foregoing, the material of the drug permeable portion is an aliphatic poly ether-based TPU which is Lubrizol Tecophilic HP-60D-35 or HP-93A-100.

[0160] In some embodiments, the drug permeable portion is permeable to erdafitinib free base formulated with HP-P-CD. In some embodiments, the drug permeable portion is permeable to erdafitinib free base formulated with HP-P-CD, and is impermeable or practically impermeable to erdafitinib free base formulated without HP-P-CD. In some embodiments of any of the foregoing, the material of the drug permeable portion is an aliphatic polyether-based TPU. In some embodiments of the foregoing, the material of the drug-permeable portion is Lubrizol TecoflexEG-80A.

[0161] Exemplary materials for the drug-permeable portion (e.g., the “stripe” material of the permeation system) include, but are not limited to, aliphatic polyether-based thermoplastic polyurethanes (TPUs) such as Lubrizol Tecophilic HP-60D-35, Tecophilic HP- 93 A- 100, and Tecoflex EG-80A. In some embodiments, the material of the drug-permeable portion is Lubrizol Tecophilic HP-60D-35, Tecophilic HP-93 A-100, or Tecoflex EG-80A. In some embodiments, the material of the drug-permeable portion is Lubrizol Tecoflex EG-80 A. In some embodiments, the drug is erdafitinib free base, and the material of the drug- permeable portion is Lubrizol Tecophilic HP-60D-35 or Tecophilic HP-93A-100. In some embodiments, the drug is erdafitinib free base, the drug is formulated with HP-P-CD, and the material of the drug-permeable portion is Lubrizol Tecophilic HP-60D-35, Tecophilic HP- 93 A-100, or Tecoflex EG-80 A. In some embodiments, the drug is erdafitinib free base, the drug is formulated with HP-P-CD, and the material of the drug-permeable portion is Lubrizol Tecoflex EG-80A. In some embodiments, the drug is erdafitinib HC1 salt, and the material of the drug-permeable portion is Lubrizol Tecophilic HP-60D-35 or Tecophilic HP-93A-100. [0162] Exemplary materials for the drug-impermeable portion (e.g., the “base” material of the permeation system) include, but are not limited to, silicone elastomer materials such as NuSil MED-4750; TPUs such as Lubrizol Carbothane Aliphatic PC-3575A, Tecothane Soft AR-62A, AR-75A-B20, AC-4075A-B20, Carbothane Aromatic AC-4075A, Tecothane TT- 1074A, Tecoflex EG-80A; and ethylene vinyl acetate such as 3M CoTran 9712. In some embodiments, the material of the drug-impermeable portion is selected from MED-4750, PC- 3575 A, PC-3575 A, AR-62A, AR-75A-B20, AC-4075 A-B20, AC-4075 A, TT-1074A, EG- 80A, and CoTran 9712. In some embodiments, the material of the drug-impermeable portion is selected from MED-4750, PC-3575 A, PC-3575 A, AR-62A, AR-75A-B20, AC-4075 A- B20, AC-4075A, TT-1074A, and CoTran 9712. In some embodiments, the material of the drug-impermeable portion is AR-75A-B20. In some embodiments, the material of the drug- impermeable portion is AC-4075A-B20.

[0163] In some embodiments, the material of the drug-permeable portion is EG-80A, and the material of the drug-impermeable portion is AR-75A-B20. In some embodiments, the material of the drug-permeable portion is EG-80A, and the material of the drug-impermeable portion is AC-4075A-B20.

[0164] It is to be understood that Lubrizol Tecophilic HP series materials are aliphatic poly ether-based TPUs formulated to absorb equilibrium water contents of up to 100% of the weight of dry resin, designed for extrusion but also processable by injection molding. HP- 60D-35 has a shore hardness of about 42D (ASTM D2240), specific gravity of about 1.12 (ASTM D792), flexural modulus (psi) of 4000 (ASTM D790), ultimate tensile (psi) of about 7,800 dry and 4900 wet (ASTM D412), ultimate elongation (%) of about 450 dry and 390 wet (D412); and water absorption (% by Lubrizol Method) of about 35. HP-93A-100 has a shore hardness of about 83 A (ASTM D2240), specific gravity of about 1.13 (ASTM D792), flexural modulus (psi) of 2900 (ASTM D790), ultimate tensile (psi) of about 2200 dry and 1400 wet (ASTM D412), ultimate elongation (%) of about 1040 dry and 620 wet (D412); and water absorption (% by Lubrizol Method) of about 100.

[0165] It is to be understood that Lubrizol Tecoflex materials are aliphatic polyether- based TPUs processable by extrusion and injection molding. EG-80A has a shore hardness of about 72A (ASTM D2240), specific gravity of about 1.04 (ASTM D792), flexural modulus (psi) of 1,000 (ASTM D790), ultimate tensile (psi) of about 5,800 (ASTM D412), ultimate elongation (%) of about 660 (D412); tensile modulus (psi) of about 300 at 100% elongation, about 500 at 200% elongation, and about 800 at 300% elongation (ASTM D412); and mold shrinkage (in/in) of about 0.008-0.012 (ASTM D955).

[0166] It is to be understood that Lubrizol Aromatic Carbothane AC series materials are radiopaque (20% BaSCh filled) polycarbonate-based aromatic TPUs, processable by extrusion or injection molding. AC-4075A-B20 has a shore hardness of about 78A (ASTM D2240), specific gravity of about 1.38 (ASTM D792), ultimate tensile (psi) of about 8300 (ASTM D412), ultimate elongation (%) of about 400 (D412); tensile modulus (psi) of about 560 at 100% elongation, about 1300 at 200% elongation, and about 3400 at 300% elongation (ASTM D412); flexural modulus (psi) of about 1800, Vicat temperature (°C) of about 55, and mold shrinkage (in/in) (1”X0.25”X6” bar) of about 0.011 (ASTM D955).

[0167] It is to be understood that Lubrizol Tecothane Soft materials are aromatic polyester hydrocarbon-based TPUs, processable by extrusion or injection molding. AR-75A has a shore hardness of about 79A (ASTM D785), a specific gravity of about 1.03 (ASTM D792), ultimate tensile (psi) of about 2000 (ASTM D412), ultimate elongation (%) of about 530 (ASTM D412), tensile modulus (psi) of about 730 at 100% elongation, about 1000 at 200% elongation, and about 1300 at 300% elongation (ASTM D412); flexural modulus (psi) of about 2500 (ASTM 790); Vicat softening point (°C) of about 75; and mold shrinkage (in/in) (1”X0.25”X6” bar) of about 0.08 (ASTM D955). AR-75A-B20 is 20% BaSO₄ filled AR-75A, and can be manufactured, for example, by Compounding Solutions.

[0168] It is to be further understood that abovementioned test results for the Lubrizol Tecophilic HP, Tecoflex, Aromatic Carbothane AC, and Tecothane Soft materials are approximated based on small samples of TPU; therefore the properties of these materials may exhibit slight variation from the properties listed herein.

[0169] In one aspect, as shown in FIG. 1, a drug delivery system 100 is provided that includes a tubular housing having a drug reservoir lumen 106 bounded by a wall structure 104, wherein (i) at least a portion of the wall structure 104 is water permeable, and (ii) at least a portion of the wall structure is permeable to the drug (contained in drug unit 108) such that the drug is releasable in vivo by diffusion through the drug permeable portion of the wall structure 104. In certain embodiments, as discussed in further detail below, the wall structure includes first and second wall structures that together form the housing. As used herein, the phrase “diffusion through the drug permeable portion” (e.g., through the “second wall structure”) refers to the drug being released by passing through the material forming the wall by molecular diffusion, and not by passing through an aperture or open structure extending through that wall.

[0170] In one aspect, as shown in FIG. 2, a drug delivery system 200 is provided that includes a housing with a first wall structure 206 formed from a first material and a second wall structure 205 formed from a second material, which are adjacent one another and together form a tube defining a drug reservoir lumen 208, wherein (i) the second wall structure 205, or both the first wall structure 206 and the second wall structure 205, are permeable to water, and (ii) the first wall structure 206 is impermeable to the drug and the second wall structure 205 is permeable to the drug, such that the drug is releasable in vivo by diffusion through the second wall structure 205. As used herein, the term “impermeable to the drug” refers to the wall being substantially impermeable to the solubilized drug, such that no substantial amount of the solubilized drug can diffuse therethrough over the therapeutic period in which the system is located in vivo.

[0171] In certain embodiments, the tube is cylindrical or another suitable shape or design. As used herein, the term “cylindrical,” when used in reference to the tubular housing, refers to the housing having a substantially cylindrical outer wall. In some embodiments, the system is “closed” and therefore does not include an aperture; drug release is only by diffusion through the second wall structure.

[0172] In some embodiments, as shown in FIGs. 2 and 3, the first wall structure 206/306 and the second wall structure 205/305 are adjacent one another and together form a cylindrical tube. For example, such systems may be formed in a coextrusion or 3D-printing process, such that the first and second wall structures are integrally formed. In one embodiment, the coextruded first and second wall structures are thermoplastic polymers possessing the desired properties.

[0173] As shown in FIG. 3, the first wall structure 306 and second wall structure 305 together form a cylindrical tube having a lumen 308 in which a drug formulation is contained. The second wall structure 305 is in the form of a longitudinal strip extending along at least a portion of the length of the first wall structure 306 and is permeable to the drug, while the first wall structure 306 is not permeable to the drug. In certain embodiments, multiple drug permeable strips may be used in a single system. In certain embodiments, one permeable strip may be used in a single system. Thus, the size, shape, thickness, and material properties of the second wall structure may be selected to achieve a desired drug release rate.

[0174] In a preferred embodiment, as discussed in further detail below, the system is elastically deformable between a low-profile deployment shape (e.g., a relatively straightened shape) suited for insertion through the urethra of a patient and into the patient’s bladder and a relatively expanded retention shape (e.g., pretzel shape, bi-oval coil shape, S-shape, etc.) suited for retention within the bladder.

[0175] In some embodiments, as shown in FIGs. 7A-7C, the system further includes retention frame lumen 734. In certain embodiments, the retention frame lumen includes an elastic wire, such as a nitinol wire. In certain other embodiments, the retention frame lumen is filled with a shape set elastic polymer.

[0176] In other embodiments, as shown in FIGs. 1-3 and 8, the system does not include a retention frame lumen or a retention frame or wire. Instead, the material of the housing is configured to be elastically deformable between the straightened shape and the retention shape, in the absence of a retention frame or wire. In certain embodiments, the tubular housing is thermally shape set to have a coiled or other retention shape. Thus, in such embodiments, the design and manufacturing of the system is simplified, and the overall size of the system is minimized (or drug payload may be increased if the size of the system remains constant). In embodiments without a retention frame, the tubular housing material serves the functions of (i) forming the drug reservoir lumen, (ii) controlling drug release, and (iii) retaining the system in the bladder upon deployment.

[0177] In one embodiment, as shown in FIGs. 7A-7C, a drug delivery system 700 is provided that includes an elongated, elastic housing 702 having a drug reservoir lumen 704 extending between a first end 706 and a second end 708. The elastic housing 702 is formed of a tubular wall structure 710 that includes a first wall structure 716 and a second wall structure 724 that are adjacent one another and together form a tube defining the drug reservoir lumen 704, wherein (i) the second wall structure 724, or both the first wall structure 716 and the second wall structure 724, are permeable to water, and (ii) the first wall structure 716 is impermeable to the drug and the second wall structure 724 is permeable to the drug, such that the drug is releasable in vivo by diffusion through the second wall structure 724. [0178] In embodiments in which the first and second wall structures together form a cylindrical tube, any suitable end plugs or closures or thermally formed seals may be used to seal the ends of the tube after the drug is loaded. These end plugs/closures ensure that the drug permeable polymer portions forming a portion of the external tube are the only path for drug release.

[0179] In some embodiments, as shown in FIGs. 2 and 3, the wall 206, 205 / 306, 305 has a substantially constant thickness over its circumference. For example, the inner diameter 210 / 310 and outer diameter 212 / 312 of the first and second wall structures 206, 205 / 306, 305 (which together form the cylindrical tube) are the same. In other embodiments, the wall may have a varied thickness over the circumference of the wall. [0180] Thus, for the systems described herein, drug release is controlled by diffusion of the drug through a drug-permeable component defining a portion of the system housing. The drug-permeable wall structure may be located, dimensioned, and have material properties to provide the desired rate of controlled drug diffusion from the system.

[0181] The particular material and arc angle of the drug permeable portion or wall structure can be selected to achieve a particular drug release profile, i.e., water and drug permeation rates. As used herein, the phrase “arc angle” refers to the angle dimension of an arc of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. [0182] For example, in certain embodiments, as shown in FIGs. 2 and 3, the second wall structure 205/305 comprises less than 90 percent of a cross sectional area of the tube, in a cross section normal to the longitudinal axis of the tube. In one embodiment, the second wall structure comprises less than 50 percent of a cross sectional area of the tube, in a cross section normal to the longitudinal axis of the tube. In one embodiment, the second wall structure comprises less than 25 percent of a cross sectional area of the tube, in a cross section normal to the longitudinal axis of the tube.

[0183] In certain embodiments, as shown at FIGs. 2, 3, 7A-C, and 8, the first and second wall structures that form the tube bounding the drug reservoir lumen are adjacent one another at two interface edges, such that the wall structures collectively form the tube defining the drug reservoir lumen. In these embodiments, the two interface edges are disposed at an arc angle of from about 15 degrees to about 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. As used herein, the phrase “about” with reference to the arc angles of the second wall structure refers to the arc angle plus or minus 3 degrees.

[0184] In one embodiment, as shown in FIG. 2, the second wall structure 205 has an arc angle 214 of about 60 degrees of a circumference of the cylindrical tube 200 in the crosssection. In one embodiment, as shown in FIG. 3, the second wall structure 305 has an arc angle 314 of about 30 degrees of a circumference of the cylindrical tube 300 in the crosssection. In one embodiment, the second wall structure has an arc angle of about 15 degrees to about 270 degrees. As will be further described below, in certain embodiments, the second wall structure has an arc angle of about 45 degrees to about 90 degrees, of about 120 degrees to about 150 degrees, of about 150 degrees to about 270 degrees, or of about 210 degrees to about 270 degrees, such as about 45 degrees, about 90 degrees, about 135 degrees, about 180 degrees, and about 240 degrees. In certain embodiments, the second wall structure has an arc angle of about 125 degrees to about 145 degrees. In certain embodiments, the second wall structure has an arc angle of about 45 degrees, about 90 degrees, about 180 degrees, about 240 degrees, or about 270 degrees.

[0185] The second wall structure can be located on the inner curvature (0 degrees), the outer curvature (180 degrees), the top (90 degrees), or in-between, when the system is formed to have a retention shape as shown in FIG. 1. The top (90 degree) location may be preferable when the second wall structure is formed of a material that significantly swells once absorbing water.

[0186] In some embodiments, the intravesical drug delivery system comprises base AC- 4075A-B20 and stripe EG-80-A as described herein, wherein the stripe angle (see, e.g., FIG.

8) is between 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the stripe angle is between 45 degrees and 90 degrees, in particular 90 degrees. In some embodiments, the intravesical drug delivery system with a stripe angle of 90 degrees releases about 2 mg/day erdafitinib. In some embodiments, the stripe angle is between 125 degrees and 145 degrees. In some embodiments, the stripe angle is 135 degrees +/- 10 degrees. In some embodiments, the intravesical drug delivery system with a stripe angle between 125 degrees and 145 degrees releases about 2.5 mg/day to about 3.5 mg/day erdafitinib. In some embodiments, the intravesical drug delivery system with a stripe angle of 135 degrees +/- 10 degrees releases about 2.5 mg/day to about 3.5 mg/day erdafitinib. In some embodiments, the stripe angle is between 150 degrees and 270 degrees, in particular 180 degrees. In some embodiments, the intravesical drug delivery system with a stripe angle of 180 degrees releases about 4 mg/day erdafitinib. In some embodiments, the stripe angle is about 135 degrees. In some embodiments, the intravesical drug delivery system with a stripe angle of 135 degrees releases about 3 mg/day erdafitinib. In some embodiments, the intravesical drug delivery system is closed at the ends. In some embodiments, the intravesical drug delivery system is sealed at the ends of the drug lumen, (e.g., FIG. 7 ref. 704) and therefore does not include an aperture for drug release. In some embodiments, the intravesical drug delivery system drug release is only by diffusion through the stripe (FIG. 7, second wall structure, ref. 724).

[0187] Accordingly, tubular systems have been developed which are designed to reduce or control drug release rates without negatively altering the mechanical properties and suitable dimensions for system deployment and tolerability. In some embodiments, the designs reduce drug release rates by reducing the length of the drug permeable regions(s) such that the length runs along only a portion of the overall length of the system. Larger arc angles of the drug permeable region(s) can therefore be employed to tailor drug release rates from the system. Additionally, by decreasing the length of the drug permeable region, a lesser amount of drug permeable material, compared to conventional systems, may be used to effect a reduced drug release rate.

[0188] Once the drug is loaded into the drug reservoir lumen, any suitable end plugs or closures or thermally formed seals may be used to seal/close the first and second ends of the drug reservoir lumen. These end plugs/closures ensure that the second material forming a portion of the elastic housing is the sole path for drug release. In certain embodiments, the end plugs are formed of the first material (i.e., the material forming the first wall structure) that is impermeable to the drug.

[0189] In the foregoing embodiments, the first material or the first wall structure, the second material or the first wall structure, or both, is formed of a water permeable material. In a preferred embodiment, as described above with reference to the erdafitinib solid formulations, the drug is in a solid form (e.g., a tablet or plurality of tablets) and at least a portion of the tubular body is water permeable to permit in vivo solubilization of the drug while in the drug reservoir lumen. In some embodiments, the first material or first wall structure may be the only water permeable portion. In other embodiments both the first and second materials/wall structures may be water permeable.

[0190] The material(s) for the wall structures of the present systems can be selected from a variety of suitable thermoplastic polyurethane (TPU)-based materials. In particular, the first material forming the first wall structure (i.e., the material that is impermeable to the drug contained in the drug reservoir) may be a polycarbonate-based aromatic thermoplastic polyurethane (e.g., a CARBOTHANE™ TPU, such as AC-4075 A, commercially available from Lubrizol) or an aromatic polyester hydrocarbon-based thermoplastic polyurethane (e.g., a TECOTHANE™ TPU, such as AR-75A, commercially available from Lubrizol). For example, CARBOTHANE polyurethanes are cycloaliphatic polymers and are of the types produced from polycarbonate-based polyols. The general structure of the polyol segment is represented as O — [(CH₂) e — CO₃]_n — (CH₂) — O-. AC-4075 A has a durometer Shore hardness of 77A, a specific gravity of 1.19, a flexural modulus of 1500 psi, and an ultimate elongation of 400%. AR-75A has a durometer Shore hardness of 79A, a specific gravity of 1.03, a flexural modulus of 2500 psi, and an ultim — e elo — ation — f 530%. In particular, the second material forming the second wall structure (i.e. — the m — erial that is permeable to the drug contained in the drug reservoir) may be an aliphatic polyether-based thermoplastic polyurethane (e.g., a TECOFLEX™ TPU, such as EG-80A, commercially available from Lubrizol). For example, TECOFLEX polyurethanes are cycloaliphatic polymers and are of the types produced from polyether-based polyols. The general structure of the polyol segment is represented as O — (CH2 — CH2 — CH2 — CH2) _x — O— . EG-80A has a durometer Shore hardness of 72A, a specific gravity of 1.04, a flexural modulus of 1000 psi, and an ultimate elongation of 660%. The TPUs may further include a radiopacity agent, such as barium sulfate, for example, AC-4075A-B20, which is a polycarbonate-based aromatic thermoplastic polyurethane having a 20% loading of barium sulfate.

[0191] In one embodiment, an inner diameter of the cylindrical tube may be from about 1.0 mm to about 2.5 mm. In one embodiment, an outer diameter of the cylindrical tube is from about 2.0 mm to about 4.1 mm. In one embodiment, a thickness of the first wall structure, the second wall structure, or both, is from about 0.2 mm to about 1.0 mm. In some embodiments, a thickness of the second wall structure is from about 0.16 mm to about 0.24 mm. In one embodiment, a thickness of the second wall structure is from about 0.16 mm to about 0.24 mm, wherein the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib.

[0192] Thus, as compared to drug delivery systems utilizing a homogenous material (e.g., a blend of permeable and impermeable thermoplastic materials) to form a drug permeable tube, the mechanical properties of a tube utilizing the dual wall structure (e.g., the drug permeable strip embodiments) can be decoupled from the drug release (e.g., diffusion) properties of the tube. For example, in a single material tube, changing the material of tube inherently affects both the mechanical and diffusion properties of the system. Being able to control release rate with stripe angle may have the added benefit of not changing the system outer diameter; in contrast, control by changing wall thickness may become too large to fit through the urethra or too thin to provide the required mechanical strength of the system. Moreover, the drug release properties of a blended polymer may not be readily predictable. In addition, it is often challenging to achieve a truly homogeneous blend when mixing two thermoplastics. Thus, it requires experimentation to modulate drug release rate with such a tubular drug delivery system. In contrast, the dual wall structure described herein may provide enhanced flexibility in tailoring a particular drug release rate from the delivery system.

[0193] For use in the bladder, it is important that the system be compliant (e.g., easily flexed, soft feeling) during detrusor muscle contraction in order to avoid or mitigate discomfort and irritation to the patient. Thus, it is noted the durometer of the first and second materials of construction are important, and the proportion of a high durometer material may be limited in constructing a system housing of a given size while keeping it suitably compliant in the bladder. For example, suitable first wall materials, such as TECOTHANE or CARBOTHANE, may have a Shore hardness greater than 70A, such as from 77A to 65D, while suitable second wall materials, such as TECOFLEX, may have a Shore hardness of less than 90A, or less than 80A, such as 72A. In some embodiments, the first material has a Shore hardness value from 70A to 80A while the second material has a Shore hardness value from 70A to 75A. Thus, in certain embodiments, the second wall material has a Shore hardness that is less than the Shore hardness of the first wall material, with both wall materials having a Shore hardness of less than 80A. Accordingly, it can be advantageous to utilize a combination of two different polymeric materials, rather than making the system housing entirely of the water-swelling hydrophilic, drug-permeable second material, to achieve desired mechanical properties of the tube.

[0194] In embodiments, the systems described herein are configured to release a therapeutically effective amount of the drug, where the rate of the release of the drug from the drug delivery system is zero order over at least 36 hours. In one embodiment, the rate of the release of the drug from the drug delivery system is essentially zero order over at least 7 days. In embodiments, the system is configured to release a therapeutically effective amount of the drug over a period from 2 days to 6 months, e.g., from 2 days to 90 days, from 7 days to 30 days, or from 7 days to 14 days. Desirably, the rate of the release of the drug from the drug delivery system is zero order over at least 7 days, e.g., from 7 to 14 days, or longer, such as up to 3 months or 90 days. In certain embodiments, the system is configured to begin release of the drug after a lag time. In certain embodiments, the lag time may be at least about 30 minutes, from about 12 hours to about 24 hours, or up to about 2 days. These systems may be effective to release a therapeutically effective amount of the drug for a period of up to 6 months, or up to 3 months (90 days).

[0195] As will be discussed in greater detail below, a drug formulation, such as those described throughout this disclosure, is disposed in the drug reservoir lumen defined by the first and second wall structures. In particular preferred embodiments, the drug is an erdafitinib-based pharmaceutical formulation, as described herein. In certain embodiments, the system is configured to release the erdafitinib at an average rate of about 2 mg/day to about 4 mg/day, for example about 2.5 mg/day to about 3.5 mg/day, depending on the desired treatment regimen. In some embodiments, the system is configured to release the erdafitinib at an average rate of about 2 mg/day to about 4 mg/day. In such embodiments, the two interface edges may be disposed at an arc angle of 45 degrees to 270 degrees, for example at an arc angle of 90 degrees to 180 degrees, more in particular at an arc angle of 125 degrees to 145 degrees.

[0196] In one embodiment, the system is configured to release the erdafitinib at an average rate of 2 mg/day and the two interface edges are disposed at an arc angle of about 90 degrees. In another embodiment, the system is configured to release the erdafitinib at an average rate of 4 mg/day and the two interface edges are disposed at an arc angle of about 180 degrees. In certain embodiments, a release profile of the drug is substantially independent of pH over a pH range of 5 to 7. In certain embodiments, a release profile of the drug is substantially independent of pH over a pH range of 5.5 to 7. In certain embodiments, a release profile of the drug is substantially independent of pH over a pH range of 5.5 to 8. In certain embodiments, the release rates are retained over a period up to 6 months, in particular up to 3 months or 90 days.

[0197] In one embodiment, a drug delivery system is provided, which has (i) a housing defining a drug reservoir lumen and a retention frame lumen, (ii) a plurality of tablets comprising erdafitinib disposed in the drug reservoir lumen, and (iii) a ni tinol wire form (retention frame) disposed in the retention frame lumen. The drug reservoir lumen is defined/bounded by a first wall structure (base) formed of a first material, which is an aromatic polyester hydrocarbon-based thermoplastic polyurethane, particularly AC-4075A- B20, and a second wall structure (stripe) formed of a second material made of an aliphatic polyether-based thermoplastic polyurethane, particularly EG-80A, where the first and second wall structures are adjacent one another at two interface edges and together forming a tube defining the closed drug reservoir lumen. In an embodiment, the closed drug reservoir lumen contains a plurality of tablets, in particular a plurality of minitablets, in particular erdafitinib minitablets as described herein. In an embodiment, the amount of erdafitinib in the drug reservoir lumen is about 500 mg. In an embodiment, the drug reservoir lumen comprises about 44 erdafitinib minitablets, in particular the erdafitinib tablets as described herein. In one embodiment, the plurality of tablets consists of 44 minitablets, having a total of about 500 mg erdafitinib. In an embodiment, the stripe angle is 90 degrees, and the average release rate of erdafitinib from the system is approximately 2 mg/day. In an embodiment, the stripe angle is 180 degrees, and the average release rate of erdafitinib from the system is approximately 4 mg/day. In an embodiment, the stripe angle is 90 degrees, and the average release rate of erdafitinib from the system is approximately 2 mg/day. In an embodiment, the stripe angle is 90 degrees, and the average release rate of erdafitinib from the system is approximately 2 mg/day at pH between about 5 and about 6.8. In an embodiment, the stripe angle is 180 degrees, and the average release rate of erdafitinib from the system is approximately 4 mg/day. In an embodiment, the stripe angle is 180 degrees, and the average release rate of erdafitinib from the system is approximately 4 mg/day at pH between about 5 and about 6.8, and approximately 2 mg/day at pH about 8. In an embodiment, the tablets have Formula 4D as described herein. In an embodiment, the tablets have Formula 4C as described herein. In an embodiment, the tablets have Formula 4B as described herein. In an embodiment, the tablets have Formula 4A as described herein. In an embodiment, the tablets have Formula 4.1 as described herein. In an embodiment, the tablets have Formula 3.4 as described herein. In an embodiment, the tablets have Formula 3.3 as described herein. In an embodiment, the tablets have Formula 3.2 as described herein.

Other Aspects of the Drug Delivery Systems

[0198] In certain embodiments, the systems are configured for intravesical insertion and retention in a patient. For example, the systems can be elastically deformable between a relatively low profile (e.g., straightened) shape suited for insertion through a lumen into a body cavity of a patient, such as shown in FIGs. 7A-B, and a relatively expanded retention shape suited to retain the system within the body cavity, e.g., the bladder, such as shown in FIGs. 1, 4, 5, and 6A. The relatively expanded shape may include a pair of overlapping coils, sometime referred to as a “pretzel” shape. In particular embodiments, the ends of the elongated system generally lie within the boundaries of a bi-oval-like shape.

[0199] When in the expanded retention shape after deployment in the bladder, for example, the systems may resist excretion in response to the forces of urination or other forces. After drug release, the systems can be removed, for example by cystoscope and forceps, or can be bioerodible, at least in part, to avoid a retrieval procedure.

[0200] The system may be loaded with at least one drug in the form of one or more drug units, such as the tablets described throughout this disclosure. Solid drug composition forms, such as tablets, can provide a relatively large drug payload volume to total system volume and potentially enhance stability of the drugs during shipping, storage, before use, or before drug release. Solid drugs, however, may need to be solubilizable in vivo in order to diffuse through the drug-permeable component and into the patient’s surrounding tissues or cavity in a therapeutically effective amount. The drug reservoir lumen may hold in an elongated form several of the disclosed drug tablets in an end-to-end serial arrangement. In some embodiments, the system holds from about 10 to 100 cylindrical drug tablets, from about 30 to 60 cylindrical drug tablets, from about 40 to 50 cylindrical drug tablets, from about 42 to 46 cylindrical drug tablets (e.g., 44 tablets), such as mini-tablets, which may be serially loaded in the drug reservoir lumen. In an aspect, the tablets are those as described herein. In an aspect, the tablets are those of Formula 4 A. In an aspect, the tablets are those of Formula 4B. In an aspect, the tablets are those of Formula 4C. In an aspect, the tablets are those of Formula 4D. In an aspect, the tablets are those of 4.1. In an aspect, the tablets are those of Formula 3.4. In an aspect, the tablets are those of Formula 3.3. In an aspect, the tablets are those of Formula 3.2.

[0201] The systems may be inserted into a patient using a cystoscope or catheter or any other suitable or customized inserter device. Typically, a cystoscope for an adult human has an outer diameter of about 5 mm and a working channel having an inner diameter of about 2.4 mm to about 2.6 mm. In embodiments, a cystoscope may have a working channel with a larger inner diameter, such as an inner diameter of 4 mm or more. Thus, the system may be relatively small in size. For example, when the system is elastically deformed to the relatively straightened shape, the system for an adult patient may have a total outer diameter that is less than about 2.6 mm, such as between about 2.0 mm and about 2.4 mm. In addition to permitting insertion, the relatively small size of the system may also reduce patient discomfort and trauma to the bladder. In one embodiment, the overall configuration of the system promotes in vivo tolerability for most patients. In a particular embodiment, the system is configured for tolerability based on bladder characteristics and design considerations described in U.S. Patent No. 11,065,426.

[0202] Within the three-dimensional space occupied by the system in the retention shape, the maximum dimension of the system in any direction preferably is less than 10 cm, the approximate diameter of the bladder when filled. In some embodiments, the maximum dimension of the system in any direction may be less than about 9 cm, such as about 8 cm, 7 cm, 6 cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 or smaller. In particular embodiments, the maximum dimension of the system in any direction is less than about 7 cm, such as about 6 cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm or smaller. In preferred embodiments, the maximum dimension of the system in any direction is less than about 6 cm, such as about 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm or smaller. More particularly, the three-dimension space occupied by the system is defined by three perpendicular directions. Along one of these directions the system has its maximum dimension, and along the two other directions the system may have smaller dimensions. For example, the smaller dimensions in the two other directions may be less than about 4 cm, such as about 3.5 cm, 3 cm, 2.5 cm or less. In a preferred embodiment, the system has a dimension in at least one of these directions that is less than 3 cm.

[0203] In some embodiments, the system may have a different dimension in at least two of the three directions, and in some cases in each of the three directions, so that the system is non-uniform in shape. Due to the non-uniform shape, the system may be able to achieve an orientation of reduced compression in the empty bladder, which also is non-uniform in shape. In other words, a particular orientation of the system in the empty bladder may allow the system to exert less contact pressure against the bladder wall, making the system more tolerable for the patient.

[0204] The overall shape of the system may enable the system to reorient itself within the bladder to reduce its engagement or contact with the bladder wall. For example, the overall exterior shape of the system may be curved, and all or a majority of the exterior or exposed surfaces of the system may be substantially rounded. The system also may be substantially devoid of sharp edges, and its exterior surfaces may be formed from a material that experiences reduced frictional engagement with the bladder wall. Such a configuration may enable the system to reposition itself within the empty bladder so that the system applies lower contact pressures to the bladder wall. In other words, the system may slip or roll against the bladder wall into a lower energy position, meaning a position in which the system experiences less compression.

[0205] In one embodiment, the system is generally planar in shape even though the system occupies three-dimensional space. Such a system may define a minor axis, about which the system is substantially symmetrical, and a major axis that is substantially perpendicular to the minor axis. The system may have a maximum dimension in the direction of the major axis that does not exceed about 6 cm, and in particular embodiments is less than 5 cm, such as about 4.5 cm, about 4 cm, about 3.5 cm, about 3 cm, or smaller. The system may have a maximum dimension in the direction of the minor axis that does not exceed about 4.5 cm, and in particular embodiments is less than 4 cm, such as about 3.5 cm, about 3 cm, or smaller. The system is curved about substantially its entire exterior perimeter in both a major cross-sectional plane and a minor cross-sectional plane. In other words, the overall exterior shape of the system is curved and the cross-sectional shape of the system is rounded. Thus, the system is substantially devoid of edges, except for edges on the two flat ends, which are completely protected within the interior of the system when the system lies in a plane. These characteristics enable the system to reorient itself into a position of reduced compression when in the empty bladder.

[0206] The system also may be small enough in the retention shape to permit intravesical mobility. In particular, the system when deployed may be small enough to move within the bladder, such as to move freely or unimpeded throughout the entire bladder under most conditions of bladder fullness, facilitating patient tolerance of the system. Free movement of the system also facilitates uniform drug delivery throughout the entire bladder. [0207] The system also may be configured to facilitate buoyancy, such as with the use of low density materials of construction for the housing components and/or by incorporating gas or gas generating materials into the housing, as described for example in U.S. Patent No. 9,457,176. In general, the system in the dry and drug-loaded state may have a density in the range of about 0.5 g/mL to about 1.5 g/mL, such as between about 0.7 g/mL to about 1.3 g/mL. In some embodiments, the system in the dry and drug-loaded state has a density that is less than 1 g/mL.

[0208] In an embodiment, the intravesical drug delivery system is non-bioerodible. In another embodiment, the intravesical drug delivery system can be made to be completely or partially bioerodible so that no explantation, or retrieval, of the system is required following release of the drug formulation. In some embodiments, the system is partially bioerodible so that the system, upon partial erosion, breaks into non-erodible pieces small enough to be excreted from the bladder. For example, the systems described herein may be designed to conform with the characteristics of those described in U.S. Patent No. 8,690,840.

[0209] The drug delivery systems are sterilized before being inserted into a patient. In one embodiment, the system is sterilized using a suitable process such as gamma irradiation or ethylene oxide sterilization, although other sterilization processes may be used.

[0210] The systems described herein may include a radio-opaque portion or structure to facilitate detection or viewing (e.g., by X-ray imaging or fluoroscopy) of the system by a medical practitioner as part of the implantation or retrieval procedure. In one embodiment, the housing is constructed of a material that includes a radio-opaque filler material, such as barium sulfate or another radio-opaque material known in the art. Some housings may be made radio-opaque by blending radio-opaque fillers, such as barium sulfate or another suitable material, during the processing of the material from which the housing is formed. The radio-opaque material may be associated with the retention frame in those embodiments that include a retention frame. Ultrasound imaging or fluoroscopy may be used to image the system in vivo.

[0211] In some embodiments, the device constituent of the system comprises a drug- impermeable base material and a drug-permeable stripe material, and the base material is a TPU having 20% BaSCU filler, such as Lubrizol’s Carbothane™ AC-4075A-B20 or Tecothane™ AR-75A-B20. (Lubrizol Life Science (Bethlehem, PA)).

[0212] The drug delivery system may further include a retrieval feature, such as a string, a loop, or other structure that facilitates removal of the system from the patient. In one case, the system may be removed from the bladder by engaging the string to pull the system through the urethra. The system may be configured to assume a relatively narrow or linear shape when pulling the system by the retrieval feature into the lumen of a catheter or cystoscope or into the urethra.

Retention Of The System In A Body Cavity

[0213] The systems described herein are elastically deformable between a relatively low profile (e.g., straightened or uncoiled) shape suited for insertion through a lumen into the bladder (or other body cavity) of a patient and a relatively expanded retention shape suited to retain the system within the urinary bladder (or other body cavity). In certain embodiments, the drug delivery system may naturally assume the retention shape and may be deformed, either manually or with the aid of an external apparatus, into the relatively straightened shape for insertion into the body. Once deployed the system may spontaneously or naturally return to the initial, retention shape for retention in the body.

[0214] For the purposes of this disclosure, the terms “retention shape,” “relatively expanded shape,” and the like, generally denote any shape suited for retaining the system in the intended implantation location, including, but not limited to, a coiled or “pretzel” shape, such as shown in FIGs. 1 and 4, which is suited for retaining the system in the bladder. Similarly, the terms “deployment shape,” “relatively low profile shape,” “relatively straightened shape,” and the like, generally denote any shape suited for deploying the drug delivery system into the body, including, but not limited to, a linear or elongated shape, such as shown in FIG. 7A-B, which is suited for deploying the system through the working channel of a catheter, cystoscope, or other deployment instrument positioned in a lumen of the body, such as the urethra. For example, the housing or tube of the system may have two opposing free ends, which are directed away from one another when the system is in a low- profile deployment shape and which are directed toward one another when the system is in a relatively expanded retention shape.

[0215] In some embodiments, as shown in FIGs. 7A-7C, the system further includes retention frame lumen 734 and a retention frame (not shown) positioned in the retention frame lumen. For example, the retention frame lumen and retention frame may be as described in U.S. Application Publication No. 2010/0331770; U.S. Application Publication No. 2010/0060309; U.S. Application Publication No. 2011/0202036; and U.S. Application Publication No. 2011/0152839, which are incorporated herein by reference. For example, the retention frame lumen may be sealed with a suitable plug or adhesive material, such as a silicone adhesive material. [0216] FIG. 4 illustrates a system 300 loaded with drug tablets 108 in the drug reservoir lumen of system housing 304. As can be seen in FIG. 5, prior to loading the tablets, the retention frame 303 urges the system housing 304 into a distinct expanded shape, as compared to the retention shape achieved when the system is loaded with drug tablets 108. [0217] In certain embodiments, in which an increased payload is desired, additional length of the drug reservoir lumen/tube may be provided. In one embodiment, as shown in FIGs. 6A-6B, the retention frame has an outer periphery defined by two overlapping portions (coils) of nitinol wire. Each end portion of the wire is inwardly directed from the periphery and includes (i) a curved transition region having a smaller radius of curvature than the peripheral portions of the wire, and (ii) a straight portion that terminates with a rounded end cap. In contrast, in the system shown in FIG. 5, the retention frame has a periphery defined by a single coil. A system having the retention frame of FIGs. 6A-6B enables a comparatively longer drug reservoir (e.g., to accommodate more tablets) in a system having the same “footprint” (outer peripheral shape and dimension) as the system illustrated in FIG.

5.

[0218] In other embodiments, as shown in FIGs. 1-3, the system does not include a retention frame lumen or a retention frame or wire. Instead, the material of the housing is configured to be elastically deformable between the straightened shape and the retention shape, in the absence of a retention frame or wire. In such embodiments, the design and manufacturing of the system is simplified, and the overall size of the system is minimized (or drug payload may be increased where the size of the system remains constant). In embodiments without a retention frame, the tubular housing material serves the functions of (i) forming the drug reservoir lumen, (ii) controlling drug release, and (iii) retaining the system in the bladder upon deployment.

[0219] For example, the tubular housing may be thermally shape set to have the retention shape. Thus, the housing may comprise one or more thermoplastic materials that are suitable to be thermally formed into the retention shape. In certain embodiments, a drug delivery system includes a tubular housing having a closed drug reservoir lumen bounded by a wall structure comprising at least one thermoplastic material, wherein (i) at least a portion of the wall structure is water permeable and at least a portion of the wall structure is drug permeable, (ii) the tubular housing is elastically deformable from a retention shape suited to retain the system within the bladder to a relatively straightened shape suited for insertion through a lumen into the bladder, and (iii) the tubular wall is thermally shaped to have the retention shape. A photograph showing the cross-section of the drug reservoir lumen of a drug delivery system without drug disposed therein is shown in FIG. 8. In FIG. 8, the second wall structure has an arc angle 802 of about 30 degrees of a circumference of the cylindrical tube in the cross-section.

[0220] In certain embodiments the first and second wall structures are each a thermoplastic polyurethane and the tubular housing is thermally shaped to have the retention shape. In one embodiment, the tubular wall has a spring constant effective to impede the system from assuming the relatively straightened shape once implanted in the bladder. Thus, the properties of the tubular wall may cause the system to function as a spring, deforming in response to a compressive load but spontaneously returning to its initial shape once the load is removed.

[0221] In certain embodiments, the systems may naturally assume the retention shape, may be deformed into the relatively straightened shape, and may spontaneously return to the retention shape upon insertion into the body. The tubular wall structure in the retention shape may be shaped for retention in a body cavity, and in the relatively straightened shape may be shaped for insertion into the body through the working channel of a deployment instrument such as a catheter or cystoscope. To achieve such a result, the tubular wall structure may have an elastic limit, modulus, and/or spring constant selected to impede the system from assuming the relatively lower-profile shape once implanted. Such a configuration may limit or prevent accidental expulsion of the system from the body under expected forces. For example, the system may be retained in the bladder during urination or contraction of the detrusor muscle.

[0222] In a preferred embodiment, the system is elastically deformable between a relatively straightened shape suited for insertion through a catheter or cystoscope extending through a patient’s urethra of a patient and a curved or coiled shape suited to retain the system within the bladder (i.e., to prevent its expulsion from the bladder during urination) following release of the system from the end of the catheter or cystoscope.

[0223] As shown in FIG. 1, the retention shape may include a coiled or “pretzel” shape. The pretzel shape essentially comprises at least two sub-circles, each having its own smaller arch and sharing a common larger arch. When the pretzel shape is first compressed, the larger arch absorbs the majority of the compressive force and begins deforming, but with continued compression the smaller arches overlap, and subsequently, all three of the arches resist the compressive force. The resistance to compression of the system as a whole increases once the two sub-circles overlap, impeding collapse and voiding of the system as the bladder contracts during urination. [0224] The wall structure in the retention shape may have a two-dimensional structure that is confined to a plane, a three-dimensional structure, such as a structure that occupies the interior of a spheroid, or some combination thereof. The retention shape may comprise one or more loops, curls, or sub-circles, connected either linearly or radially, turning in the same or in alternating directions, and overlapping or not overlapping. The retention shape may comprise one or more circles or ovals arranged in a two-dimensional or a three-dimensional configuration, the circles or ovals may be either closed or opened, having the same or different sizes, overlapping or not overlapping, and joined together at one or more connecting points. The retention shape also may be a three-dimensional structure that is shaped to occupy or wind about a spheroid-shaped space, such as a spherical space, a space having a prorate spheroid shape, or a space having an oblate spheroid shape. The wall structure in the retention shape may be shaped to occupy or wind about a spherical space. The wall structure in the retention shape may generally take the shape of two intersecting circles lying in different planes, two intersecting circles lying in different planes with inwardly curled ends, three intersecting circles lying in different planes, or a spherical spiral. In each of these examples, the wall structure can be stretched to the linear shape for deployment through a deployment instrument. The wall structure may wind about or through the spherical space, or other spheroid-shaped space, in a variety of other manners.

[0225] Drug delivery systems utilizing thermally formed coextruded tubing with drug permeable and drug impermeable portions may integrate three functional components (drug reservoir/housing, drug permeation route, and retentive feature) into a single thermally shaped co-extruded tubing component, which may simplify the system design and the ability to control the drug release rate. As discussed herein, in such systems, the drug release rate can be relatively easily modified by controlling the angle and thickness of the drug permeable portion (e.g., strip) without changing whole tube housing material.

[0226] A thermally shaped coextruded tubular housing may be loaded with drug tablets and both ends may be sealed thermally or with adhesive (such as with the first wall material). If the local tube cross-section deformation or tube kinking occurs, the tablet loading will be difficult. Therefore, the tube dimensions should be chosen to prevent kinking when the tube is thermally shaped. The critical bending radius of curvature (R*) of elastic tubes under pure bending condition can be approximated using the following equation:

where v is Poisson’s ratio, r is the mean radius (i.e. (ID+0D)/4), w is the tube wall thickness, ID is tube inner diameter, and OD is tube outer diameter. With a Poisson’s ratio v of 0.49 for polyurethanes, the estimated critical radius is 0.5 cm. Therefore, in some embodiments, when thermally shaping a polyurethane tube, the radius of curvature should preferably be above 0.5 cm all along the length of the tube to prevent kinking. Thus, in one embodiment, the retention shape comprises at least one loop having a radius of curvature of at least 0.5 cm.

Drug Delivery System

[0227] In some embodiments, provided herein is a drug delivery system, comprising a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 2 mg/day to about 4 mg/day, optionally wherein the system is configured to release the erdafitinib at an average rate of about 2.5 mg/day to about 3.5 mg/day, and wherein the two interface edges are disposed at an arc angle of about 90 degrees to about 180 degrees, preferably about 125 degrees to about 145 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the drug delivery system comprises about 40 to about 50, about 42 to about 48, or about 44 to about 46 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 42 to 46 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the drug delivery system is configured to release the erdafitinib at an average rate of 3 mg/day and the two interface edges are disposed at an arc angle of 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the drug delivery system comprises AC-4075A-B20 and EG-80-A. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl -beta- cyclodextrin; (c) 1 wt% meglumine; (d) 17.5 wt% microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25 wt% colloidal silicon dioxide; (h) 1.5 wt% hydroxypropyl methylcellulose; and (i) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 24.5 wt% microcrystalline cellulose; (e) 6.0 wt% silicified microcrystalline cellulose; (f) 6.0 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 2.0 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition.

[0228] In some embodiments, provided herein is a drug delivery system, comprising a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 3 mg/day and wherein the two interface edges are disposed at an arc angle of about 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the drug delivery system comprises about 40 to about 50, about 42 to about 48, or about 44 to about 46 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 42 to 46 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the drug delivery system is configured to release the erdafitinib at an average rate of 3 mg/day and the two interface edges are disposed at an arc angle of 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the drug delivery system comprises AC- 4075A-B20 and EG-80-A. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl -beta-cyclodextrin; (c) 1 wt% meglumine; (d)

17.5 wt% microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f)

7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25 wt% colloidal silicon dioxide;

(h) 1.5 wt% hydroxypropyl methylcellulose; and (i) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer;

(f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h)

1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 24.5 wt% microcrystalline cellulose; (e) 6.0 wt% silicified microcrystalline cellulose; (f) 6.0 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 2.0 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition.

[0229] FIGS. 27A to 29 depict an embodiment of a drug delivery system in accordance with the present disclosure. The drug delivery system 2700 of FIGS. 27A to 29 is referred to herein as “TAR-210-C” and is designed to release approximately 3 mg of erdafitinib per day. FIG. 27A is a top, schematic view of the drug delivery system 2700 shown in a coiled retention shape. FIG. 27B is a bottom, schematic view of the drug delivery system 2700 shown in a coiled retention shape. FIG. 28 is a transverse cross-sectional view of the drug delivery system 2700, taken along lines A-A of FIG. 27A. FIG. 29A is a side, schematic view of the drug delivery system 2700 shown in a relatively straightened insertion shape. FIG. 29B is a side cross-sectional view of a portion of the drug delivery system 2700 shown in a relatively straightened insertion shape.

[0230] Referring to FIGS. 27A and 27B, in some embodiments, the drug delivery system 2700 includes a housing 2704. The housing 2704 defines a drug reservoir lumen 2732 and a retention frame lumen 2734 (visible in FIG. 27B only). In FIGS. 27A and 27B, the portion of the housing 2704 bounding the drug reservoir lumen 2732 is shown as being translucent, revealing erdafitinib minitablets 2708 contained therein.

[0231] As with other embodiments disclosed herein, the drug reservoir lumen 2732 and retention frame lumen 2734 can be monolithic with one another, e.g., co-molded in an extrusion process. As mentioned above, the drug reservoir lumen 2732 contains a plurality of erdafitinib minitablets 2708 to be described in more detail below. The retention frame lumen 2734 houses a retention frame 2903 (visible in FIGS. 28 and 29B), such as an elastic or superelastic nitinol wire. As described with other embodiments of the drug delivery systems disclosed herein, the drug delivery system 2700 is elastically deformable between a low- profile deployment shape (e.g., a relatively straightened shape; see FIGS. 29A, 29B) suited for insertion through the urethra of a patient and into the patient’s bladder, and a relatively expanded retention shape (e.g., bi-oval coil shape; FIGS. 27A and 27B) suited for retention of the drug delivery system 2700 within the bladder. According to embodiments, when in the deployment shape, the drug delivery system 2700 can be inserted through the urethra of a patient using a urinary placement catheter. Due to the elastic nature of the retention frame 2903, the drug delivery system 2700 naturally returns to the retention shape when free of external constraints, e.g., upon exiting a urinary placement catheter.

[0232] Referring to FIG. 27A, in some embodiments, when in the coiled retention shape, the drug delivery system 2700 has a maximum dimension (e.g., L in FIG. 27A) in any direction (X, Y) that is equal to or less than about 6 cm. In some embodiments, when in the coiled retention shape, the drug delivery system 2700 has a maximum dimension (e.g., L in FIG. 27A) in any direction (X, Y) that is equal to or less than about 5.5 cm. In some embodiments, when in the coiled retention shape, the drug delivery system 2700 fits within an envelope (X, Y) of 5.5 cm by 4.5 cm.

[0233] Referring to the transverse cross-sectional view of FIG. 28, the drug reservoir lumen 2732 and retention frame lumen 2734 of the housing 2704 are shown. According to embodiments, the drug reservoir lumen 2732 is bounded by a first wall structure formed of a first material 2906 and a second wall structure formed of a second material 2905. According to embodiments, the second material 2905 of the second wall structure, or both the first material 2906 of the first wall structure and the second material 2905 of the second wall structure, are permeable to water. According to some embodiments, both the first material 2906 of the first wall structure and the second material 2905 of the second wall structure are permeable to water. According to some embodiments, the first material 2906 of the first wall structure is impermeable to the erdafitinib and the second material 2905 of the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material 2905 forming the second wall structure. According to embodiments, the first material 2906 comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material 2905 comprises an aliphatic polyether- based thermoplastic polyurethane. In some embodiments, the first material 2906 is AC- 4075A and the second material 2905 is EG-80-A. In some embodiments, the first material 2906 is AC-4075A-B20 and the second material 2905 is EG-80-A.

[0234] Still referring to FIG. 28, in some embodiments, the first and second wall structures are adjacent one another at two interface edges 2905A, 2905B and together form a tube. For example, the first and second wall structures can be bonded together or co-extruded at the interface edges 2905A, 2905B. The two interface edges 2905A, 2905B can be disposed at an arc angle 2914 of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis Z of the tube. In some embodiments, as shown in FIG. 28, the arc angle 2914 is about 135 degrees. In some embodiments, the arc angle 2914 is about 135 degrees and contains the second material 2905 forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle 2914. According to embodiments, the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material 2905 forming the second wall structure.

[0235] As recited herein, the phrase “arc angle” refers to the angle dimension of an arc of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. For example, in some embodiments, the arc angle 2914 is about 135 degrees such that the second wall structure occupies about 135 degrees of the circumference of the drug reservoir lumen 2704 and the first wall structure occupies about 225 degrees of the circumference of the drug reservoir lumen 2704. Unless indicated otherwise, the terms “arc angle” and “stripe angle” are used interchangeably throughout this disclosure.

[0236] Still referring to FIG. 28, in some embodiments, the second material 2905 of the drug delivery system 2700 defines a wall thickness T extending along the diameter of the drug reservoir lumen 2732 that is 0.2 ± 0.04 mm. In some embodiments, the drug reservoir lumen 2732 defines an inner diameter D that is 2.64 ± 0.05 mm.

[0237] As discussed above, in some embodiments, the housing 2704 of the drug delivery system 2700 comprises a retention frame lumen 2734. According to embodiments, the wireform 2903 is disposed within the retention frame lumen 2734 and defines a diameter d that is about 0.305 mm. [0238] Referring to FIGS. 29A-29B, the drug delivery system 2700 is shown in a relatively straightened, insertion shape. In FIG. 29A, the portion of the housing bounding the drug reservoir lumen 2732 is shown as being translucent, revealing the erdafitinib minitablets 2708 contained therein. In FIG. 29B, the housing is shown in cross-section to reveal the erdafitinib minitablets 2708 located in the drug reservoir lumen 2732 and the retention frame 2903 located in the retention frame lumen 2734. In FIG. 29B, the ends 2808, 2810 of the drug delivery system 2700 are truncated.

[0239] As shown in FIG. 29A, and as mentioned above, some embodiments of the drug delivery system 2700 include first and second opposed ends, 2808, 2810, e.g., defined by the housing 2704. Still referring to FIG 29A, according to some embodiments, the drug delivery system 2700 defines a length 2812 between the first and second opposed ends 2808, 2810 that is about 17 cm. According to some embodiments, the drug reservoir lumen 2732 is sealed at the first and second opposed ends, 2808, 2810, e.g., with plugs 2820 (see FIG. 29B), thermoplastic, and/or sealant. Being sealed at the opposed ends 2808, 2810 ensures that the drug-permeable second wall structure of the drug reservoir lumen 2732 is the only path for drug release.

[0240] In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose;

(d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire drug formulation.

[0241] Referring to FIGS. 29A and 29B, in some embodiments the drug formulation comprises minitablets 2708. n some embodiments the drug formulation consists of minitablets 2708. In some embodiments, the drug delivery system 2700 comprises about 42 to 44 erdafitinib minitablets 2708. In some embodiments, the drug delivery system 2700 comprises 43 erdafitinib minitablets 2708. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg erdafitinib. In some embodiments, the drug formulation comprises about 500 mg erdafitinib.

[0242] In some embodiments, each minitablet 2708 has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet 2708 has a weight that is about 23 mg. [0243] Referring to FIG. 29A, in some embodiments, each minitablet 2708 defines a thickness 2802 that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet 2708 defines a thickness 2802 that is about 3.2 mm.

[0244] Still referring to FIG. 29A, in some embodiments, each minitablet 2708 defines a diameter 2806 is that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet 2708 defines a diameter 2806 that is about 2.63 mm.

[0245] Referring to FIG. 29B, in some embodiments, the plurality of the minitablets 2708 are arranged in series and define a drug core 2822. For example, the drug core 2822 may comprise 43 erdafitinib minitablets 2708. The drug core 2822 may define a drug core length 2824 between an outside face of a first minitablet 2708a in the drug core 2822 and an opposite-facing outside face of a last minitablet 2708b in the drug core 2822. According to embodiments, the drug core length 2824 can be about 15 cm.

[0246] In some embodiments, provided herein is a drug delivery system, comprising a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl- beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire drug formulation.

[0247] In some embodiments, provided herein is a drug delivery system, comprising a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl -beta- cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; I 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire drug formulation.

[0248] In some embodiments, provided herein is a drug delivery system, comprising a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl -beta- cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib.

[0249] In some embodiments, provided herein is a drug delivery system, comprising a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl- beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. [0250] In some embodiments, provided herein is a drug delivery system, comprising a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, whereinthe arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. [0251] In some embodiments, provided herein is a drug delivery system, comprising a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, whereinthe arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm.

[0252] In some embodiments, provided herein is a drug delivery system, comprising a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, whereinthe arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter that is about 2.63 mm.

[0253] In some embodiments, provided herein is a drug delivery system, comprising a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, whereinthe arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer;

(f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter that is about 2.63 mm. In some embodiments, the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposed ends, for example, with plugs, thermoplastic, and/or sealant.

[0254] In some embodiments, provided herein is a drug delivery system, comprising a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, whereinthe arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter that is about 2.63 mm. In some embodiments, the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposed ends, for example, with plugs, thermoplastic, and/or sealant. In some embodiments, the housing of the drug delivery system comprises a retention frame lumen and a wireform disposed in the retention frame lumen. In some embodiments, the wireform has a diameter that is about 0.305 mm and a length that is about 156 mm. In some embodiments, the wireform is a nitinol wire.

[0255] In some embodiments, provided herein is a drug delivery system, comprising a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, whereinthe arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter that is about 2.63 mm. In some embodiments, the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposed ends, for example, with plugs, thermoplastic, and/or sealant. In some embodiments, the housing of the drug delivery system comprises a retention frame lumen and a wireform disposed in the retention frame lumen. In some embodiments, the wireform has a diameter that is about 0.305 mm and a length that is about 156 mm. In some embodiments, the wireform is a nitinol wire. In some embodiments, the plurality of the minitablets are arranged in series and define a drug core length between a first face of a first minitablet and an opposed second face of a last minitablet in the drug core, wherein the drug core length is about 15 cm.

[0256] In some embodiments, provided herein is a drug delivery system, comprising a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl -beta- cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter that is about 2.63 mm. In some embodiments, the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposed ends, for example, with plugs, thermoplastic, and/or sealant. In some embodiments, the housing of the drug delivery system comprises a retention frame lumen and a wireform disposed in the retention frame lumen. In some embodiments, the wireform has a diameter that is about 0.305 mm and a length that is about 156 mm. In some embodiments, the wireform is a nitinol wire. In some embodiments, the plurality of the minitablets are arranged in series and define a drug core length between a first face of a first minitablet and an opposed second face of a last minitablet in the drug core, wherein the drug core length is about 15 cm. In some embodiments, the second material of the drug delivery system, defines a wall thickness extending along the diameter of the drug reservoir lumen that is 0.2 ± 0.04 mm.

[0257] In some embodiments, provided herein is a drug delivery system, comprising a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, whereinthe arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter that is about 2.63 mm. In some embodiments, the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposed ends, for example, with plugs, thermoplastic, and/or sealant. In some embodiments, the housing of the drug delivery system comprises a retention frame lumen and a wireform disposed in the retention frame lumen. In some embodiments, the wireform has a diameter that is about 0.305 mm and a length that is about 156 mm. In some embodiments, the wireform is a nitinol wire. In some embodiments, the plurality of the minitablets are arranged in series and define a drug core length between a first face of a first minitablet and an opposed second face of a last minitablet in the drug core, wherein the drug core length is about 15 cm. In some embodiments, the second material of the drug delivery system, defines a wall thickness extending along the diameter of the drug reservoir lumen that is 0.2 ± 0.04 mm. In some embodiments, the drug reservoir lumen defines an inner diameter that is 2.64 ± 0.05 mm.

[0258] In some embodiments, provided herein is a drug delivery system, comprising a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, whereinthe arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter that is about 2.63 mm. In some embodiments, the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposed ends, for example, with plugs, thermoplastic, and/or sealant. In some embodiments, the housing of the drug delivery system comprises a retention frame lumen and a wireform disposed in the retention frame lumen. In some embodiments, the wireform has a diameter that is about 0.305 mm and a length that is about 156 mm. In some embodiments, the wireform is a nitinol wire. In some embodiments, the plurality of the minitablets are arranged in series and define a drug core length between a first face of a first minitablet and an opposed second face of a last minitablet in the drug core, wherein the drug core length is about 15 cm. In some embodiments, the second material of the drug delivery system, defines a wall thickness extending along the diameter of the drug reservoir lumen that is 0.2 ± 0.04 mm. In some embodiments, the drug reservoir lumen defines an inner diameter that is 2.64 ± 0.05 mm. In some embodiments, the drug delivery system is elastically deformable between a coiled retention shape and a relatively straightened insertion shape. In some embodiments, the coiled retention shape comprises a bioval shape.

[0259] In some embodiments, provided herein is a drug delivery system, comprising a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl -beta- cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter that is about 2.63 mm. In some embodiments, the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposed ends, for example, with plugs, thermoplastic, and/or sealant. In some embodiments, the housing of the drug delivery system comprises a retention frame lumen and a wireform disposed in the retention frame lumen. In some embodiments, the wireform has a diameter that is about 0.305 mm and a length that is about 156 mm. In some embodiments, the wireform is a nitinol wire. In some embodiments, the plurality of the minitablets are arranged in series and define a drug core length between a first face of a first minitablet and an opposed second face of a last minitablet in the drug core, wherein the drug core length is about 15 cm. In some embodiments, the second material of the drug delivery system, defines a wall thickness extending along the diameter of the drug reservoir lumen that is 0.2 ± 0.04 mm. In some embodiments, the drug reservoir lumen defines an inner diameter that is 2.64 ± 0.05 mm. In some embodiments, the drug delivery system is elastically deformable between a coiled retention shape and a relatively straightened insertion shape. In some embodiments, the coiled retention shape comprises a bioval shape. In some embodiments, when in the coiled retention shape, the drug delivery system has a maximum dimension in any direction that is equal to or less than about 6 cm. In some embodiments, when in the coiled retention shape, the drug delivery system has a maximum dimension in any direction that is equal to or less than about 5.5 cm. In some embodiments, when in the coiled retention shape, the drug delivery system fits within an envelope of 5.5 cm by 4.5 cm.

[0260] In some embodiments, the first wall structure and the second wall structure are permeable to water. In some embodiments, the first wall structure is impermeable to the erdafitinib, and the second wall structure is permeable to the erdafitinib. In some embodiments, the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube.

[0261] In some embodiments, provided herein is a drug delivery system, comprising a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube.

[0262] In some embodiments, the drug delivery system described herein is configured to release the erdafitinib at an average rate of about 2 mg/day and the two interface edges are disposed at an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein a thickness of the first wall structure, a second wall structure, or both, is from about 0.2 mm to about 1.0 mm, wherein the thickness of the second wall structure is from about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib.

[0263] In some embodiments, the drug delivery system described herein is configured to release the erdafitinib at an average rate of about 2.5 mg/day to about 3.5 mg/day and the two interface edges are disposed at an arc angle of about 125 degrees to about 145 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein a thickness of the first wall structure, a second wall structure, or both, is from about 0.2 mm to about 1.0 mm, wherein the thickness of the second wall structure is from about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib.

[0264] In some embodiments, the drug delivery system described herein is configured to release the erdafitinib at an average rate of about 3 mg/day and the two interface edges are disposed at an arc angle of about 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein a thickness of the first wall structure, a second wall structure, or both, is from about 0.2 mm to about 1.0 mm, wherein the thickness of the second wall structure is from about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib.

[0265] In some embodiments, the drug delivery system described herein is configured to release the erdafitinib at an average rate of about 4 mg/day and the two interface edges are disposed at an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein a thickness of the first wall structure, a second wall structure, or both, is from about 0.2 mm to about 1.0 mm, wherein the thickness of the second wall structure is from about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib.

Drug Tablets

[0266] As discussed herein with reference to the erdafitinib pharmaceutical formulations, the drug may be provided in a solid form suitable for being loaded within the drug reservoir lumen of the system (e.g., solid mini-tablets). In a preferred embodiment, as shown in FIG.

1, a drug formulation is formed into drug units 108 that are loaded into the drug reservoir lumen of the system 100. Each of the drug units is a solid, discrete object that substantially retains a selectively imparted shape (at the temperature and pressure conditions to which the drug units (e.g., tablets) and the delivery system normally will be exposed during assembly (e.g., loading into the system drug reservoir), storage, and handling before in vivo insertion). [0267] The individual drug units may have essentially any selected shape and dimension that fits within the systems described herein. In one embodiment, the drug units are sized and shaped such that the drug reservoir lumens in the housings are substantially filled by a select number of drug units. Each drug unit may have a cross-sectional shape that substantially corresponds to a cross-sectional shape of the drug reservoir lumen of a particular housing. For example, the drug units may be substantially cylindrical in shape for positioning in a substantially cylindrical drug reservoir lumen. Once loaded, the drug units can, in some embodiments, substantially fill the drug reservoir lumen forming the drug housing portion. [0268] In one embodiment, the drug units are shaped to align in a row when the system is in its deployment configuration. For example, each drug unit may have a cross-sectional shape that corresponds to the cross-sectional shape of the drug reservoir lumens in the housing, and each drug unit may have end face shapes that correspond to the end faces of adjacent drug units. The interstices or breaks between drug units can accommodate deformation or movement of the system, such as during deployment, while permitting the individual drug units to retain their solid form. Thus, the drug delivery system may be relatively flexible or deformable despite being loaded with a solid drug composition, such as a tablet, as each drug unit may be permitted to move with reference to adjacent drug units. [0269] In embodiments in which the drug units are designed for insertion or implantation in a lumen or cavity in the body, such as the bladder, via a drug delivery system, the drug units may be “mini-tablets” that are suitably sized and shaped for insertion through a natural lumen of the body, such as the urethra. For the purpose of this disclosure, the term “minitablet” generally indicates a solid drug unit that is substantially cylindrical in shape, having end faces and a side face that is substantially cylindrical. The mini-tablet has a diameter, extending along the end face, in the range of about 1.0 to about 3.2 mm, such as between about 1.5 and about 3.1 mm. The mini -tablet has a length, extending along the side face, in the range of about 1.7 mm to about 4.8 mm, such as between about 2.0 mm and about 4.5 mm. The friability of the tablet may be less than about 2%. In an aspect, the tablets are those as described herein. In an aspect, the tablets are those of Formula 4 A. In an aspect, the tablets are those of Formula 4B. In an aspect, the tablets are those of Formula 4C. In an aspect, the tablets are those of Formula 4D. Methods of Treatment

[0270] In some aspects, provided herein is a method of treating HR-NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib, for example, about 2.5 mg/day to about 3.5 mg/day of erdafitinib, for at least about 90 days locally to the bladder of the patient, in particular wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein.

[0271] In other aspects, provided herein is a method of treating HR-NMIBC, e.g., recurrent, BCG-experienced HR-NMIBC in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later. In some embodiments, the method of treating results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent, BCG-experienced HR-NMIBC. In some embodiments, the second wall structure, or both the first wall structure and the second wall structure, are permeable to water. In some embodiments, the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure. In some embodiments, the arc angle is 45 degrees to 90 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the arc angle is 150 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the arc angle is 125 degrees to 145 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube.

[0272] In some embodiments, the method comprises administering about 2 mg/day to about 4 mg/day of erdafitinib for at least about 90 days locally to the bladder of a patient with HR-NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high risk nonmuscle invasive bladder cancer (HR-NMIBC). In some embodiments, the method comprises administering about 2 mg/day of erdafitinib to the patient with recurrent bacillus Calmette- Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC). In some embodiments, the method comprises administering about 4 mg/day of erdafitinib to the patient with recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC).

[0273] In some embodiments, the method of treatment results in a recurrence-free rate of at least 50% in the population of patients receiving treatment, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent BCG-experienced HR-NMIBC. In some embodiments, the recurrence-free rate in the population of patients is at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%. In some embodiments, the recurrence-free rate in the population of patients is at least 50%. In some embodiments, the recurrence-free rate in the population of patients is at least 55%. In some embodiments, the recurrence-free rate in the population of patients is at least 60%. In some embodiments, the recurrence-free rate in the population of patients is at least 65%. In some embodiments, the recurrence-free rate in the population of patients is at least 70%. In some embodiments, the recurrence-free rate in the population of patients is at least 75%. In some embodiments, the recurrence-free rate in the population of patients is at least 80%. In some embodiments, the recurrence-free rate in the population of patients is at least 85%. In some embodiments, the recurrence-free rate in the population of patients is about 80% for patients treated with about 2 mg/day of erdafitinib. In some embodiments, the recurrence-free rate in the population of patients is about 80% for patients treated with about 2 mg/day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the recurrence-free rate in the population of patients is at least 88.9% for patients treated with about 2 mg/day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the recurrence-free rate in the population of patients is about 83%, such as about 83.3%, for patients treated with about 4 mg/day of erdafitinib. In some embodiments, the recurrence-free rate in the population of patients is about 83%, such as about 83.3%, for patients treated with about 4 mg/day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the recurrence-free rate in the population of patients is at least 85.7% for patients treated with about 4 mg/day, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the recurrence-free rate in the population of patients is about 82%, such as about 81.8%, for patients treated with about 2 mg/day to about 4 mg/day of erdafitinib. In some embodiments, the recurrence-free rate in the population of patients is about 82%, such as about 81.8%, for patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments the recurrence- free rate is assessed at 3 months or 90 days of the erdafitinib treatment.

[0274] In some embodiments, the method further comprises performing a transurethral resection of bladder tumor (TURBT) prior to administering the erdafitinib.

[0275] In some embodiments, the method comprises administering about 2 mg/day to about 4 mg/day of erdafitinib for at least about 90 days locally to the bladder of the patient, where the patient has high-grade Ta or T1 bladder cancer. In some embodiments, the population of patients have high-grade Ta or T1 bladder cancer. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent BCG-experienced HR-NMIBC. In some embodiments, the patient has a histologically confirmed high-grade Ta or T1 lesion. In some embodiments, the population of patients have a histologically confirmed high-grade Ta or T1 lesion. In some embodiments, the patient does not have carcinoma in situ (CIS). In some embodiments, the population of patients do not have carcinoma in situ (CIS). In some embodiments, the patient has recurrent high-grade Ta or T1 bladder cancer within 18 months of completion of prior BCG therapy. In some embodiments, the population of patients have recurrent high-grade Ta or T1 bladder cancer within 18 months of completion of prior BCG therapy. In some embodiments, the patient has previously received at least 5 of 6 full doses of an induction course of BCG. In some embodiments, the population of patients have previously received at least 5 of 6 full doses of an induction course of BCG. In some embodiments, the patient has high-risk papillary-only NMIBC. In some embodiments, the population of patients have high-risk papillary-only NMIBC. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. [0276] In other aspects, provided herein is a method of treating IR-NMIBC, e.g., recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib, for example, about 2.5 mg/day to about 3.5 mg/day of erdafitinib, for at least about 90 days locally to the bladder of the patient, in particular wherein such treatment results in an at least 50% complete response rate in a population of patients receiving such treatment. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR-NMIBC.

[0277] In other aspects, provided herein is a method of treating IR-NMIBC, e.g., recurrent, IR-NMIBC in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later. In some embodiments, the method of treating results in a complete response rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR- NMIBC. In some embodiments, the second wall structure, or both the first wall structure and the second wall structure, are permeable to water. In some embodiments, the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure. In some embodiments, the two interface edges are disposed at an arc angle of 45 degrees to 90 degrees of a circumference of the tube in crosssection normal to the longitudinal axis of the tube, in particular at an arc angle of 90 degrees. In some embodiments, the two interface edges are disposed at an arc angle of 150 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, in particular at an arc angle of 180 degrees. In some embodiments, the two interface edges are disposed at an arc angle of 125 degrees to 145 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, in particular at an arc angle of 135 degrees.

[0278] In some embodiments, the method comprises administering about 2 mg/day to about 4 mg/day of erdafitinib for at least about 90 days locally to the bladder of a patient with IR-NMIBC, e.g., recurrent IR-NMIBC. In some embodiments, the method comprises administering about 2 mg/day of erdafitinib to a patient with recurrent IR-NMIBC. In some embodiments, the method comprises administering about 4 mg/day of erdafitinib to a patient with recurrent IR-NMIBC.

[0279] In some embodiments, the method of treatment results in a complete response rate of at least 50% in the population of patients with recurrent IR-NMIBC receiving treatment. In some embodiments, the complete response rate in the population of patients is at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%. In some embodiments, the complete response rate in the population of patients is at least 50%. In some embodiments, the complete response rate in the population of patients is at least 55%. In some embodiments, the complete response rate in the population of patients is at least 60%. In some embodiments, the complete response rate in the population of patients is at least 65%. In some embodiments, the complete response rate in the population of patients is at least 70%. In some embodiments, the complete response rate in the population of patients is at least 75%. In some embodiments, the complete response rate in the population of patients is at least 80%. In some embodiments, the complete response rate in the population of patients is at least 85%. In some embodiments, the complete response rate in the population of patients is about 75% for patients treated with about 2 mg/day erdafitinib. In some embodiments, the complete response rate in the population of patients is 75% for patients treated with about 2 mg/day, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein. In some embodiments, the complete response rate in the population of patients is about 100% for patients treated with about 4 mg/day erdafitinib. In some embodiments, the complete response rate in the population of patients is 100% for patients treated with about 4 mg/day, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein. In some embodiments, the complete response rate in the population of patients is about 87%, such as about 86.7%, for patients treated with about 2 mg/day to about 4 mg/day of erdafitinib. In some embodiments, the complete response rate in the population of patients is about 87%, such as about 86.7%, for patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein. In some embodiments the complete response rate is assessed at 3 months or 90 days of the erdafitinib treatment.

[0280] In some embodiments, the method comprises administering about 2 mg/day to about 4 mg/day of erdafitinib for at least about 90 days locally to the bladder of the patient, where the patient has a history of only low-grade disease. In some embodiments, the population of patients have a history of only low-grade disease. In some embodiments, the patient has recurrent intermediate risk papillary disease. In some embodiments, the population of patients have recurrent intermediate risk papillary disease. In some embodiments, the patient has not previously had carcinoma in situ. In some embodiments, the population of patients have not previously had carcinoma in situ. In some embodiments, the patient has visible disease at the time that the erdafitinib is administered. In some embodiments, the population of patients have visible disease at the time that the erdafitinib is administered. In some embodiments, the patient has Ta or T1 bladder cancer. In some embodiments, the population of patients have Ta or T1 bladder cancer. In some embodiments, the patient has not undergone TURBT prior to administering the erdafitinib. In some embodiments, the population of patients have not undergone TURBT prior to administering the erdafitinib. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR-NMIBC as described herein.

[0281] In some embodiments, the method comprises administering about 2 mg/day of erdafitinib to the patient. In some embodiments, the method comprises administering about 4 mg/day of erdafitinib to the patient.

[0282] In some embodiments, the method of treating HR-NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR- NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day, more in particular about 3 mg/day, of erdafitinib for at least about 90 days locally to the bladder of the patient, wherein the erdafitinib formulation is Formula 4B formulation as described herein. In some embodiments, the solid pharmaceutical composition includes (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 24.5 wt% microcrystalline cellulose; (e) 6.0 wt% silicified microcrystalline cellulose; (f) 6.0 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 2.0 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, in particular wherein the delivery system comprises AC- 4075 A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed.

[0283] In other aspects, provided herein is a method of treating IR-NMIBC, e.g., recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day, more in particular about 3 mg/day, of erdafitinib for at least about 90 days locally to the bladder of the patient, wherein the erdafitinib formulation is Formula 4B formulation as described herein. In some embodiments, the solid pharmaceutical composition includes (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 24.5 wt% microcrystalline cellulose; (e) 6.0 wt% silicified microcrystalline cellulose; (f) 6.0 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 2.0 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, in particular wherein the delivery system comprises AC- 4075 A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed.

[0284] In some embodiments, the method of treating HR-NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR- NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day, more in particular about 3 mg/day, of erdafitinib for at least about 90 days locally to the bladder of the patient, wherein the erdafitinib formulation is Formulation 3.4 as described herein. In some embodiments, the solid pharmaceutical composition includes: (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 17.5 wt% microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25 wt% colloidal silicon dioxide; (h) 1.5 wt% hydroxypropyl methylcellulose; and (i) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. [0285] In other aspects, provided herein is a method of treating IR-NMIBC, e.g., recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib, more in particular about 3 mg/day, for at least about 90 days locally to the bladder of the patient, wherein the erdafitinib formulation is Formulation 3.4 as described herein. Accordingly, Formulation 3.4 is encompassed by the disclosure, in which the solid pharmaceutical composition includes: (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl -beta-cyclodextrin; (c) 1 wt% meglumine; (d) 17.5 wt% microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25 wt% colloidal silicon dioxide; (h) 1.5 wt% hydroxypropyl methylcellulose; and (i) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed.

[0286] In some embodiments, the method of treating HR-NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR- NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day, more in particular about 3 mg/day, of erdafitinib for at least about 90 days locally to the bladder of the patient, wherein the erdafitinib formulation is Formulation 4.1 as described herein. In some embodiments, the solid pharmaceutical composition includes: (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed.

[0287] In other aspects, provided herein is a method of treating IR-NMIBC, e.g., recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day, more in particular about 3 mg/day, of erdafitinib for at least about 90 days locally to the bladder of the patient, wherein the erdafitinib formulation is Formulation 4.1 as described herein. Accordingly, Formulation 4.1 is encompassed by the disclosure, in which the solid pharmaceutical composition includes: (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e)

7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g)

1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. [0288] In some embodiments, the method of treating HR-NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR- NMIBC) in a patient comprises deploying an intravesical drug delivery system as described herein. In some embodiments, the drug delivery system comprises a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material the first and second wall structures being are one another at two interface edges and together forming a tube defining the closed drug reservoir; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure.

[0289] In some embodiments, the method of treating IR-NMIBC, e.g., recurrent intermediate risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprises deploying an intravesical drug delivery system as described herein. In some embodiments, the drug delivery system comprises a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material the first and second wall structures being are one another at two interface edges and together forming a tube defining the closed drug reservoir; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure.

[0290] In some embodiments, the method of treating HR-NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR- NMIBC) in a patient comprises deploying an intravesical drug delivery system as described herein, wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. [0291] In some embodiments, the method of treating IR-NMIBC, e.g., recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprises deploying an intravesical drug delivery system as described herein, wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the device are closed.

[0292] In some embodiments, the method comprises administering about 2 mg/day to about 4 mg/day of erdafitinib for at least about 90 days locally to the bladder of the patient, wherein the patient has not had prior treatment with an FGFR inhibitor. In some embodiments, the population of patients have not had prior treatment with an FGFR inhibitor. [0293] In some embodiments, the patient harbors at least one FGFR2 genetic alteration. In some embodiments, the patient harbors at least one FGFR3 genetic alteration. In some embodiments, the patient harbors at least one FGFR2 and at least one FGFR3 genetic alteration. In some embodiments, the population of patients harbor at least one FGFR2 genetic alteration. In some embodiments, the population of patients harbor at least one FGFR3 genetic alteration. In some embodiments, the population of patients harbor at least one FGFR2 and at least one FGFR3 genetic alteration.

[0294] In some embodiments, the FGFR2 genetic alteration comprises an activating tumor FGFR2 mutation or fusion. In some embodiments, the FGFR2 genetic alteration comprises an activating tumor FGFR2 fusion. In some embodiments, the FGFR3 genetic alteration comprises an activating tumor FGFR3 mutation or fusion. In some embodiments, the FGFR3 genetic alteration comprises an activating tumor FGFR3 mutation. In some embodiments, the FGFR3 genetic alteration comprises an activating tumor FGFR3 fusion. In some embodiments, the FGFR2 genetic alteration and the FGFR3 genetic alteration comprise activating tumor FGFR2 or 3 mutations or fusions. In some embodiments, the FGFR3 genetic alteration is an FGFR3 mutation selected from the group consisting of FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, and FGFR3 G370C. In some embodiments, the FGFR3 genetic alteration is a gene fusion comprising FGFR3:TACC3 VI. In some embodiments, the FGFR genetic alteration is detected using a PCR or NGS assay of a urine sample obtained from the patient. In some embodiments the FGFR genetic alteration is detected using a PCR or NGS assay of a tumor tissue sample obtained from the patient. In some embodiments the FGFR genetic alteration is detected using a histopathological image of the tumor tissue via digital histopathology analysis.

[0295] In some embodiments, the FGFR genetic alteration is detected using a NGS or PCR assay of a urine sample and a tumor tissue sample obtained from the patient. In some embodiments, there is high concordance between FGFR alterations detected with a urine sample assay and a tumor tissue sample assay. In some embodiments, a urine sample assay identifies bladder cancer patients that are not identified by a tumor tissue sample assay. In some embodiments, the patient is identified by a urine sample assay alone. In some embodiments, the patient is identified by a urine sample assay alone due to no available sample or insufficient tumor tissue. In some embodiments, a urine sample assay identifies at least about 5%, 10%, 15%, 20%, 25%, or 27% more bladder cancer patients than a tumor tissue sample assay. In some embodiments, a urine sample assay identifies between about 5% and 50%, 10% and 45%, 15% and 40%, 20% and 35%, or 25% and 30% more bladder cancer patients than a tumor tissue sample assay. In some embodiments, a urine sample assay identifies about 29% more bladder cancer patients than a tumor tissue sample assay. In an embodiment, the urine sample assay is a NGS (next-generation sequencing) assay, in particular the PredicineCare™ (NGS) assay. In an embodiment, the tumor tissue sample assay is a PCR (polymerase chain reaction) assay, in particular the QIAGEN therascreen® FGFR RGQ RT-PCR kit.

[0296] In some embodiments, at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of treated patients identified by a urine sample assay alone were recurrence-free or achieved a complete response. In some embodiments, between about 50% and 100%, 55% and 95%, 60% and 90%, 65% and 85%, or 70% and 80% of treated patients identified by a urine sample assay alone were recurrence-free or achieved a complete response. In some embodiments, at least about 80%, 90%, 95%, or 100% of treated patients identified by a urine sample assay alone were recurrence-free or achieved a complete response. In some embodiments, at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of treated patients identified by a urine sample assay alone were recurrence-free or achieved a complete response. In some embodiments, all of the treated patients identified by a urine sample assay alone were recurrence-free or achieved a complete response. In an embodiment, the urine sample assay is a NGS (next-generation sequencing) assay, in particular the PredicineCare™ (NGS) assay.

[0297] In some embodiments, the method comprising administering erdafitinib comprises deploying an intravesical drug delivery system comprising erdafitinib to the bladder of the patient. In some embodiments, the method comprises administering about 2 mg/day to about 4 mg/day of erdafitinib, where administering erdafitinib comprises deploying an intravesical drug delivery system as described herein. In some embodiments, the method comprises removing the drug delivery system about 90 days later. In some embodiments, the drug delivery system comprises about 400, about 450, about 500, about 550, or about 600 mg erdafitinib. In some embodiments, the drug delivery system comprises about 480, about 485, about 490, about 495, about 500, about 505, about 510, about 515, or about 520 mg erdafitinib. In some embodiments, the drug delivery system comprises about 500 mg erdafitinib.

[0298] In some embodiments, the method comprises administering about 2 mg/day to about 4 mg/day of erdafitinib, where administering erdafitinib comprises deploying an intravesical drug delivery system as described herein. In some embodiments, the method comprises administering about 2.5 mg/day to about 3.5 mg/day of erdafitinib, where administering erdafitinib comprises deploying an intravesical drug delivery system as described herein. In some embodiments, the method comprises administering about 2 mg/day, about 3 mg/day, or about 4 mg/day of erdafitinib, where administering erdafitinib comprises deploying an intravesical drug delivery system as described herein.

[0299] In some embodiments, the drug delivery system comprises a dual lumen tube comprising a drug reservoir lumen comprising the erdafitinib and a small lumen comprising an elastic nitinol wire. In some embodiments, the drug reservoir lumen is bounded by a first wall structure formed of a first material and a second wall structure formed of a second material. In some embodiments, the first and second wall structures being adjacent to one another at two interface edges and together forming a tube defining a closed drug reservoir lumen, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable by diffusion through the second wall structure. In some embodiments, the second wall structure forms a longitudinal strip extending along the length of the tube. In some embodiments, the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the two interface edges are disposed at an arc angle of 45 degrees to 90 degrees, in particular 90 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the two interface edges are disposed at an arc angle of 150 degrees to 270 degrees, in particular 180 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the two interface edges are disposed at an arc angle of 125 degrees to 145 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the two interface edges are disposed at an arc angle of 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

[0300] In some embodiments, the drug delivery system is elastically deformable. In some embodiments, the drug delivery system has a bi-oval retention shape. In some embodiments, the drug delivery system is elastically deformable and has a bi-oval retention shape.

[0301] In some embodiments, the erdafitinib is in the form of a plurality of mini-tablets serially arranged in the drug lumen. In some embodiments, the drug lumen comprises about 40 to 43 erdafitinib containing minitablets. In some embodiments, the drug lumen comprises 40 erdafitinib containing minitablets. In some embodiments, the drug lumen comprises 41 erdafitinib containing minitablets. In some embodiments, the drug lumen comprises 42 erdafitinib containing minitablets. In some embodiments, the drug lumen comprises 43 erdafitinib containing minitablets. In some embodiments, the plurality of mini-tablets are arranged in the drug lumen of an intravesical drug delivery system, wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. In some embodiments, the erdafitinib containing minitablet comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 17.5 wt% microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidonevinyl acetate copolymer; (g) 0.25 wt% colloidal silicon dioxide; (h) 1.5 wt% hydroxypropyl methylcellulose; and (i) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire minitablet. In some embodiments, the erdafitinib containing minitablet comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl -beta-cyclodextrin; (c)

17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e)

1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire minitablet. In some embodiments, the erdafitinib containing minitablet comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl- beta-cyclodextrin; (c) 1 wt% meglumine; (d) 24.5 wt% microcrystalline cellulose; (e) 6.0 wt% silicified microcrystalline cellulose; (f) 6.0 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 2.0 wt% magnesium stearate, wherein these weight percentages are relative to the entire minitablet.

[0302] In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment of bladder cancer, wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient with a urine based PCR or NGS assay. In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations comprising, consisting of, or consisting essential of: (a) evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations, in particular evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a urine based PCR or NGS assay; and (b) delivering locally erdafitinib if the one or more FGFR genetic alterations, is present in the sample. In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment, wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a urine sample from the patient, in particular wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a urine sample from the patient with a urine based PCR or NGS assay. In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment, wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient with a urine based PCR or NGS assay. In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is locally delivered into the bladder of the patient and wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient with a urine based PCR or NGS assay. In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient comprising, consisting of, or consisting essential of (a) evaluating a urine sample from a patient with bladder cancer for the presence of one or more FGFR genetic alterations, in particular evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a urine based PCR or NGS assay; and (b) delivering locally erdafitinib to the patient if the one or more FGFR genetic alterations, is present in the sample. In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a urine sample from the patient, in particular wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a urine sample from the patient with a urine based PCR or NGS assay. In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient with a urine based PCR or NGS assay. In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient, wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a urine sample from the patient with a urine based PCR or NGS assay. In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient comprising, consisting of, or consisting essential of: (a) evaluating a urine sample from the patient with bladder cancer for the presence of the one or more FGFR genetic alterations, in particular evaluating a urine sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a urine based PCR or NGS assay; and (b) delivering locally erdafitinib if the one or more FGFR genetic alterations, is present in the sample. In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a urine sample from the patient, in particular wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a urine sample from the patient with a urine based PCR or NGS assay. In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a urine sample from the patient with a urine based PCR or NGS assay. The methods or uses may include locally delivering or locally administering erdafitinib (such as in any of the formulations described herein) into the bladder of a patient in need of treatment, in particular a cancer patient, in an amount effective for the treatment of bladder cancer (e.g., from about 2 mg/day to about 4 mg/day, as described herein). In an aspect the patient, in particular a human, is a recurrent BCG-experienced HR-NMIBC patient. In an aspect the patient, in particular a human, is a recurrent, bacillus Calmette-Guerin (BCG)-experienced high-risk papillary-only NMIBC (high-grade Ta/Tl) cancer patient, refusing or ineligible for radical cystectomy (Rcy). In an aspect the patient, in particular a human, is a recurrent, BCG- experienced high-risk papillary-only NMIBC (high-grade Ta/Tl) cancer patient, scheduled for Rcy. In an aspect the patient, in particular a human, is a recurrent, intermediate-risk NMIBC (Ta and Tl) cancer patient with a previous history of only low-grade disease.

[0303] In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment of bladder cancer, wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient with a tissue based PCR or NGS assay, or wherein the one or more FGFR genetic alterations are detected in a histopathological image of the tumor tissue via digital histopathology analysis. In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations comprising, consisting of, or consisting essential of: (a) evaluating a tumor tissue sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations, in particular evaluating a tumor tissue sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a tissue based PCR or NGS assay, or evaluating a histopathological image of a tumor tissue from a patient with bladder cancer for the presence of one or more FGFR genetic alterations via digital histopathology analysis; and (b) delivering locally erdafitinib if the one or more FGFR genetic alterations, is present in the sample. In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment, wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a histopathological image of the tumor tissue via digital histopathology analysis. In a certain embodiment, there is provided a method of treating bladder cancer harboring one or more FGFR genetic alterations, comprising locally delivering erdafitinib into the bladder of a patient in need thereof, in an amount effective for the treatment, wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a histopathological image of the tumor tissue via digital histopathology analysis. In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is locally delivered into the bladder of the patient and wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein the one or more FGFR alterations are detected in a histopathological image of the tumor tissue via digital histopathology analysis. In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient comprising, consisting of, or consisting essential of (a) evaluating a tumor tissue sample from a patient with bladder cancer for the presence of one or more FGFR genetic alterations, in particular evaluating a tumor tissue sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a tissue based PCR or NGS assay, or evaluating a histopathological image of a tumor tissue from a patient with bladder cancer for the presence of one or more FGFR genetic alterations via digital histopathology analysis; and (b) delivering locally erdafitinib to the patient if the one or more FGFR genetic alterations, is present in the sample. In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a histopathological image of the tumor tissue via digital histopathology analysis. In a certain embodiment, there is provided erdafitinib for use in the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a histopathological image of the tumor tissue via digital histopathology analysis. In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient, wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient, in particular wherein the one or more FGFR genetic alterations are detected in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein the one or more FGFR alterations are detected in a histopathological image of the tumor tissue via digital histopathology analysis. In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient comprising, consisting of, or consisting essential of: (a) evaluating a tumor tissue sample from the patient with bladder cancer for the presence of the one or more FGFR genetic alterations, in particular evaluating a tumor tissue sample from a patient with bladder cancer for the presence of the one or more FGFR genetic alterations with a tissue based PCR or NGS assay or evaluating a histopathological image of a tumor tissue from a patient with bladder cancer for the presence of one or more FGFR genetic alterations via digital histopathology analysis; and (b) delivering locally erdafitinib if the one or more FGFR genetic alterations, is present in the sample. In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein the patient is selected for the treatment based on the detection of the one or more FGFR genetic alterations in a histopathological image of the tumor tissue via digital histopathology analysis. In a certain embodiment, there is provided use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer harboring one or more FGFR genetic alterations in a patient wherein erdafitinib is to be locally delivered into the bladder of the patient and wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient, in particular wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a tumor tissue sample from the patient with a tissue based PCR or NGS assay or wherein eligibility of the patient for the treatment is determined by detecting the one or more FGFR genetic alterations in a histopathological image of the tumor tissue via digital histopathology analysis. The methods or uses may include locally delivering or locally administering erdafitinib (such as in any of the formulations described herein) into the bladder of a patient in need of treatment, in particular a cancer patient, in an amount effective for the treatment of bladder cancer (e.g., from about 2 mg/day to about 4 mg/day, as described herein). In an aspect the patient, in particular a human, is a recurrent BCG- experienced HR-NMIBC patient. In an aspect the patient, in particular a human, is a recurrent, bacillus Calmette-Guerin (BCG)-experienced high-risk papillary-only NMIBC (high-grade Ta/Tl) cancer patient, refusing or ineligible for radical cystectomy (Rcy). In an aspect the patient, in particular a human, is a recurrent, BCG-experienced high-risk papillary- only NMIBC (high-grade Ta/Tl) cancer patient, scheduled for Rcy. In an aspect the patient, in particular a human, is a recurrent, intermediate-risk NMIBC (Ta and Tl) cancer patient with a previous history of only low-grade disease.

[0304] In some embodiments, provided herein is a method of treating recurrent, BCG- experienced HR-NMIBC in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later, wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the drug delivery system comprises Formula 4B formulation, wherein Formula 4B formulation is encompassed by this disclosure, in which the solid pharmaceutical composition includes (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl -beta-cyclodextrin; (c) 1 wt% meglumine; (d) 24.5 wt% microcrystalline cellulose; (e) 6.0 wt% silicified microcrystalline cellulose; (f) 6.0 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 2.0 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the delivery system comprises AC- 4075 A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed.

[0305] In some embodiments, provided herein is a method of treating recurrent, BCG- experienced HR-NMIBC in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later, wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the drug delivery system comprises Formulation 4.1, wherein Formula 4.1 is encompassed by the disclosure, in which the solid pharmaceutical composition includes: (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition.

[0306] In some embodiments, provided herein is a method of treating recurrent, BCG- experienced HR-NMIBC in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later, wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the drug delivery system comprises Formulation 3.4, wherein Formula 3.4 is encompassed by the disclosure, in which the solid pharmaceutical composition includes: (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 17.5 wt% microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidonevinyl acetate copolymer; (g) 0.25 wt% colloidal silicon dioxide; (h) 1.5 wt% hydroxypropyl methylcellulose; and (i) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition.

[0307] In some embodiments, the method of treating recurrent, IR-NMIBC in a patient comprises deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later, wherein such treatment results in a complete response of at least 50% in a population of patients receiving such treatment. In some embodiments, the drug delivery system comprises Formula 4B formulation, wherein Formula 4B formulation is encompassed by this disclosure, in which the solid pharmaceutical composition includes (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl -beta- cyclodextrin; (c) 1 wt% meglumine; (d) 24.5 wt% microcrystalline cellulose; (e) 6.0 wt% silicified microcrystalline cellulose; (f) 6.0 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 2.0 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. [0308] In some embodiments, the method of treating recurrent, IR-NMIBC in a patient comprises deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later, wherein such treatment results in a complete response of at least 50% in a population of patients receiving such treatment. In some embodiments, the drug delivery system comprises Formulation 4.1, wherein Formula 4.1 is encompassed by the disclosure, in which the solid pharmaceutical composition includes: (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e)

1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition.

[0309] In some embodiments, the method of treating recurrent, IR-NMIBC in a patient comprises deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later, wherein such treatment results in a complete response of at least 50% in a population of patients receiving such treatment. In some embodiments, the drug delivery system comprises Formulation 3.4, wherein Formula 3.4 is encompassed by the disclosure, in which the solid pharmaceutical composition includes: (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 17.5 wt% microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25 wt% colloidal silicon dioxide; (h) 1.5 wt% hydroxypropyl methylcellulose; and (i) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition.

[0310] All method claims provided herein can be rephrased as use for manufacture of a medicament or for use embodiments. For example, in some aspects, provided herein are uses of an intravesical drug delivery system for the manufacture of a medicament for the treatment of recurrent BCG-experienced HR-NMIBC, wherein the drug delivery system comprises a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material the first and second wall structures being are one another at two interface edges and together forming a tube defining the closed drug reservoir; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube wall structure to the bladder of a patient; and removing the drug delivery system about 90 days later, where such treatment results in a recurrence-free rate of at least 50% in a population of patients comprising, consisting of, or consisting essentially of Cohort 1 patients as described herein. For example, in some aspects, provided herein are an intravesical drug delivery system for or for use for the treatment of recurrent BCG- experienced HR-NMIBC, wherein the drug delivery system comprises a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material the first and second wall structures being are one another at two interface edges and together forming a tube defining the closed drug reservoir; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube wall structure to the bladder of a patient; and removing the drug delivery system about 90 days later, where such treatment results in a recurrence-free rate of at least 50% in a population of patients comprising, consisting of, or consisting essentially of Cohort 1 patients as described herein. For example, in some aspects, provided herein are uses of an intravesical drug delivery system for the manufacture of a medicament for the treatment of recurrent IR- NMIBC, wherein the drug delivery system comprises a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material the first and second wall structures being are one another at two interface edges and together forming a tube defining the closed drug reservoir; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube wall structure to the bladder of a patient; and removing the drug delivery system about 90 days later, where such treatment results in a complete response of at least 50% in a population of patients comprising, consisting of, or consisting essentially of Cohort 3 patients as described herein. For example, in some aspects, provided herein are an intravesical drug delivery system for or for use for the treatment of recurrent IR-NMIBC, wherein the drug delivery system comprises a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material the first and second wall structures being are one another at two interface edges and together forming a tube defining the closed drug reservoir; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube wall structure to the bladder of a patient; and removing the drug delivery system about 90 days later, where such treatment results in a complete response of at least 50% in a population of patients comprising, consisting of, or consisting essentially of Cohort 3 patients as described herein.

[0311] In some embodiments, provided herein is a method of treating recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR- NMIBC) in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall no structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of about 135 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; removing the drug delivery system at least about 90 days later; wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the method comprises administering about 3 mg/day of erdafitinib to the patient. In some embodiments, the drug delivery system is configured to release the erdafitinib at an average rate of 3 mg/day and the two interface edges are disposed at an arc angle of 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

[0312] In some aspects, provided herein is a method of treating recurrent, intermediaterisk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of about 135 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; and removing the drug delivery system at least about 90 days later; wherein such treatment results in an at least 50% complete response rate in a population of patients receiving such treatment. In some embodiments, the method comprises administering about 3 mg/day of erdafitinib to the patient. In some embodiments, the drug delivery system is configured to release the erdafitinib at an average rate of 3 mg/day and the two interface edges are disposed at an arc angle of 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. [0313] In some embodiments, the method provided herein comprises administering about 3 mg/day of erdafitinib comprises deploying an intravesical drug delivery system comprising erdafitinib to the bladder of the patient and removing the drug delivery system about 90 days later. In some embodiments, the drug delivery system comprises about 500 mg erdafitinib. In some embodiments, the method comprises i) deploying a first drug delivery system comprising erdafitinib to the bladder of the patient on day 0; ii) removing the first drug delivery system on about day 90; iii) deploying a second drug delivery system comprising erdafitinib to the bladder of the patient on about day 90; iv) removing the second drug delivery system on about day 180; v) deploying a third drug delivery system comprising erdafitinib to the bladder of the patient on day 180; vi) removing the third drug delivery system on about day 270; vii) deploying a fourth drug delivery system comprising erdafitinib to the bladder of the patient on about day 270; and viii) removing the fourth drug delivery system on about day 360. In some embodiments, the method comprises deploying an intravesical drug delivery system, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure. In some embodiments, the two interface edges are disposed at an arc angle of about 135 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the drug delivery system is configured to release the erdafitinib at an average rate of 3 mg/day and the two interface edges are disposed at an arc angle of 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

[0314] In some embodiments, the method provided herein comprises treating non-muscle invasive bladder cancer in a patient comprising deploying the drug delivery system to the bladder of the patient; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; and removing the drug delivery system at least about 90 days later, wherein the drug delivery system is as described herein. In some embodiments, the drug delivery system comprises a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees, in particular about 135 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube and the arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, both the first wall structure and the second wall structure are permeable to water. In some embodiments, the arc angle is about 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight that is between about 22 mg and about 24 mg. In some embodiments, each minitablet has a weight that is about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm. In some embodiments, each minitablet has a thickness that is about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, wherein each minitablet has a diameter that is between about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter that is about 2.63 mm. In some embodiments, the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposed ends, for example, with plugs, thermoplastic, and/or sealant. In some embodiments, the housing of the drug delivery system comprises a retention frame lumen and a wireform disposed in the retention frame lumen. In some embodiments, the wireform has a diameter that is about 0.305 mm and a length that is about 156 mm. In some embodiments, the wireform is a nitinol wire. In some embodiments, the plurality of the minitablets are arranged in series and define a drug core length between a first face of a first minitablet and an opposed second face of a last minitablet in the drug core, wherein the drug core length is about 15 cm. In some embodiments, the second material of the drug delivery system, defines a wall thickness extending along the diameter of the drug reservoir lumen that is 0.2 ± 0.04 mm. In some embodiments, the drug reservoir lumen defines an inner diameter that is 2.64 ± 0.05 mm. In some embodiments, the drug delivery system is elastically deformable between a coiled retention shape and a relatively straightened insertion shape. In some embodiments, the coiled retention shape comprises a bioval shape. In some embodiments, when in the coiled retention shape, the drug delivery system has a maximum dimension in any direction that is equal to or less than about 6 cm. In some embodiments, when in the coiled retention shape, the drug delivery system has a maximum dimension in any direction that is equal to or less than about 5.5 cm. In some embodiments, when in the coiled retention shape, the drug delivery system fits within an envelope of 5.5 cm by 4.5 cm. In some embodiments, the cancer is intermediate-risk nonmuscle invasive bladder cancer (IR-NMIBC). In some embodiments, the cancer is newly diagnosed intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC). In some embodiments, the cancer is recurrent intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC). In some embodiments, the cancer harbors an FGFR alteration. In some embodiments, the FGFR alteration is a FGFR2 alteration or a FGFR3 alteration. In some embodiments, the FGFR alteration is a FGFR3 alteration, in particular a FGFR3 mutation or a FGFR3 fusion. In some embodiments, the FGFR3 alteration is at least one of FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, in particular FGFR3-TACC3 variant 1 (FGFR3-TACC3 VI) or FGFR3-TACC3 variant 3 (FGFR3- TACC3 V3), FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

Patient Populations

[0315] The present invention, in some aspects, provides a method of treating HR- NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient. In some embodiments, the patient has a histologically variant subtype of a urothelial carcinoma of the lower tract, such as papillary. In some embodiments, the patient has mixed histology tumors, where the tumors are without the presence of micropapillary, signet ring cell, plasmacytoid, neuroendocrine, or sarcomatoid features. In some embodiments, the patient has high-risk papillary disease, where the disease is histologically confirmed as a high-grade Ta or T1 lesion. In some embodiments, the patient has intermediate-risk papillary disease, where all previous tumors were low grade, Ta or T1. In some embodiments, the patient had no previous carcinoma in situ (CIS).

[0316] In some embodiments, the patient has a FGFR genetic alteration. In some embodiments, the patient harbors at least one FGFR2 genetic alteration and/or FGFR3 genetic alteration. In some embodiments, the FGFR genetic alteration is a mutation or fusion. In some embodiments, the FGFR2 genetic alteration and/or the FGFR3 genetic alteration comprises an activating tumor FGFR2 and/or FGFR3 mutation or fusion. In some embodiments, the FGFR2 genetic alteration comprises an activating tumor FGFR2 fusion. In some embodiments, the FGFR3 genetic alteration comprises an activating tumor FGFR3 fusion. In some embodiments, the FGFR3 genetic alteration comprises an activating tumor FGFR3 mutation. In some embodiments, the FGFR genetic alteration is detected by PCR or NGS assay from a biological sample. In some embodiments, the biological sample is a liquid sample. In some embodiments, the biological sample is a urine sample. In some embodiments, the urine sample is obtained from the patient receiving treatment. In some embodiments, the urine sample is obtained from the patient that will receive treatment when at least one FGFR genetic alteration, in particular at least one FGFR genetic alteration as described herein is detected. In some embodiments, the FGFR genetic alteration is detected using a urine-based PCR or NGS assay. In some embodiments, the biological sample is a tumor tissue sample. In some embodiments, the tumor tissue sample is obtained from the patient receiving treatment. In some embodiments, the tumor tissue sample is obtained from the patient that will receive treatment when at least one FGFR genetic alteration, in particular at least one FGFR genetic alteration as described herein is detected. In some embodiments the FGFR genetic alteration is detected using a histopathological image of the tumor tissue via digital histopathology analysis. In some embodiments the detection of the at least one FGFR genetic alteration, in particular the at least one FGFR genetic alteration as described herein, is performed prior to administering erdafitinib to the patient.

[0317] In some embodiments, the patient has not received an FGFR inhibitor.

[0318] In some embodiments, the patient is unfit or not eligible for a cystectomy or has refused a cystectomy. In some embodiments, the patient is ineligible for radical cystectomy under the National Comprehensive Cancer Network (NCCN) guidelines. For example, the patient is unfit for surgery due to frailty. In some embodiments, the patient cannot tolerate radical cystectomy based upon the American Society of Anesthesiology (ASA) guidelines. For example, the patient who cannot tolerate radial cystectomy may be deemed medically unfit for surgery requiring general or epidural anesthesia.

[0319] In other embodiments, the patient may not be suitable for radical cystectomy due to a lack of post-operative care infrastructure (e.g., as determined by the Comprehensive Geriatric Assessment provided by the American Society of Anesthesiologists). In some embodiments, a patient is not suitable for radical cystectomy due to frailty (e.g., as determined by the Comprehensive Geriatric Assessment provided by the American Society of Anesthesiologists). Under these guidelines, a patient is deemed frail if he or she shows abnormal independent activities of daily living, severe malnutrition, cognitive impairment, or comorbidities cumulative illness rating scale for geriatrics (CISR-G) grades 3-4. Furthermore, under current guidelines, subjects must be deemed unfit for radical cystectomy (RC) due to comorbid conditions with a risk of mortality >5% as estimated by the American College of Surgeons risk calculator using the current procedure terminology code 51595 or 51596 for cystectomy.

[0320] In some embodiments, the patient is eligible for a radical cystectomy but elects not to undergo the radical cystectomy due to quality-of-life considerations. In some embodiments, the quality-of-life impacts of radical cystectomy include, but are not limited to, mortality, incontinence, decreased sexual function, subfertility or infertility, and decreased bowel function. In some embodiments, the patient is either ineligible for or has elected not to undergo radical cystectomy (RC).

[0321] In some embodiments, the method comprises administering about 2 mg/day to about 4 mg/day of erdafitinib for at least about 90 days locally to the bladder of the patient, where the patient has high-grade Ta or T1 bladder cancer. In some embodiments, the population of patients have high-grade Ta or T1 bladder cancer. In some embodiments, the patient has a histologically confirmed high-grade Ta or T1 lesion. In some embodiments, the population of patients have a histologically confirmed high-grade Ta or T1 lesion. In some embodiments, the patient does not have carcinoma in situ (CIS). In some embodiments, the population of patients do not have carcinoma in situ (CIS). In some embodiments, the patient has recurrent high-grade Ta or T1 bladder cancer within 18 months of completion of prior BCG therapy. In some embodiments, the population of patients have recurrent high-grade Ta or T1 bladder cancer within 18 months of completion of prior BCG therapy. In some embodiments, the patient has previously received at least 5 of 6 full doses of an induction course of BCG. In some embodiments, the population of patients have previously received at least 5 of 6 full doses of an induction course of BCG. In some embodiments, the patient has high-risk papillary-only NMIBC. In some embodiments, the population of patients have high- risk papillary-only NMIBC.

[0322] In some embodiments, the patient has high-risk NMIBC. In some embodiments, the patient has high-risk papillary NMIBC having prior experience with intravesical Bacillus Calmette-Guerin (BCG) therapy. In some embodiments, the patient has high-risk papillary NMIBC having no prior experience with intravesical BCG therapy because it was not available as a treatment option. In some embodiments, the patient has high-risk papillary NMIBC having abbreviated experience with intravesical BCG therapy due to toxicity. In some embodiments, the patient has recurrent NMIBC high-grade (Tl, high-grade Ta) disease within 18 months of completion of prior BCG therapy. In some embodiments, the patient has had prior BCG-experienced comprising at least 5 of 6 full doses, where a full dose of BCG is defined as one full vial containing a minimum of 1 X 10⁸ colony forming units. In some embodiments, the patient is eligible for a radical cystectomy. In some embodiments, the patient is either ineligible for or has elected not to undergo radical cystectomy (RC). In some embodiments, the patient has refused radical cystectomy.

[0323] In some embodiments, the NMIBC is staged using the tumor, node, metastasis (TNM) staging system. In some embodiments, Ta stage bladder cancer is defined as a non- invasive papillary carcinoma. In some embodiments, Ta stage bladder cancer has grown toward the hollow center of the bladder but has not grown into the connective tissue or muscle of the bladder wall. In some embodiments, Ta stage bladder cancer is further delineated into either low-grade (LG) or high-grade (HG) subtypes, with LG referring to a slow growing, less aggressive form of the disease and HG referring to a rapidly growing, more aggressive form of the disease. In some embodiments, CIS is defined as a flat lesion comprising of cytologically malignant cells which may involve either full or partial thickness of the urothelium. In some embodiments, the NMIBC is identified by clinical staging (cTa, cTl) based on endoscopic surgery (biopsy or TURBT).

[0324] In some embodiments, the patient has undergone prior BCG therapy. In some embodiments, the prior BCG treatment comprises intravesical instillations of hundreds of millions of Mycobacterium bovis Bacillus Calmette-Calmette-Guerin bacilli applied weekly over the course of a six week induction treatment. In some embodiments, the bladder cancer is resected following the six-week BCG induction treatment. In some embodiments, the prior BCG therapy further comprises a maintenance treatment consisting of six-week periods of intravesical BCG instillation every three months for one to three years.

[0325] In some embodiments, the patient has undergone at least 5 of 6 full courses of BCG induction treatment. In some embodiments, the patient has undergone 5 courses of BCG induction treatment during the prior BCG therapy. In some embodiments, the patient has undergone at least 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 prior courses of BCG therapy. In some embodiments, the patient has undergone prior BCG therapy, where prior BCG therapy is defined as a minimum of 5 of 6 full doses, where a full dose of BCG defined as one full vial containing a minimum of 1 X 10⁸ colony forming units.

[0326] In some embodiments, the patient has an Eastern Cooperative Oncology Group (ECOG) performance status score of <2.

[0327] In some embodiments, the patient has adequate bone marrow, liver, and renal function. In some embodiments, the patient has bone marrow function without the support of growth factors or transfusions in preceding 2 weeks, where the Absolute neutrophil count (ANC) >l,000/mm³, the platelet count >75,000/mm³, and hemoglobin >8.0 g/dL. In some embodiments, the patient has liver function, where total bilirubin <1.5 x the upper limit of normal (ULN) or direct bilirubin <1.5 x ULN for participants with Gilbert’s syndrome who had total bilirubin levels >1.5 x ULN and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 x ULN. In some embodiments, the patient has renal function, where the estimated glomerular filtration rate is >30 mL/min and was calculated using the Modified Diet in Renal Disease (MDRD) formula.

[0328] In some embodiments, the bladder cancer is resected prior to administration of the drug delivery system. In some embodiments, the patient undergoes a transurethral resection of bladder tumor (TURBT) prior to administration of the drug delivery system to the bladder. In some embodiments is administered within four weeks following a TURBT. In some embodiments, the tumor is maximally resected prior to administration of the intravesical drug delivery system such that no visible tumor is present. In some embodiments, the tumor is non-maximally resected prior to administration of the intravesical drug delivery system. In some embodiments, the tumor is non-maximally resected prior to administration of the intravesical drug delivery system such that residual tumor is present.

[0329] In some embodiments, the patient has undergone a TURBT and has residual tumor at the site of resection. In some embodiments, the patient has stage Ta or T1 cancer following TURBT.

[0330] In some embodiments, two cohorts of patients are enrolled in the clinical study described herein. In some embodiments, a first cohort includes patients having recurrent, BCG-experienced high-risk papillary NMIBC (high-grade Ta/Tl). In some embodiments, the first cohort of patients have refused or are ineligible for radical cystectomy (RC). In some embodiments, the first cohort of patients are in Cohort 1 as described herein.

[0331] In some embodiments, a second cohort includes patients having IR-NMIBC, e.g., recurrent, intermediate-risk NMIBC (Ta and Tl). In some embodiments, the second cohort of patients have a previous history of only low-grade disease. In some embodiments, the second cohort of patients are in Cohort 3, where patients have recurrent IR-NMIBC. In some embodiments, patients in Cohort 3 did not undergo complete transurethral resection of bladder tumor (TURBT). Patients in Cohort 3 were required to have visible tumor.

[0332] In some embodiments, the patient or population of patients have intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) and select FGFR alterations, including newly diagnosed or recurrent patients without prior BCG treatment. In some embodiments, the patient or population of patients have recurrent IR-NMIBC without prior BCG treatment and select FGFR alterations. In some embodiments, the patient or population of patients have newly diagnosed or recurrent IR-NMIBC and select FGFR alterations, with 1 or more of the following risk factors: multiple low grade (LG) tumors, solitary LG tumor >3 cm, frequent recurrence (> 1 per year), or recurrence after prior intravesical chemotherapy. In some embodiments, the patient or population of patients have newly diagnosed or recurrent IR- NMIBC and select FGFR alterations, with multiple low grade (LG) tumors. In some embodiments, the patient or population of patients have newly diagnosed or recurrent IR- NMIBC and select FGFR alterations, with solitary LG tumor >3 cm. In some embodiments, the patient or population of patients have newly diagnosed or recurrent IR-NMIBC and select FGFR alterations, with frequent recurrence (> 1 per year). In some embodiments, the patient or population of patients have newly diagnosed or recurrent IR-NMIBC and select FGFR alterations, with recurrence after prior intravesical chemotherapy. In some embodiments, the patient or population of patients have newly diagnosed or recurrent IR-NMIBC and select FGFR alterations, with 2 or more of the following risk factors: multiple low grade (LG) tumors, solitary LG tumor >3 cm, frequent recurrence (> 1 per year), or recurrence after prior intravesical chemotherapy. In some embodiments, the patient or population of patients have undergone TURBT with complete resection of all papillary disease prior to treatment. In some embodiments, the patient or population of patients are disease-free prior to treatment. In some embodiments, the patient or population of patients have not had prior treatment with an FGFR inhibitor.

[0333] In some embodiments, the patient or population of patients have histologically confirmed diagnosis of IR-NMIBC, wherein the disease is characterized as one or more of i) Ta LG/G1 : recurrent, ii) Ta LG/G1 : primary & (multifocal or > 3 cm), or iii) Ta G2: primary or recurrent. In some embodiments, the patient or population of patients have histologically confirmed diagnosis of IR-NMIBC, wherein the disease is characterized as one or more of i) Ta LG/G1, wherein the disease is recurrent, ii) Ta LG/G1, wherein the disease is primary and multifocal or > 3 cm, or iii) Ta G2, wherein the disease is primary or recurrent. In some embodiments, the patient or population of patients further have one or more risk factors selected from the group consisting of multiple LG tumors (Ta), solitary LG tumor >3 cm, frequent recurrence (> 1 per year), and recurrence after prior intravesical chemotherapy. [0334] In some embodiments, the patient or population of patients have histologically confirmed diagnosis of IR-NMIBC, wherein the disease is characterized as one or more of i) Ta LG/G1 : recurrent, ii) Ta LG/G1 : primary & (multifocal or > 3 cm), or iii) Ta G2: primary or recurrent, wherein the patient or population of patients further have one or more risk factors selected from the group consisting of multiple LG tumors (Ta), solitary LG tumor >3 cm, frequent recurrence (> 1 per year), and recurrence after prior intravesical chemotherapy. In some embodiments, the patient or population of patients have mixed histology tumors, wherein urothelial differentiation is predominant. In some embodiments, the patient or population of patients have one or more activating tumor FGFR mutation or fusion detected either by urine or tissue testing. In some embodiments, the patient or population of patients have undergone TURBT with complete resection of all papillary disease prior to treatment. In some embodiments, the patient or population of patients are disease-free prior to treatment. In some embodiments, the patient or population of patients have not had prior treatment with an FGFR inhibitor.

Dosing Regimens [0335] The following section describes various aspects and embodiments of dosing and treatment regimens, any and all of which apply to the methods described herein.

[0336] The present application in one aspect provides a method of treating bladder cancer in a patient comprising administering erdafitinib locally to the bladder of the patient, where the erdafitinib is administered continuously for at least about 90 days at a dose of about 2 mg/day to about 4 mg/day of erdafitinib.

[0337] In some aspect, provided herein is a method of treating HR-NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib for at least about 90 days locally to the bladder of the patient, where such treatment results in a recurrence-free rate of at least 50% in a population of patients comprising, consisting of, or consisting essentially of Cohort 1 patients as described herein. In some embodiments, the method comprises administering about 2 mg/day or about 4 mg/day of erdafitinib. In some embodiments, the method comprises administering about 2 mg/day of erdafitinib. In some embodiments, the method comprises administering about 3 mg/day of erdafitinib. In some embodiments, the method comprises administering about 4 mg/day of erdafitinib. In some embodiments, the method comprises administering 2 mg/day of erdafitinib. In some embodiments, the method comprises administering 3 mg/day of erdafitinib. In some embodiments, the method comprises administering 4 mg/day of erdafitinib.

[0338] In some aspect, provided herein is a method of treating HR-NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later. In some embodiments, the method of treating results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent, BCG-experienced HR-NMIBC. In some embodiments, the second wall structure, or both the first wall structure and the second wall structure, are permeable to water. In some embodiments, the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure. In some embodiments, the two interface edges are disposed at an arc angle of 45 degrees to 90 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, in particular at an arc angle of 90 degrees. In some embodiments, the two interface edges are disposed at an arc angle of 150 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, in particular at an arc angle of 180 degrees. In some embodiments, the two interface edges are disposed at an arc angle of 125 degrees to 145 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, in particular at an arc angle of 135 degrees.

[0339] In some embodiments, the method comprises administering erdafitinib locally to the bladder for at least about 90 days of a patient, where the patient comprises, consists of, or consists essentially of a Cohort 1 patient as described herein. In some embodiments, the method comprises administering erdafitinib for at least 90 days. In some embodiments, the method comprises administering erdafitinib for about 90 days one time, two times, three times, or four times. In some embodiments, the method comprises administering erdafitinib for about 90 days at least two times. In some embodiments, the method comprises administering erdafitinib for about 90 days at least three times. In some embodiments, the method comprises administering erdafitinib for about 90 days at least four times. In some embodiments, the method comprises administering erdafitinib for about 90 days, 180 days, 270 days, or 360 days. In some embodiments, the method comprises administering erdafitinib for 1 year. In an embodiment, the administering of erdafitinib for the about 90 days period is by an intravesical drug delivery system as described herein. The next period of about 90 days is by another intravesical delivery system as described herein that is deployed in the bladder of the patient after the first intravesical drug delivery system has been removed.

[0340] In some aspects, the method comprises deploying and removing one or more drug delivery systems in a patient, where the patient comprises, consists of, or consists essentially of a Cohort 1 patient as described herein. In some embodiments, a first drug delivery system comprising erdafitinib is deployed to the bladder of the patient on day 0. In some embodiments, the first drug delivery system is removed on about day 90. In some embodiments, a second drug delivery system comprising erdafitinib is deployed to the bladder of the patient on about day 90. In some embodiments, the second drug delivery system is removed on about day 180. In some embodiments, a third drug delivery system comprising erdafitinib is deployed to the bladder of the patient on about day 180. In some embodiments, the third drug delivery system is removed on about day 270. In some embodiments, a fourth drug delivery system comprising erdafitinib is deployed to the bladder of the patient on about day 270. In some embodiments, the fourth drug delivery system is removed on about day 360.

[0341] In some aspect, provided herein is a method of treating IR-NMIBC, e.g., recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib for at least about 90 days locally to the bladder of the patient, where such treatment results in a complete response rate of at least 50% in a population of patients, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR-NMIBC. In some embodiments, the method comprises administering about 2 mg/day or about 4 mg/day of erdafitinib. In some embodiments, the method comprises administering about 2 mg/day of erdafitinib. In some embodiments, the method comprises administering about 3 mg/day of erdafitinib. In some embodiments, the method comprises administering about 4 mg/day of erdafitinib. In some embodiments, the method comprises administering 2 mg/day of erdafitinib. In some embodiments, the method comprises administering 3 mg/day of erdafitinib. In some embodiments, the method comprises administering 4 mg/day of erdafitinib.

[0342] In some aspect, provided herein is a method of treating IR-NMIBC, e.g., recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, in particular at 90 degrees. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later, wherein such treatment results in an at least 50% complete response rate in a population of patients receiving such treatment. In some embodiments, the two interface edges are disposed at an arc angle of between 45 degrees and 90 degrees, in particular at an arc angle of 90 degrees. In some embodiments, the two interface edges are disposed at an arc angle of between 150 degrees and 270 degrees, in particular at an arc angle of 180 degrees. In some embodiments, the two interface edges are disposed at an arc angle of between 125 degrees and 145 degrees, in particular at an arc angle of 135 degrees.

[0343] In some embodiments, the method comprises administering erdafitinib locally to the bladder for at least about 90 days of the patient, wherein the patient comprises, consists of, or consists essentially of a Cohort 3 patient with recurrent IR-NMIBC. In some embodiments, the method comprises administering erdafitinib for at least 90 days. In some embodiments, the method comprises administering erdafitinib for about 90 days one time, two times, three times, or four times. In some embodiments, the method comprises administering erdafitinib for about 90 days at least two times. In some embodiments, the method comprises administering erdafitinib for about 90 days at least three times. In some embodiments, the method comprises administering erdafitinib for about 90 days at least four times. In some embodiments, the method comprises administering erdafitinib for about 90 days, 180 days, 270 days, or 360 days. In some embodiments, the method comprises administering erdafitinib for 1 year. In an embodiment, the administering of erdafitinib for the about 90 days period is by an intravesical drug delivery system as described herein. The next period of about 90 days is by another intravesical delivery system as described herein that is deployed in the bladder of the patient after the first intravesical drug delivery system has been removed. [0344] In some aspects, the method comprises deploying and removing one or more drug delivery systems in a patient, wherein the patient comprises, consists of, or consists essentially of a Cohort 3 patient with recurrent IR-NMIBC. In some embodiments, a first drug delivery system comprising erdafitinib is deployed to the bladder of the patient on day 0. In some embodiments, the first drug delivery system is removed on at least about day 90. In some embodiments, a second drug delivery system comprising erdafitinib is deployed to the bladder of the patient on about day 90. In some embodiments, the second drug delivery system is removed on about day 180. In some embodiments, a third drug delivery system comprising erdafitinib is deployed to the bladder of the patient on about day 180. In some embodiments, the third drug delivery system is removed on about day 270. In some embodiments, a fourth drug delivery system comprising erdafitinib is deployed to the bladder of the patient on about day 270. In some embodiments, the fourth drug delivery system is removed on about day 360.

[0345] In some embodiments, the patient achieves a complete response (CR), when being administered about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days following a low grade papillary only recurrence. In some embodiments, the patient comprises, consists of, or consists essentially of a Cohort 3 patient with recurrent IR-NMIBC. In some embodiments, the method comprises administering about 2 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days following a low grade papillary only recurrence. In some embodiments, the method comprises administering about 3 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days following a low grade papillary only recurrence. In some embodiments, the method comprises administering about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days following a low grade papillary only recurrence. In some embodiments, patients initially achieving a complete response (CR) and completing 4 cycles, each cycle of about 90 days as described above, of treatment are eligible for retreatment. In some embodiments, patients achieving a CR following the first retreatment cycle, are able to continue treatment for a total of 4 cycles or until disease recurrence or progression, wherein each cycle is about 90 days as described above.

[0346] Because the intravesical drug delivery system is delivered locally to the bladder, upon delivery of intravesical drug delivery system, the concentration of erdafitinib present in the urine of the individual is higher than the plasma, which may be beneficial for reducing side effects of the erdafitinib. For example, local delivery of erdafitinib to the bladder may result in decreased eye problems and/or hyperphosphatemia. For example, in some embodiments, the ratio of concentration of erdafitinib in the urine of the individual to the concentration of erdafitinib in the plasma of the individual is greater than about 20: 1, greater than about 30: 1, greater than about 40: 1, greater than about 50: 1, greater than about 60: 1, greater than about 70: 1, greater than about 80: 1, greater than about 90: 1, or greater than about 100: 1. In some embodiments, the ratio of concentration of erdafitinib in the urine of the individual to the concentration of erdafitinib in the plasma of the individual is about 50: 1 to about 70: 1, about 50: 1 to about 60: 1, or about 60: 1 to about 70: 1.

[0347] In some embodiments, the ratio of mean concentration of erdafitinib in the urine for the patient population to the mean concentration of erdafitinib in the plasma for the patient population is greater than about 20: 1, greater than about 30: 1, greater than about 40: 1, greater than about 50: 1, greater than about 60: 1, greater than about 70: 1, greater than about 80: 1, greater than about 90: 1, or greater than about 100: 1. In some embodiments, the ratio of mean concentration of erdafitinib in the urine for the patient population to the mean concentration of erdafitinib in the plasma for the patient population is about 50: 1 to about 70: 1, about 50: 1 to about 60: 1, or about 60: 1 to about 70: 1.

[0348] In some embodiments, the erdafitinib is delivered to the urine in the bladder of the patient. In some embodiments, the erdafitinib is administered continuously to the bladder of the patient for at least about 90 days. In some embodiments, the erdafitinib is locally administered to the bladder for about 90 days, about 180 days, about 270 days, or about 360 days. In some embodiments, the erdafitinib is locally administered to the bladder of the patient during one or more administration periods of about 90 days. In some embodiments, the erdafitinib is locally administered to the bladder of the patient during two or more administration periods of about 90 days. In some embodiments, the erdafitinib is locally administered to the bladder of the patient during four administration periods of about 90 days. In some embodiments, there is no rest period between the two or more administration periods. In some embodiments, erdafitinib is administered for a total of about 1 year. In some embodiments, erdafitinib is administered during multiple administration periods over the course of a year. In some embodiments, each administration period is about 90 days. In some embodiments, the method comprises one, two, three, or four administration periods. In some embodiments, erdafitinib is administrated at a dose of about 2 mg/day to about 4 mg/day during the administration period. In some embodiments, an intravesical drug delivery system is retained in the bladder of the patient during the entire administration period (e.g., 90 days). In some embodiments, an intravesical drug delivery system is removed and replaced with another intravesical drug delivery system on the same day. In some embodiments, about 2 mg/day of erdafitinib is administered to the patient. In some embodiments, about 3 mg/day of erdafitinib is administered to the patient. In some embodiments, about 4 mg/day of erdafitinib is administered to the patient. In some embodiments, the method comprises administering about 2 mg/day to about 4 mg/day of erdafitinib for about 90 days at least four times. In some embodiments, the method comprises administering about 2 mg/day of erdafitinib for about 90 days at least four times. In some embodiments, the method comprises administering about 3 mg/day of erdafitinib for about 90 days at least four times. In some embodiments, the method comprises administering about 4 mg/day of erdafitinib for about 90 days at least four times. In some embodiments, administering about 2 mg/day to about 4 mg/day of erdafitinib comprises deploying an intravesical drug delivery system comprising erdafitinib to the bladder of the patient and removing the drug delivery system about 90 days later. In some embodiments, the drug delivery system comprises about 500 mg erdafitinib. In some embodiments, the formulation contained within the intravesical drug delivery system is Formula 4B as described herein, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. In some embodiments, the formulation contained within the intravesical drug delivery system is Formula 3,4 as described herein, in particular wherein the delivery system comprises AC- 4075 A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. In some embodiments, the formulation contained within the intravesical drug delivery system is Formula 4,1 as described herein, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. [0349] In some embodiments, the method comprises deploying a first drug delivery system comprising erdafitinib to the bladder of the patient on day 0; removing the first drug delivery system on about day 90; deploying a second drug delivery system comprising erdafitinib to the bladder of the patient on about day 90; removing the second drug delivery system on about day 180; deploying a third drug delivery system comprising erdafitinib to the bladder of the patient on day 180; removing the third drug delivery system on about day 270; deploying a fourth drug delivery system comprising erdafitinib to the bladder of the patient on about day 270; and removing the fourth drug delivery system on about day 360. In some embodiments, the drug delivery system comprises a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material the first and second wall structures being are one another at two interface edges and together forming a tube defining the closed drug reservoir; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure.

[0350] In other embodiments, the method of treating recurrent, BCG-experienced HR- NMIBC in a patient comprises deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later. In some embodiments, the two interface edges are disposed at an arc angle of 45 degrees to 90 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, in particular at 90 degrees, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg/day. In some embodiments, the two interface edges are disposed at an arc angle of 150 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, in particular at 180 degrees, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 4 mg/day. In some embodiments, the two interface edges are disposed at an arc angle of 125 degrees to 145 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 2.5 mg/day to about 3.5 mg/day. In some embodiments, the two interface edges are disposed at an arc angle of 135 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 3 mg/day.

[0351] In other embodiments, the method of treating recurrent, IR-NMIBC in a patient comprises deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later. In some embodiments, the two interface edges are di posed at an arc angle of 45 degrees to 90 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, in particular at 90 degrees, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg/day. In some embodiments, the two interface edges are disposed at an arc angle is 150 degrees to 270 degrees of a circumference of the tube in crosssection normal to the longitudinal axis of the tube, in particular at 180 degrees, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 4 mg/day. In some embodiments, the two interface edges are disposed at an arc angle of 125 degrees to 145 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 2.5 mg/day to about 3.5 mg/day. In some embodiments, the two interface edges are disposed at an arc angle of 135 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 3 mg/day.

[0352] In some embodiments, the method comprises administering about 2 mg/day to about 4 mg/day of erdafitinib, where administering erdafitinib comprises deploying an intravesical drug delivery system as described herein. In some embodiments, the method comprises administering about 2.5 mg/day to about 3.5 mg/day of erdafitinib, where administering erdafitinib comprises deploying an intravesical drug delivery system as described herein. In some embodiments, the method comprises administering about 2 mg/day of erdafitinib, where administering erdafitinib comprises deploying an intravesical drug delivery system as described herein. In some embodiments, the method comprises administering about 3 mg/day of erdafitinib, where administering erdafitinib comprises deploying an intravesical drug delivery system as described herein. In some embodiments, the method comprises administering about 4 mg/day of erdafitinib, where administering erdafitinib comprises deploying an intravesical drug delivery system as described herein.

[0353] In some embodiments, the two interface edges of the method described herein are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in crosssection normal to the longitudinal axis of the tube, wherein the two interface edges are disposed at an arc angle of 45 degrees to 90 degrees, 125 degrees to 145 degrees, or 150 degrees to 180 degrees. In some embodiments, the two interface edges are disposed at an arc angle of 45 degrees to 90 degrees, in particular at 90 degrees, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 2 mg/day. In some embodiments, the two interface edges are disposed at an arc angle of 125 degrees to 145 degrees, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 2.5 mg/day to about 3.5 mg/day. In some embodiments, the two interface edges are disposed at an arc angle of 135 degrees, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 3 mg/day. In some embodiments, the two interface edges are disposed at an arc angle of 150 degrees to 180 degrees, in particular at 180 degrees, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 4 mg/day.

[0354] In some embodiments, the method comprises administering erdafitinib locally to the bladder of the patient for at least about 90 days via an intravesical erdafitinib delivery system, wherein the patient is a patient having non-muscle invasive bladder cancer (NMIBC) described herein, in particular IR-NMIBC. In some embodiments, the method comprises administering the intravesical erdafitinib delivery system, wherein the intravesical erdafitinib delivery system releases about 2 mg/day of erdafitinib to about 4 mg/day of erdafitinib, in particular TAR-210-C releasing approximately 3 mg/day for up to 12 months. In some embodiments, the 12 months erdafitinib administration comprises 4 cycles of administration of an intravesical erdafitinib delivery system, wherein each cycle lasts about 90 days. In some embodiments, the intravesical erdafitinib delivery system releases about 2 mg/day of erdafitinib to about 4 mg/day of erdafitinib, in particular TAR-210-C releasing approximately 3 mg/day for at least 90 days or for about 90 days (1 cycle). In some embodiments, the method comprises administering erdafitinib for about 90 days one time, two times (180 days), three times (270 days), or four times (360 days). In some embodiments, the method comprises administering erdafitinib for about 90 days at least two times (2 cycles, 180 days). In some embodiments, the method comprises administering erdafitinib for about 90 days at least three times (3 cycles, 270 days). In some embodiments, the method comprises administering erdafitinib for about 90 days at least four times (4 cycles, 360 days). In some embodiments, the method comprises administering erdafitinib for about 90 days, 180 days, 270 days, or 360 days. In some embodiments, the method comprises administering erdafitinib for 1 year. In some embodiments, the administering of erdafitinib for the about 90 days period is by an intravesical drug delivery system, wherein the intravesical erdafitinib delivery system releases about 2 mg/day of erdafitinib to about 4 mg/day of erdafitinib, in particular TAR-210-C releasing approximately 3 mg/day as described herein. The next period of about 90 days is by another intravesical delivery system as described herein that is deployed locally to the bladder of the patient after the first intravesical drug delivery system has been removed.

[0355] In some embodiments, the method comprises administering erdafitinib locally to the bladder of the patient for at least about 12 weeks via an intravesical erdafitinib delivery system, wherein the patient is a patient having non-muscle invasive bladder cancer (NMIBC) described herein, in particular IR-NMIBC. In some embodiments, the method comprises administering the intravesical erdafitinib delivery system, wherein the intravesical erdafitinib delivery system releases about 2 mg/day of erdafitinib to about 4 mg/day of erdafitinib, in particular TAR-210-C releasing approximately 3 mg/day for up to 48 weeks. In some embodiments, the 48 weeks of erdafitinib administration comprises 4 cycles of administration of an intravesical erdafitinib delivery system, wherein each cycle lasts about 12 weeks. In some embodiments, the intravesical erdafitinib delivery system releases about 2 mg/day of erdafitinib to about 4 mg/day of erdafitinib, in particular TAR-210-C releasing approximately 3 mg/day for at least 12 weeks or for about 12 weeks (1 cycle). In some embodiments, the method comprises administering erdafitinib for about 12 weeks one time, two times (24 weeks), three times (36 weeks), or four times (48 weeks). In some embodiments, the method comprises administering erdafitinib for about 12 weeks at least two times (2 cycles, 24 weeks). In some embodiments, the method comprises administering erdafitinib for about 12 weeks at least three times (3 cycles, 36 weeks). In some embodiments, the method comprises administering erdafitinib for about 12 weeks at least four times (4 cycles, 48 weeks). In some embodiments, the method comprises administering erdafitinib for about 12 weeks, 24 weeks, 36 weeks, or 48 weeks. In some embodiments, the method comprises administering erdafitinib for 1 year. In some embodiments, the administering of erdafitinib for the about 12 weeks period is by an intravesical drug delivery system, wherein the intravesical erdafitinib delivery system releases about 2 mg/day of erdafitinib to about 4 mg/day of erdafitinib, in particular TAR-210-C releasing approximately 3 mg/day as described herein. The next period of about 12 weeks is by another intravesical delivery system as described herein that is deployed locally to the bladder of the patient after the first intravesical drug delivery system has been removed. In some embodiments, each period of 12 weeks is 12 weeks +/- 1 week. In some embodiments, each period is between about 11-13 weeks.

[0356] In some embodiments, the formulation contained within the intravesical drug delivery system is Formula 4B as described herein, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. In some embodiments, the formulation contained within the intravesical drug delivery system is Formula 3,4 as described herein, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. In some embodiments, the formulation contained within the intravesical drug delivery system is Formula 4,1 as described herein, in particular wherein the delivery system comprises AC- 4075 A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed.

[0357] In some embodiments, the drug delivery system is elastically deformable and has a bi-oval retention shape.

Endpoints

[0358] Provided herein is a method of treating HR-NMIBC, e.g., recurrent bacillus Calmette-Guerin (BCG)-experienced high-risk non-muscle invasive bladder cancer (HR- NMIBC) in a patient, where such treatment results in an improved recurrence-free (RF) rate and an improved recurrence-free survival time. In other aspects, provided herein is a method of treating IR-NMIBC, e.g., recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient, where such treatment results in an improved complete response (CR) rate and an improved duration of response (DOR) time in a population of patients receiving such treatment. In some embodiments, one or more endpoints are improved compared to standard of care. In some embodiments, the methods of treating provided herein improve one or more endpoints with an improved safety profile compared to standard of care. In some embodiments, the methods of treating provided herein improve one or more endpoints with an improved safety profile.

[0359] In some embodiments, provided herein is a method of treating high-risk nonmuscle invasive bladder cancer (HR-NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein the ratio of the concentration erdafitinib in the urine of the individual to the concentration of erdafitinib in the plasma of the individual is greater than 20: 1, greater than 30: 1, greater than 40: 1, or greater than 50: 1. In some embodiments, the HR-NMIBC is recurrent bacillus Calmette-Guerin (BCG)-experienced HR-NMIBC. In some embodiments, the erdafitinib is delivered to the urine in the bladder of the patient. In some embodiments, the concentration of erdafitinib in the urine of the individual is about 500 ng/mL to about 3,500 ng/mL. In some embodiments, the method provided herein comprises administering about 2 mg/day erdafitinib to the patient, wherein the urine concentration of erdafitinib is about 500 ng/mL to about 2000 ng/mL, about 500 ng/mL to about 1500 ng/mL, or about 1000 ng/mL to about 2000 ng/mL. In some embodiments, the method provided herein comprises administering about 4 mg/day erdafitinib to the patient, wherein the urine concentration of erdafitinib is about 1000 ng/mL to about 3500 ng/mL, about 1000 ng/mL to about 2500 ng/mL, or about 2000 ng/mL to about 3500 ng/mL. In some embodiments, the ratio of the concentration erdafitinib in the urine of the individual to the concentration of erdafitinib in the plasma of the individual is about 20: 1 to about 100: 1, 30:1 to about 80: 1, or about 40: 1 to about 60: 1. In some embodiments, the ratio of the concentration erdafitinib in the urine of the individual to the concentration of erdafitinib in the plasma of the individual is about 40:1 to about 60: 1. In some embodiments, the erdafitinib is administered continuously to the bladder of the patient for at least about 90 days, optionally wherein the erdafitinib is locally administered to the bladder for about 90 days, about 180 days, about 270 days, or about 360 days. In some embodiments, the erdafitinib is locally administered to the bladder of the patient during one or more administration periods of about 90 days, optionally wherein the erdafitinib is locally administered to the bladder of the patient during three or more, or four or more administration periods, optionally wherein there is no rest period between the administration periods.

[0360] In some embodiments, provided herein is a method of treating high-risk nonmuscle invasive bladder cancer (HR-NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein the concentration of erdafitinib in the urine is about 500 ng/mL and 3500 ng/mL. In some embodiments, the concentration of erdafitinib in the urine is about 750 ng/mL and 3250 ng/mL. In some embodiments, the HR-NMIBC is recurrent bacillus Calmette-Guerin (BCG)-experienced HR-NMIBC. In some embodiments, the erdafitinib is delivered to the urine in the bladder of the patient. In some embodiments, the concentration of erdafitinib in the urine of the individual is about 500 ng/mL to about 3,500 ng/mL. In some embodiments, the method provided herein comprises administering about 2 mg/day erdafitinib to the patient, wherein the urine concentration of erdafitinib is about 500 ng/mL to about 2000 ng/mL, about 500 ng/mL to about 1500 ng/mL, or about 1000 ng/mL to about 2000 ng/mL. In some embodiments, the method provided herein comprises administering about 4 mg/day erdafitinib to the patient, wherein the urine concentration of erdafitinib is about 1000 ng/mL to about 3500 ng/mL, about 1000 ng/mL to about 2500 ng/mL, or about 2000 ng/mL to about 3500 ng/mL. In some embodiments, the ratio of the concentration erdafitinib in the urine of the individual to the concentration of erdafitinib in the plasma of the individual is about 20: 1 to about 100: 1, 30: 1 to about 80: 1, or about 40: 1 to about 60: 1. In some embodiments, the ratio of the concentration erdafitinib in the urine of the individual to the concentration of erdafitinib in the plasma of the individual is about 40: 1 to about 60: 1. In some embodiments, the erdafitinib is administered continuously to the bladder of the patient for at least about 90 days, optionally wherein the erdafitinib is locally administered to the bladder for about 90 days, about 180 days, about 270 days, or about 360 days. In some embodiments, the erdafitinib is locally administered to the bladder of the patient during one or more administration periods of about 90 days, optionally wherein the erdafitinib is locally administered to the bladder of the patient during three or more, or four or more administration periods, optionally wherein there is no rest period between the administration periods.

[0361] In some embodiments, provided herein is a method of treating intermediate risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein the ratio of the concentration erdafitinib in the urine of the individual to the concentration of erdafitinib in the plasma of the individual is greater than 20: 1, greater than 30: 1, greater than 40: 1, or greater than 50: 1. In some embodiments, the IR-NMIBC is recurrent IR-NMIBC. In some embodiments, the erdafitinib is delivered to the urine in the bladder of the patient. In some embodiments, the concentration of erdafitinib in the urine of the individual is about 500 ng/mL to about 3,500 ng/mL. In some embodiments, the method provided herein comprises administering about 2 mg/day erdafitinib to the patient, wherein the urine concentration of erdafitinib is about 500 ng/mL to about 2000 ng/mL, about 500 ng/mL to about 1500 ng/mL, or about 1000 ng/mL to about 2000 ng/mL. In some embodiments, the method provided herein comprises administering about 4 mg/day erdafitinib to the patient, wherein the urine concentration of erdafitinib is about 1000 ng/mL to about 3500 ng/mL, about 1000 ng/mL to about 2500 ng/mL, or about 2000 ng/mL to about 3500 ng/mL. In some embodiments, the ratio of the concentration erdafitinib in the urine of the individual to the concentration of erdafitinib in the plasma of the individual is about 20: 1 to about 100: 1, 30: 1 to about 80: 1, or about 40: 1 to about 60: 1. In some embodiments, the ratio of the concentration erdafitinib in the urine of the individual to the concentration of erdafitinib in the plasma of the individual is about 40: 1 to about 60: 1. In some embodiments, the erdafitinib is administered continuously to the bladder of the patient for at least about 90 days, optionally wherein the erdafitinib is locally administered to the bladder for about 90 days, about 180 days, about 270 days, or about 360 days. In some embodiments, the erdafitinib is locally administered to the bladder of the patient during one or more administration periods of about 90 days, optionally wherein the erdafitinib is locally administered to the bladder of the patient during three or more, or four or more administration periods, optionally wherein there is no rest period between the administration periods.

[0362] In some embodiments, provided herein is a method of treating intermediate risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein the concentration of erdafitinib in the urine is about 500 ng/mL and 3500 ng/mL. In some embodiments, the IR-NMIBC is recurrent IR-NMIBC. In some embodiments, the erdafitinib is delivered to the urine in the bladder of the patient. In some embodiments, the concentration of erdafitinib in the urine of the individual is about 500 ng/mL to about 3,500 ng/mL. In some embodiments, the method provided herein comprises administering about 2 mg/day erdafitinib to the patient, wherein the urine concentration of erdafitinib is about 500 ng/mL to about 2000 ng/mL, about 500 ng/mL to about 1500 ng/mL, or about 1000 ng/mL to about 2000 ng/mL. In some embodiments, the method provided herein comprises administering about 4 mg/day erdafitinib to the patient, wherein the urine concentration of erdafitinib is about 1000 ng/mL to about 3500 ng/mL, about 1000 ng/mL to about 2500 ng/mL, or about 2000 ng/mL to about 3500 ng/mL. In some embodiments, the ratio of the concentration erdafitinib in the urine of the individual to the concentration of erdafitinib in the plasma of the individual is about 20: 1 to about 100: 1, 30:1 to about 80: 1, or about 40: 1 to about 60: 1. In some embodiments, the ratio of the concentration erdafitinib in the urine of the individual to the concentration of erdafitinib in the plasma of the individual is about 40: 1 to about 60: 1. In some embodiments, the erdafitinib is administered continuously to the bladder of the patient for at least about 90 days, optionally wherein the erdafitinib is locally administered to the bladder for about 90 days, about 180 days, about 270 days, or about 360 days. In some embodiments, the erdafitinib is locally administered to the bladder of the patient during one or more administration periods of about 90 days, optionally wherein the erdafitinib is locally administered to the bladder of the patient during three or more, or four or more administration periods, optionally wherein there is no rest period between the administration periods.

[0363] In some embodiments, the method of treating recurrent bacillus Calmette-Guerin (BCG)-experienced high-risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient results in a recurrence-free (RF) rate of at least 50% in a population of patients receiving such treatment, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the method results in a RF rate of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% in a population of patients receiving such treatment. In some embodiments, the method results in a RF rate of at least 50%. In some embodiments, the method results in a RF rate of at least 55%. In some embodiments, the method results in a RF rate of at least 60%. In some embodiments, the method results in a RF rate of at least 65%. In some embodiments, the method results in a RF rate of at least 70%. In some embodiments, the method results in a RF rate of at least 75%. In some embodiments, the method results in a RF rate of at least 80%. In some embodiments, the method results in a RF rate of at least 85%. In some embodiments, the method results in a RF rate of between about 50% to 100%, 55% to 95%, 60% to 90%, 65% to 85%, or 70% to 75% in a population of patients receiving such treatment. In some embodiments, the method results in a RF rate of at least 75%. In some embodiments, the method results in a RF rate of at least 80%. In some embodiments, the method results in a RF rate of at least 85%. In some embodiments, the recurrence-free rate in the population of patients is about 80% for patients treated with about 2 mg/day of erdafitinib. In some embodiments, the recurrence-free rate in the population of patients is about 80% for patients treated with about 2 mg/day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the RF rate in the population of patients is 88.9% for patients treated with about 2 mg/day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the recurrence-free rate in the population of patients is about 83%, such as about 83.3%, for patients treated with about 4 mg/day of erdafitinib. In some embodiments, the recurrence-free rate in the population of patients is about 83%, such as about 83.3%, for patients treated with about 4 mg/day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the RF rate in the population of patients is 85.7% for patients treated with about 4 mg/day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the recurrence-free rate in the population of patients is about 82%, such as about 81.8%, for patients treated with about 2 mg/day to about 4 mg/day of erdafitinib. In some embodiments the recurrence-free rate is assessed at 3 months or 90 days of the erdafitinib treatment.

[0364] In some embodiments, the method of treating recurrent BCG-experienced HR- NMIBC in a patient comprises deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later, wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the RF rate in the population of patients is about 80% for patients treated with a drug delivery system comprising an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the RF rate in the population of patients is 88.9% for patients treated with a drug delivery system comprising an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent BCG-experienced HR-NMIBC. In some embodiments, the RF rate in the population of patients is about 83%, such as about 83.3%, for patients treated with a drug delivery system comprising an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the RF rate in the population of patients is 85.7% for patients treated with a drug delivery system comprising an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the RF rate in the population of patients is about 82%, such as about 81.8%, for patients treated with a drug delivery system comprising an arc angle of about 90 degrees to about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments the RF rate is assessed at 3 months or 90 days of the erdafitinib treatment. In some embodiments, the formulation contained within the intravesical drug delivery system is Formula 4B as described herein, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. In some embodiments, the formulation contained within the intravesical drug delivery system is Formula 3,4 as described herein, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. In some embodiments, the formulation contained within the intravesical drug delivery system is Formula 4,1 as described herein, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed.

[0365] In some embodiments, the RF rate in the population of patients is at least 75%, 80%, or 85% for patients treated with about 2 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient. In some embodiments, the RF rate in the population of patients is between about 50% to 100%, 55% to 95%, 60% to 90%, 65% to 85%, or 70% to 75% for patients treated with about 2 mg/day of erdafitinib locally to the bladder for about 90 days of the patient. In some embodiments, the RF rate in the population of patients is about 80% for patients treated with about 2 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days. In some embodiments the RF rate is assessed at 3 months or 90 days of the erdafitinib treatment. In some embodiments, the RF rate in the population of patients is at least 88.9% for patients treated with about 2 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent BCG-experienced HR- NMIBC. In some embodiments, the RF rate in the population of patients is about 82%, such as about 81.8%, for patients treated with about 2 mg/day to about 4 mg/day of erdafitinib. In some embodiments, the RF rate in the population of patients is about 82%, such as about 81.8%, for patients treated with about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days. In some embodiments the RF rate is assessed at 3 months or 90 days of the erdafitinib treatment.

[0366] In some embodiments, the method of treating results in a high-grade recurrence and a progressive disease rate in the population of patients treated with about 2 mg/day of erdafitinib, wherein the high-grade recurrence and the progressive disease rate is less than 20%. In some embodiments, the high-grade recurrence rate in the population of patients treated with about 2 mg/day of erdafitinib is less than 20%, 18%, 16%, 14%, or 12%. In some embodiments, the high-grade recurrence rate in the population of patients treated with about 2 mg/day of erdafitinib is between about 10% to 20%, 12% to 18%, or 14% to 16%. In some embodiments, the high-grade recurrence rate in the population of patients treated with about 2 mg/day of erdafitinib is 11.1%, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent BCG-experienced HR-NMIBC. In some embodiments, the progressive disease rate in the population of patients treated with about 2 mg/day of erdafitinib is less than 10%, 8%, 6%, 4%, 2%, or 1%. In some embodiments, the progressive disease rate in the population of patients treated with about 2 mg/day of erdafitinib is between about 0% to 10%, 2% to 8%, or 4% to 6%. In some embodiments, the progressive disease rate in the population of patients treated with about 2 mg/day of erdafitinib is 0%, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. [0367] In some embodiments, the RF rate in the population of patients is at least 75%, 80%, or 85% for patients administered about 4 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient. In some embodiments, the RF rate in the population of patients is between about 50% to 100%, 55% to 95%, 60% to 90%, 65% to 85%, or 70% to 75% for patients administered about 4 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient. In some embodiments, the RF rate in the population of patients is about 83%, such as about 83.3%, for patients treated with about 4 mg/day of erdafitinib. In some embodiments, the RF rate in the population of patients is about 83%, such as about 83.3%, for patients treated with about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days. In some embodiments the RF rate is assessed at 3 months or 90 days of the erdafitinib treatment. In some embodiments the population of patients comprises, consists of, or consists essentially of patients with recurrent BCG-experienced HR-NMIBC. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent BCG-experienced HR-NMIBC. In some embodiments, the RF rate in the population of patients is at least 85.7% for patients administered about 4 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent BCG-experienced HR-NMIBC. In some embodiments, the RF rate in the population of patients is about 82%, such as about 81.8%, for patients treated with about 2 mg/day to about 4 mg/day of erdafitinib. In some embodiments, the RF rate in the population of patients is about 82%, such as about 81.8%, for patients treated with about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days. In some embodiments the RF rate is assessed at 3 months or 90 days of the erdafitinib treatment. In some embodiments the population of patients comprises, consists of, or consists essentially of patients with recurrent BCG-experienced HR-NMIBC. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent BCG-experienced HR-NMIBC.

[0368] In some embodiments, the high-grade recurrence and progressive disease rate in the population of patients administered about 4 mg/day of erdafitinib is less than 20%. In some embodiments, the high-grade recurrence rate in the population of patients treated with about 4 mg/day of erdafitinib is less than 20%, 19%, 18%, 17%, 16%, or 15%. In some embodiments, the high-grade recurrence rate in the population of patients treated with about 4 mg/day of erdafitinib is between about 10% to 20%, 12% to 18%, or 14% to 16%. In some embodiments, the high-grade recurrence rate in the population of patients treated with about 4 mg/day of erdafitinib is less than 14.3%, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent BCG-experienced HR- NMIBC. In some embodiments, the progressive disease rate in the population of patients treated with about 4 mg/day of erdafitinib is less than 10%, 8%, 6%, 4%, 2%, or 1%. In some embodiments, the progressive disease rate in the population of patients treated with about 4 mg/day of erdafitinib is between about 0% to 10%, 2% to 8%, or 4% to 6%. In some embodiments, the progressive disease rate in the population of patients treated with about 4 mg/day of erdafitinib is 0%, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent BCG-experienced HR-NMIBC.

[0369] In some embodiments, the method of treating results in an event-free survival rate of at least 3 months. In some embodiments, the method of treating results in event free survival of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some embodiments, the method of treating results in event free survival between about 3 to 12 months, 4 to 11 months, 5 to 10 months, 6 to 9 months, or 7 to 8 months. In some embodiments, the method of treating results in event free survival of at least 6 months. In some embodiments, the method of treating results in event free survival of at least 9 months. In some embodiments, the method of treating results in event free survival of at least 12 months. In some embodiments, the method comprises administering about 2 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein such treatment results in RFS of at least 6 months, and wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent BCG-experienced HR-NMIBC. In some embodiments, the method comprises administering about 4 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein such treatment results in event free survival of at least 6 months, and wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein.

[0370] In some embodiments, the method comprises administering about 2 mg/day of erdafitinib locally to the bladder for about 90 days of the patient, wherein such treatment results in 6-month event free survival rate of at least 0.8 in the population of patients. In some embodiments, the method comprises administering about 2 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein such treatment results in 9- month event free survival rate of at least 0.8 in the population of patients. In some embodiments, the method comprises administering about 2 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein such treatment results in 12- month event free survival rate of 0.8 in the population of patients, and wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent BCG-experienced HR-NMIBC. In some embodiments, the method comprises administering about 4 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein such treatment results in 6-month event free survival rate of 0.83 in the population of patients, and wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein.

[0371] In some embodiments, the method of treating recurrent BCG-experienced HR- NMIBC in a patient results in a RF rate of about 80% for the population of patients treated with about 2 mg/day of erdafitinib and a RF rate of about 83%, such as about 83.3%, for the population of patients treated with about 4 mg/day of erdafitinib. In some embodiments, the erdafitinib is administered locally to the bladder of the patient for at least about 90 days. In some embodiments the RF rate is assessed at 3 months or 90 days of the erdafitinib treatment. In some embodiments, the method of treating recurrent BCG-experienced HR-NMIBC in a patient results in a RF rate of 88.9% for the population of patients treated with about 2 mg/day of erdafitinib and RF rate in the population of patients is 85.7% for patients treated with about 4 mg/day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent BCG-experienced HR-NMIBC. In some embodiments, the RF rate in the population of patients is about 82%, such as about 81.8%, for patients treated with about 2 mg/day to about 4 mg/day of erdafitinib. In some embodiments, the erdafitinib is administered locally to the bladder of the patient for at least about 90 days. In some embodiments the RF rate is assessed at 3 months or 90 days of the erdafitinib treatment. In some embodiments, the method of treating as described herein results in a high-grade recurrence rate and a progressive disease rate in the population of patients treated with about 2 mg/day of erdafitinib, wherein the high-grade recurrence rate is 11.1% and the progressive disease rate is 0%, and wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the method of treating as described herein results in a high-grade recurrence rate and a progressive disease rate in the population of patients treated with about 4 mg/day of erdafitinib, wherein the high-grade recurrence rate is 14.3% and the progressive disease rate is 0%, and wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the method of treating as described herein results in a 12-month event free survival rate of 0.8 in the population of patients treated with 2 mg/day of erdafitinib and 6-month event free survival rate of 0.83 in the population of patients treated with 4 mg/day of erdafitinib, and wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the patient and/or population of patients of Cohort 1 have high-grade Ta or T1 bladder cancer. In some embodiments, the patient and/or population of patients have a histologically confirmed high-grade Ta or T1 lesion. In some embodiments, the patient and/or population of patients do not have carcinoma in situ (CIS). In some embodiments, the patient and/or population of patients have recurrent high-grade Ta or T1 bladder cancer within 18 months of completion of prior BCG therapy. In some embodiments, the patient and/or population of patients have previously received at least 5 of 6 full doses of an induction course of BCG. In some embodiments, the patient and/or population of patients have high-risk papillary-only NMIBC. In some embodiments, the methods of treating described herein provides significant improvement in efficacy and safety. [0372] In some embodiments, the proportion of patients with at least one disease assessment who were free of recurrence in a population of patients treated with about 2 mg/day of erdafitinib is at least 75%, 80%, or 85%, in particular, wherein the proportion is about 80%, wherein the proportion is assessed at about 3 months or about 90 days of the erdafitinib treatment. In some embodiments, the proportion of patients with at least one disease assessment who were free of recurrence in a population of patients treated with about 2 mg/day of erdafitinib is about 80%, wherein the proportion is assessed at about 3 months or about 90 days of the erdafitinib treatment. In some embodiments, such treatment results in a 6-month recurrence-free survival rate in a population of patients treated with about 2 mg/day of erdafitinib of at least about 0.8, in particular a recurrence-free survival rate of about 0.82. In some embodiments, such treatment results in a 6-month recurrence-free survival rate in a population of patients treated with about 2 mg/day of erdafitinib of about 0.82. In some embodiments, the proportion of patients with at least one disease assessment who were free from recurrence is at least 75%, 80%, or 85 % in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the proportion is about 83%, such as about 83.3%, wherein the proportion is assessed at 3 months or 90 days of the erdafitinib treatment. In some embodiments, the proportion of patients with at least one disease assessment who were free from recurrence is about 83%, wherein the proportion is assessed at 3 months or 90 days of the erdafitinib treatment. In some embodiments, the proportion of patients with at least one disease assessment who were free from recurrence is about 83.3%, wherein the proportion is assessed at 3 months or 90 days of the erdafitinib treatment. In some embodiments, the proportion of patients with at least one disease assessment who were free from recurrence in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib is at least 75%, 80%, or 85%, in particular wherein the proportion is about 82%, such as about 81.8%, wherein the recurrence-free rate is assessed at 3 months or 90 days of the erdafitinib treatment. In some embodiments, the proportion of patients with at least one disease assessment who were free from recurrence in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib is about 82%, wherein the recurrence-free rate is assessed at 3 months or 90 days of the erdafitinib treatment. In some embodiments, the proportion of patients with at least one disease assessment who were free from recurrence in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib is about 81.8%, wherein the recurrence-free rate is assessed at 3 months or 90 days of the erdafitinib treatment.

[0373] In some embodiments, the methods of treating recurrent bacillus Calmette-Guerin (BCG)-experienced high-risk non-muscle invasive bladder cancer (HR-NMIBC) provided herein result in an improved an improved recurrence-free survival (RFS) rate. In some embodiments, the 12-month recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib is at least 75%, at least 80%, or at least 85%. In some embodiments, the 12-month recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib is at least 90%. In some embodiments, the 12-month recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day of erdafitinib is at least 75%, at least 80%, or at least 85%. In some embodiments, the 12-month recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day of erdafitinib is at least 90%. In some embodiments, the 12-month recurrence-free survival (RFS) rate in a population of patients treated with about 3 mg/day of erdafitinib is at least 75%, at least 80%, or at least 85%. In some embodiments, the 12-month recurrence-free survival (RFS) rate in a population of patients treated with about 3 mg/day of erdafitinib is at least 90%. In some embodiments, the 12- month recurrence-free survival (RFS) rate in a population of patients treated with about 4 mg/day of erdafitinib is at least 75%, at least 80%, or at least 85%. In some embodiments, the 12-month recurrence-free survival (RFS) rate in a population of patients treated with about 4 mg/day of erdafitinib is at least 90%. In some embodiments, the 12-month recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib ranges between 75 % and 90 %. In some embodiments, the 12-month recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib ranges between 80 % and 90 %. In some embodiments, the 12- month recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib ranges between 85 % and 90 %. In some embodiments, the 12-month recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib ranges between 85 % and 88 %. In some embodiments, the 12-month recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib is about 88%. In some embodiments, the 12-month recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib is about 90%. In some embodiments, the 12-month recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib is at least about 75%. In some embodiments, the 12-month recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib ranges between 75% and 80% or ranges between 78% and 80%. In some embodiments, the 12-month recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib is about 79%.

[0374] In some embodiments, the method of treating recurrent BCG-experienced HR- NMIBC in a patient results in a RF rate of about 80% for the population of patients, wherein the method of treating comprises deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, in particular at 90 degrees. In some embodiments, the RF rate in the population of patients is about 80% for patients treated with a drug delivery system comprising an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the method of treating recurrent BCG-experienced HR-NMIBC in a patient results in a RF rate of 88.9% for the population of patients. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later. In some embodiments, the RF rate in the population of patients is about 83%, such as about 83.3%, for patients treated with a drug delivery system comprising an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the RF rate in the population of patients is 85.7% for patients treated with a drug delivery system comprising an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients with recurrent BCG- experienced HR-NMIBC. In some embodiments, the RF rate in the population of patients is about 82%, such as about 81.8%, for patients treated with a drug delivery system comprising an arc angle of about 90 degrees to about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments the RF rate is assessed at 3 months or 90 days of the erdafitinib treatment. In some embodiments, the method of treating as described herein results in a high-grade recurrence rate and a progressive disease rate in the population of patients treated with a drug delivery system comprising an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the high-grade recurrence rate is 11.1% and the progressive disease rate is 0%, and wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the method of treating as described herein results in a high-grade recurrence rate and a progressive disease rate in the population of patients treated a drug delivery system comprising an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the high-grade recurrence rate is 14.3% and the progressive disease rate is 0%, and wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the method of treating as described herein results in a 12-month event free survival rate of 0.8 in the population of patients treated with a drug delivery system comprising an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube and 6-month event free survival rate of 0.83 in the population of patients treated a drug delivery system comprising an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, and wherein the population of patients comprises, consists of, or consists essentially of Cohort 1 patients as described herein. In some embodiments, the patient and/or population of patients of Cohort 1 have high-grade Ta or T1 bladder cancer. In some embodiments, the patient and/or population of patients have a histologically confirmed high-grade Ta or T1 lesion. In some embodiments, the patient and/or population of patients do not have carcinoma in situ (CIS). In some embodiments, the patient and/or population of patients have recurrent highgrade Ta or T1 bladder cancer within 18 months of completion of prior BCG therapy. In some embodiments, the patient and/or population of patients have previously received at least 5 of 6 full doses of an induction course of BCG. In some embodiments, the patient and/or population of patients have high-risk papillary-only NMIBC. In some embodiments, the methods of treating described herein provides significant improvement in efficacy and safety. [0375] In some embodiments, the method of treating recurrent, intermediate-risk nonmuscle invasive bladder cancer (IR-NMIBC) in a patient results in a complete response (CR) rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the CR rate in the population of patients is at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. In some embodiments, the method results in a complete response (CR) rate between about 50% to 100%, 55% to 95%, 60% to 90%, 65% to 85%, or 70% to 75% in a population of patients receiving such treatment. In some embodiments, the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR-NMIBC. In some embodiments, the method results in a CR rate of at least 60%. In some embodiments, the CR rate of at least 70%. In some embodiments, the method results in a CR rate of at least 80%. In some embodiments, the method results in a CR rate of at least 85%. In some embodiments, the method results in a CR rate of at least 85% at week 12 (or at 3 months) for a population of patients with IR-NMIBC. In some embodiments, the method results in a CR rate of at least 90%. In some embodiments, the method results in a CR rate of at least 90% at week 12 for a population of patients with recurrent IR-NMIBC. In some embodiments, the CR rate in the population of patients is about 75% for patients treated with about 2 mg/day erdafitinib. In some embodiments, the CR rate in the population of patients is 75% for patients treated with about 2 mg/day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein. In some embodiments, the CR rate in the population of patients is about 100% for patients treated with about 4 mg/day erdafitinib. In some embodiments, the CR rate in the population of patients is 100% for patients treated with about 4 mg/day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein. In some embodiments, the CR rate in the population of patients is about 87%, such as about 86.7%, for patients treated with about 2 mg/day to about 4 mg/day of erdafitinib. In some embodiments the CR rate is assessed at 3 months or 90 days of the erdafitinib treatment. In some embodiments the CR rate is assessed at 12 weeks. In some embodiments, the formulation contained within the intravesical drug delivery system is Formula 4B as described herein, in particular wherein the delivery system comprises AC- 4075 A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. In some embodiments, the formulation contained within the intravesical drug delivery system is Formula 3,4 as described herein, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. In some embodiments, the formulation contained within the intravesical drug delivery system is Formula 4,1 as described herein, in particular wherein the delivery system comprises AC- 4075 A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed.

[0376] In some embodiments, the method of treating recurrent, intermediate-risk nonmuscle invasive bladder cancer (IR-NMIBC) in a patient comprises , wherein the method of treatment comprises deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later., wherein such treatment results in a complete response of at least 50% in a population of patients receiving such treatment. In some embodiments, the CR rate in the population of patients is about 75% for patients treated with a drug delivery system comprising an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the CR rate in the population of patients is 75% for patients treated with a drug delivery system comprising an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR-NMIBC. In some embodiments, the CR rate in the population of patients is about 100% for patients treated with a drug delivery system comprising an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. In some embodiments, the CR rate in the population of patients is 100% for patients treated with a drug delivery system comprising an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein. In some embodiments the CR rate is assessed at 3 months or 90 days of the erdafitinib treatment.

[0377] In some embodiments, the CR rate in the population of patients is at least 65%, 70%, or 75% for patients treated with about 2 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient. In some embodiments, the CR rate in the population of patients is between about 60% to 90%, 65% to 85%, or 70% to 75% for patients treated with about 2 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient. In some embodiments, the CR rate in the population of patients is about 75% for patients treated with about 2 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days. In some embodiments, the CR rate in the population of patients is 75% for patients treated with about 2 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein. In some embodiments the CR rate is assessed at 3 months or 90 days of the erdafitinib treatment.

[0378] In some embodiments, such treatment results in a complete response (CR) rate of at least 80%, at least 85%, or at least 90% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib. In some embodiments, such treatment results in a CR rate of at least 80%, at least 85%, or at least 90% in the population of patients treated with about 2 mg/day of erdafitinib. In some embodiments, such treatment results in a CR rate of at least 80%, at least 85%, or at least 90% in the population of patients treated with about 3 mg/day of erdafitinib. In some embodiments, such treatment results in a CR rate of at least 80%, at least 85%, or at least 90% in the population of patients treated with about 4 mg/day of erdafitinib. In some embodiments, such treatment results in a CR rate of at least 80%, at least 85%, or at least 90% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular wherein the CR rate is about 93%. In some embodiments, such treatment results in a CR rate that ranges between 80% and 95% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib. In some embodiments, such treatment results in a CR rate that ranges between 85% and 95% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib. In some embodiments, such treatment results in a CR rate that ranges between 90% and 95% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib. In some embodiments, such treatment results in a CR rate of at least 80%, at least 85%, or at least 90% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib, in particular wherein the complete response rate is about 93%. In some embodiments the CR rate is assessed at 3 months or 90 days of the erdafitinib treatment.

[0379] In some embodiments, the method of treating described herein results in a low- grade recurrence, a high-grade recurrence, and a progressive disease rate in the population of patients treated with about 2 mg/day of erdafitinib, wherein the low-grade recurrence, the high-grade recurrence, and the progressive disease rate is less than 5%. In some embodiments, the low-grade recurrence rate in the population of patients treated with about 2 mg/day of erdafitinib is less than 5%, 4%, 3%, 2%, or 1%. In some embodiments, the low- grade recurrence rate in the population of patients treated with about 2 mg/day of erdafitinib is between about 0% to 10%, 2% to 8%, or 4% to 6%. In some embodiments, the low-grade recurrence rate in the population of patients treated with about 2 mg/day of erdafitinib is 0%, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR-NMIBC. In some embodiments, the high-grade recurrence rate in the population of patients treated with about 2 mg/day of erdafitinib is less than 5%, 4%, 3%, 2%, or 1%. In some embodiments, the high-grade recurrence rate in the population of patients treated with about 2 mg/day of erdafitinib is between about 0% to 10%, 2% to 8%, or 4% to 6%. In some embodiments, the high-grade recurrence rate in the population of patients treated with about 2 mg/day of erdafitinib is 0%, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein. In some embodiments, the progressive disease rate in the population of patients treated with about 2 mg/day of erdafitinib is less than 5%, 4%, 3%, 2%, or 1%. In some embodiments, the progressive disease rate in the population of patients treated with about 2 mg/day of erdafitinib is between about 0% to 10%, 2% to 8%, or 4% to 6%. In some embodiments, the progressive disease rate in the population of patients treated with about 2 mg/day of erdafitinib is 0%, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein.

[0380] In some embodiments, the CR rate in the population of patients is at least 80%, 85%, 90%, or 95% for patients treated with about 4 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient. In some embodiments, the CR rate in the population of patients is between about 70% to 100%, 75% to 95%, or 80% to 90% for patients treated with about 4 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient. In some embodiments, the CR rate in the population of patients is about 100% for patients treated with about 4 mg/day erdafitinib locally to the bladder of the patient for at least about 90 days. In some embodiments, the CR rate in the population of patients is 100% for patients treated with about 4 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR-NMIBC. In some embodiments the CR rate is assessed at 3 months or 90 days of the erdafitinib treatment.

[0381] In some embodiments, the method of treating described herein results in a low- grade recurrence, a high-grade recurrence, and a progressive disease rate in the population of patients treated with about 4 mg/day of erdafitinib, wherein the low-grade recurrence, the high-grade recurrence, and the progressive disease rate is less than 5%. In some embodiments, the low-grade recurrence rate in the population of patients treated with about 4 mg/day of erdafitinib is less than 5%, 4%, 3%, 2%, or 1%. In some embodiments, the low- grade recurrence rate in the population of patients treated with about 4 mg/day of erdafitinib is between about 0% to 10%, 2% to 8%, or 4% to 6%. In some embodiments, the low-grade recurrence rate in the population of patients treated with about 4 mg/day of erdafitinib is 0%, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR-NMIBC. In some embodiments, the high-grade recurrence rate in the population of patients treated with about 4 mg/day of erdafitinib is less than 5%, 4%, 3%, 2%, or 1%. In some embodiments, the high-grade recurrence rate in the population of patients treated with about 4 mg/day of erdafitinib is between about 0% to 10%, 2% to 8%, or 4% to 6%. In some embodiments, the high-grade recurrence rate in the population of patients treated with about 4 mg/day of erdafitinib is 0%, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein. In some embodiments, the progressive disease rate in the population of patients treated with about 4 mg/day of erdafitinib is less than 5%, 4%, 3%, 2%, or 1%. In some embodiments, the progressive disease rate in the population of patients treated with about 4 mg/day of erdafitinib is between about 0% to 10%, 2% to 8%, or 4% to 6%. In some embodiments, the progressive disease rate in the population of patients treated with about 4 mg/day of erdafitinib is 0%, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein.

[0382] In some embodiments, the method results in a duration of response (DOR) of at least 3 months. In some embodiments, the method results in a DOR of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some embodiments, the method results in a DOR of about 12 months. In some embodiments, the method results in a DOR between about 3 to 12 months, 4 to 11 months, 5 to 10 months, 6 to 9 months, or 7 to 8 months. In some embodiments, the method results in a DOR between about 3 to 12 months. In some embodiments, the method results in a DOR of at least 6 months. In some embodiments, the method results in a DOR of at least 9 months. In some embodiments, the method results in a DOR of at least 12 months. In some embodiments, the method results in a DOR of about 12 months. In some embodiments, the method comprises administering about 2 mg/day of erdafitinib for at least about 90 days locally to the bladder of the patient, wherein such treatment results in a DOR of at least 6 months, and wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR-NMIBC. In some embodiments, the method comprises administering about 4 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein such treatment results in a DOR of at least 6 months, and wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein. In some embodiments, the method comprises administering about 2 mg/day of erdafitinib for at least about 90 days locally to the bladder of the patient, wherein such treatment results in a DOR of at least 12 months or is about 12 months, and wherein the population of patients comprises, consists of, or consists essentially of patients with recurrent IR-NMIBC, in particular Cohort 3 patients as described herein.. In some embodiments, the method comprises administering about 4 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein such treatment results in a DOR of at least 12 months or is about 12 months, and wherein the population of patients comprises, consists of, or consists essentially of patients with recurrent IR-NMIBC, in particular Cohort 3 patients as described herein.

[0383] In some embodiments, the method comprises administering about 2 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein such treatment results in 6-month DOR rate of at least 0.8, 0.85, 0.9, or 0.95 in the population of patients. In some embodiments, the method comprises administering about 2 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein such treatment results in a median duration of response of at least 12 months, or is about 12 months. In some embodiments, the method comprises administering about 2 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein such treatment results in 6-month DOR rate between about 0.7 to 1.0, 0.75 to 0.95, or 0.8 to 0.9 in the population of patients. In some embodiments, the method comprises administering about 2 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein such treatment results in 6-month DOR rate of 1.00 in the population of patients, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR-NMIBC. In some embodiments, the method comprises administering about 4 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein such treatment results in 6-month DOR rate of at least 0.8, 0.85, 0.9, or 0.95 in the population of patients. In some embodiments, the method comprises administering about 4 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein such treatment results in a median duration of response of at least 12 months or is about 12 months. In some embodiments, the method comprises administering about 4 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein such treatment results in 6-month DOR rate of between about 0.7 to 1.0, 0.75 to 0.95, or 0.8 to 0.9 in the population of patients. In some embodiments, the method comprises administering about 4 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient, wherein such treatment results in 6-month DOR rate of 1.00 in the population of patients, wherein the population of p patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein.

[0384] In some embodiments, the CR rate in the population of patients is about 75% for patients treated with about 2 mg/day erdafitinib. In some embodiments, the CR rate in the population of patients is about 100% for patients treated with about 4 mg/day erdafitinib. In some embodiments, the method of treating recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient results in a CR rate of 75% for the population of patients treated with about 2 mg/day of erdafitinib and CR rate in the population of patients is 100% for patients treated with about 4 mg/day of erdafitinib, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR- NMIBC. In some embodiments, the CR rate in the population of patients is about 87%, such as about 86.7%, for patients treated with about 2 mg/day to about 4 mg/day of erdafitinib. In some embodiments the CR rate is assessed at 3 months or 90 days of the erdafitinib treatment. In some embodiments, the method of treating as described herein results in a low- grade recurrence rate, a high-grade recurrence rate, and a progressive disease rate in the population of patients treated with about 2 mg/day of erdafitinib, wherein the low-grade recurrence rate is 0%, the high-grade recurrence rate is 0% and the progressive disease rate is 0%, and wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein. In some embodiments, wherein the population of patients treated with about 4 mg/day of erdafitinib, the low-grade recurrence rate is 0%, the high-grade recurrence rate is 0% and the progressive disease rate is 0%, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR-NMIBC. In some embodiments, the method as described herein results in 6- month DOR rate of 1.00 in the population of patients treated with 2 mg/day of erdafitinib or 4 mg/day of erdafitinib, wherein each population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein. In some embodiments, the patient and/or population of patients of Cohort 3 have a history of only low-grade disease. In some embodiments, the patient and/or population of patients have intermediate risk papillary disease. In some embodiments, the patient and/or population of patients have not previously had carcinoma in situ. In some embodiments, the patient and/or population of patients have visible disease at the time that the erdafitinib is administered. In some embodiments, the patient and/or population of patients have Ta or T1 bladder cancer. In some embodiments, the patient and/or population of patients have not undergone TURBT prior to administering the erdafitinib. In some embodiments, the methods of treating described herein provides significant improvement in efficacy and safety compared to current standard of care.

[0385] In some embodiments, the method of treating recurrent, intermediate-risk nonmuscle invasive bladder cancer (IR-NMIBC) in a patient results in a CR rate of about 75% for the population of patients treated with a drug delivery system, wherein the method of treating comprises deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, in particular at 90 degrees. In some embodiments, the method of treating comprises releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the method of treating comprises removing the drug delivery system at least about 90 days later. In some embodiments, the CR rate in the population of patients is about 100% for patients treated with a drug delivery system comprising an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, e.g., wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR-NMIBC. In some embodiments the CR rate is assessed at 3 months or 90 days of the erdafitinib treatment. In some embodiments, the method of treating as described herein results in a low-grade recurrence rate, a high-grade recurrence rate, and a progressive disease rate in the population of patients treated with a drug delivery system comprising an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the low-grade recurrence rate is 0%, the high-grade recurrence rate is 0% and the progressive disease rate is 0%, and wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein. In some embodiments, wherein the population of patients treated with a drug delivery system comprising an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, the low-grade recurrence rate is 0%, the high-grade recurrence rate is 0% and the progressive disease rate is 0%, wherein the population of patients comprises, consists of, or consists essentially of Cohort 3 patients with recurrent IR-NMIBC. In some embodiments, the method as described herein results in 6-month DOR rate of 1.00 in the population of patients treated with a drug delivery system comprising an arc angle of about 90 degrees or 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein each population of patients comprises, consists of, or consists essentially of Cohort 3 patients as described herein. In some embodiments, the patient and/or population of patients have a history of only low-grade disease. In some embodiments, the patient and/or population of patients have intermediate risk papillary disease. In some embodiments, the patient and/or population of patients have not previously had carcinoma in situ. In some embodiments, the patient and/or population of patients have visible disease at the time that the erdafitinib is administered. In some embodiments, the patient and/or population of patients have Ta or T1 bladder cancer. In some embodiments, the patient and/or population of patients have not undergone TURBT prior to administering the erdafitinib. In some embodiments, the methods of treating described herein provides significant improvement in efficacy and safety.

[0386] In some aspects, the methods provided herein for treating non-muscle invasive bladder cancer (NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient are associated with low-grade treatment-emergent adverse effects (TEAEs) comprising haematuria, dysuria, and urinary tract infection. In some embodiments, the most common TEAE were Grade < 2 and were associated with lower urinary tract symptoms. In some embodiments, such treatment results in TEAEs in no more than about 80%, 70%, 60%, or 50% of patients receiving such treatment. In some embodiments, such treatment results in TEAEs in no more than about 50% to 80%, 55% to 75%, or 60% to 70% of patients receiving such treatment. In some embodiments, such treatment results in TEAEs in 62.8% of patients receiving such treatment. In some embodiments, such treatment results in serious TEAEs in no more than about 10%, 8%, 6%, or 4% of patients receiving such treatment. In some embodiments, such treatment results in serious TEAEs in between about 0% to 10%, 2% to 8%, or 4% to 6% of patients receiving such treatment. In some embodiments, such treatment results in serious TEAEs in 4.7% of patients receiving such treatment. In some embodiments, serious TEAEs were not reporting in more than one patient. In some embodiments, such treatment results in Grade >=3 TEAEs in 4.7% of patients receiving such treatment. In some embodiments, such treatment results in Grade >=3 TEAEs in no more than 5% of patients receiving such treatment. In some embodiments, Grade >=3 TEAEs were not reporting in more than one patient.

[0387] In some embodiments, the methods provided herein for treating non-muscle invasive bladder cancer (NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder for at least about 90 days of the patient resulted in no (zero) dose-limiting toxicities (DLT) and no (zero) deaths. In some embodiments, no more than about 5% of patients discontinued study treatment. In some embodiments, about 4.7% of patients discontinued study treatment.

FGFR Genetic Alterations

[0388] As used herein, “FGFR genetic alteration” refers to an alteration in the wild type FGFR gene, including, but not limited to, FGFR fusion genes, FGFR mutations, FGFR amplifications, or any combination thereof, in particular FGFR fusion genes, FGFR mutations, or any combination thereof. In certain embodiments, the FGFR2 or FGFR3 genetic alteration is an FGFR gene fusion. “FGFR fusion” or “FGFR gene fusion” refers to a gene encoding a portion of FGFR (e.g., FGRF2 or FGFR3) and one of the herein disclosed fusion partners, or a portion thereof, created by a translocation between the two genes. The terms “fusion” and “translocation” are used interchangeable herein. The presence of one or more of the following FGFR fusion genes in a biological sample from a patient can be determined using the disclosed methods or uses or by methods known to those of ordinary skill in the art : FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof. In certain embodiments, FGFR3-TACC3 is FGFR3-TACC3 variant 1 (FGFR3-TACC3 VI) or FGFR3-TACC3 variant 3 (FGFR3-TACC3 V3). Table A provides the FGFR fusion genes and the FGFR and fusion partner exons that are fused. The sequences of the individual FGFR fusion genes are disclosed in Table A2. The underlined sequences correspond to either FGFR3 or FGFR2, the sequences represent the fusion partners.

Table A

Table A2

[0389] FGFR genetic alterations include FGFR single nucleotide polymorphism (SNP). “FGFR single nucleotide polymorphism” (SNP) refers to a FGFR2 or FGFR3 gene in which a single nucleotide differs among individuals. In certain embodiments, the FGFR2 or FGFR3 genetic alteration is an FGFR3 gene mutation. In particular, “FGFR single nucleotide polymorphism” (SNP) refers to a FGFR3 gene in which a single nucleotide differs among individuals. The presence of one or more of the following FGFR SNPs in a biological sample from a patient can be determined by methods known to those of ordinary skill in the art or methods disclosed in WO 2016/048833, FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, FGFR3 Y373C, or any combination thereof. The sequences of the FGFR SNPs are provided in Table B.

Table B

Sequences correspond to nucleotides 920-1510 of FGFR3 (Genebank ID # NM_000142.4).

Nucleotides in bold underline represent the SNP.

*Sometimes mistakenly referred to as Y375C in the literature.

[0390] In certain embodiments, the methods of or uses for treating an urothelial carcinoma as described herein comprise, consist of, or consist essentially of administering the drug delivery system as described herein to a patient that has been diagnosed with an urothelial carcinoma as described herein and harbors at least one FGFR2 genetic alteration and/or FGFR3 genetic alteration (i.e., one or more FGFR2 genetic alteration, one or more FGFR3 genetic alteration, or a combination thereof). In certain embodiments, the at least one FGFR2 genetic alteration and/or FGFR3 genetic alteration (i.e., one or more FGFR2 genetic alteration, one or more FGFR3 genetic alteration, or a combination thereof) is selected from R248C, S249C, G370C, Y373C, FGFR3-TACC3 (for example FGFR3-TACC3vl or FGFR3-TACC3v3), FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof. In certain embodiments, the at least one FGFR2 genetic alteration and/or FGFR3 genetic alteration (i.e., one or more FGFR2 genetic alteration, one or more FGFR3 genetic alteration, or a combination thereof) is selected from R248C, S249C, G370C, Y373C, FGFR3-TACC3 (for example FGFR3-TACC3vl or FGFR3-TACC3v3), FGFR3- BAIAP2L1, or any combination thereof. In certain embodiments, the at least one FGFR2 genetic alteration and/or FGFR3 genetic alteration (i.e., one or more FGFR2 genetic alteration, one or more FGFR3 genetic alteration, or a combination thereof) is selected from R248C, S249C, G370C, Y373C, FGFR3-TACC3 (for example FGFR3-TACC3vl or FGFR3-TACC3v3), or any combination thereof. In certain embodiments, the at least one FGFR2 genetic alteration and/or FGFR3 genetic alteration (i.e., one or more FGFR2 genetic alteration, one or more FGFR3 genetic alteration, or a combination thereof) is selected from R248C, S249C, G370C, Y373C, FGFR3-TACC3vl, FGFR3-TACC3v3, or any combination thereof. In certain embodiments, the FGFR2 genetic alteration and/or FGFR3 genetic alteration is an FGFR3 gene mutation, FGFR2 gene fusion, or FGFR3 gene fusion. In certain embodiments, the FGFR2 genetic alteration and/or FGFR3 genetic alteration is a FGFR3 genetic alteration. In certain embodiments, the FGFR2 genetic alteration and/or FGFR3 genetic alteration is an FGFR3 gene mutation or FGFR3 gene fusion. In some embodiments, the FGFR3 gene mutation is R248C, S249C, G370C, Y373C, or any combination thereof. In still further embodiments, the FGFR2 or FGFR3 gene fusion is FGFR3-TACC3, FGFR3- BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof. In some embodiments, the FGFR2 or FGFR3 gene fusion is FGFR3-TACC3, FGFR3-BAIAP2L1, or any combination thereof. In some embodiments, the FGFR2 or FGFR3 gene fusion is FGFR3-TACC3vl, FGFR3-TACC3v3, FGFR3-BAIAP2L1, or any combination thereof. In some embodiments, the FGFR2 or FGFR3 gene fusion is FGFR3-TACC3. In some embodiments, the FGFR2 or FGFR3 gene fusion is FGFR3-TACC3vl or FGFR3-TACC3v3. [0391] Also described herein are methods or uses of treating an urothelial carcinoma as described herein comprising, consisting of, or consisting essential of: (a) evaluating a biological sample from a patient with an urothelial carcinoma as described herein for the presence of one or more FGFR gene alterations, in particular one or more FGFR2 or FGFR3 gene alterations; and (b) administering a drug delivery system as described herein to the patient if one or more FGFR gene alterations, in particular one or more FGFR2 or FGFR3 gene alterations, is present in the sample. [0392] The following methods for evaluating a biological sample for the presence of one or more FGFR genetic alterations apply equally to any of the above disclosed methods of treatment and uses.

[0393] Suitable methods for evaluating a biological sample for the presence of one or more FGFR genetic alterations are described herein and in WO 2016/048833 and U.S. Patent Application Serial No. 16/723,975, which are incorporated herein in their entireties. For example, and without intent to be limiting, evaluating a biological sample for the presence of one or more FGFR genetic alterations can comprise any combination of the following steps: isolating RNA from the biological sample; synthesizing cDNA from the RNA; and amplifying the cDNA (preamplified or non-preamplified). In some embodiments, evaluating a biological sample for the presence of one or more FGFR genetic alterations can comprise: amplifying cDNA from the patient with a pair of primers that bind to and amplify one or more FGFR genetic alterations; and determining whether the one or more FGFR genetic alterations are present in the sample. In some aspects, the cDNA can be pre-amplified. In some aspects, the evaluating step can comprise isolating RNA from the sample, synthesizing cDNA from the isolated RNA, and pre-amplifying the cDNA.

[0394] Suitable primer pairs for performing an amplification step include, but are not limited to, those disclosed in WO 2016/048833, as exemplified below in Table C:

Table C

[0395] The presence of one or more FGFR genetic alterations can be evaluated at any suitable time point including upon diagnosis, following tumor resection, following first-line therapy, during clinical treatment, or any combination thereof.

[0396] The methods and uses can further comprise evaluating the presence of one or more FGFR genetic alterations in the biological sample before the administering step.

[0397] The diagnostic tests and screens are typically conducted on a biological sample selected from blood, lymph fluid, bone marrow, a solid tumor sample, or any combination thereof. In certain embodiments, the biological sample is a solid tumor sample. In certain embodiments, the biological sample is a blood sample, or a urine sample.

[0398] Methods of identification and analysis of genetic alterations and up-regulation of proteins are known to a person skilled in the art. Screening methods could include, but are not limited to, standard methods such as reverse-transcriptase polymerase chain reaction (RT PCR) or in-situ hybridization such as fluorescence in situ hybridization (FISH).

[0399] Identification of an individual carrying a genetic alteration in FGFR, in particular an FGFR genetic alteration as described herein, may mean that the patient would be particularly suitable for treatment with erdafitinib. Tumors may preferentially be screened for presence of a FGFR variant prior to treatment. The screening process will typically involve direct sequencing, oligonucleotide microarray analysis, or a mutant specific antibody. In addition, diagnosis of tumor with such genetic alteration could be performed using techniques known to a person skilled in the art and as described herein such as RT-PCR, FISH, next-generation sequencing (NGS). [0400] In addition, genetic alterations of, for example FGFR, can be identified by direct sequencing of, for example, tumor biopsies using PCR and methods to sequence PCR products directly as hereinbefore described. The skilled artisan will recognize that all such well-known techniques for detection of the over expression, activation or mutations of the aforementioned proteins could be applicable in the present case.

[0401] In screening by RT-PCR, the level of mRNA in the tumor is assessed by creating a cDNA copy of the mRNA followed by amplification of the cDNA by PCR. Methods of PCR amplification, the selection of primers, and conditions for amplification, are known to a person skilled in the art. Nucleic acid manipulations and PCR are carried out by standard methods, as described for example in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc., or Innis, M.A. et al., eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al., (2001), 3^rd Ed, Molecular Cloning: A Laboratory Manual, Cold spring Harbor Laboratory Press. Alternatively, a commercially available kit for RT-PCR (for example Roche Molecular Biochemicals) may be used, or methodology as set forth in United States patents 4,666,828; 4,683,202; 4,801,531; 5,192,659, 5,272,057, 5,882,864, and 6,218,529 and incorporated herein by reference. An example of an in-situ hybridization technique for assessing mRNA expression would be fluorescence in-situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152: 649).

[0402] Generally, in situ hybridization comprises the following major steps: (1) fixation of tissue to be analyzed; (2) prehybridization treatment of the sample to increase accessibility of target nucleic acid, and to reduce nonspecific binding; (3) hybridization of the mixture of nucleic acids to the nucleic acid in the biological structure or tissue; (4) post-hybridization washes to remove nucleic acid fragments not bound in the hybridization, and (5) detection of the hybridized nucleic acid fragments. The probes used in such applications are typically labelled, for example, with radioisotopes or fluorescent reporters. Preferred probes are sufficiently long, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to enable specific hybridization with the target nucleic acid(s) under stringent conditions. Standard methods for carrying out FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M. S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2^nd ed.; ISBN: 1-59259-760-2; March 2004, pps. 077-088; Series: Methods in Molecular Medicine. [0403] Methods for gene expression profiling are described by (DePrimo et al. (2003), BMC Cancer, 3:3). Briefly, the protocol is as follows: double-stranded cDNA is synthesized from total RNA Using a (dT)24 oligomer (SEQ ID NO: 38 : tttttttttt tttttttttt tttt) for priming first-strand cDNA synthesis, followed by second strand cDNA synthesis with random hexamer primers. The double-stranded cDNA is used as a template for in vitro transcription of cRNA using biotinylated ribonucleotides. cRNA is chemically fragmented according to protocols described by Affymetrix (Santa Clara, CA, USA), and then hybridized overnight on Human Genome Arrays.

[0404] Alternatively, the protein products expressed from the mRNAs may be assayed by immunohistochemistry of tumor samples, solid phase immunoassay with microtitre plates, Western blotting, 2-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and other methods known in the art for detection of specific proteins. Detection methods would include the use of site-specific antibodies. The skilled person will recognize that all such well-known techniques for detection of upregulation of FGFR or detection of FGFR variants or mutants could be applicable in the present case.

[0405] Abnormal levels of proteins such as FGFR can be measured using standard enzyme assays, for example, those assays described herein. Activation or overexpression could also be detected in a tissue sample, for example, a tumor tissue, by measuring the tyrosine kinase activity with an assay such as that from Chemicon International. The tyrosine kinase of interest would be immunoprecipitated from the sample lysate and its activity measured.

[0406] Alternative methods for the measurement of the over expression or activation of FGFR including the isoforms thereof, include the measurement of microvessel density. This can for example be measured using methods described by Orre and Rogers (Int J Cancer (1999), 84(2) 101-8). Assay methods also include the use of markers.

[0407] Therefore, all of these techniques could also be used to identify tumors particularly suitable for treatment with the drug delivery systems of the invention.

[0408] According to certain embodiments, FGFR2 and/or FGFR3 genetic alterations can be identified using commercially available kits including, but not limiting to, a QIAGEN therascreen® FGFR RGQ RT-PCR kit.

[0409] According to certain embodiments, FGFR2 and/or FGFR3 genetic alterations can be identified in a liquid biological sample of the cancer patient, e.g., a urine sample.

Exfoliated urothelial bladder cancer cells can enter die urine. [0410] According to certain embodiments, the analytes that can be used for FGFR genetic alteration screening or detection in urine include pellet DNA, cell-free DNA (cfDNA), non- coding-RNA, exfoliated tumor cells, proteins.

[0411] According to certain embodiments, cfDNA can be analyzed in urine samples by ultracentrifugation or by molecular weight-based DNA separation techniques. For example, DNA extraction from urine samples can be performed with the QIAamp DNA Blood Mini Kit (Qiagen, Valencia, CA, USA) according to the manufacturer’s instructions. The extracted cfDNA can be amplified and analyzed using the various procedures that include the polymerase chain reaction (PCR) and/or gene sequencing.

[0412] According to certain embodiments, urine-based molecular profiling can be performed using available kits including, but not limiting to, PCR and NGS assays. Nonlimiting examples of available kits include: Urodiag® PCR Kit, which includes a mutation assay MASO (“Mutated Allele Specific Oligonucleotide)-PCR; AssureMDX which is a urine-based test, that studies e.g,, mutations in FGFR3; PredicineCARE^iM, a urine cfDNA- based targeted NGS assay.

[0413] In certain embodiments, a method of administering a drug to a patient includes inserting a drug delivery system as described herein into a patient and permitting the drug to be released from the system. For example, the system may include any features, or combinations of features, described herein. In one embodiment, the drug is released from the drug reservoir lumen via diffusion through the second material of the wall structure. In certain embodiments, a release profile of the drug is substantially independent of pH over a pH range of 5 to 7. In certain embodiments, a release profile of the drug is substantially independent of pH over a pH range of 5.5 to 7. In certain embodiments, a release profile of the drug is substantially independent of pH over a pH range of 5.5 to 8.

[0414] In certain embodiments, permitting the drug to be released from the system includes permitting water to be imbibed through the water permeable wall portions (e.g., through only the second wall structure/second material or through both the first and second wall structures/materials to solubilize the drug), and permitting the solubilized drug to be released from the system by diffusion through the second wall structure/material. That is, in certain embodiments, elution of drug from the system occurs following dissolution of the drug within the system. Bodily fluid enters the system, contacts the drug and solubilizes the drug, and thereafter the dissolved drug diffuses from the system. For example, the drug may be solubilized upon contact with urine in cases in which the system is inserted into the bladder. In one embodiment, releasing the drug from the system includes solubilizing the drug with water or an aqueous medium, such as for example urine, imbibed through the second wall structure/material, or both the first and second wall structures/materials.

[0415] In some embodiments, the device constituent of the system comprises a water- permeable and drug-impermeable base material and a water- and drug-permeable stripe material. For example, the base material may be a TPU such as Lubrizol’s Carbothane™ AC-4075 A or Tecothane™ AR-75A, and the stripe material may be a TPU such as a Lubrizol TECOFLEX™ TPU, such as EG-80A. (Lubrizol Life Science (Bethlehem, PA)).

[0416] In certain embodiments, the inserting comprises deploying the system through the patient’s urethra and into the patient’s urinary bladder. The system may release drug for several days, weeks, months, or more after the implantation procedure has ended. In one embodiment, deploying the drug delivery system in the patient includes inserting the system into a body cavity or lumen of the patient via a deployment instrument. For example, the system may be deployed through a deployment instrument, such as a catheter or cystoscope, positioned in a natural lumen of the body, such as the urethra, or into a body cavity, such as the bladder. The deployment instrument typically is removed from the body lumen while the drug delivery system remains in the bladder or other body cavity for a prescribed treatment period.

[0417] In one example, the system is deployed by passing the drug delivery system through a deployment instrument and releasing the system from the deployment instrument into the body of the patient, e.g., in a body cavity such as the bladder. In embodiments, the system assumes a retention shape, such as an expanded or higher profile shape, once the system emerges from the deployment instrument into the cavity. The deployment instrument may be a commercially available system or a system specially adapted for the present drug delivery systems. In one embodiment, deploying the drug delivery system in the patient includes (i) elastically deforming the system into the relatively straightened shape; (ii) inserting the system through the patient’s urethra; and (iii) releasing the system into the patient’s bladder such that it assumes a coiled retention shape.

[0418] The drug delivery system may be passed through the deployment instrument, for example driven by a stylet, typically with aid of a lubricant, until the drug delivery system exits a lumen of the instrument and passes into the bladder.

[0419] In particular embodiments, the drug delivery systems described herein are deployed into a patient’s bladder transurethrally using a Urinary Placement Catheter, which comprises two components: a catheter-like shaft and a stylet that fits inside the shaft. The shaft may include a single lumen extrusion with an atraumatic distal tip that includes a Coude bend, an exit port near the distal tip, and an internal lumen that extends from the exit port to an open proximal end. Depth markings on the shaft indicate insertion depth and orientation of the Coude tip to assist with the intravesical drug delivery system insertion procedure. The stylet is a single lumen extrusion and is used to advance the drug delivery system through the clear shaft lumen and into the bladder.

[0420] Once deployed in vivo, the system subsequently releases the drug (e.g., erdafitinib) for the treatment of one or more conditions or diseases, locally to tissues at the deployment site. The release is controlled to release the drug in an effective amount over an extended period. Thereafter, the system may be removed, resorbed, excreted, or some combination thereof. In certain embodiments, the system resides in the bladder releasing the drug over a predetermined period, such as two weeks, three weeks, four weeks, a month, two months, three months or more.

[0421] The deployed system releases a desired quantity of drug over a desired, predetermined period. In embodiments, the system can deliver the desired dose of drug over an extended period, such as 12 hours, 24 hours, 2 days, 3 days, 5 days, 7 days, 10 days, 14 days, or 20, 25, 30, 45, 60, or 90 days, 6 months, or more. The rate of delivery and dosage of the drug can be selected depending upon the drug being delivered and the disease or condition being treated. In one embodiment, a rate of release of the drug from the drug delivery system is zero order over at least 36 hours. In one embodiment, a rate of the release of the drug from the drug delivery system is essentially zero order over at least 7 days, two weeks, three weeks, four weeks, a month, two months, three months or more.

[0422] Subsequently, the system may be retrieved from the body, such as in cases in which the system is non-bioerodible or otherwise needs to be removed. Retrieval systems for this purpose are known in the art or can be specially produced. The system also may be completely or partially bioerodible, resorbable, or biodegradable, such that retrieval is unnecessary, as either the entire system is resorbed or the system sufficiently degrades for expulsion, for example, from the bladder during urination. The system may not be retrieved or resorbed until some of the drug, or preferably most or all of the drug, has been released. If needed, a new drug-loaded system may subsequently be implanted, during the same procedure as the retrieval or at a later time.

Methods of Making the Drug Delivery System

[0423] The systems described herein generally are formed by using a co-extrusion or 3D- printing process to form the elongated, elastic housing of the system; loading the drug reservoir lumen with a suitable quantity of the drug (e.g., with a suitable number of drug tablets); and closing off the ends of the tubular housing.

[0424] In some embodiments, the tubular wall structure may include a retention lumen extending through or along the structure. The retention lumen optionally may be loaded with an elastic retention frame, such as a nitinol wire or other superelastic wire, and then sealed to keep the frame inside the lumen and/or optionally may be filled with a gas (e.g., air) and then sealed at its ends prior or subsequent to drug loading of the system. In another embodiment, the retention lumen may be filled with high durometer silicone, prior to drug loading of the system, which is then cured into a solid, elastic form effective to bias the tubular wall structure in the coiled bladder retention shape.

[0425] In other embodiments, the method includes thermally shape setting the tubular structure to have a coiled retention shape which is elastically deformable into an uncoiled shape. In such embodiments, a retention lumen and frame may not be necessary.

[0426] Some steps or sub-steps of the method of making a drug delivery system may be performed in other orders or simultaneously.

[0427] The present disclosure may be further understood with reference to the following non-limiting examples.

FIRST LIST OF ENUMERATED EMBODIMENTS

1. A method of treating recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment.

2. A method of treating recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; removing the drug delivery system at least about 90 days later; wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment.

3. The method of embodiment 1 or 2, wherein the patient and/or population of patients have high grade Ta or T1 bladder cancer.

4. The method of any one of embodiments 1-3, wherein the recurrence-free rate in a population of patients treated with about 2 mg/day of erdafitinib is at least 75%, 80%, or 85%, in particular wherein the recurrence-free rate is about 80%.

5. The method of any one of embodiments 1-4, wherein such treatment results in a highgrade recurrence of less than 20%, 18%, 16%, 14%, or 12% in a population of patients treated with about 2 mg/day of erdafitinib, in particular wherein the high-grade recurrence is about 11.1%.

6. The method of any one of embodiments 1-5, wherein such treatment results in progressive disease rate of less than 10%, 8%, 6%, 4%, 2%, or 1% in a population of patients treated with about 2 mg/day of erdafitinib, in particular wherein the progressive disease rate is about 0%.

7. The method of any one of embodiments 1-3, wherein such treatment results in a 6- month recurrence-free survival rate of at least 0.7 in a population of patients treated with about 2 mg/day of erdafitinib, in particular a recurrence-free survival rate of about 0.82.

8. The method of any one of embodiments 1-2 and 7, wherein the recurrence-free rate is at least 75%, 80%, or 85 % in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the recurrence-free rate is about 83%, such as about 83.3%. 9. The method of any one of embodiments 1-2 and 7-8, wherein such treatment results in a high-grade recurrence of less than 20%, 19%, 18%, 17%, 16%, or 15% in the population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the high-grade recurrence is about 14.3%.

10. The method of any one of embodiments 1-2 and 7-9 wherein such treatment results in a progressive disease rate of less than 10%, 8%, 6%, 4%, 2%, or 1% in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the progressive disease rate is about 0%.

11. The method of any one of embodiments 1-2 and 7-10, wherein the 6-month recurrence-free survival rate is at least 0.7 in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the 6-month recurrence-free survival rate is about 0.83.

12. The method of any one of embodiments 1-3, wherein the recurrence-free rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib is at least 75%, 80%, or 85%, in particular wherein the recurrence-free rate is about 82%, such as about 81.8%.

13. The method of any one of embodiments 1-12, further comprising performing a transurethral resection of bladder tumor (TURBT) prior to administering the erdafitinib.

14. The method of any one of embodiments 1-13, wherein the patient and/or population of patients have a histologically confirmed high-grade Ta lesion.

15. The method of any one of embodiments 1-14, wherein the patient and/or population of patients have a histologically confirmed high-grade T1 lesion.

16. The method of any one of embodiments 1-15, wherein the patient and/or population of patients do not have carcinoma in situ (CIS). 17. The method of any one of embodiments 1-16, wherein the patient and/or population of patients have recurrent high-grade Ta or T1 bladder cancer within 18 months of completion of prior BCG therapy.

18. The method of any one of embodiments 1-17, wherein the patient and/or population of patients have previously received at least 5 of 6 full doses of an induction course of BCG.

19. The method of any one of embodiments 1-18, wherein the patient and/or population of patients has high-risk papillary-only NMIBC.

20. A method of treating recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein such treatment results in an at least 50% complete response rate in a population of patients receiving such treatment.

21. A method of treating recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising: deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; and removing the drug delivery system at least about 90 days later; wherein such treatment results in an at least 50% complete response rate in a population of patients receiving such treatment. 22. The method of embodiment 20 or 21, wherein such treatment results in a complete response rate of at least 60%, 65%, 70%, or 75% in the population of patients treated with about 2 mg/day of erdafitinib, in particular, wherein the complete response rate is about 75%, in particular wherein the complete response rate is assessed at about 3 months or about 90 days of the erdafitinib treatment.

23. The method of any one of embodiments 20-22, wherein such treatment results in a low-grade recurrence rate of less than 5%, 4%, 3%, 2%, or 1% in the population of patients treated with about 2 mg/day of erdafitinib, in particular, wherein the low-grade recurrence rate is about 0%.

24. The method of any one of embodiments 20-23, wherein such treatment results in a high-grade recurrence rate less than 5%, 4%, 3%, 2%, or 1% in the population of patients treated with about 2 mg/day of erdafitinib, in particular, wherein the high-grade recurrence rate is about 0%.

25. The method of any one of embodiments 20-24, wherein such treatment results in a progressive disease rate is less than 5%, 4%, 3%, 2%, or 1% in a population of patients treated with about 2 mg/day of erdafitinib, in particular, wherein the progressive disease rate is about 0%.

26. The method of any one of embodiments 20-21, wherein such treatment results in a complete response rate of at least 85%, 90%, 95%, or 99% in the population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the complete response rate is about 100%, in particular wherein the complete response rate is assessed at 3 months or 90 days of the erdafitinib treatment.

27. The method of any one of embodiments 20-21 and 26, wherein such treatment results in a low-grade recurrence rate less than 5%, 4%, 3%, 2%, or 1%. In the population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the low-grade recurrence rate is about 0%.

28. The method of any one of embodiments 20-21 and 26-27, wherein such treatment results in a high-grade recurrence rate less than 5%, 4%, 3%, 2%, or 1% in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the high-grade recurrence rate about 0%.

29. The method of any one of embodiments 20-21 and 26-28, wherein such treatment results in a progressive disease rate less than 5%, 4%, 3%, 2%, or 1% in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the progressive disease rate is about 0%.

30 The method of any one of embodiments 20-21 and 26-29, wherein such treatment results in a 6-month duration of response of at least 0.8, 0.85, 0.9, or 0.95.

31. The method of any one of embodiments 20-21, wherein such treatment results in a complete response rate of at least 60%, 65%, 70%, or 75% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular, wherein the complete response rate is about 87%, such as about 86.7%, wherein the complete response rate is assessed at 3 months or 90 days of the erdafitinib treatment.

32. The method of any one of embodiments 20-31, wherein the patient and/or population of patients have a history of only low-grade disease.

33. The method of any one of embodiments 20-32, wherein the patient and/or population of patients have intermediate risk papillary disease.

34. The method of any one of embodiments 20-33 wherein the patient and/or population of patients have not previously had carcinoma in situ.

35. The method of any one of embodiments 20-34, wherein the patient and/or population of patients have visible disease at the time that the erdafitinib is administered.

36. The method of any one of embodiments 20-35, wherein the patient and/or population of patients have Ta or T1 bladder cancer.

37. The method of any one of embodiments 20-36, wherein the patient and/or population of patients have not undergone TURBT prior to administering the erdafitinib. 38. The method of any one of embodiments 1-37 wherein the erdafitinib is delivered to the urine in the bladder of the patient.

39. The method of any one of embodiments 1-38, wherein the erdafitinib is administered continuously to the bladder of the patient for at least about 90 days.

40. The method of any one of embodiments 1-39, wherein the erdafitinib is locally administered to the bladder for about 90 days, about 180 days, about 270 days, or about 360 days.

41. The method of any one of embodiments 1-40, wherein the erdafitinib is locally administered to the bladder of the patient during one or more administration periods of about 90 days.

42. The method of any one of embodiments 1-41, wherein the erdafitinib is locally administered to the bladder of the patient during two or more administration periods of about 90 days.

43. The method of any one of embodiments 1-42, wherein the erdafitinib is locally administered to the bladder of the patient during four administration periods of about 90 days.

44. The method of any one of embodiments 42-43, wherein there is no rest period between the two or more administration periods.

45. The method of any one of embodiments 1-6, 12-26, and 31-44, wherein about 2 mg/day of erdafitinib is administered to the patient.

46. The method of any one of embodiments 1-2, 7-11, and 27-44, wherein about 4 mg/day of erdafitinib is administered to the patient.

47. The method of any one of embodiments 1-46, wherein the method comprises administering about 2 mg/day to about 4 mg/day of erdafitinib for about 90 days at least two times, at least three times, or at least four times. 48. The method of any one of embodiments 1, 3-20, and 23-47, wherein administering about 2 mg/day to about 4 mg/day of erdafitinib comprises deploying an intravesical drug delivery system comprising erdafitinib to the bladder of the patient and removing the drug delivery system about 90 days later.

49. The method of any one of embodiments 2, 21, and 48, wherein the drug delivery system comprises about 500 mg erdafitinib.

50. The method of any one of embodiments 48-49 comprising i) deploying a first drug delivery system comprising erdafitinib to the bladder of the patient on day 0; ii) removing the first drug delivery system on about day 90; iii) deploying a second drug delivery system comprising erdafitinib to the bladder of the patient on about day 90; iv) removing the second drug delivery system on about day 180; v) deploying a third drug delivery system comprising erdafitinib to the bladder of the patient on day 180; vi) removing the third drug delivery system on about day 270; vii) deploying a fourth drug delivery system comprising erdafitinib to the bladder of the patient on about day 270; and viii) removing the fourth drug delivery system on about day 360.

51. The method of any one of embodiments 48-50, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure.

52. The method of embodiment 51, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees, in particular at an arc angle of 90 degrees to 180 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. 53. The method of embodiment 52, wherein the two interface edges are disposed at an arc angle of 45 degrees to 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

54. The method of embodiment 53, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg/day and the two interface edges are disposed at an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

55. The method of embodiment 52, wherein the two interface edges are disposed at an arc angle of 150 degrees to 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

56. The method of embodiment 55, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 4 mg/day and the two interface edges are disposed at an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

57. The method of any one of embodiments 48-56, further comprising elastically deforming the drug delivery system from a low-profile deployment shape suited for insertion through the urethra of a patient and into the patient’s bladder to a relatively expanded retention shape suited for retention of the drug delivery system within the bladder.

58 The method of any one of embodiments 48-57, wherein the erdafitinib is in the form of a plurality of mini-tablets serially arranged in the drug lumen.

59. The method of any one of embodiments 1-58, wherein the patient and/or population of patients are ineligible for radical cystectomy or refuse radical cystectomy.

60. The method of any one of embodiments 1-59, wherein the patient or population of patients have not had prior treatment with an FGFR inhibitor.

61. The method of any one of embodiments 1-60, wherein the patient and/or population of patients harbor at least one FGFR2 genetic alteration and/or FGFR3 genetic alteration. 62. The method of embodiment 61, wherein the FGFR2 genetic alteration and/or the FGFR3 genetic alteration comprises an activating tumor FGFR2 or FGFR3 mutation or fusion.

63. The method of any one of embodiments 2, 20, and 48-62, wherein the drug formulation comprises:

(a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N’-(l-methylethyl)-N-[3-(l-methyl- l/Z-pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition;

(b) hydroxypropyl -beta-cyclodextrin in a concentration of 10 wt% of the solid pharmaceutical composition;

(c) meglumine in a concentration of 1 wt% of the solid pharmaceutical composition;

(d) microcrystalline cellulose in a concentration of 17.5 wt% of the solid pharmaceutical composition;

(e) silicified microcrystalline cellulose in a concentration of 10.75 wt% of the solid pharmaceutical composition;

(f) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.5 wt% of the solid pharmaceutical composition;

(g) colloidal silicon dioxide in a concentration of 0.25 wt% of the solid pharmaceutical composition;

(h) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the solid pharmaceutical composition; and

(i) magnesium stearate in a concentration of 1.5 wt% of the solid pharmaceutical composition; or

(a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N’-(l-methylethyl)-N-[3-(l-methyl- 17/-pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the solid pharmaceutical composition;

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer; (g) colloidal silicon dioxide;

(h) hydroxypropyl methylcellulose; and

(i) magnesium stearate.

64. The method of any one of embodiments 2, 20, and 48-62, wherein the drug formulation comprises

(c) microcrystalline cellulose in a concentration of 17.5 wt% of the solid pharmaceutical composition;

(d) silicified microcrystalline cellulose in a concentration of 11.75 wt% of the solid pharmaceutical composition;

(e) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.5 wt% of the solid pharmaceutical composition;

(f) colloidal silicon dioxide in a concentration of 0.25 wt% of the solid pharmaceutical composition;

(g) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the solid pharmaceutical composition; and

(h) magnesium stearate in a concentration of 1.5 wt% of the solid pharmaceutical composition; or

(b) hydroxypropyl -beta-cyclodextrin;

(c) microcrystalline cellulose;

(d) silicified microcrystalline cellulose;

(e) vinylpyrrolidone-vinyl acetate copolymer;

(f) colloidal silicon dioxide;

(g) hydroxypropyl methylcellulose; and

(h) magnesium stearate. 65. The method of any one of embodiments 2, 20, and 48-62, wherein the drug formulation comprises:

(d) microcrystalline cellulose in a concentration of 24.5 wt% of the solid pharmaceutical composition;

(e) silicified microcrystalline cellulose in a concentration of 6 wt% of the solid pharmaceutical composition;

(f) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 6 wt% of the solid pharmaceutical composition;

(g) colloidal silicon dioxide in a concentration of 0.5 wt% of the solid pharmaceutical composition;

(h) magnesium stearate in a concentration of 2 wt% of the solid pharmaceutical composition; or

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide; and

(h) magnesium stearate.

66. The method of any one of embodiments 2, 20, and 48-65, wherein the delivery system comprises AC-4075A-B20 and EG-80-A.

67. A method of treating non-muscle invasive bladder cancer in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein the ratio of the concentration of erdafitinib in the urine of the patient to the concentration of erdafitinib in the plasma of the patient is greater than 20: 1, greater than 30: 1, greater than 40: 1, or greater than 50: 1.

68. A method of treating non-muscle invasive bladder cancer in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein the concentration of erdafitinib in the urine is in the range of about 500 ng/mL to about 3500 ng/mL, optionally wherein the concentration of erdafitinib in the urine is in the range of about 750 ng/mL to about 3250 ng/mL.

69. The method of any one of embodiments 66-68, wherein the cancer is high-risk nonmuscle invasive bladder cancer (HR-NMIBC).

70. The method of embodiment 69, wherein the high-risk non-muscle invasive bladder cancer is recurrent bacillus Calmette-Guerin (BCG)-experienced HR-NMIBC.

71. A method of embodiment 69 or embodiment 70, wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment.

72. A method of embodiment 69 or embodiment 70 comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; removing the drug delivery system at least about 90 days later; wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment.

73. The method of any one of embodiments 69-72, wherein the patient and/or population of patients have high grade Ta or T1 bladder cancer.

74. The method of any one of embodiments 69-72, wherein the recurrence-free rate in a population of patients treated with about 2 mg/day of erdafitinib is at least 75%, 80%, or 85%, in particular wherein the recurrence-free rate is about 80%.

75. The method of any one of embodiments 69-74, wherein such treatment results in a high-grade recurrence of less than 20%, 18%, 16%, 14%, or 12% in a population of patients treated with about 2 mg/day of erdafitinib, in particular wherein the high-grade recurrence is about 11.1%.

76. The method of any one of embodiments 69-75, wherein such treatment results in progressive disease rate of less than 10%, 8%, 6%, 4%, 2%, or 1% in a population of patients treated with about 2 mg/day of erdafitinib, in particular wherein the progressive disease rate is about 0%.

77. The method of embodiment 69 or embodiment 70, wherein such treatment results in a 6-month recurrence-free survival rate of at least 0.7 in a population of patients treated with about 2 mg/day of erdafitinib, in particular a recurrence-free survival rate of about 0.82.

78. The method of any one of embodiments 69-73, wherein the recurrence-free rate is at least 75%, 80%, or 85 % in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the recurrence-free rate is about 83%, such as about 83.3%.

79. The method of any one of embodiments 69-73, wherein such treatment results in a high-grade recurrence of less than 20%, 19%, 18%, 17%, 16%, or 15% in the population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the high-grade recurrence is about 14.3%. 80. The method of any one of embodiments 69-73 wherein such treatment results in a progressive disease rate of less than 10%, 8%, 6%, 4%, 2%, or 1% in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the progressive disease rate is about 0%.

81. The method of any one of embodiments 69-73, wherein the 6-month recurrence-free survival rate is at least 0.7 in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the 6-month recurrence-free survival rate is about 0.83.

82. The method of any one of embodiments 69-73, wherein the recurrence-free rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib is at least 75%, 80%, or 85%, in particular wherein the recurrence-free rate is about 82%, such as about 81.8%.

83. The method of any one of embodiments 69-82, further comprising performing a transurethral resection of bladder tumor (TURBT) prior to administering the erdafitinib.

84. The method of any one of embodiments 69-83, wherein the patient and/or population of patients have a histologically confirmed high-grade Ta lesion.

85. The method of any one of embodiments 69-84, wherein the patient and/or population of patients have a histologically confirmed high-grade T1 lesion.

86. The method of any one of embodiments 69-85, wherein the patient and/or population of patients do not have carcinoma in situ (CIS).

87. The method of any one of embodiments 69-86, wherein the patient and/or population of patients have recurrent high-grade Ta or T1 bladder cancer within 18 months of completion of prior BCG therapy.

88. The method of any one of embodiments 69-87, wherein the patient and/or population of patients have previously received at least 5 of 6 full doses of an induction course of BCG. 89. The method of any one of embodiments 69-88, wherein the patient and/or population of patients has high-risk papillary-only NMIBC.

90. The method of any one of embodiments 66-68, wherein the cancer is intermediate risk non-muscle invasive bladder cancer (IR-NMIBC).

91. The method of embodiment 90 wherein the IR-NMIBC is recurrent IR-NMIBC.

92. The method of embodiment 90 or embodiment 91, wherein such treatment results in an at least 50% complete response rate in a population of patients receiving such treatment.

93. The method of embodiment 90 or embodiment 91, comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; and removing the drug delivery system at least about 90 days later; wherein such treatment results in an at least 50% complete response rate in a population of patients receiving such treatment.

94. The method of any one of embodiments 90-93, wherein such treatment results in a complete response rate of at least 60%, 65%, 70%, or 75% in the population of patients treated with about 2 mg/day of erdafitinib, in particular, wherein the complete response rate is about 75%, in particular wherein the complete response rate is assessed at about 3 months or about 90 days of the erdafitinib treatment. 95. The method of any one of embodiments 90-94, wherein such treatment results in a low-grade recurrence rate of less than 5%, 4%, 3%, 2%, or 1% in the population of patients treated with about 2 mg/day of erdafitinib, in particular, wherein the low-grade recurrence rate is about 0%.

96. The method of any one of embodiments 90-95, wherein such treatment results in a high-grade recurrence rate less than 5%, 4%, 3%, 2%, or 1% in the population of patients treated with about 2 mg/day of erdafitinib, in particular, wherein the high-grade recurrence rate is about 0%.

97. The method of any one of embodiments 90-96, wherein such treatment results in a progressive disease rate is less than 5%, 4%, 3%, 2%, or 1% in a population of patients treated with about 2 mg/day of erdafitinib, in particular, wherein the progressive disease rate is about 0%.

98. The method of any one of embodiments 90-93, wherein such treatment results in a complete response rate of at least 85%, 90%, 95%, or 99% in the population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the complete response rate is about 100%, in particular wherein the complete response rate is assessed at 3 months or 90 days of the erdafitinib treatment.

99. The method of any one of embodiments 90-93, and 98, wherein such treatment results in a low-grade recurrence rate less than 5%, 4%, 3%, 2%, or 1%. In the population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the low-grade recurrence rate is about 0%.

100. The method of any one of embodiments 90-93, 98 and 99, wherein such treatment results in a high-grade recurrence rate less than 5%, 4%, 3%, 2%, or 1% in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the high-grade recurrence rate is about 0%.

101. The method of any one of embodiments 90-93 and 98-100, wherein such treatment results in a progressive disease rate less than 5%, 4%, 3%, 2%, or 1% in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the progressive disease rate is about 0%.

102 The method of any one of embodiments 90-93 and 98-101, wherein such treatment results in a 6-month duration of response of at least 0.8, 0.85, 0.9, or 0.95.

103. The method of any one of embodiments 90-93, wherein such treatment results in a complete response rate of at least 60%, 65%, 70%, or 75% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular, wherein the complete response rate is about 87%, such as about 86.7%, wherein the complete response rate is assessed at 3 months or 90 days of the erdafitinib treatment.

104. The method of any one of embodiments 90-103, wherein the patient and/or population of patients have a history of only low-grade disease.

105. The method of any one of embodiments 90-104, wherein the patient and/or population of patients have intermediate risk papillary disease.

106. The method of any one of embodiments 90-105 wherein the patient and/or population of patients have not previously had carcinoma in situ.

107. The method of any one of embodiments 90-106, wherein the patient and/or population of patients have visible disease at the time that the erdafitinib is administered.

108. The method of any one of embodiments 90-107, wherein the patient and/or population of patients have Ta or T1 bladder cancer.

109. The method of any one of embodiments 90-108, wherein the patient and/or population of patients have not undergone TURBT prior to administering the erdafitinib.

110. The method of any one of embodiments 1-109, wherein the erdafitinib is delivered to the urine in the bladder of the patient.

111. The method of any one of embodiments 66-77, 83-87, and 102-110, comprising administering about 2 mg/day erdafitinib to the patient, wherein the urine concentration of erdafitinib is about 500 ng/mL to about 2000 ng/mL, about 500 ng/mL to about 1500 ng/mL, or about 1000 ng/mL to about 2000 ng/mL.

112. The method of any one of embodiments 66-73, 78-82, 83-93, and 98-110, comprising administering about 4 mg/day erdafitinib to the patient, wherein the urine concentration of erdafitinib is about 1000 ng/mL to about 3500 ng/mL, about 1000 ng/mL to about 2500 ng/mL, or about 2000 ng/mL to about 3500 ng/mL.

113. The method of any one of embodiments 66-112, wherein the ratio of the concentration of erdafitinib in the urine of the patient to the concentration of erdafitinib in the plasma of the patient is about 40: 1 to about 60: 1.

114. The method of any one of embodiments 66-113, wherein the erdafitinib is administered continuously to the bladder of the patient for at least about 90 days, optionally wherein the erdafitinib is locally administered to the bladder for about 90 days, about 180 days, about 270 days, or about 360 days.

115. The method of any one of embodiments 66-114, wherein the erdafitinib is locally administered to the bladder of the patient during one or more administration periods of about 90 days, optionally wherein the erdafitinib is locally administered to the bladder of the patient during three or more, or four or more administration periods, optionally wherein there is no rest period between the administration periods.

116. The method of any one of embodiments 66-77, 83-97, and 102-115, wherein about 2 mg/day of erdafitinib is administered to the patient.

117. The method of any one of embodiments 66-73, 78-82, 83-93, and 98-115, wherein about 4 mg/day of erdafitinib is administered to the patient.

118. The method of any one of embodiments 66-117, wherein the method comprises administering about 2 mg/day to about 4 mg/day of erdafitinib for about 90 days at least two times, at least three times, or at least four times. 119. The method of any one of embodiments 66-118, wherein administering about 2 mg/day to about 4 mg/day of erdafitinib comprises deploying an intravesical drug delivery system comprising erdafitinib to the bladder of the patient and removing the drug delivery system about 90 days later.

120. The method of any one of embodiments 72, 93, and 119, wherein the drug delivery system comprises about 500 mg erdafitinib.

121. The method of embodiment 72, 93, 119, and 120, comprising i) deploying a first drug delivery system comprising erdafitinib to the bladder of the patient on day 0; ii) removing the first drug delivery system on about day 90; iii) deploying a second drug delivery system comprising erdafitinib to the bladder of the patient on about day 90; iv) removing the second drug delivery system on about day 180; v) deploying a third drug delivery system comprising erdafitinib to the bladder of the patient on day 180; vi) removing the third drug delivery system on about day 270; vii) deploying a fourth drug delivery system comprising erdafitinib to the bladder of the patient on about day 270; and viii) removing the fourth drug delivery system on about day 360.

122. The method of any one of embodiments 72, 93, and 119-121, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure.

123. The method of embodiment 122, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees, in particular at an arc angle of 90 degrees to 180 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube. 124. The method of embodiment 122, wherein the two interface edges are disposed at an arc angle of 45 degrees to 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

125. The method of embodiment 124, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg/day and the two interface edges are disposed at an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

126. The method of embodiment 122, wherein the two interface edges are disposed at an arc angle of 150 degrees to 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

127. The method of embodiment 126, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 4 mg/day and the two interface edges are disposed at an arc angle of about 180 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

128. The method of any one of embodiments 119-127, further comprising elastically deforming the drug delivery system from a low-profile deployment shape suited for insertion through the urethra of a patient and into the patient’s bladder to a relatively expanded retention shape suited for retention of the drug delivery system within the bladder.

129. The method of any one of embodiments 119-128, wherein the erdafitinib is in the form of a plurality of mini-tablets serially arranged in the drug lumen.

130. The method of any one of embodiments 66-129, wherein the patient and/or population of patients are ineligible for radical cystectomy or refuse radical cystectomy.

131. The method of any one of embodiments 66-130, wherein the patient or population of patients have not had prior treatment with an FGFR inhibitor.

132. The method of any one of embodiments 66-131, wherein the patient and/or population of patients harbor at least one FGFR2 genetic alteration and/or FGFR3 genetic alteration. 133. The method of embodiment 132, wherein the FGFR2 genetic alteration and/or the FGFR3 genetic alteration comprises an activating tumor FGFR2 or FGFR3 mutation or fusion.

134. The method of any one of embodiments 72, 73, 119-133, wherein the drug formulation comprises:

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer; (g) colloidal silicon dioxide;

(h) hydroxypropyl methylcellulose; and

(i) magnesium stearate.

135. The method of any one of embodiments 72, 73, and 119-133, wherein the drug formulation comprises

(b) hydroxypropyl -beta-cyclodextrin;

(c) microcrystalline cellulose;

(d) silicified microcrystalline cellulose;

(e) vinylpyrrolidone-vinyl acetate copolymer;

(f) colloidal silicon dioxide;

(g) hydroxypropyl methylcellulose; and

(h) magnesium stearate. 136. The method of any one of embodiments 72, 73, and 119-133, wherein the drug formulation comprises:

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide; and

(h) magnesium stearate.

137. The method of any one of embodiments 72, 73, and 119-136, wherein the delivery system comprises AC-4075A-B20 and EG-80-A. 138. A method of treating intermediate-risk non-muscle invasive bladder cancer (IR- NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein: i) the patient is newly diagnosed or recurrent IR-NMIBC; ii) the patient is determined to have intermediate risk of recurrence or progression; iii) the patient has select FGFR genetic alterations; iv) the patient is without prior bacillus Calmette-Guerin (BCG) treatment; and v) the patient comprises one or more of the following risk factors selected from the list consisting of: a) multiple low grade (LG) tumors, b) solitary LG tumor >3 cm, c) frequent recurrence (> 1 per year), and d) recurrence after prior intravesical chemotherapy.

139. The method of embodiment 138, wherein the patient and/or population of patients have histologically confirmed diagnosis of IR-NMIBC with at least one of the following disease characterizations: i) Ta LG/G1 : recurrent; ii) Ta LG/G1 : primary & (multifocal or > 3 cm); and/or iii) Ta G2: primary or recurrent.

140. The method of any one of embodiments 1-3, 12-21, 30-44, 47-52, 57-73, 82-93, 102- 110. 113-115, 118-123, and 128-139, comprising administering about 3 mg/day of erdafitinib to the patient.

141. The method of embodiment 52 or embodiment 123, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 3 mg/day and the two interface edges are disposed at an arc angle of about 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

142. A drug delivery system, comprising: a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 3 mg/day and wherein the two interface edges are disposed at an arc angle of about 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

143. The drug delivery system of embodiment 142, comprising 42-46 erdafitinib mini tablets.

144. The drug delivery system of embodiment 143, comprising 43 erdafitinib minitablets.

145. The drug delivery system of any one of embodiments 142-144, wherein the delivery system comprises AC-4075A-B20 and EG-80-A.

146. The drug delivery system of any one of embodiments 142-145, wherein the drug formulation comprises:

(d) microcrystalline cellulose in a concentration of 17.5 wt% of the solid pharmaceutical composition; (e) silicified microcrystalline cellulose in a concentration of 10.75 wt% of the solid pharmaceutical composition;

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide;

(h) hydroxypropyl methylcellulose; and

(i) magnesium stearate.

147. The drug delivery system of any one of embodiments 142-145, wherein the drug formulation comprises

(d) silicified microcrystalline cellulose in a concentration of 11.75 wt% of the solid pharmaceutical composition; (e) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.5 wt% of the solid pharmaceutical composition;

(b) hydroxypropyl -beta-cyclodextrin;

(c) microcrystalline cellulose;

(d) silicified microcrystalline cellulose;

(e) vinylpyrrolidone-vinyl acetate copolymer;

(f) colloidal silicon dioxide;

(g) hydroxypropyl methylcellulose; and

(h) magnesium stearate.

148. The drug delivery system of any one of embodiments 142-145, wherein the drug formulation comprises:

(f) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 6 wt% of the solid pharmaceutical composition; (g) colloidal silicon dioxide in a concentration of 0.5 wt% of the solid pharmaceutical composition;

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide; and

(h) magnesium stearate.

149. The method of any one of embodiments 20-21, 32-66, 90-93, and 104-140, wherein such treatment results in a median duration of response of at least about 12 months, or of about 12 months.

150. The method of any one of embodiments 20-21, 32-66, 90-93 and 104-140, wherein such treatment results in a complete response rate of about 90% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, the complete response rate assessed at 12 weeks.

151. The method of any one of embodiments 1-19, 38-73, 83-89, and 110-137, wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib, and in particular the 12-month RFS rate, is about 90%.

152. The method of any one of embodiments 20-21, 32-66, 90-93, and 104-140, wherein such treatment results in a complete response rate of about 85% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, the complete response rate assessed at 12 weeks. 153. The method of any one of embodiments 1-19, 38-73, 83-89, and 110-137, wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib, and in particular the 12-month RFS rate, is about 75% or about 79% or about 80%.

154. The drug delivery system of any one of embodiments 142-145, wherein the erdafitinib is erdafitinib free base.

SECOND LIST OF ENUMERATED EMBODIMENTS

2. A method of treating recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; removing the drug delivery system at least about 90 days later; wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment. 3. The method of embodiment 1 or 2, wherein the patient and/or population of patients have high grade Ta or T1 bladder cancer.

7. The method of any one of embodiments 1-6, wherein such treatment results in a 6- month recurrence-free survival rate of at least 0.7 in a population of patients treated with about 2 mg/day of erdafitinib, in particular a recurrence-free survival rate of about 0.82.

8. The method of any one of embodiments 1-3, wherein the recurrence-free rate is at least 75%, 80%, or 85 % in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the recurrence-free rate is about 83%, such as about 83.3%.

9. The method of any one of embodiments 1-3 and 8, wherein such treatment results in a high-grade recurrence of less than 20%, 19%, 18%, 17%, 16%, or 15% in the population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the high-grade recurrence is about 14.3%.

10. The method of any one of embodiments 1-3 and 8-9 wherein such treatment results in a progressive disease rate of less than 10%, 8%, 6%, 4%, 2%, or 1% in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the progressive disease rate is about 0%. 11. The method of any one of embodiments 1-3 and 8-10, wherein the 6-month recurrence-free survival rate is at least 0.7 in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the 6-month recurrence-free survival rate is about 0.83.

16. The method of any one of embodiments 1-15, wherein the patient and/or population of patients do not have carcinoma in situ (CIS).

17. The method of any one of embodiments 1-16, wherein the patient and/or population of patients have recurrent high-grade Ta or T1 bladder cancer within 18 months of completion of prior BCG therapy.

19. The method of any one of embodiments 1-18, wherein the patient and/or population of patients has high-risk papillary-only NMIBC. 20. A method of treating recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein such treatment results in an at least 50% complete response rate in a population of patients receiving such treatment.

21. A method of treating recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; and removing the drug delivery system at least about 90 days later; wherein such treatment results in an at least 50% complete response rate in a population of patients receiving such treatment.

22. The method of embodiment 20 or 21, wherein such treatment results in a complete response rate of at least 60%, 65%, 70%, or 75% in the population of patients treated with about 2 mg/day of erdafitinib, in particular, wherein the complete response rate is about 75%, in particular wherein the complete response rate is assessed at about 3 months or about 90 days of the erdafitinib treatment.

23. The method of any one of embodiments 20-22, wherein such treatment results in a low-grade recurrence rate of less than 5%, 4%, 3%, 2%, or 1% in the population of patients treated with about 2 mg/day of erdafitinib, in particular, wherein the low-grade recurrence rate is about 0%. 24. The method of any one of embodiments 20-23, wherein such treatment results in a high-grade recurrence rate less than 5%, 4%, 3%, 2%, or 1% in the population of patients treated with about 2 mg/day of erdafitinib, in particular, wherein the high-grade recurrence rate is about 0%.

25. The method of any one of embodiments 20-24, wherein such treatment results in a progressive disease rate less than 5%, 4%, 3%, 2%, or 1% in a population of patients treated with about 2 mg/day of erdafitinib, in particular, wherein the progressive disease rate is about 0%.

30. The method of any one of embodiments 20-21 and 26-29, wherein such treatment results in a 6-month duration of response of at least 0.8, 0.85, 0.9, or 0.95. 31. The method of any one of embodiments 20-21, wherein such treatment results in a complete response rate of at least 60%, 65%, 70%, or 75% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular, wherein the complete response rate is about 87%, such as about 86.7%, wherein the complete response rate is assessed at 3 months or 90 days of the erdafitinib treatment.

37. The method of any one of embodiments 20-36, wherein the patient and/or population of patients have not undergone TURBT prior to administering the erdafitinib.

38. The method of any one of embodiments 1-37 wherein the erdafitinib is delivered to the urine in the bladder of the patient.

40. The method of any one of embodiments 1-39, wherein the erdafitinib is locally administered to the bladder for about 90 days, about 180 days, about 270 days, or about 360 days. 41. The method of any one of embodiments 1-40, wherein the erdafitinib is locally administered to the bladder of the patient during one or more administration periods of about 90 days.

43. The method of any one of embodiments 1-42, wherein the erdafitinib is locally administered to the bladder of the patient during four administration periods of about 90 days

45. The method of any one of embodiments 1-7, 12-25, and 31-44, wherein about 2 mg/day of erdafitinib is administered to the patient.

46. The method of any one of embodiments 1-3, 8-21, and 26-44, wherein about 4 mg/day of erdafitinib is administered to the patient.

47. The method of any one of embodiments 1-46, wherein the method comprises administering about 2 mg/day to about 4 mg/day of erdafitinib for about 90 days at least two times, at least three times, or at least four times.

48. The method of any one of embodiments 1, 3-20, and 22-47, wherein administering about 2 mg/day to about 4 mg/day of erdafitinib comprises deploying an intravesical drug delivery system comprising erdafitinib to the bladder of the patient and removing the drug delivery system about 90 days later, in particular wherein the intravesical drug delivery system comprises a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube.

49. The method of any one of embodiments 2, 21, and 48, wherein the drug formulation comprises about 500 mg of erdafitinib, optionally wherein the erdafitinib is erdafitinib free base.

58. The method of any one of embodiments 48-57, wherein the erdafitinib is in the form of a plurality of mini-tablets serially arranged in the drug lumen.

63. The method of any one of embodiments 2, 21, and 48-62, wherein the drug formulation comprises:

(a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl- l/7-pyrazol-4-yl)quinoxalin-6-yl] ethane- 1,2-diamine) in a concentration of 50 wt% of the drug formulation;

(b) hydroxypropyl -beta-cyclodextrin in a concentration of 10 wt% of the drug formulation;

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(d) microcrystalline cellulose in a concentration of 17.5 wt% of the drug formulation;

(e) silicified microcrystalline cellulose in a concentration of 10.75 wt% of the drug formulation;

(f) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.5 wt% of the drug formulation;

(g) colloidal silicon dioxide in a concentration of 0.25 wt% of the drug formulation;

(h) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the drug formulation; and

(i) magnesium stearate in a concentration of 1.5 wt% of the drug formulation; or

(a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl- 177-pyrazol-4-yl)quinoxalin-6-yl] ethane- 1,2-diamine) in a concentration of 50 wt% of the drug formulation;

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide;

(h) hydroxypropyl methylcellulose; and

(i) magnesium stearate. 64. The method of any one of embodiments 2, 21, and 48-62, wherein the drug formulation comprises

(c) microcrystalline cellulose in a concentration of 17.5 wt% of the drug formulation;

(d) silicified microcrystalline cellulose in a concentration of 11.75 wt% of the drug formulation;

(e) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 7.5 wt% of the drug formulation;

(f) colloidal silicon dioxide in a concentration of 0.25 wt% of the drug formulation;

(g) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the drug formulation; and

(h) magnesium stearate in a concentration of 1.5 wt% of the drug formulation; or

(b) hydroxypropyl -beta-cyclodextrin;

(c) microcrystalline cellulose;

(d) silicified microcrystalline cellulose;

(e) vinylpyrrolidone-vinyl acetate copolymer;

(f) colloidal silicon dioxide;

(g) hydroxypropyl methylcellulose; and

(h) magnesium stearate.

65. The method of any one of embodiments 2, 21, and 48-62, wherein the drug formulation comprises:

(a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl- l/7-pyrazol-4-yl)quinoxalin-6-yl] ethane- 1,2-diamine) in a concentration of 50 wt% of the drug formulation; (b) hydroxypropyl -beta-cyclodextrin in a concentration of 10 wt% of the drug formulation;

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(d) microcrystalline cellulose in a concentration of 24.5 wt% of the drug formulation;

(e) silicified microcrystalline cellulose in a concentration of 6 wt% of the drug formulation;

(f) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 6 wt% of the drug formulation;

(g) colloidal silicon dioxide in a concentration of 0.5 wt% of the drug formulation;

(h) magnesium stearate in a concentration of 2 wt% of the drug formulation; or

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide; and

(h) magnesium stearate.

66. The method of any one of embodiments 2, 21, and 48-65, wherein the first material comprises AC-4075A and the second material comprises EG-80-A, optionally wherein the first material comprises AC-4075A-B20.

73. The method of any one of embodiments 69-72, wherein the patient and/or population of patients have high grade Ta or T1 bladder cancer. 74. The method of any one of embodiments 69-73, wherein the recurrence-free rate in a population of patients treated with about 2 mg/day of erdafitinib is at least 75%, 80%, or 85%, in particular wherein the recurrence-free rate is about 80%.

77. The method of any one of embodiments 69-76, wherein such treatment results in a 6- month recurrence-free survival rate of at least 0.7 in a population of patients treated with about 2 mg/day of erdafitinib, in particular a recurrence-free survival rate of about 0.82.

79. The method of any one of embodiments 69-73 and 78, wherein such treatment results in a high-grade recurrence of less than 20%, 19%, 18%, 17%, 16%, or 15% in the population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the high-grade recurrence is about 14.3%.

80. The method of any one of embodiments 69-73 and 78-79, wherein such treatment results in a progressive disease rate of less than 10%, 8%, 6%, 4%, 2%, or 1% in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the progressive disease rate is about 0%.

81. The method of any one of embodiments 69-73 and 78-80, wherein the 6-month recurrence-free survival rate is at least 0.7 in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the 6-month recurrence-free survival rate is about 0.83.

88. The method of any one of embodiments 69-87, wherein the patient and/or population of patients have previously received at least 5 of 6 full doses of an induction course of BCG.

89. The method of any one of embodiments 69-88, wherein the patient and/or population of patients has high-risk papillary-only NMIBC.

91. The method of embodiment 90 wherein the IR-NMIBC is recurrent IR-NMIBC. 92. The method of embodiment 90 or embodiment 91, wherein such treatment results in an at least 50% complete response rate in a population of patients receiving such treatment.

94. The method of any one of embodiments 90-93, wherein such treatment results in a complete response rate of at least 60%, 65%, 70%, or 75% in the population of patients treated with about 2 mg/day of erdafitinib, in particular, wherein the complete response rate is about 75%, in particular wherein the complete response rate is assessed at about 3 months or about 90 days of the erdafitinib treatment.

95. The method of any one of embodiments 90-94, wherein such treatment results in a low-grade recurrence rate of less than 5%, 4%, 3%, 2%, or 1% in the population of patients treated with about 2 mg/day of erdafitinib, in particular, wherein the low-grade recurrence rate is about 0%.

97. The method of any one of embodiments 90-96, wherein such treatment results in a progressive disease rate less than 5%, 4%, 3%, 2%, or 1% in a population of patients treated with about 2 mg/day of erdafitinib, in particular, wherein the progressive disease rate is about 0%.

100. The method of any one of embodiments 90-93 and 98-99, wherein such treatment results in a high-grade recurrence rate less than 5%, 4%, 3%, 2%, or 1% in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the high-grade recurrence rate about 0%.

102. The method of any one of embodiments 90-101, wherein such treatment results in a 6- month duration of response of at least 0.8, 0.85, 0.9, or 0.95.

111. The method of any one of embodiments 66-77, 82-97, and 102-110, comprising administering about 2 mg/day erdafitinib to the patient, wherein the urine concentration of erdafitinib is about 500 ng/mL to about 2000 ng/mL, about 500 ng/mL to about 1500 ng/mL, or about 1000 ng/mL to about 2000 ng/mL.

112. The method of any one of embodiments 66-73, 78-93, and 98-110, comprising administering about 4 mg/day erdafitinib to the patient, wherein the urine concentration of erdafitinib is about 1000 ng/mL to about 3500 ng/mL, about 1000 ng/mL to about 2500 ng/mL, or about 2000 ng/mL to about 3500 ng/mL. 113. The method of any one of embodiments 66-112, wherein the ratio of the concentration of erdafitinib in the urine of the patient to the concentration of erdafitinib in the plasma of the patient is about 40: 1 to about 60: 1.

116. The method of any one of embodiments 66-77, 82-97, 102-111, and 113-115, wherein about 2 mg/day of erdafitinib is administered to the patient.

117. The method of any one of embodiments 66-73, 78-93, 98-110, and 112-115, wherein about 4 mg/day of erdafitinib is administered to the patient.

118. The method of any one of embodiments 66-117, wherein the method comprises administering about 2 mg/day to about 4 mg/day of erdafitinib for about 90 days at least two times, at least three times, or at least four times.

119. The method of any one of embodiments 66-118, wherein administering about 2 mg/day to about 4 mg/day of erdafitinib comprises deploying an intravesical drug delivery system comprising erdafitinib to the bladder of the patient and removing the drug delivery system about 90 days later.

120. The method of any one of embodiments 72, 93, and 119, wherein the drug formulation comprises about 500 mg of erdafitinib, optionally wherein the erdafitinib is erdafitinib free base. 121. The method of embodiment 72, 93, 119, and 120, comprising i) deploying a first drug delivery system comprising erdafitinib to the bladder of the patient on day 0; ii) removing the first drug delivery system on about day 90; iii) deploying a second drug delivery system comprising erdafitinib to the bladder of the patient on about day 90; iv) removing the second drug delivery system on about day 180; v) deploying a third drug delivery system comprising erdafitinib to the bladder of the patient on day 180; vi) removing the third drug delivery system on about day 270; vii) deploying a fourth drug delivery system comprising erdafitinib to the bladder of the patient on about day 270; and viii) removing the fourth drug delivery system on about day 360.

123. The method of embodiment 122, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees, in particular at an arc angle of 90 degrees to 180 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube.

124. The method of embodiment 123, wherein the two interface edges are disposed at an arc angle of 45 degrees to 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

125. The method of embodiment 124, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg/day and the two interface edges are disposed at an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. 126. The method of embodiment 123, wherein the two interface edges are disposed at an arc angle of 150 degrees to 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

132. The method of any one of embodiments 66-131, wherein the patient and/or population of patients harbor at least one FGFR2 genetic alteration and/or FGFR3 genetic alteration.

133. The method of embodiment 132, wherein the FGFR2 genetic alteration and/or the FGFR3 genetic alteration comprises an activating tumor FGFR2 or FGFR3 mutation or fusion.

134. The method of any one of embodiments 72, 73, 119-133, wherein the drug formulation comprises: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl- l/7-pyrazol-4-yl)quinoxalin-6-yl] ethane- 1,2-diamine) in a concentration of 50 wt% of the drug formulation;

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide;

(h) hydroxypropyl methylcellulose; and

(i) magnesium stearate.

(a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl- 177-pyrazol-4-yl)quinoxalin-6-yl] ethane- 1,2-diamine) in a concentration of 50 wt% of the drug formulation; (b) hydroxypropyl -beta-cyclodextrin in a concentration of 10 wt% of the drug formulation;

(b) hydroxypropyl -beta-cyclodextrin;

(c) microcrystalline cellulose;

(d) silicified microcrystalline cellulose;

(e) vinylpyrrolidone-vinyl acetate copolymer;

(f) colloidal silicon dioxide;

(g) hydroxypropyl methylcellulose; and

(h) magnesium stearate.

136. The method of any one of embodiments 72, 73, and 119-133, wherein the drug formulation comprises:

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(e) silicified microcrystalline cellulose in a concentration of 6 wt% of the drug formulation; (f) vinylpyrrolidone-vinyl acetate copolymer in a concentration of 6 wt% of the drug formulation;

(h) magnesium stearate in a concentration of 2 wt% of the drug formulation; or

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide; and

(h) magnesium stearate.

137. The method of any one of embodiments 72, 73, and 119-136, wherein the first material comprises AC-4075A and the second material comprises EG-80-A, optionally wherein the first material comprises AC-4075A-B20.

138. A method of treating intermediate-risk non-muscle invasive bladder cancer (IR- NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein: i) the patient is newly diagnosed or recurrent IR-NMIBC; ii) the patient is determined to have intermediate risk of recurrence or progression; iii) the patient has select FGFR genetic alterations; iv) the patient is without prior bacillus Calmette-Guerin (BCG) treatment; and v) the patient comprises one or more of the following risk factors selected from the list consisting of: a) multiple low grade (LG) tumors, b) solitary LG tumor >3 cm, c) frequent recurrence (> 1 per year), and d) recurrence after prior intravesical chemotherapy. 139. The method of embodiment 138, wherein the patient and/or population of patients have histologically confirmed diagnosis of IR-NMIBC with at least one of the following disease characterizations: i) Ta LG/G1 : recurrent; ii) Ta LG/G1 : primary & (multifocal or > 3 cm); and/or iii) Ta G2: primary or recurrent.

142. The method of embodiment 93, wherein the drug formulation comprises:

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(i) magnesium stearate in a concentration of 1.5 wt% of the drug formulation; or (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl- 177-pyrazol-4-yl)quinoxalin-6-yl] ethane- 1,2-diamine) in a concentration of 50 wt% of the drug formulation;

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide;

(h) hydroxypropyl methylcellulose; and

(i) magnesium stearate. . The method of embodiment 93, wherein the drug formulation comprises

(b) hydroxypropyl -beta-cyclodextrin;

(c) microcrystalline cellulose;

(d) silicified microcrystalline cellulose;

(e) vinylpyrrolidone-vinyl acetate copolymer; (f) colloidal silicon dioxide;

(g) hydroxypropyl methylcellulose; and

(h) magnesium stearate.

144. The method of embodiment 93, wherein the drug formulation comprises:

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(h) magnesium stearate in a concentration of 2 wt% of the drug formulation; or

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide; and

(h) magnesium stearate.

145. The method of any one of embodiments 93, and 142-144, wherein the first material comprises AC-4075A and the second material comprises EG-80-A, optionally wherein the first material comprises AC-4075A-B20. 146. The method of any one of embodiments 1-3, 12-21, 30-44, 47-52, 57-73, 82-93, 102- 110, 113-115, 118-123, 128-139, and 142-145, comprising administering about 2.5 mg/day to about 3.5 mg/day of erdafitinib to the patient.

147. The method of embodiment 52 or embodiment 123, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 2.5 mg/day to about 3.5 mg/day and the two interface edges are disposed at an arc angle of about 125 degrees to about 145 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

148. The method of any one of embodiments 142-145, comprising administering about 3 mg/day of erdafitinib to the patient.

149. The method of any one of embodiments 142-145, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 3 mg/day and the two interface edges are disposed at an arc angle of about 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

150. The method of any one of embodiments 2-19, 21-149, wherein the thickness of the second wall structure is from about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib.

151. The method of any one of embodiments 1-150, wherein the method further comprises using a urine sample assay to select patients for treatment.

152. The method of embodiment 151, wherein the urine sample assay is a urine sample NGS or PCR assay, in particular a urine sample NGS assay.

153. The method of embodiment 151 or embodiment 152, wherein the urine sample assay detects the presence of at least one FGFR2 genetic alteration and/or FGFR3 genetic alteration. 154. The method of embodiment 153, wherein the FGFR2 genetic alteration and/or the FGFR3 genetic alteration comprises an activating tumor FGFR2 or FGFR3 mutation or fusion.

155. The method of embodiment 154, wherein the FGFR2 genetic alteration and/or the FGFR3 genetic alteration is selected from FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, in particular FGFR3-TACC3 VI or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof, in particular wherein the FGFR2 genetic alteration and/or the FGFR3 genetic alteration is selected from FGFR3-TACC3 variant 1 (FGFR3-TACC3 VI) , FGFR3 G370C, FGFR3 S249C, FGFR3 Y373C, and FGFR3 R248C.

156. The method of any one of embodiments 151-155, wherein at least 50%, 60%, 70%, 80%, or 90% of treated patients selected by the urine sample assay were recurrence-free or achieved a complete response.

157. The method of any one of embodiments 151-156, wherein at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% of treated patients selected by the urine sample assay were recurrence-free or achieved a complete response.

158. A drug delivery system, comprising: a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 2.5 mg/day to about 3.5 mg/day, and wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

159. A drug delivery system, comprising: a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 3 mg/day and wherein the two interface edges are disposed at an arc angle of about 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

160. The drug delivery system of embodiment 158 or embodiment 159, comprising 42-46 erdafitinib minitablets.

161. The drug delivery system of embodiment 160, comprising 43 erdafitinib minitablets.

162. The drug delivery system of any one of embodiments 158-161, wherein the first material comprises AC-4075A and the second material comprises EG-80-A, optionally wherein the first material comprises AC-4075A-B20. 163. The drug delivery system of any one of embodiments 158-162, wherein the drug formulation comprises:

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide;

(h) hydroxypropyl methylcellulose; and

(i) magnesium stearate.

164. The drug delivery system of any one of embodiments 158-162, wherein the drug formulation comprises (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl- 177-pyrazol-4-yl)quinoxalin-6-yl] ethane- 1,2-diamine) in a concentration of 50 wt% of the drug formulation;

(b) hydroxypropyl -beta-cyclodextrin;

(c) microcrystalline cellulose;

(d) silicified microcrystalline cellulose;

(e) vinylpyrrolidone-vinyl acetate copolymer;

(f) colloidal silicon dioxide;

(g) hydroxypropyl methylcellulose; and

(h) magnesium stearate.

165. The drug delivery system of any one of embodiments 158-162, wherein the drug formulation comprises:

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(d) microcrystalline cellulose in a concentration of 24.5 wt% of the drug formulation; (e) silicified microcrystalline cellulose in a concentration of 6 wt% of the drug formulation;

(h) magnesium stearate in a concentration of 2 wt% of the drug formulation; or

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide; and

(h) magnesium stearate.

166. The drug delivery system of any one of embodiments 158-165, wherein the first wall structure and the second wall structure have a thickness between about 0.2 mm to about 1.0 mm.

167. The drug delivery system of any one of embodiments 158-166, wherein the second wall structure has a thickness, wherein the thickness of the second wall structure is from about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib.

168. The drug delivery system of any one of embodiments 158-167, wherein the drug formulation comprises minitablets, wherein each minitablet has a weight that is between about 22 mg and about 24 mg.

169. The drug delivery system of any one of embodiments 158-168, wherein the drug formulation comprises minitablets, wherein each minitablet has a weight that is about 23 mg. 170. The drug delivery system of any one of embodiments 158-169, wherein the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm.

171. The drug delivery system of any one of embodiments 158-170, wherein the drug formulation comprises minitablets, wherein each minitablet has a thickness that is about 3.2 mm.

172. The drug delivery system of any one of embodiments 158-171, wherein the drug formulation comprises minitablets, wherein each minitablet has a diameter is that between about 2.60 mm to about 2.66 mm.

173. The drug delivery system of any one of embodiments 158-172, wherein the drug formulation comprises minitablets, wherein each minitablet has a diameter that is about 2.63 mm.

174. The drug delivery system of any one of embodiments 158-173, wherein the tube of the drug reservoir lumen has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm.

175. The drug delivery system of any one of embodiments 158-174, wherein the housing of the drug delivery system comprises a retention frame lumen and a wireform disposed in the retention frame lumen.

176. The drug delivery system of embodiment 175, wherein the wireform has a diameter that is about 0.305 mm and a length that is about 156 mm.

177. The drug delivery system of embodiment 175 or embodiment 176, wherein the wireform is a ni tinol wire.

178. The drug delivery system of any one of embodiments 158-177, comprising a plurality of the minitablets arranged in series and defining a drug core length between a first face of a first minitablet and an opposed second face of a last minitablet. 179. The drug delivery system of embodiment 178, wherein the drug core length is about 15 cm.

180. The drug delivery system of any one of embodiments 158-179, wherein the second material of the drug delivery system defines a wall thickness extending along the diameter of the of the drug reservoir lumen that is 0.2 ± 0.04 mm.

181. The drug delivery system of any one of embodiments 158-180, wherein the drug reservoir lumen defines an inner diameter that is 2.64 ± 0.05 mm.

182. The drug delivery system of any one of embodiments 158-181, wherein the drug delivery system is elastically deformable between a coiled retention shape and a relatively straightened insertion shape.

183. The drug delivery system of embodiment 182, wherein the coiled retention shape comprises a bi-oval shape.

184. The drug delivery system of embodiment 182 or embodiment 183, wherein, when in the coiled retention shape, the drug delivery system has a maximum dimension in any direction that is less than about 6 cm.

185. The drug delivery system of any one of embodiments 182-184, wherein, when in the coiled retention shape, the drug delivery system has a maximum dimension in any direction that is less than about 5.5 cm.

186. The drug delivery system of any one of embodiments 182-185, wherein, when in the coiled retention shape, the drug delivery system fits within an envelope of 5.5 cm by 4.5 cm.

187. The method of any one of embodiments 1-19, 38-89, and 110-137 wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib, is at least 75%, at least 80%, or at least 85%, in particular wherein the 12-month RFS rate is about 88%. 188. The method of embodiment 20-68 and 90-137, wherein such treatment results in a complete response rate of at least 80%, at least 85%, or at least 90% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib.

189. The method of embodiment 20-68, 90-137 and 188, wherein such treatment results in a complete response rate of about 93% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib.

190. The method of any one of embodiments 20-68, 90-137, and 188-189, wherein the patient achieves a complete response (CR), further comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days following a low grade papillary only recurrence.

191. A method of treating non-muscle invasive bladder cancer in a patient comprising: deploying the drug delivery system according to any one of embodiments 158 to 186 to the bladder of the patient; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; and removing the drug delivery system at least about 90 days later.

192. The method of embodiment 191, wherein the cancer is intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC).

193. The method of embodiment 192, wherein the cancer is newly diagnosed intermediaterisk non-muscle invasive bladder cancer (IR-NMIBC).

194. The method of embodiment 192, wherein the cancer is recurrent intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC).

195. The method of any one of embodiments 191 to 194, wherein the cancer harbors an FGFR alteration. 196. The method of any one of embodiments 191 to 195, wherein the patient did not receive recent bacillus Calmette-Guerin (BCG) treatment.

197. The method of any one of embodiments 191 to 196, wherein the patient has 1 or more of the following risk factors: multiple low grade (LG) tumors, solitary LG tumor >3 cm, early recurrence of LG tumor (<1 year), frequent recurrence (> 1 per year), or recurrence after prior intravesical chemotherapy.

198. The method of embodiment 2-19, 21-66, 72-137, and 150-157, wherein the second wall structure forms an arc that corresponds to the arc angle.

199. The method of any one of embodiments 20-21, 32-66, 90-93, 104-140, and 198, wherein such treatment results in a median duration of response of at least 12 months, or is about 12 months.

200. The method of any one of embodiments 20-21, 32-66, 90-93, 104-140, and 198, wherein such treatment results in a complete response rate of about 90% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, the complete response rate assessed at 12 weeks.

201. The method of any one of embodiments 1-19, 38-73, 83-89, 110-137, 146-147, 150, 187 and 198, wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib, and in particular the 12-month RFS rate, is about 90%.

202. The method of any one of embodiments 20-21, 32-66, 90-93, 104-140, and 198, wherein such treatment results in a complete response rate of about 85% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, the complete response rate assessed at 12 weeks.

203. The method of any one of embodiments 1-19, 38-73, 83-89, 110-137, 146-147, 150, and 187, wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib, and in particular the 12-month RFS rate, is about 75% or about 79% or about 80%.

204. The drug delivery system of any one of embodiments 158-162 and 166-186, wherein the erdafitinib is erdafitinib free base.

THIRD LIST OF ENUMERATED EMBODIMENTS

2. A method of treating recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; removing the drug delivery system at least about 90 days later; wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment.

3. The method of embodiment 1 or 2, wherein the patient and/or population of patients have high grade Ta or T1 bladder cancer. 4. The method of any one of embodiments 1-3, wherein the recurrence-free rate in a population of patients treated with about 2 mg/day of erdafitinib is at least 75%, 80%, or 85%, in particular wherein the recurrence-free rate is about 80%.

10. The method of any one of embodiments 1-3 and 8-9, wherein such treatment results in a progressive disease rate of less than 10%, 8%, 6%, 4%, 2%, or 1% in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the progressive disease rate is about 0%. 11. The method of any one of embodiments 1-3 and 8-10, wherein the 6-month recurrence-free survival rate is at least 0.7 in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the 6-month recurrence-free survival rate is about 0.83.

21. A method of treating recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising: deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; and removing the drug delivery system at least about 90 days later; wherein such treatment results in an at least 50% complete response rate in a population of patients receiving such treatment.

38. The method of any one of embodiments 1-37, wherein the erdafitinib is delivered to the urine in the bladder of the patient.

48. The method of any one of embodiments 1, 3-20, and 22-47, wherein administering about 2 mg/day to about 4 mg/day of erdafitinib comprises deploying an intravesical drug delivery system comprising erdafitinib to the bladder of the patient and removing the drug delivery system about 90 days later, in particular wherein the intravesical drug delivery system comprises a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure.

50. The method of any one of embodiments 48-49 comprising: i) deploying a first drug delivery system comprising erdafitinib to the bladder of the patient on day 0; ii) removing the first drug delivery system on about day 90; iii) deploying a second drug delivery system comprising erdafitinib to the bladder of the patient on about day 90; iv) removing the second drug delivery system on about day 180; v) deploying a third drug delivery system comprising erdafitinib to the bladder of the patient on day 180; vi) removing the third drug delivery system on about day 270; vii) deploying a fourth drug delivery system comprising erdafitinib to the bladder of the patient on about day 270; and viii) removing the fourth drug delivery system on about day 360.

(a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl-17T- pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the drug formulation;

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide;

(h) hydroxypropyl methylcellulose; and

(i) magnesium stearate. 64. The method of any one of embodiments 2, 21, and 48-62, wherein the drug formulation comprises:

(b) hydroxypropyl -beta-cyclodextrin;

(c) microcrystalline cellulose;

(d) silicified microcrystalline cellulose;

(e) vinylpyrrolidone-vinyl acetate copolymer;

(f) colloidal silicon dioxide;

(g) hydroxypropyl methylcellulose; and

(h) magnesium stearate.

(a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl-17T- pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the drug formulation; (b) hydroxypropyl -beta-cyclodextrin in a concentration of 10 wt% of the drug formulation;

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(h) magnesium stearate in a concentration of 2 wt% of the drug formulation; or

(a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl-lJT- pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the drug formulation;

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide; and

(h) magnesium stearate.

72. A method of embodiment 69 or embodiment 70 comprising: deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; removing the drug delivery system at least about 90 days later; wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment.

80. The method of any one of embodiments 69-73 and 78-79, wherein such treatment results in a progressive disease rate of less than 10%, 8%, 6%, 4%, 2%, or 1% in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the progressive disease rate is about 0%. 81. The method of any one of embodiments 69-73 and 78-80, wherein the 6-month recurrence-free survival rate is at least 0.7 in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the 6-month recurrence-free survival rate is about 0.83.

90. The method of any one of embodiments 66-68, wherein the cancer is intermediate risk non-muscle invasive bladder cancer (IR-NMIBC). 91. The method of embodiment 90 wherein the IR-NMIBC is recurrent IR-NMIBC.

93. The method of embodiment 90 or embodiment 91, comprising: deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; and removing the drug delivery system at least about 90 days later; wherein such treatment results in an at least 50% complete response rate in a population of patients receiving such treatment.

95. The method of any one of embodiments 90-94, wherein such treatment results in a low-grade recurrence rate of less than 5%, 4%, 3%, 2%, or 1% in the population of patients treated with about 2 mg/day of erdafitinib, in particular, wherein the low-grade recurrence rate is about 0%. 96. The method of any one of embodiments 90-95, wherein such treatment results in a high-grade recurrence rate less than 5%, 4%, 3%, 2%, or 1% in the population of patients treated with about 2 mg/day of erdafitinib, in particular, wherein the high-grade recurrence rate is about 0%.

100. The method of any one of embodiments 90-93 and 98-99, wherein such treatment results in a high-grade recurrence rate less than 5%, 4%, 3%, 2%, or 1% in a population of patients treated with about 4 mg/day of erdafitinib, in particular, wherein the high-grade recurrence rate is about 0%.

102. The method of any one of embodiments 90-101, wherein such treatment results in a 6- month duration of response of at least 0.8, 0.85, 0.9, or 0.95. 103. The method of any one of embodiments 90-93, wherein such treatment results in a complete response rate of at least 60%, 65%, 70%, or 75% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular, wherein the complete response rate is about 87%, such as about 86.7%, wherein the complete response rate is assessed at 3 months or 90 days of the erdafitinib treatment.

106. The method of any one of embodiments 90-105, wherein the patient and/or population of patients have not previously had carcinoma in situ.

111. The method of any one of embodiments 66-77, 82-97, and 102-110, comprising administering about 2 mg/day erdafitinib to the patient, wherein the urine concentration of erdafitinib is about 500 ng/mL to about 2000 ng/mL, about 500 ng/mL to about 1500 ng/mL, or about 1000 ng/mL to about 2000 ng/mL. 112. The method of any one of embodiments 66-73, 78-93, and 98-110, comprising administering about 4 mg/day erdafitinib to the patient, wherein the urine concentration of erdafitinib is about 1000 ng/mL to about 3500 ng/mL, about 1000 ng/mL to about 2500 ng/mL, or about 2000 ng/mL to about 3500 ng/mL.

119. The method of any one of embodiments 66-118, wherein administering about 2 mg/day to about 4 mg/day of erdafitinib comprises deploying an intravesical drug delivery system comprising erdafitinib to the bladder of the patient and removing the drug delivery system about 90 days later. 120. The method of any one of embodiments 72, 93, and 119, wherein the drug formulation comprises about 500 mg of erdafitinib, optionally wherein the erdafitinib is erdafitinib free base.

121. The method of any one of embodiments 72, 93, 119, and 120, comprising: i) deploying a first drug delivery system comprising erdafitinib to the bladder of the patient on day 0; ii) removing the first drug delivery system on about day 90; iii) deploying a second drug delivery system comprising erdafitinib to the bladder of the patient on about day 90; iv) removing the second drug delivery system on about day 180; v) deploying a third drug delivery system comprising erdafitinib to the bladder of the patient on day 180; vi) removing the third drug delivery system on about day 270; vii) deploying a fourth drug delivery system comprising erdafitinib to the bladder of the patient on about day 270; and viii) removing the fourth drug delivery system on about day 360.

124. The method of embodiment 123, wherein the two interface edges are disposed at an arc angle of 45 degrees to 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. 125. The method of embodiment 124, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg/day and the two interface edges are disposed at an arc angle of about 90 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

126. The method of embodiment 123, wherein the two interface edges are disposed at an arc angle of 150 degrees to 270 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube.

133. The method of embodiment 132, wherein the FGFR2 genetic alteration and/or the FGFR3 genetic alteration comprises an activating tumor FGFR2 or FGFR3 mutation or fusion. 134. The method of any one of embodiments 72, 73, 119-133, wherein the drug formulation comprises:

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide;

(h) hydroxypropyl methylcellulose; and

(i) magnesium stearate.

135. The method of any one of embodiments 72, 73, and 119-133, wherein the drug formulation comprises: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl- IT/- pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the drug formulation;

(b) hydroxypropyl -beta-cyclodextrin;

(c) microcrystalline cellulose;

(d) silicified microcrystalline cellulose;

(e) vinylpyrrolidone-vinyl acetate copolymer;

(f) colloidal silicon dioxide;

(g) hydroxypropyl methylcellulose; and

(h) magnesium stearate.

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(h) magnesium stearate in a concentration of 2 wt% of the drug formulation; or

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide; and

(h) magnesium stearate.

138. A method of treating intermediate-risk non-muscle invasive bladder cancer (IR- NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein: i) the patient is newly diagnosed or recurrent IR-NMIBC; ii) the patient is determined to have intermediate risk of recurrence or progression; iii) the patient has select FGFR genetic alterations; iv) the patient is without prior bacillus Calmette-Guerin (BCG) treatment; and v) the patient comprises one or more of the following risk factors selected from the list consisting of a) multiple low grade (LG) tumors, b) solitary LG tumor >3 cm, c) frequent recurrence (> 1 per year), and d) recurrence after prior intravesical chemotherapy.

140. The method of any one of embodiments 1-3, 12-21, 30-44, 47-52, 57-73, 82-93, 102- 110, 113-115, 118-123, and 128-139, comprising administering about 3 mg/day of erdafitinib to the patient.

142. The method of embodiment 93, wherein the drug formulation comprises:

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(a) erdafitinib free base (N-(3,5-dirnethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl- l//- pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the drug formulation;

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide;

(h) hydroxypropyl methylcellulose; and

(i) magnesium stearate. . The method of embodiment 93, wherein the drug formulation comprises:

(b) hydroxypropyl -beta-cyclodextrin;

(c) microcrystalline cellulose;

(d) silicified microcrystalline cellulose; (e) vinylpyrrolidone-vinyl acetate copolymer;

(f) colloidal silicon dioxide;

(g) hydroxypropyl methylcellulose; and

(h) magnesium stearate.

144. The method of embodiment 93, wherein the drug formulation comprises:

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(h) magnesium stearate in a concentration of 2 wt% of the drug formulation; or

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide; and

(h) magnesium stearate.

155. The method of embodiment 153 or 154, wherein the FGFR2 genetic alteration and/or the FGFR3 genetic alteration is selected from FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, in particular FGFR3-TACC3 VI or FGFR3- TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof, in particular wherein the FGFR2 genetic alteration and/or the FGFR3 genetic alteration is selected from FGFR3-TACC3 variant 1 (FGFR3-TACC3 VI) , FGFR3 G370C, FGFR3 S249C, FGFR3 Y373C, and FGFR3 R248C.

158. A drug delivery system, comprising: a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 2.5 mg/day to about 3.5 mg/day, and wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure.

159. A drug delivery system, comprising: a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 3 mg/day and wherein the two interface edges are disposed at an arc angle of about 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure.

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide;

(h) hydroxypropyl methylcellulose; and

(i) magnesium stearate.

164. The drug delivery system of any one of embodiments 158-162, wherein the drug formulation comprises: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl- IT/- pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the drug formulation;

(b) hydroxypropyl -beta-cyclodextrin;

(c) microcrystalline cellulose;

(d) silicified microcrystalline cellulose;

(e) vinylpyrrolidone-vinyl acetate copolymer;

(f) colloidal silicon dioxide;

(g) hydroxypropyl methylcellulose; and

(h) magnesium stearate.

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(h) magnesium stearate in a concentration of 2 wt% of the drug formulation; or

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide; and

(h) magnesium stearate.

174. The drug delivery system of any one of embodiments 158-173, wherein the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm.

180. The drug delivery system of any one of embodiments 158-179, wherein the second material of the drug delivery system defines a wall thickness extending along the diameter of the drug reservoir lumen that is 0.2 ± 0.04 mm.

184. The drug delivery system of embodiment 182 or embodiment 183, wherein, when in the coiled retention shape, the drug delivery system has a maximum dimension in any direction that is equal to or less than about 6 cm.

185. The drug delivery system of any one of embodiments 182-184, wherein, when in the coiled retention shape, the drug delivery system has a maximum dimension in any direction that is equal to or less than about 5.5 cm.

187. The drug delivery system of any one of embodiments 158-186, wherein the erdafitinib is erdafitinib free base.

188. The method of any one of embodiments 1-19, 38-89, and 110-137, wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib, is at least 75%, at least 80%, or at least 85%, in particular wherein the 12-month RFS rate is about 88%.

189. The method of any one of embodiments 20-68 and 90-137, wherein such treatment results in a complete response rate of at least 80%, at least 85%, or at least 90% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib.

190. The method of any one of embodiments 20-68, 90-137 and 189, wherein such treatment results in a complete response rate of about 93% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib.

191. The method of any one of embodiments 20-68, 90-137, and 189-190, wherein the patient achieves a complete response (CR), further comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days following a low grade papillary only recurrence.

192. A method of treating non-muscle invasive bladder cancer in a patient comprising: deploying the drug delivery system according to any one of embodiments 158 to 187 to the bladder of the patient; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; and removing the drug delivery system at least about 90 days later.

193. The method of embodiment 192, wherein the cancer is intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC).

194. The method of embodiment 193, wherein the cancer is newly diagnosed intermediaterisk non-muscle invasive bladder cancer (IR-NMIBC).

195. The method of embodiment 193, wherein the cancer is recurrent intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC). 196. The method of any one of embodiments 192 to 195, wherein the cancer harbors an FGFR alteration.

197. The method of embodiment 196, wherein the FGFR alteration is a FGFR2 alteration or a FGFR3 alteration.

198. The method of embodiment 196 or 197, wherein the FGFR alteration is a FGFR3 alteration, in particular a FGFR3 mutation or a FGFR3 fusion.

199. The method of embodiment 198, wherein the FGFR3 alteration is at least one of FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, in particular FGFR3-TACC3 variant 1 (FGFR3-TACC3 VI) or FGFR3-TACC3 variant 3 (FGFR3-TACC3 V3), FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

200. The method of any one of embodiments 192 to 199, wherein the patient did not receive recent bacillus Calmette-Guerin (BCG) treatment.

201. The method of any one of embodiments 192 to 200, wherein the patient has 1 or more of the following risk factors: multiple low grade (LG) tumors, solitary LG tumor >3 cm, early recurrence of LG tumor (<1 year), frequent recurrence (> 1 per year), or recurrence after prior intravesical chemotherapy.

202. The method of any one of embodiments 51-58, 122-137 and 142-157, wherein both the first wall structure and the second wall structure are permeable to water.

203. The method of any one of embodiments 2, 21, 48, 72, 93, and 119, wherein the drug formulation comprises about 480 mg to about 510 mg of erdafitinib, optionally wherein the erdafitinib is erdafitinib free base.

204. The method of any one of embodiments 20-21, 32-66, 90-93, and 104-140, wherein such treatment results in a median duration of response of at least 12 months, or is about 12 months. 205. The method of any one of embodiments 20-21, 32-66, 90-93, and 104-140, wherein such treatment results in a complete response rate of about 90% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, the complete response rate assessed at 12 weeks.

206. The method of any one of embodiments 1-19, 38-73, 83-89, 110-137, 146-147, 150, and 188, wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib, and in particular the 12-month RFS rate, is about 90%.

207. The method of any one of embodiments 20-21, 32-66, 90-93, and 104-140, wherein such treatment results in a complete response rate of about 85% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, the complete response rate assessed at 12 weeks.

208. The method of any one of embodiments 1-19, 38-73, 83-89, 110-137, 146-147, 150, and 188, wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib, and in particular the 12-month RFS rate, is about 75% or about 79% or about 80%.

FOURTH LIST OF ENUMERATED EMBODIMENTS

1. A drug delivery system, comprising: a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising a salt of erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release erdafitinib at an average rate of about 2.5 mg/day to about 3.5 mg/day, and wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure.

2. A drug delivery system, comprising: a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising a salt of erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release erdafitinib at an average rate of about 3 mg/day and wherein the two interface edges are disposed at an arc angle of about 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure.

3. The drug delivery system of embodiment 2 or embodiment 3, comprising 42-46 erdafitinib minitablets.

4. The drug delivery system of embodiment 3, comprising 43 erdafitinib minitablets. 5. The drug delivery system of any one of embodiments 1-4, wherein the first material comprises AC-4075A and the second material comprises EG-80-A, optionally wherein the first material comprises AC-4075A-B20.

6. The drug delivery system of any one of embodiments 1-5, wherein the drug formulation comprises:

(a) a pharmaceutically acceptable salt of erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(l- methylethyl)-N-[3-(l-methyl-17/-pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the drug formulation;

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide;

(h) hydroxypropyl methylcellulose; and

(i) magnesium stearate. 7. The drug delivery system of any one of embodiments 1-5, wherein the drug formulation comprises:

(b) hydroxypropyl -beta-cyclodextrin;

(c) microcrystalline cellulose;

(d) silicified microcrystalline cellulose;

(e) vinylpyrrolidone-vinyl acetate copolymer;

(f) colloidal silicon dioxide;

(g) hydroxypropyl methylcellulose; and

(h) magnesium stearate.

8. The drug delivery system of any one of embodiments 1-5, wherein the drug formulation comprises:

(a) a pharmaceutically acceptable salt of erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(l- methylethyl)-N-[3-(l-methyl-17/-pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the drug formulation; (b) hydroxypropyl -beta-cyclodextrin in a concentration of 10 wt% of the drug formulation;

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(h) magnesium stearate in a concentration of 2 wt% of the drug formulation; or

(a) a pharmaceutically acceptable salt of erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(l- methylethyl)-N-[3-(l-methyl-lJ/-pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the drug formulation;

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide; and

(h) magnesium stearate.

9. The drug delivery system of any one of embodiments 1-8, wherein the first wall structure and the second wall structure have a thickness between about 0.2 mm to about 1.0 mm.

10. The drug delivery system of any one of embodiments 1-9, wherein the second wall structure has a thickness, wherein the thickness of the second wall structure is from about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to erdafitinib.

11. The drug delivery system of any one of embodiments 1-10, wherein the drug formulation comprises minitablets, wherein each minitablet has a weight that is between about 22 mg and about 24 mg. 12. The drug delivery system of any one of embodiments 1-11, wherein the drug formulation comprises minitablets, wherein each minitablet has a weight that is about 23 mg.

13. The drug delivery system of any one of embodiments 1-12, wherein the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm.

14. The drug delivery system of any one of embodiments 1-13, wherein the drug formulation comprises minitablets, wherein each minitablet has a thickness that is about 3.2 mm.

15. The drug delivery system of any one of embodiments 1-14, wherein the drug formulation comprises minitablets, wherein each minitablet has a diameter is that between about 2.60 mm to about 2.66 mm.

16. The drug delivery system of any one of embodiments 1-15, wherein the drug formulation comprises minitablets, wherein each minitablet has a diameter that is about 2.63 mm.

17. The drug delivery system of any one of embodiments 1-16, wherein the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm.

18. The drug delivery system of any one of embodiments 1-17, wherein the housing of the drug delivery system comprises a retention frame lumen and a wireform disposed in the retention frame lumen.

19. The drug delivery system of embodiment 18, wherein the wireform has a diameter that is about 0.305 mm and a length that is about 156 mm.

20. The drug delivery system of embodiment 18 or embodiment 19, wherein the wireform is a nitinol wire. 21. The drug delivery system of any one of embodiments 1-20, comprising a plurality of the minitablets arranged in series and defining a drug core length between a first face of a first minitablet and an opposed second face of a last minitablet.

22. The drug delivery system of embodiment 21, wherein the drug core length is about 15 cm.

23. The drug delivery system of any one of embodiments 1-22, wherein the second material of the drug delivery system defines a wall thickness extending along the diameter of the drug reservoir lumen that is 0.2 ± 0.04 mm.

24. The drug delivery system of any one of embodiments 1-23, wherein the drug reservoir lumen defines an inner diameter that is 2.64 ± 0.05 mm.

25. The drug delivery system of any one of embodiments 1-24, wherein the drug delivery system is elastically deformable between a coiled retention shape and a relatively straightened insertion shape.

26. The drug delivery system of embodiment 25, wherein the coiled retention shape comprises a bi-oval shape.

27. The drug delivery system of embodiment 25 or embodiment 26, wherein, when in the coiled retention shape, the drug delivery system has a maximum dimension in any direction that is equal to or less than about 6 cm.

28. The drug delivery system of any one of embodiments 25-27, wherein, when in the coiled retention shape, the drug delivery system has a maximum dimension in any direction that is equal to or less than about 5.5 cm.

29. The drug delivery system of any one of embodiments 25-28, wherein, when in the coiled retention shape, the drug delivery system fits within an envelope of 5.5 cm by 4.5 cm.

30. The drug delivery system of any one of embodiments 1-29, wherein the salt of erdafitinib is erdafitinib HC1. 31. A method of treating non-muscle invasive bladder cancer in a patient comprising: deploying the drug delivery system according to any one of embodiments 1-30 to the bladder of the patient; releasing erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; and removing the drug delivery system at least about 90 days later.

32. The method of embodiment 31, wherein the cancer is intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC).

33. The method of embodiment 32, wherein the cancer is newly diagnosed intermediaterisk non-muscle invasive bladder cancer (IR-NMIBC).

34. The method of embodiment 32, wherein the cancer is recurrent intermediate-risk non- muscle invasive bladder cancer (IR-NMIBC).

35. The method of any one of embodiments 31-34, wherein the cancer harbors an FGFR alteration.

36. The method of embodiment 35, wherein the FGFR alteration is a FGFR2 alteration or a FGFR3 alteration.

37. The method of embodiment 36, wherein the FGFR alteration is a FGFR3 alteration, in particular a FGFR3 mutation or a FGFR3 fusion.

38. The method of embodiment 38, wherein the FGFR3 alteration is at least one of FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, in particular FGFR3-TACC3 variant 1 (FGFR3-TACC3 VI) or FGFR3-TACC3 variant 3 (FGFR3-TACC3 V3), FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

39. The method of any one of embodiments 31-38, wherein the patient did not receive recent bacillus Calmette-Guerin (BCG) treatment. 40. The method of any one of embodiments 31-39, wherein the patient has 1 or more of the following risk factors: multiple low grade (LG) tumors, solitary LG tumor >3 cm, early recurrence of LG tumor (<1 year), frequent recurrence (> 1 per year), or recurrence after prior intravesical chemotherapy.

41. The drug delivery system of any one of embodiments 1-30, wherein both the first wall structure and the second wall structure, are permeable to water.

42. The drug delivery system of any one of embodiments 1-41, wherein the drug formulation comprises about 480 mg to about 510 mg of a salt of erdafitinib.

43. The method of any one of embodiments 31-40, wherein such treatment results in a median duration of response of at least 12 months, or is about 12 months.

44. The method of any one of embodiments 32-40, wherein such treatment results in a complete response rate of about 90% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, the complete response rate assessed at 12 weeks.

45. The method of any one of embodiments 32-40, wherein such treatment results in a complete response rate of about 85% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, the complete response rate assessed at 12 weeks.

46. The method of embodiment 31, wherein the cancer is high-risk non-muscle invasive bladder cancer (HR-NMIBC).

47. The method of embodiment 46, wherein the cancer harbors an FGFR alteration.

48. The method of embodiment 47, wherein the FGFR alteration is a FGFR2 alteration or a FGFR3 alteration.

49. The method of embodiment 48, wherein the FGFR alteration is a FGFR3 alteration, in particular a FGFR3 mutation or a FGFR3 fusion. 50. The method of embodiment 49, wherein the FGFR3 alteration is at least one of FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, in particular FGFR3-TACC3 variant 1 (FGFR3-TACC3 VI) or FGFR3-TACC3 variant 3 (FGFR3-TACC3 V3), FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

51. The method of any one of embodiments 46-50, wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib, and in particular the 12-month RFS rate, is about 90%.

52. The method of any one of embodiments 46-50, wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib, and in particular the 12-month RFS rate, is about 75% or about 79% or about 80%.

EXAMPLES

[0428] The examples below are intended to be purely exemplary of the invention and should therefore not be considered to limit the invention in any way. The following examples and detailed description are offered by way of illustration and not by way of limitation.

[0429] Organ-confined bladder cancer is a global unmet need as reflected by high morbidity and limited improvements in treatment over the past 2 decades. Globally, bladder cancer is the sixth and the 17^th most commonly occurring cancer in men and women, respectively. There were nearly 550,000 new cases of bladder cancer diagnosed worldwide in 2018. Most bladder cancers are initially diagnosed in the early stages of the disease with 70% to 75% presenting as non -muscle invasive bladder cancer (NMIBC) and 25% to 30% as muscle invasive bladder cancer (MIBC).

[0430] Progression of the disease is a devastating life-changing event that often results in bladder removal for patients eligible for surgery. Following surgery, and for a large proportion of patients who are unfit for surgery, tumors often reoccur and progress to metastatic disease where the 5-year survival rate is 5%. New therapies are particularly difficult to develop because only a small fraction of systemically administered agents reach the tumors located in the urothelium. Therefore, there is a significant need for new targeted therapies to treat early disease and prevent progression to the invasive forms of bladder cancer.

[0431] The following examples are included for illustrative purposes only and are not intended to limit the scope of the present disclosure.

Example 1: Clinical Evaluation of Intravesical Drug Delivery System in Participants with Bladder Cancer

Study Design

[0432] This study was an open-label, multicenter, clinical study of the safety and efficacy of the intravesical drug delivery system in two cohorts of adult participants with either high- risk papillary non-muscle invasive bladder cancer (NMIBC) (Cohort 1) or intermediate-risk NMIBC (Cohort 3) who had select FGFR mutations or fusions.

[0433] The two cohorts enrolled in this study included: Cohort 1, recurrent, BCG- experienced high-risk papillary NMIBC (high-grade Ta/Tl), no carcinoma in situ (CIS), refusing or ineligible for radical cystectomy (RC); participants with no BCG experience because BCG was not available as a treatment option in the participant’s location within the previous 2 years and was unavailable at the time of the study as well as participants who received an abbreviated course of BCG due to toxicity were also eligible; and Cohort 3, recurrent, intermediate-risk NMIBC (Ta and Tl) with previous history of only low-grade disease. For Cohort 1, all visible tumor(s) had to be completely resected prior to the start of study treatment and documented on screening cystoscopy. For Cohort 3, participants did not undergo complete TURBT, as visible tumor (e.g., visible target lesions) were required at the start of study treatment.

[0434] This dose escalation study evaluated the intravesical drug delivery system (comprising about 500 mg erdafitinib) having two different release rates: about 2 mg/day of erdafitinib (TAR-210-B) and about 4 mg/day of erdafitinib (TAR-210-D) (FIG. 9A). Treatment response was assessed every 3 months with continued treatment up to 1 year if recurrence-free (RF) in Cohort 1 or in complete response (CR) in Cohort 3 (FIG. 9B).

[0435] According to the timeline in FIG. 9B, prior to treatment, TURBT was performed to resect all (Cohort 1) or some (Cohort 3) of the existing tumor. On Day 1, the intravesical drug delivery system was delivered to the patient’s bladder for 3 months (about 90 days). On day 43 (-/+ 2 days) and day 90 (-/+ 2 days), patients were examined by cystoscopy (with a biopsy of visible lesions if present). On day 90 (-/+ 4 days), the first intravesical drug delivery system was removed and a response assessment and/or biopsy was conducted on the patient. If the patient was RF or achieved a CR, a second intravesical drug delivery system was delivered to the patient’s bladder for 3 months (about 90 days). During the second treatment window of about 90 days, the patient was examined by cystoscopy (with a biopsy of visible lesions if present) on day 180 (-/+ 4 days). On day 180 (-/+ 4 days), the second intravesical drug delivery system was removed and a response assessment and/or biopsy was conducted on the patient. If the patient was RF or achieved a CR, a third intravesical drug delivery system was delivered to the patient’s bladder for 3 months (about 90 days). During the third treatment window of about 90 days, the patient was examined by cystoscopy (with a biopsy of visible lesions if present) on day 270 (-/+ 4 days). On day 270 (-/+ 4 days), the third intravesical drug delivery system was removed and a response assessment and/or biopsy was conducted on the patient. If the patient was RF or achieved a CR, a fourth intravesical drug delivery system was delivered to the patient’s bladder for 3 months (about 90 days). During the fourth treatment window of about 90 days, the patient was examined by cystoscopy (with a biopsy of visible lesions if present) on day 360 (-/+ 4 days). On day 360 (-/+ 4 days), the fourth intravesical drug delivery system was removed and a response assessment and/or biopsy was conducted on the patient.

Study Primary Objectives

[0436] For part 1 of the study (dose escalation), the primary study objective was to determine the RP2D(s) (recommended phase 2 dose(s)) for TAR-210 or to determine the clinical dose(s) for the next clinical trial(s). For part 2 of the study (dose expansion), the primary study objective was to determine the safety of intravesical drug delivery system, wherein the intravesical drug delivery system releases erdafitinib at about 2 mg/day of erdafitinib (TAR-210-B) and at about 4 mg/day of erdafitinib (TAR-210-D) for up to 12 months.

[0437] Part 3 was added to the dose expansion part of the study to evaluate TAR-210-C (releasing approximately 3 mg/day of erdafitinib). In part 3, the primary objective was to determine the safety of intravesical drug delivery system (TAR-210) administered at the recommended clinical dose(s) (TAR-210-C) for up to 12 months.

Study Primary Endpoint

[0438] The primary endpoint evaluated in this study was incidence and severity of adverse effects (AE), including dose-limiting toxicity (DLT).

Study Secondary Objectives [0439] The secondary objectives evaluated in this study included 1) assessing pharmacokinetics (PK) of intravesical drug delivery system administered at the recommended clinical dose(s) in urine and plasma from adult participants and 2) assessing preliminary clinical activity of intravesical drug delivery system in participants with pre-specified FGFR alterations, where recurrence-free survival (RFS) was assessed for Cohorts 1 and complete response (CR) rate and duration of complete response (DoCR) was assessed for Cohorts 3. [0440] The exploratory objections evaluated in this study included 1) exploring the relationships between PK, AE profile, and clinical activity, 2) investigating erdafitinib concentrations in tumor and/or bladder tissue, 3) investigating biomarkers indicative of target engagement, and predictive of clinical response or resistance to erdafitinib, and a fourth exploratory objective is to evaluate the safety and preliminary clinical efficacy in Cohort 3 participants who receive retreatment with the intravesical drug delivery system delivering erdafitinib.

Overview

[0441] This dose escalation study (FIG. 26A) enrolled participants from Cohorts 1 and 3 to evaluate the efficacy and safety of TAR-210-B (about 2 mg/day of erdafitinib) and TAR- 210-D (about 4 mg/day of erdafitinib). The safety of the erdafitinib formulation was confirmed in at least 3 participants, where the erdafitinib formulation composition is as described herein. Each intravesical drug delivery system included approximately 500 mg erdafitinib, with TAR-210-B having an estimated release of about 2 mg/day of erdafitinib and TAR-210-D having an estimated release of about 4 mg/day of erdafitinib. Each intravesical drug delivery system was oriented such that the two interface edges were disposed at an arc angle of 45 degrees to 90 degrees, in particular 90 degrees, or 150 degrees to 270 degrees, in particular 180 degrees, of a circumference of the tube in a cross section normal to a longitudinal axis of the tube (FIG. 2 and FIG. 3). This system provided about 90 days of local administration of erdafitinib to the bladder of each participant. The formulation contained within the intravesical drug delivery system is Formula 4B as described herein, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. In some embodiments, the formulation contained within the intravesical drug delivery system is Formula 3,4 as described herein, in particular wherein the delivery system comprises AC- 4075 A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. In some embodiments, the formulation contained within the intravesical drug delivery system is Formula 4,1 as described herein, in particular wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the ends of the intravesical drug delivery system are closed. [0442] The study included molecular eligibility, screening, treatment, and follow-up phases. Molecular eligibility was established for each potential participant before screening for other eligibility criteria, unless a fresh tumor biopsy was required to obtain tissue for FGFR testing. Tissue testing to document FGFR alterations was performed on an archived sample or from a fresh biopsy from recurrent disease. In tissue testing for FGFR alterations, local or central tumor tissue was tested by NGS or PCR. Urine circulating tumor DNA (ctDNA) was also tested for FGFR alterations. In urine testing for FGFR alterations, central urine cell-free DNA was tested by NGS. For Cohorts 1 and 3, an eligible FGFR alteration was identified prior to starting study treatment.

[0443] Treatment began on Day 1 for participants meeting all eligibility criteria, at which time participants had either TAR-210-B (about 2 mg/day of erdafitinib) or TAR-210-D (about 4 mg/day of erdafitinib) placed in the bladder with the urinary placement catheter (UPC). Following completion of the first dosing cycle, participants in Cohorts 1 and 3 underwent cystoscopy with biopsy and clinical response was assessed. Participants with a complete response (CR; Cohort 3) after cycle 2 (180 days) or who were recurrence-free (RF; Cohort 1) after cycle 1 (90 days) were able to continue to receive additional 3 -month dosing cycles with additional intravesical drug delivery systems, for a treatment duration of 1 year, so long as there is no disease recurrence or progression or unmanageable toxicity.

[0444] Participants in Cohort 3 with either a non-CR/non-progressive disease (PD) response at the end of cycle 1 received a new drug delivery system for an additional cycle. If a Cohort 3 participant did not achieve a CR following Cycle 2, therapy was discontinued. For Cycle 2, re-insertion of TAR-210 may occur if no disease is visible on cystoscopy, while biopsy results and urine cytology are pending. However, TAR-210 will be removed if pathology or imaging results confirm recurrence or progression. Non-CR/non-PD Response was defined as no new tumors or larger tumors identified on cystoscopy. Disease Progression (Cohorts 1 and 3) was defined as having post-baseline assessments of > T2 disease or positive lymph nodes or metastases.

[0445] Upon discontinuing treatment with the intravesical drug delivery system, participants had an End of Treatment (EOT) visit (30 [+7] days after last system removal). Participants in Cohorts 1 and 3, who had not recurred or progressed entered a follow-up phase and underwent disease surveillance with cystoscopy, urine cytology, and upper tract imaging for up to 3 years after Day 1, until disease recurrence or progression, a new anticancer therapy was initiated, or until the participant withdrew from the study.

[0446] The dose expansion study (Part 2, FIG. 26B) enrolled participants from Cohorts 1 and 3 to expand the investigation using TAR-210-B (about 2 mg/day of erdafitinib) or TAR- 210-D (about 4 mg/day of erdafitinib) for the treatment of additional patients, in view of the totality of the data (e.g., safety, pharmacokinetics, efficacy) collected in Part 1 dose escalation study.

[0447] The Part 3 dose expansion study (FIG. 26C) will enroll participants from Cohorts 1 and 3 to confirm the safety and evaluate pharmacokinetics and preliminary clinical activity at the selected recommended dose, TAR-210-C (about 3 mg/day of erdafitinib), which was not evaluated in Parts 1 and 2.

[0448] In Part 3, an additional dose expansion study (FIG. 26C) was performed using the recommended clinical dose, TAR-210 C (new dose with an erdafitinib release of about 3 mg/day), to (1) confirm the safety and evaluate the pharmacokinetics and preliminary clinical activity of the recommended clinical dose TAR-210 C (about 3 mg/day of erdafitinib) in approximately 12 patients in total, enrolled across both Cohorts 1 and 3; (2) to allow participants in Cohort 3 with a non-complete response (CR) and/or non-progressive disease (PD) response following Cycle 1 to continue treatment for an additional cycle; If a participant does not achieve a CR following Cycle 2, therapy should be discontinued. Note that for Cycle 2, re-insertion of TAR-210 may occur if no disease is visible on cystoscopy, while biopsy results and urine cytology are pending. However, TAR-210 will be removed if pathology or imaging results confirm recurrence or progression; (3) to allow participants in Cohort 3 who initially achieve a CR to complete 4 treatment cycles and, if participants recur while in the follow-up phase, to be retreated with TAR-210; if they achieve a CR following Cycle 1 they can continue for a total of 4 cycles of retreatment; and (4) to clarify that participants with cytology positive for high-grade urothelial carcinoma without histologic or imaging confirmation of recurrence may continue to receive TAR-210.

Inclusion Criteria

[0449] Each participant had to satisfy all of the following criteria to be enrolled in the study. Each participant was:

[0450] 1) at least 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent; [0451] 2) had muscle invasive or recurrent, non-muscle-invasive urothelial carcinoma of the bladder, where mixed histology tumors were allowed if urothelial differentiation is predominant (i.e., <20% variant histology) without the presence of micropapillary, signet ring cell, plasmacytoid, neuroendocrine, or sarcomatoid features; high-risk papillary disease (Cohort 1), defined as histologically confirmed high-grade Ta/Tl lesion, without concurrent CIS and with all visible tumor completely resected prior to the start of study treatment and documented on screening cystoscopy; or intermediate-risk papillary disease (Cohort 3) defined as all previous tumors being low grade, Ta or Tl, and no previous CIS, where cystoscopic documentation of recurrence was sufficient, negative urine cytology for high grade urothelial carcinoma was required, and visible disease (e.g., visible target lesions) was present at the time of the first intravesical drug delivery system insertion;

[0452] 3) for each Cohort: had an activating tumor FGFR mutation or fusion prior to the start of study treatment;

[0453] 4) for Cohort 1 : BCG experienced, or participants with no BCG experience because BCG was not available as a treatment option in the participant’s location within the previous 2 years or during the study, where participants who received an abbreviated course of BCG due to toxicity were still eligible, and where BCG experienced was defined as i) recurrent high-grade Ta/Tl disease within 18 months of completion of prior BCG therapy, or ii) prior BCG having minimum treatment requirements of at least 5 of 6 full doses of an initial induction course, where a full dose BCG was defined as 1 full vial containing a minimum of lxl0^A8 colony forming units; and Cohorts 3 had no predefined prior BCG or intravesical chemotherapy requirement;

[0454] 5) for Cohort 1 only, refused or was not eligible for RC;

[0455] 6) Eastern Cooperative Oncology Group (ECOG) performance status score of <2;

[0456] 7) Adequate bone marrow, liver, and renal function, where i) bone marrow function (without the support of growth factors or transfusions in preceding 2 weeks), absolute neutrophil count (ANC) >l,000/mm3, Platelet count >75,000/mm3, and hemoglobin >8.0 g/dL; ii) liver function, where total bilirubin <1.5 x the upper limit of normal (ULN) OR direct bilirubin <1.5 x ULN for participants with Gilbert’s syndrome who had total bilirubin levels >1.5 x ULN and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 x ULN; and iii) renal function, where estimated glomerular filtration rate >30 mL/min was calculated using the Modified Diet in Renal Disease (MDRD) formula.

Exclusion Criteria [0457] Any potential participant who met any of the following criteria were excluded from participating in the study:

[0458] 1) concurrent extra-vesical (i.e., urethra, ureter, renal pelvis) transitional cell carcinoma of the urothelium;

[0459] 2) prior treatment with an FGFR inhibitor;

[0460] 3) known hypersensitivity to any study component including, i) erdafitinib (or other drug excipients) or chemically related drugs, ii) the intravesical drug delivery system constituent materials, iii) urinary placement catheter (UPC) materials;

[0461] 4) received pelvic radiotherapy <6 months prior to the start of study treatment, where if received pelvic radiotherapy >6 months prior to the start of study treatment, there was no cystoscopic evidence of radiation cystitis;

[0462] 5) presence of any bladder or urethral anatomic feature that could prevent the safe placement, indwelling use, or removal of the intravesical drug delivery system;

[0463] 6) indwelling urinary catheter, where intermittent catheterization was acceptable;

[0464] 7) cystoscopic evidence of bladder perforation unless such perforation had resolved prior to dosing;

[0465] 8) bladder post-void residual volume (PVR) >350 mL after second voided urine;

[0466] 9) history of clinically significant polyuria with recorded 24-hour urine volumes

>4,000 mL;

[0467] 10) subjects with active bladder stones or history of bladder stones <6 months prior to the study treatment.

[0468] 11) active malignancies (i.e., progressing or requiring treatment change in the last

24 months) other than the disease being treated under study. Potential allowed exceptions included the following (others may be allowed with sponsor approval): (i) skin cancer (nonmelanoma or melanoma) that was considered completely cured; (ii) non-invasive cervical cancer that was considered completely cured; (iii) adequately treated lobular carcinoma in situ (LCIS) and ductal CIS; (iv) history of localized breast cancer and receiving antihormonal agents; (v) history of localized prostate cancer (N0M0) and received androgen deprivation therapy; (vi) localized prostate cancer (N0M0): (a) with a Gleason score of 6, treated within the last 24 months or untreated and under surveillance, (b) with a Gleason score of 3+4 that has been treated more than 6 months prior to full study Screening and considered to have a very low risk of recurrence, or (c) history of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence. [0469] 12) current central serous retinopathy or retinal pigment epithelial detachment of any grade.

[0470] 13) history of uncontrolled cardiovascular disease including: (i) any of the following within 3 months prior to the start of study treatment: unstable angina, myocardial infarction, ventricular arrhythmias or clinically significant atrial arrythmias (e.g., atrial fibrillation with uncontrolled rate), cardiac arrest, or known congestive New York Heart Association Class III-IV heart failure, cerebrovascular accident, or transient ischemic attack, or (ii) pulmonary embolism or other venous thromboembolism within 1 month prior to the planned start of study treatment.

[0471] 14) active or chronic hepatitis B or C infection according to the following criteria:

(i) seropositive for hepatitis B: defined by a positive test for hepatitis B surface antigen [HBsAg], Participants with resolved infection (i.e., participants who are HBsAg negative with antibodies to total hepatitis B core antigen [anti-HBc] with or without the presence of hepatitis B surface antibody [anti-HBs]) were screened using real-time polymerase chain reaction (RT-PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who were RT-PCR positive were excluded. Participants with anti-HBs positivity as the only serologic marker AND a known history of prior HBV vaccination did not need to be tested for HBV DNA by RT-PCR; or (ii) Hepatitis C infection defined by a positive hepatitis C antibody (anti-HCV) test. Participants who tested positive for anti-HCV were eligible if RNA viral load was undetectable (spontaneous recovery or after completing treatment for hepatitis C virus infection).

[0472] 15) major surgery within 4 weeks before Day 1 (TURBT was not considered major surgery).

[0473] 16) active bacterial, viral, fungal infection, including urinary tract infection*, requiring oral or systemic therapy within 7 days prior to Day 1.

[0474] *Urinary tract infection is defined as a symptomatic infection with a positive urine culture with a bacterial count of >10⁵ colony forming units (CFU)/mL in urine voided from women, or >104 CFU/mL in urine voided from men, or in straight-catheter urine from women. Symptoms may include dysuria, urgency, frequency, and/or systemic symptoms such as fever, chills, elevated white blood cell, and/or abdominal/flank pain. Participants free from symptoms for 7 days with no culture evidence of >10⁵ CFUs were eligible.

[0475] 17) toxicity from prior anticancer therapy did not resolve to baseline levels or to

Grade <1 (except alopecia, vitiligo, peripheral neuropathy, or endocrinopathies that were stable on hormone replacement, which may be Grade 2). [0476] 18) known human immunodeficiency virus (HlV)-positive participants with 1 or more of the following: (i) not receiving highly active antiretroviral therapy (ART); (ii) had a change in ART within 6 months of the start of screening; (iii) receiving ART that may have interfered with study treatment; (iv) CD4+ count <350 at screening; (v) acquired immunodeficiency syndrome (AIDS)-defming opportunistic infection within 6 months of start of screening; (vi) did not agree to start ART and be on ART >4 weeks prior to the start of study treatment. Only participants who had HIV viral load <400 copies/mL at the end of the 4-week period and agree to continue on ART, were eligible (to ensure ART is tolerated and HIV controlled).

[0477] Prior/Concurrent Clinical Study Experience

[0478] 19) received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 28 days before the planned start of study treatment or is currently enrolled in an investigational study.

[0479] 20) prior anticancer therapy within 4 weeks before the planned start of study treatment. Exception: a single intravesical chemotherapy treatment immediately after TURBT was allowed.

[0480] 21) any condition for which, in the opinion of the investigator, participation was not in the best interest of the participant (e.g., compromise the well-being) or that prevented, limited, or confounded the protocol-specified assessments.

Subject and Treatment Information

[0481] Treatment began on Day 1 with the first insertion of TAR-210-B (about 2 mg/day of erdafitinib) or TAR-210-D (about 4 mg/day of erdafitinib) (FIG. 9A and FIG. 26A), and treatment was continued as described above (FIG. 9B and FIG. 26D), until the participant had their previously scheduled radical cystectomy (RC), disease recurrence or progression, intolerable toxicity, withdrew consent, there was a decision by the investigator to discontinue treatment, or the study was terminated. For Cohorts 1 and 3, after 90 days of study treatment (1 cycle) a disease evaluation including cystoscopy with biopsy of visible disease (or biopsy of previous sites of disease if no disease is visible) and urine cytology was performed. Participants with complete response (CR; Cohort 3) after cycle 2 (180 days) or who were recurrence-free (RF; Cohort 1) after cycle 1 (90 days) continued to receive a new intravesical drug delivery system on 90-day cycles for up to 1 -year total duration, unless they experienced disease recurrence or progression, intolerable toxicity, withdrew consent, there was a decision by the investigator to discontinue treatment, or the study was terminated by the sponsor. Participants with cytology positive for high-grade urothelial carcinoma without histologic or imaging confirmation of recurrence were able to continue to receive TAR-210 per investigator’s discretion.

[0482] Participants in Cohort 1 without CR or with recurrent or progressive disease at or before the Day 90 assessment were discontinued from study treatment. Participants in Cohort 3 with either a non-CR/non-progressive disease (PD) response following cycle 1 received a new drug delivery system for an additional cycle before discontinuing for lack of CR. If a Cohort 3 participant did not achieve a CR following Cycle 2, therapy was discontinued. Note that for Cycle 2, the intravesical drug delivery system was reinserted if no disease was visible on cystoscopy, while biopsy results and urine cytology were pending. However, the intravesical drug delivery system was removed if pathology or imaging results confirm persistent or recurrent disease (i.e., recurrence or progression).

[0483] For all cohorts, transurethral resection of bladder tumor (TURBT) was performed earlier as clinically indicated if cystoscopy and/or imaging showed recurrence or progression after the first 6 weeks or 4 weeks of treatment, respectively.

[0484] An end of treatment (EOT) visit was performed within 30 (+7) days after removal of the participant’s last intravesical drug delivery system. Participants in Cohorts 1 and 3 who did not recur or progress entered a follow-up phase and underwent cystoscopy and urine cytology assessment (continuing every 3 months through end of Year 2 and every 6 months in Year 3) and CT or MR urography scans (every 12 months from cycle 1 day 1 (C1D1) through end of Year 3) until recurrence or progression is detected, a new anticancer therapy is started, or until the participant withdraws from the study.

[0485] Two dose levels were evaluated in Parts 1 and 2 of this study, TAR-210-B (with an estimated release of approximately 2 mg/day of erdafitinib) and TAR-210-D (with an estimated release of approximately 4 mg/day of erdafitinib). Participants were included from Cohorts 1 and 3, who were evaluated together using a model-assisted Bayesian Optimal Interval (BOIN) design with a DLT evaluation period of 28 days.

Retreatment

[0486] For participants in Cohort 3 who had a biopsy proven low grade papillary only recurrence in the follow-up phase, retreatment with TAR-210 may be considered. Only participants who initially achieved a complete response (CR) and completed 4 cycles of treatment can be considered for retreatment. Biopsy of recurrent tumor must have a local pathology evaluation and was submitted for central biomarker analysis. Participants must have remaining visible tumor at recurrence after biopsy demonstrated on a cystoscopy a maximum of 4 weeks prior to retreatment cycle 1 day 1. Participants must undergo screening evaluations in the inclusion and exclusion criteria. Post-void residual (PVR), ophthalmologic exam, CT/MR urography, viral serologies, and ECG did not have to be repeated prior to retreatment, and exclusion criteria prohibiting prior treatment with an FGFR inhibitor did not apply for retreatment. Retreatment may be applied with the TAR 210 dose initially received or with the recommended clinical dose (TAR-210-C; about 3 mg/day erdafitinib). Only participants who achieve a CR following the first retreatment cycle, were able to continue treatment for a total of 4 cycles or until disease recurrence or progression. On-treatment study assessments and a second EOT visit should be performed. No additional follow-up is required after the EOT visit for participants who receive treatment.

[0487] Retreatment is not considered for participants who discontinue treatment for disease recurrence or progression or for unacceptable toxicity.

Results - Part A

[0488] As of August 29, 2023, there were 16 patients in Cohort 1 and 27 patients in Cohort 3 who have been treated in this study. Patients in Cohort 1 (n=16) had a median age of 73.5 (range of 62-90) and were 75% male (FIG. 10), wherein 75% of patients had tumor stage Ta, 25% of patients had tumor stage Tl, 44% of patients had multiple tumors, and 100% had prior BCG experience (FIG. 11 A). Patients in Cohort 3 (n=27) had a median age of 67 (range of 41-87) and were 85% male (FIG. 10), wherein 100% of patients had tumor stage Ta, 41% of patients had multiple tumors, 59% had prior intravesical chemotherapy, and 22% had prior BCG experience (FIG. 11 A). A summary of patient demographics (FIG. 10) and a summary of baseline disease characterization (FIGS. 11A-11B) are included.

[0489] Of these treated patients, 11 Cohort 1 patients and 15 Cohort 3 patients, respectively, had >1 response assessment (Table El). Of the 11 patients with a response assessment for Cohort 1, 9 patients (81.9%) were RF in Cohort 1 (FIG. 12A). Of the 15 patients with a response assessment for Cohort 3, 13 patients (86.7%) achieved CR in Cohort 3 (FIG. 12B) In cohort 1 the median recurrence-free survival was not estimable (NE) (95% CI, 2.96 months-NE). In cohort 1 the median recurrence-free survival was not estimable (NE) (95% CI, NE-NE). In Cohort, 1 the 12-month recurrence-free survival and corresponding 95% confidence interval (CI) was 0.8 (0.2, 0.97) for TAR-210-B (FIG. 13). For TAR-210-D, the 6-month recurrence-free survival rate and corresponding 95% CI was 0.83 (0.27, 0.97), with longer DOR not yet estimable (FIG. 13). In the evaluable analysis set for Cohort 3, the overall CR rate and corresponding 95% CI was 75% (34.9%, 96.8%) for TAR-210-B and 100% (59%, 100%) for TAR-210-D (FIG. 14). For the 13 patients achieving CR in the Cohort 3 evaluable analysis set, 100% patients showed a duration of response (DOR) of 6 months, with longer DOR not yet estimable (FIG. 15).

Table El: Intravesical Drug Delivery System Efficacy Outcomes and Treatment Exposure

CI, confidence interval; mo, months; NE, non-estimable; RF, recurrence-free; RFS, recurrence- free survival.

[0490] Patient samples were analyzed for urine and plasma concentration of erdafitinib to determine steady-state mean concentrations. Shown in FIG. 18 (left panel), TAR-210-B (n=10) and TAR-210-D (n=6) showed sustained erdafitinib release in urine for at least 90 days. Urine concentrations ranged between 500 ng/mL and 2000 ng/mL for TAR-210-B and between 1000 and 3500 ng/mL for TAR-210-D. The plasma concentrations for TAR-210-B (n=l 1) and TAR-210-D (n=8) were significantly lower, and were thus plotted using a different scale, as shown in FIG. 18 (right panel). Notably, the steady-state mean plasma concentrations observed in patient samples were more than 50-fold lower than samples derived from patients taking oral erdafitinib 9 mg daily (data not shown). No hyperphosphatemia was observed in any of the patient samples. [0491] The summary of treatment disposition (FIG. 16) is also included. Of the 43 patients enrolled, only 4 patients have discontinued the study, with only 1 patient having disease recurrence and 2 patients having adverse effects leading to discontinuation (FIG. 16), of which were low-grade urinary symptoms. The remaining discontinuation was a patient refusing to continue the study.

[0492] The summary of treatment-emergent adverse effects (TEAE) is shown in (FIG. 17). Of the 16 enrolled patients in Cohort 1, 9 (100%) patients administered TAR-210-B and 6 (85.7%) patients administered TAR-210-D experienced at least one treatment-emergent adverse event (TEAE) during the reporting period. Of the 27 enrolled patients in Cohort 3, 13 (92.9%) patients administered TAR-210-B and 7 (53.8%) patients administered TAR-210-D experienced at least one treatment-emergent adverse event (TEAE) during the reporting period. The most common TEAEs (at least in 20% across the 43 total patients) were as follows: haematuria (16, 37.2%), dysuria (10, 23.3%), and urinary tract infection (11, 25.6%) (FIG. 17). After further analysis, as shown in Table E2, haematuria (10, 23%), dysuria (10, 19%), micturition urgency (4, 9%), and urinary tract infection (3, 7%) was observed in less than 25% of all patients.

[0493] FIG. 17 provides the numbers of subjects who experienced TEAEs, grade 3 or higher TEAEs, serious TEAEs, TEAEs leading to treatment discontinuation, TEAEs with fatal outcome, and the associated relationships to study treatment, procedure or device. In total, 35 patient (81.4%) experienced at least one TEAE, but nearly 20% of these were not related to study treatment per investigator assessment.

Table E2: Safety and Tolerability of the Intravesical Drug Delivery System

AE=adverse events; ^a : listed are treatment-related AEs by preferred term that were reported on > 1 patient in either cohort

[0494] Grade 3 or higher TEAEs occurred in 1 patient in Cohort 1, and 1 patient in Cohort 3, accounting for 4.7% of the patients in the study.

[0495] One patient experienced a serious TEAE in Cohort 1, and one participant experienced a serious TEAE in Cohort 3, accounting for 4.7% of the patients in the study. None of these serious TEAEs were reported in more than 1 participant and the majority were not related to study treatment per investigator assessment.

[0496] There were no dose-limiting toxicides (DLT) and no deaths during the study in the reporting period.

[0497] There were 2 (18.2%) patients in Cohorts 3 who experienced TEAEs leading to discontinuation of TAR-210-B. Most TEAEs were Grade < 2 and were associated with lower urinary tract symptoms.

Conclusions - Part A

[0498] This analysis included data from 43 patients treated in Cohort 1 or Cohort 3 with TAR-210-B or TAR-210-D. Across patient populations and intravesical drug delivery system doses, the intravesical drug delivery system was shown to be safe and well-tolerated with predominantly low-grade urinary system AEs and limited systemic toxicity. Grade >2 AEs and discontinuations were infrequent, with predominately grade 1 urinary system AEs. This represents a significant advance in treatment of individuals with recurrent high- and intermediate-risk NMIBC over the currently available therapies and makes this therapy a viable alternative to radical cystectomy for these high-risk patients.

Results - Part B

[0499] There were 21 patients in Cohort 1 and 35 patients in Cohort 3 who have been treated. For patients treated in Cohort 1, the estimated 12-month recurrence-free (RF) survival (RFS) rate was 88% (Table E3). 28 patients treated in Cohort 3 were efficacy evaluable with a complete response (CR) rate of 93% (Table E3). Further, patient CRs were ongoing in 92% (24/26) of patients.

[0500] The most common treatment-related adverse events (TRAEs) were grade 1/2 lower urinary tract events. There were no dose-limiting toxicides or deaths. Two patients discontinued treatment due to adverse events (AEs), and 1 patient had serious grade 3 pyelonephritis/sepsis related to the insertion/removal procedure. Pharmacokinetics data showed sustained erdafitinib concentrations in urine with very low plasma exposures.

Table E3: Intravesical Drug Delivery System Efficacy Outcomes and Treatment Exposure

CI, confidence interval; CR, complete response; mo, months; NE, non-estimable; PD, progressive disease; RFS, recurrence-free survival. aAll treated patients were evaluable for RFS using the Kaplan-Meier method. bCR and duration of response were calculated in the efficacy evaluable patients.

* 10 received TAR-210-B and 11 received TAR-210-D

** 15 received TAR-210-B and 13 received TAR-210-D

Conclusions - Part B

[0501] TAR-210 appears safe and well-tolerated with manageable, predominantly low- grade urinary tract treatment-related adverse events (TRAEs) and elicits high complete response (CR) and recurrence-free survival (RFS) rates in patients with NMIBC and select fibroblast growth factor receptor (FGFR) genetic alterations (FGFRa/t).

Results - Part C

[0502] There were 21 patients in Cohort 1 and 43 patients in Cohort 3 who have been treated in this study. Patients in Cohort 1 (n=21) had a median age of 73 (range of 62-90) and were 71% male (FIG. 30A), wherein 76% of patients had tumor stage Ta, 24% of patients had tumor stage Tl, 43% of patients had multiple tumors, 10% had prior intravesical chemotherapy, and 100% had prior BCG experience (FIG. 30B). Patients in Cohort 3 (n=43) had a median age of 67 (range of 41-89) and were 79% male (FIG. 30A), wherein 95% of patients had tumor stage Ta (n=42), 5% had tumor stage T1 (n=42), 43% of patients had multiple tumors (n=42), 51% had prior intravesical chemotherapy, and 21% had prior BCG experience (FIG. 30B). All patients in Cohorts 1 and 3 were screened for the presence of FGFR alterations. FGFR3 mutations were reported in 90% of patients in Cohort 1 and 95% of patients in Cohort 3. FGFR3 fusions were observed in 10% and 5% of patients in Cohort 1 and Cohort 3, respectively. A summary of patient demographics (FIG. 30A) and a summary of baseline disease characterization (FIG. 30B) are included.

[0503] In Cohort 1, all 21 treated patients were evaluable for RFS using the Kaplan- Meier method. Nineteen (19) patients (90.5%) were recurrence-free (RF) (FIG. 31A) and 2 recurrences in the 21 patients. The estimated 12 month recurrence-free survival rate was 90% (95% CI, 66-97) (Table E4). In Cohort 1, with 2 recurrence events and a median duration of follow-up of 8.9 months, the median recurrence-free survival was not reached (not estimable (NE) (95% CI, NE-NE)). No difference was observed in RFS between the 2 mg/day and 4 mg/day TAR-210 doses. In cohort 1, the median duration of follow-up was 8.9 months. In Cohort 1, the median duration of treatment with TAR-210-B was 10.0 months (range, 4-14). In cohort 1, the median duration of treatment with TAR-210-D was 8.9 months (range, 3-12). [0504] In Cohort 3, 43 patients were treated; 31 patients were efficacy evaluable for CR and DOR. Efficacy evaluable patients were those having at least one disease evaluation or discontinuing treatment prior to their first disease evaluation for either PD or recurrence. The CR rate was 90% (95% CI, 74-98) with 90% (28/31) efficacy evaluable patients reaching a CR at Week 12. Overall, 100 % of patients achieved a clinical response; 3 patients had a non- CR/non-PD response. Both doses of TAR-210 (2 mg/day and 4 mg/day) had consistent CR rate. 86% (24/28) of CRs were ongoing at time of clinical cut-off (March 22, 2024) (FIG. 31B) (Table E4) . In Cohort 3, the median duration of treatment with TAR-210-B was 6.8 months (range, 0.6-12). In Cohort 3, the median duration of treatment with TAR-210-D was 7.6 months (range, 0.6-12).

Table E4: Intravesical Drug Delivery System Efficacy Outcomes and Treatment Exposure

CI, confidence interval; mo, months; NE, non-estimable; RF, recurrence-free; RFS, recurrence-free survival. aAll treated patients were evaluable for RFS using the Kaplan-Meier method. bCR was calculated in the efficacy evaluable patients. cDurable response rate was calculated in the efficacy evaluable patients having an initial CR. dDOR was estimated using the Kaplan-Meier method.

*10 received TAR-210-B and 11 received TAR-210-D

**21 received TAR-210-B and 22 received TAR-210-D

[0505] Patient samples were analyzed for urine and plasma concentration of erdafitinib to determine mean concentrations. Shown in FIG. 32A, TAR-210-B (n=25) and TAR-210-D (n=23) showed sustained erdafitinib release in urine for at least 90 days. The plasma concentrations for TAR-210-B (n=25) and TAR-210-D (n=24) were significantly lower, and were thus plotted using a different scale, as shown in FIG. 32B. No hyperphosphatemia was reported in any of the patient samples, consistent with the very low plasma concentrations observed with TAR-210. Mean plasma erdafitinib concentrations were approximately >50 times lower than mean urine concentrations.

[0506] The summary of adverse events and treatment-related adverse effects (TRAE) is shown in Table E5. The majority of adverse events were grade 1 or 2 lower urinary tract AEs. Few patients discontinued due to AEs, with 2 patients (3%) discontinued due to TRAEs of low-grade urinary symptoms. Two patients had serious TRAEs with pyelonephritis and sepsis or urinary tract infection (UTI) and sepsis, respectively. Both events resolved with antibiotics and patients were able to continue TAR-210. There were no dose-limiting toxicities identified.

Table E5: Safety and Tolerability of the Intravesical Drug Delivery System

AE=adverse events; ^alisted are treatment-related AEs by preferred term that were reported on > 1 patient in either cohort

Conclusions - Part C

[0507] TAR-210 shows promising clinical activity in patients with FGFR-altered HR and

IR-NMIBC. In BCG-experienced HR-NMIBC (Cohort 1), the estimated 12-month RFS rate was 90% (95% CI, 66-97). With 2 recurrence events and a median follow-up of 8.9 months, the median RFS was not reached in Cohort 1. In IR-NMIBC (Cohort 3), 90% (95% CI, 74- 98) of patients achieved a CR at Week 12. 86% of CRs are ongoing in Cohort 3 at the time of clinical cutoff. TAR-210 provided high erdafitinib concentrations in urine with very low plasma concentrations, limiting systemic toxicities. Oral erdafitinib-associated eye and skin toxi cities and hyperphosphatemia were not observed. The majority of TRAEs were grade 1 or 2 lower urinary tract adverse events (AEs), with low rates of treatment discontinuation (3%) due to TRAEs. These results support further study of TAR-210 in FGFR-altered intermediate-risk NMIBC.

Results - Part D

Participant Characteristics [0508] As of July 30, 2024, there were 21 HR-NMIBC (Cohort 1) patients and 49 IR-

NMIBC (Cohort 3) patients (FIG. 35). The median (range) age for HR-NMIBC and IR- NMIBC patients was 73 (62-90) and 67 (41-89), respectively (FIG. 35). The proportion of male HR-NMIBC and IR-NMIBC patients was 71% and 82%, respectively (FIG. 35). 81% of HR-NMIBC patients were white, whereas the remaining 19% of HR-NMIBC patients were Asian (FIG. 35). 59% of IR-NMIBC patients were white, whereas the other 41% of IR- NMIBC patients were Asian (FIG. 35). The proportion of HR-NMIBC patients having an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 were 62%, 24%, and 14%, respectively (FIG. 35). The proportion of IR-NMIBC patients having an ECOG performance status of 0, 1, or 2 were 80%, 14%, and 6%, respectively (FIG. 35). [0509] The proportion of HR-NMIBC patients having a tumor stage Ta or T1 were 76% and 24%, respectively (FIG. 35). The proportion of IR-NMIBC patients having a tumor stage Ta or T1 were 96% and 4%, respectively (FIG. 35). The proportion of HR-NMIBC and IR- NMIBC patients having multiple tumors were 52% and 49%, respectively (FIG. 35). The proportion of HR-NMIBC and IR-NMIBC patients having prior BCG were 100% and 22%, respectively (FIG. 35). The proportion of HR-NMIBC and IR-NMIBC patients having prior intravesical chemotherapy were 10% and 49%, respectively (FIG. 35). The median number (range) of HR-NMIBC and IR-NMIBC patients having prior TURBT and tumor ablative procedures²¹ were 4 (1-12) and 2 (1-14), respectively (FIG. 35). Trior cancer-related surgery/procedures of interest were counted only once on a given date and included the following procedures: TURBT, fulguration, cauterization, and laser photoablation.

Efficacy

[0510] Of the 21 HR-NMIBC (Cohort 1) patients, all of whom were efficacy evaluable, the estimated 12-month recurrence-free survival (RFS) rate was 79% (95% CI, 54-92%) (FIG. 36A). The 6-month RFS was 90% (95% CI, 67-98%) (FIG. 36A). The 9-month RFS was 85% (95% CI, 61-95%) (FIG. 36A). Median RFS was not yet estimable. Four patients have recurred, and one patient progressed (FIG. 36A). Median duration of follow-up was 12 months (range 3-21) (FIG. 36A). The 12-month RFS rate was similar between the TAR-210 dose levels (80% for TAR-210-B (about 2 mg/day) and 78% for TAR-210-D (about 4 mg/day) (FIG. 36A). RFS and confidence intervals (Cis) were estimated using the Kaplan- Meier method. Patients follow up is ongoing.

[0511] Of the 49 IR-NMIBC (Cohort 3) patients, 47 were efficacy evaluable (FIG. 36B). Efficacy evaluable patients were those having at least one disease evaluation or discontinuing treatment prior to their first disease evaluation for either progressive disease (PD) or recurrence or patients who ended study participation prior to their first disease evaluation. Of the efficacy evaluable IR-NMIBC patients, the complete response (CR) rate at three months was 85% (40/47 patients) (95% CI, 72-94%) (FIG. 36B). Four patients had a non-CR/non- PD response, and two of those four patients were able to continue treatment and achieved CR at six months (FIG. 36B). A consistent CR rate was observed across both TAR-210 (TAR- 210-B (about 2 mg/day) and TAR-210-D (about 4 mg/day)) levels (FIG. 36B). The CR rate for TAR-210-B was 83.3% (95% CI: 62.6-95.3%), and the CR rate for TAR-210-D was 87% (95% CI: 66.4-97.2%) (FIG. 36B). 88% (35/40 patients) of CRs were ongoing at the clinical cutoff date (FIG. 36B). The duration of response (DOR) rate measured at six months and nine months was 97% (95% CI, 79-100%) and 92% (95% CI, 70-98%), respectively (FIG. 36B). The DOR and Cis were estimated using the Kaplan-Meier method. Patients follow up is ongoing.

Pharmacokinetics

[0512] Concentration of erdafitinib in both urine and plasma, delineated by dose level (TAR-210-B and TAR-210-D) is provided in FIGS. 37A-B. As shown, TAR-210 delivers steady release of erdafitinib in the bladder for 90 days across both dose levels (TAR-210-B (about 2 mg/day) and TAR-210-D (about 4 mg/day)) with very low plasma concentration ((FIGS. 37A-B). The steady-state plasma concentrations for TAR-210-B (about 2 mg/day) and TAR-210-D (about 4 mg/day) were approximately 96 times and 55 times lower, respectively, than the maximum concentration measured with oral erdafitinib 9 mg once daily.

Safety

[0513] A summary of adverse events (AEs) and treatment-related AEs as of the July 30, 2024 cutoff date is provided below in Table E6. A majority of the AEs were grade 1 or 2 lower urinary tract AEs. Three patients (4%) discontinued treatment due to TRAEs of low- grade urinary symptoms. Two patients had serious TRAEs with pyelonephritis and sepsis or hematuria, respectively. No dose-limiting toxicities were identified. Oral erdafitinib- associated eye and skin toxicities and hyperphosphatemia were not observed.

Table E6: Safety and Tolerability of the Intravesical Drug Delivery System

AE=adverse events; TRAE=treatment-related adverse event; UTI=urinary tract infection. ^aListed are related AEs by preferred term that were reported in > 1 patient in either cohort

Conclusions - Part D

[0514] Overall, TAR-210 shows promising clinical activity in patients with FGFR-altered HR-NMIBC or IR-NMIBC. In BCG-experienced HR-NMIBC (Cohort 1), the estimated 12- month recurrence-free survival (RFS) rate was 79% (95% CI, 54-92%). With a median follow-up of 12 months, there were four recurrences and one progression. In IR-NMIBC (Cohort 3), 85% (95% CI, 72-94%) of patients achieved a complete response (CR) at three months. 88% (35/40) of CRs were ongoing at the clinical cutoff date. Follow-up is ongoing. [0515] TAR-210 provided adequate erdafitinib concentrations in urine with very low plasma concentrations, limiting systemic toxicities. Oral erdafitinib-associated eye and skin toxi cities and hyperphosphatemia were not observed. The majority of treatment related adverse events (TRAEs) were grade 1 or 2 lower urinary tract AEs, with low rates of treatment discontinuation (4%) due to TRAEs.

Example 2: Clinical Evaluation of Intravesical Drug Delivery System in Participants with Bladder Cancer

Study Design [0516] This is a multi-center, open-label, randomized Phase III study evaluating the efficacy and safety of the intravesical erdafitinib delivery system, wherein the intravesical erdafitinib delivery system releases about 2 mg/day of erdafitinib to about 4 mg/day of erdafitinib, in particular TAR-210-C releasing approximately 3 mg/day, versus investigator’s choice of single agent intravesical chemotherapy (mitomycin C (MMC) or gemcitabine (Gem)) in participants with newly diagnosed or recurrent intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) and select FGFR alterations and without recent BCG treatment, with 1 or more of the following risk factors: multiple low grade (LG) tumors, solitary LG tumor >3 cm, early recurrence of LG tumor (<1 year), frequent recurrence (> 1 per year), or recurrence after prior intravesical chemotherapy. A schematic overview of the study is shown in FIG. 19A, and a schematic of the treatment phase is shown is FIG. 19B.

Primary Objective

[0517] The primary objective of this study is to compare disease-free survival (DFS) between participants receiving the intravesical erdafitinib delivery system TAR-210-C (releasing about 3 mg/day of erdafitinib) (group A), versus investigator’s choice of intravesical chemotherapy (MMC or gemcitabine) (group B).

[0518] DFS is defined as the time from randomization to the date of the first documented recurrence of non-muscle invasive bladder cancer (NMIBC) of any grade, disease progression, or death due to any cause, whichever occurs first (i.e., up to 5 years).

[0519] Recurrence is defined as reappearance of NMIBC independent of grade based on pathological assessment.

[0520] Progression is defined as progression to a higher stage NMIBC (i.e., from Ta to Tl) or muscle invasive bladder cancer (MIBC) (T2) of any grade (as confirmed by cystoscopic biopsy or TURBT), or diagnosis of metastatic urothelial cancer (mUC) or upper tract urothelial carcinoma (UTUC) (confirmed by biopsy or cytology plus upper tract imaging). Participants who do not have DFS events will be censored at the last disease assessment date.

[0521] Analyses of the primary endpoint using the Kaplan-Meier method, and comparison using a stratified log-rank test, will be conducted using the intent-to-treat (ITT) analysis set. The stratification factors planned for the analysis are anticipated choice of intravesical chemotherapy (MMC versus gemcitabine), disease status (newly diagnosed versus recurrent disease), and cystoscopic assessment method (white light versus enhanced assessment method [e.g., blue light]). An estimate of the true hazard ratio, and a corresponding 95% CI, summarizing the magnitude of the benefit of the experimental treatment relative to the comparator, will be derived from a stratified Cox proportional hazards model with treatment as the sole independent variable.

[0522] The intent-to-treat (ITT) analysis set includes all randomized participants. Participants in this population will be analyzed according to the treatment to which they are randomized. Enrolled participants are all participants who sign the study informed consent form (ICF).

Secondary Endpoints and Objectives

[0523] The key secondary objectives of this study are to compare time to next treatment (TTNT), high-grade recurrence-free survival (HG RFS), progression-free survival (PFS), rate of diagnostic and therapeutic urological interventions, safety, and tolerability between the intravesical erdafitinib delivery system, in particular the intravesical erdafitinib delivery system releasing about 3 mg/day of erdafitinib (TAR-210-C), and investigator’s choice of intravesical chemotherapy (MMC or gemcitabine).

[0524] Key secondary efficacy endpoints evaluated in the study are the following:

[0525] 1) Time to next treatment (TTNT) is measured as the time from randomization to the date of first documented subsequent treatment (local, systemic, surgical, or interventional) for bladder cancer (i.e., up to 4 years and 2 months). Participants who have not started subsequent treatment are censored at the last date known alive or date of death.

[0526] 2) High-grade recurrence-free survival (HG RFS) is measured as the time from randomization to the date of first documented evidence of HGNMIBC or death, whichever occurs first (i.e., up to 4 years and 2 months). Participants who do not have HG RFS events are censored at the last disease assessment date.

[0527] 3) Progression-free survival (PFS) is measured as the time from randomization to the date of first documented evidence of disease progression or death, whichever occurs first (i.e., up to 4 years and 2 months). Participants who do not have PFS events are censored at the last disease assessment date.

[0528] 4) Rate of diagnostic and therapeutic invasive urological interventions after study treatment (i.e., up to 4 years and 2 months). Rate of diagnostic and therapeutic invasive urological interventions after study treatment, i.e., endoscopic procedures (e.g., cystoscopies, TURBTs, ureteroscopies, urethral interventions, urethral stricture/bladder neck incision), catheterization (intravesical, suprapubic), intravesical treatments, major surgeries (e.g., radical cystectomy, simple cystectomy, urethroplasty). [0529] 5) Number of participants with adverse events by severity measured from first dose up to 30 days after last dose of study treatment (i.e., up to 4 years and 2 months). An AE is any untoward medical occurrence in a participant participating in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product, that does not necessarily have a causal relationship with the treatment. AEs are evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. Severity of AEs has 5 grades based on CTCAE criteria: Grade 1 : Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening and Grade 5: Death. [0530] 6) Number of participants with physical examination abnormalities measured from first dose up to 30 days after last dose of study treatment (i.e., up to 4 years and 2 months). Physical examinations including head, ears, eyes, nose, throat, and neck, cardiovascular, abdomen, musculoskeletal, skin, and genitourinary systems assessments are performed. Physical examination abnormalities are based on investigator discretion.

[0531] 7) Number of participants with vital sign abnormalities measured from first dose up to 30 days after last dose of study treatment (i.e., up to 4 years and 2 months). Number of participants with vital sign abnormalities (temperature, heart rate, blood pressure (systolic and diastolic), and weight) is assessed.

[0532] 8) Number of participants with laboratory abnormalities from first dose up to 30 days after last dose of study treatment (i.e., up to 4 years and 2 months). Blood samples for serum chemistry and hematology and urine samples for urinalysis are collected. Laboratory abnormalities are based on investigator discretion.

[0533] 9) Overall survival (OS) is measured from randomization to the date of death (i.e., up to 4 years and 2 months). OS is defined as the time from randomization to the date of death from any cause.

[0534] 10) Change from baseline in European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire Core-30 items (EORTC-QLQ-C30) Total Scores at Weeks 6, 12, 24, 36 and 48. The EORTC-QLQ-C30, is a self-administered, 30-item questionnaire developed to assess the health-related quality of life (HRQoL) of cancer patients. EORTC-QLQ-C30 includes 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), a global health status/quality of life scale, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Responses to items 1 to 28 are rated on 4-point Likert response scale ranging from 1 “Not at all” to 4 “Very much.” Two global health status items are rated on a 7-point numeric rating scale from 1 “Very Poor” to 7 “Excellent.” A high score for a functional scale represents a high/healthy level of functioning and a high score for the global health status represents HRQoL. High score for a symptom scale/item represents a high level of symptomatology/problems.

[0535] 11) Change from baseline in European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire for Non-muscle Invasive Bladder Cancer (EORTC- QLQ-NMIBC24) Total Scores at Weeks 6, 12, 24, 36 and 48. The EORTC QLQ-NMIBC24, is a self-administered, 24-item questionnaire measuring the HRQoL of participants with NMIBC. The questionnaire is a supplementary module to be employed in conjunction with the QLQ-C30. There are 6 multi-item scales (urinary symptoms, malaise, future worries, bloating and flatulence, sexual function, and sexual problems) and 5 single items (intravesical treatment issues, sexual intimacy, worries about risk of contaminating partner, sexual enjoyment, and sexual problems). Responses for all items are rated on a 4-point Likert response scale ranging from 1 “Not at all” to 4 “Very much”. Higher scores represent a high level of symptomatology or problems, except for sexual function and sexual enjoyment where a higher score represents a higher level of functioning.

[0536] 12) Percentage of participants with significant change from baseline in EORTC-

QLQ-C30 scores at weeks 6, 12, 24, 36 and 48. The EORTC-QLQ-C30 is as described above.

[0537] 13) Percentage of participants with significant change from baseline in EORTC-

QLQ-NMIBC24 Scores at Weeks 6, 12, 24, 36 and 48. The EORTC QLQ-NMIBC24 is as described above.

[0538] Analyses of the secondary efficacy endpoints are conducted using the intent-to- treat (ITT) analysis set. The interim and final analyses of the key secondary endpoints are conducted with same timing as specified for the interim and final analyses of DFS. Analyses of TTNT, HG RFS, and PFS are conducted similarly as described for DFS. Testing of the key secondary endpoints are conducted hierarchically in the order of TTNT, HG RFS, PFS, and the rate of diagnostic and therapeutic invasive urological interventions to control the familywise Type I error rate at 0.05 (2-sided) if DFS is statistically significant at the interim or primary analyses.

[0539] For safety analysis, the safety analysis set includes all randomized participants who received at least 1 dose of study treatment. Participants will be analyzed according to the actual treatment received.

Overview [0540] The intravesical drug delivery system used in this Phase III study, TAR-210-C, comprises approximately 500 mg of erdafitinib and has an estimated release of about 3 mg/day of erdafitinib. The intravesical drug delivery system, as shown in FIG. 29, is oriented such that the two interface edges are disposed at an arc angle 2914 of about 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube. The system provides for about 90 days or 12 weeks of local administration of erdafitinib to the bladder of each participant. The drug formulation contained within the intravesical drug delivery system is Formula 4.1 as described herein. The delivery system comprises AC- 4075 A-B20 as the first wall material and EG-80-A as the second wall material. The ends of the intravesical drug delivery system are closed. In particular, the TAR-210 erdafitinib delivery system administered in the phase III study is the delivery system described in [0201 ]-[0217] hereinabove.

[0541] All study participants will have undergone TURBT with complete resection of all papillary disease and confirmed disease-free status prior to randomization. Participants will be stratified based on anticipated choice of intravesical chemotherapy (mitomycin C (MMC) versus gemcitabine), disease status (newly diagnosed versus recurrent disease), and cystoscopic assessment method (white light versus enhanced assessment method [e.g., blue light]).

[0542] This study is randomizing approximately 540 participants to Group A or Group B in a 1 : 1 randomization ratio. Participants in Group A have the intravesical drug delivery system TAR-210-C inserted in the bladder on Day 1 and removed after 12 weeks. One intravesical drug delivery system is inserted about every 12 weeks (Q12W) (+/- 1 week) over a treatment duration of approximately 1 year. Participants in Group B receive 40 mg (1 mg/mL) mitomycin C (MMC) or 2,000 mg (100 mg/mL) gemcitabine per intravesical instillation once weekly (QW) for 4 to 6 induction doses followed by a maintenance phase for a minimum of 6 months and up to 1 year with a minimum number of 6 treatment cycles. For all participants, an end of treatment (EOT) visit takes place at the time of last dose of the participant’s treatment or discontinuation of study treatment. For the intravesical drug delivery system, the date of the removal of the last intravesical drug delivery system is considered to be the time of last dose. After the EOT visit, participants continue into the Follow-up Phase of the study, comprised of a 30-day safety follow-up period, a posttreatment follow-up until disease-free survival (DFS) event, and a subsequent long-term follow-up period, until the time of death, withdrawal of consent, or end of study, whichever occurs first. The Follow-up Phase for patients meeting the primary endpoint is about 5 years. [0543] Efficacy evaluations include cystoscopy, ultrasound, CT (with contrast) or IV urography, urine cytology, pathologic assessment after biopsy/transurethral resection of bladder tumor (TURBT), and PROs (patient-reported outcomes), wherein PROs are reports directly from the participant without interpretation by clinician or anyone else.

[0544] Blood samples and urine samples are collected from participants at multiple timepoints to characterize the plasma and urine PK of erdafitinib.

[0545] Urine and tissue samples are used to characterize molecular markers at baseline and at the time of recurrence/progression. Longitudinal urine samples are collected to assess genomic markers of disease burden.

[0546] Safety assessments are based on medical review of adverse event (AE) reports, vital sign measurements, physical examination (PE), clinical laboratory tests, and other safety evaluations at specified timepoints. Concomitant medication usage will be recorded. AEs will be graded using NCI CTCAE, Version 5.0.

Inclusion Criteria

[0547] Each potential participant must satisfy all of the following criteria to be enrolled in the study:

Disease Characteristics

[0548] 1) Histologically confirmed diagnosis of IR-NMIBC based on International

Bladder Cancer Group (IBCG) risk definition with at least one of the following criteria fulfilled:

[0549] i) Ta LG/G1 : recurrent

[0550] ii) Ta LG/G1 : primary & (multifocal or > 3 cm)

[0551] iii) Ta G2: primary or recurrent

[0552] 2) Plus 1 or more of the following risk factors according to IBCG:

[0553] i) Multiple LG tumors (Ta)

[0554] ii) Solitary LG tumor >3 cm

[0555] iii)Frequent recurrence (> 1 per year)

[0556] iv) Recurrence after prior intravesical chemotherapy.

[0557] Note: Mixed histology tumors are allowed if urothelial differentiation is predominant.

[0558] 3) Activating tumor FGFR mutation or fusion either by urine or tissue testing, as determined by central testing. [0559] 4) All visible papillary disease must be fully resected (absent) prior to randomization and documented at Screening cystoscopy.

Type of Participant

[0560] 5) Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2.

[0561] 6) Adequate bone marrow, liver, and renal function.

Updated Inclusion Criteria

[0562] The inclusion criteria of this study have been updated and are provided below:

[0563] Each potential participant must satisfy all of the following criteria to be enrolled in the study:

Age

[0564] 1) Be >18 years of age (or the legal age of majority in the jurisdiction in which the study is taking place, whichever is greater) at the time of informed consent.

Disease Characteristics

[0565] 2) Have a histologically confirmed diagnosis (within 90 days of randomization) of

IR-NMIBC with at least one of the following criteria fulfilled:

[0566] (i) Ta LG/G1 : recurrent

[0567] (ii) Ta LG/G1 : primary and multifocal, or primary and >3 cm

[0568] (iii) Ta G2: primary or recurrent

[0569] And >1 of the following risk factors:

[0570] (i) Multiple Ta LG tumors

[0571] (ii) Solitary LG tumor >3 cm

[0572] (iii) Early recurrence (within 1 year)

[0573] (iv) Frequent recurrence (>1 per year)

[0574] (v) Recurrence after prior intravesical chemotherapy.

[0575] Note: Mixed histology tumors are allowed if urothelial differentiation is predominant.

[0576] 3) Have a susceptible FGFR (e.g., FGFR2 and/or FGFR3) mutation or fusion either by urine testing or tumor tissue testing (from transurethral resection of bladder tumor (TURBT) tissue), as determined by central or local testing.

[0577] 4) Participants must be willing to undergo all study procedures (e.g., multiple cystoscopies from Screening through the end of study and TURBT for assessment of recurrence/progression) and receive the assigned treatment, including intravesical chemotherapy if randomized into that arm.

[0578] 5) Visible papillary disease must be fully resected prior to randomization and absence of disease must be documented at Screening cystoscopy. The same method for visualizing disease at Screening cystoscopy should be used throughout for the participant (white light versus enhanced assessment method [e.g., blue light]).

Prior Malignancies

[0579] 6) Can have a prior or concurrent second malignancy (other than the disease under study) which natural history or treatment is unlikely to interfere with any study endpoints of safety or the efficacy of the study treatment.

Performance Status

[0580] 7) Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

Renal Function

[0581] 8) Have an eGFR, based on the MDRD 4-variable formula of >30 mL/min.

Hepatic Function

[0582] 9) (i) AST <3 xULN; (ii) ALT <3 xULN; (iii) Total bilirubin <2xULN. For participants with known congenital nonhemolytic hyperbilirubinemias, such as Gilbert’s syndrome, isolated total bilirubin >2xULN with conjugated [direct] bilirubin <2xULN is allowed.

Hematologic Values

[0583] 10) Participants should have adequate bone marrow function: (i) Hemoglobin >8.0 g/dL, without transfusion or growth factors within 1 week; (ii) Neutrophils >1.0x l0³/pL, without transfusion or growth factors within 2 weeks; (iii) Platelets >50x 10³/pL, without transfusion or growth factors within 1 week.

Sex and Contraceptive/Barrier Requirements

[0584] 11) While on study treatment and for 6 months after the last dose of study treatment, a participant must: (i) Not breastfeed or be pregnant; (ii) Not donate gametes (i.e., eggs or sperm) or freeze for future use for the purposes of assisted reproduction; (iii) Wear an external condom; (iv) If of childbearing potential: (a) have a negative highly sensitive (e.g., P-hCG) pregnancy test at Screening and within 24 hours before the first dose of study treatment, and agree to further pregnancy tests, and (b) practice at least 1 highly effective method of contraception; if oral contraceptives are used, a barrier method of contraception must also be used; (v) If a participant’s partner is of childbearing potential, the partner must practice a highly effective method of contraception unless the participant is vasectomized. Informed Consent

[0585] 12) Must sign an ICF (or their legally acceptable representative must sign) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study and agree to store samples for research when appropriate.

[0586] 13) Be willing and able to adhere to the lifestyle restrictions specified in this protocol.

[0587] The table below contains the specific FGFR gene alterations considered eligible for enrollment. Local tissue or urine-based results from NGS or PCR test performed in CLIA- certified or equivalent laboratories, or results from commercially available PCR or NGS test can be used to determine molecular eligibility.

Exclusion Criteria

[0588] Any potential participant who meets any of the following criteria will be excluded from participating in the study:

Disease Characteristics

[0589] 1) Histologically confirmed diagnosis of high-risk (HR)-NMIBC (Any high grade

(HG) (G3) Ta or Tl, or CIS) or muscle invasive, locally advanced, nonresectable, or metastatic urothelial carcinoma (i.e., >T2) at any time prior to enrollment.

2) Must not have had urothelial carcinoma outside of the urinary bladder (ie, urethra, ureter, or renal pelvis). Ta/any Tl, CIS of the upper urinary tract (including renal pelvis and ureter) is allowable if treated with complete nephroureterectomy more than 24 months prior to initiating study.

[0590] 3) Participants with tumors involving the prostatic urethra (ductal or stromal).

[0591] 4) N+ and/or M+ per CT/MR Urography.

Medical Conditions

[0592] 5) Active malignancies (i.e., progressing or requiring treatment change in the last

24 months) other than the disease being treated under study. Allowed recent second or prior malignancies include:

[0593] i) Any malignancy that was not progressing nor requiring treatment change in the last 12 months [and not considered at high risk of recurrence requiring systemic therapy], [0594] ii) Malignancies treated within the last 12 months and considered at very low risk for recurrence:

[0595] a) Non-melanoma skin cancers treated with curative therapy or localized melanoma treated with curative surgical resection alone.

[0596] b) Non-invasive cervical cancer.

[0597] c) Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, localized breast cancer and receiving antihormonal agents.

[0598] d) Localized prostate cancer (M0, NO) with a Gleason Score <7a, treated locally only (RP/RT/focal treatment).

[0599] e) Any other malignancy with minimal risk of recurrence.

[0600] 6) Presence of any bladder or urethral anatomic feature (e.g., urethral stricture) that, in the opinion of the Investigator, may prevent the safe insertion, indwelling use, removal of TAR-210 or passage of a urethral catheter for intravesical chemotherapy.

[0601] 7) Current indwelling catheters are not permitted; however, intermittent or prior catheterization is acceptable.

[0602] 8) Major surgery or significant traumatic injury and/or not fully recovered within

4 weeks before first dose (TURBT is not considered major surgery).

[0603] 9) Any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the participants (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

[0604] 10) Participants with active bladder stones or persistent risk of bladder stones, e.g. severe bladder outlet obstruction or residual urine > 350 ml.

Prior/Concomitant Therapy [0605] 11) Received adjuvant induction intravesical chemotherapy or immunotherapy from the time of pre-Screening (diagnostic) or Screening (completion) cystoscopy/TURBT to randomization. Peri-operative instillation of a single dose of intravesical chemotherapy is allowed per institutional guidelines.

[0606] 12) Received prior intravesical treatment with BCG

[0607] 13) Received prior treatment with an FGFR inhibitor.

[0608] 14) Symptomatic, active infection requiring systemic therapy (See exclusion criterion below for information regarding urinary tract infection (UTI)).

[0609] 15) Concurrent UTI

Prior/Concurrent Clinical Study Experience

[0610] 16) Currently participating or has participated in a study of an investigational agent and received study therapy or investigational device within 4 weeks prior or the agent/therapy washout period, whichever is longer, to randomization.

Updated Exclusion Criteria

[0611] The exclusion criteria of this study have been updated and are provided below: [0612] Any potential participant who meets any of the following criteria will be excluded from participating in the study:

Medical Conditions

[0613] 1) Known allergies, hypersensitivity, or intolerance to any study component or its excipients, including: (a) Erdafitinib excipients; (b) TAR-210 intravesical drug delivery system constituent materials (i.e., nitinol, dyes); (c) urinary placement catheter (UPC) materials; (d) MMC or chemically related drugs (participants fulfilling this criterion may be treated with the other comparator drug); (e) Gemcitabine or chemically related drugs (participants fulfilling this criterion may be treated with the other comparator drug).

[0614] 2) Presence of any bladder or urethral anatomic feature (e.g., urethral stricture) that, in the opinion of the investigator, may prevent the safe insertion, indwelling use, removal of the intravesical drug delivery system (TAR-210) or passage of a urethral catheter for intravesical chemotherapy.

[0615] 3) Polyuria with recorded 24-hour urine volumes >4000 mL.

[0616] 4) Current indwelling urinary catheters, however, intermittent catheterization is acceptable.

[0617] 5) Had major surgery or had significant traumatic injury and/or not fully recovered within 4 weeks before first dose (transurethral resection of bladder tumor (TURBT) is not considered major surgery). Participants with planned surgical procedures to be conducted under local anesthesia may participate.

[0618] 6) Has active bladder stones or persistent risk of bladder stones, e.g., severe bladder outlet obstruction or post void residual urine >350 mL.

[0619] 7) Concurrent urinary tract infection (UTI) defined as a symptomatic infection with a positive urine culture with a bacterial count of >10⁵ CFU/mL in urine voided from participants without a penile urethra, or >10⁴ CFU/mL in urine voided from participants with a penile urethra or in straight-catheter urine from participants without penile urethra. Must be free from symptoms for 7 days with no evidence of UTI in urine culture.

Cardiovascular Dysfunction

[0620] 8) Any of the following within 3 months prior to first dose of study treatment: severe or unstable angina, myocardial infarction, major thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident), clinically significant ventricular arrhythmias or heart failure New York Heart Association functional classification Class III to IV.

Uncomplicated deep vein thrombosis (DVT) is not considered exclusionary.

Disease Characteristics

[0621] 9) Histologically confirmed diagnosis of HR-NMIBC (any HG [G3] Ta or Tl, or

CIS) or MIBC, locally advanced, nonresectable, or metastatic urothelial carcinoma at any time prior to enrollment.

[0622] 10) Has or had urothelial carcinoma outside of the urinary bladder (i.e., urethra, ureter, or renal pelvis, N+, M+) or has a histological variant of urothelial cancer (UC). Ta/any Tl, CIS of the upper urinary tract is allowable if treated with complete nephroureterectomy more than 24 months prior to initiating study and without any evidence of disease following nephroureterectomy .

HIV Status

[0623] 11) HIV-positive participants with AIDS-related symptoms.

Prior/Concomitant Therapy or Clinical Study Experience

[0624] 12) Received an investigational treatment for bladder cancer after transurethral resection of bladder tumor (TURBT) for the current NMIBC diagnosis or within 4 weeks of the agent/therapy washout period, whichever is longer, before the planned first dose of study treatment, or is currently enrolled in an investigational study.

[0625] 13) Received adjuvant induction intravesical chemotherapy within 6 months of current diagnosis. Peri-operative instillation of a single dose of intravesical chemotherapy is allowed per institutional guidelines (No washout period is required for this single dose). [0626] 14) Received prior intravesical treatment with immunotherapy including Bacillus

Calmette-Guerin (BCG) within 2 years prior to randomization.

[0627] 15) Received prior treatment with an FGFR inhibitor.

[0628] 16) Not recovered (defined as CTCAE version 5.0 Grade >2) from AEs associated with any prior surgery or prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration).

[0629] 17) Symptomatic, active infection requiring systemic therapy (See Exclusion

Criterion 7 for information regarding UTI).

Diagnostic Assessments

[0630] 18) Evidence of current bladder perforation by cystoscopy or imaging. If prior bladder perforation occurred and has resolved, it is not an exclusion.

Other Exclusions

[0631] 19) Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

[0632] 20) The participant is unable to comply with the requirements of this protocol, including any factors that are likely to affect the participant’s return for scheduled visits and follow-up.

Example 3: Evaluation of Urine cell-free DNA (cfDNA) NGS Assay for Screening Patients having Bladder Cancer

[0633] This example describes a urine-based test for identifying bladder cancer biomarkers in urine samples from bladder cancer patients. The performance of a urine-based NGS assay is assessed by contrasting the results with those from a FDA-approved tissuebased PCR CDx assay that detects alterations in FGFR genes.

Methods

[0634] Paired urine and tissue samples were collected from 107 (muscled and non-muscle invasive) bladder cancer patients from the Bladder BRIDGister clinical trial in Germany (FIG. 20). Tissue samples were analyzed using FDA approved Qiagen therascreen® FGFR RGQ RT-PCR kit while matched urine samples were processed using the PredicineCARE™ urine (cell-free DNA) cfDNA next-generation sequencings (NGS) assay with a detection sensitivity of 0.3% (0.1% for hotspot mutations). 107 paired bladder cancer urine cfDNA NGS and tissue RT-PCR results were analyzed to determine the concordance (PPA, positive percent agreement; and NPA, negative percent agreement) between these two assays. A smaller sample set was also used to compare tissue NGS to therascreen® RT-PCR and tissue NGS to urine cfDNA NGS. A subset of discordant mutations was additionally validated by droplet digital PCR (ddPCR).

Results

[0635] Results of the concordance analysis between PredicineCARE™ urine cfDNA NGS and Qiagen therascreen® FGFR RGQ RT-PCR of 107 samples are shown in Tables E7-E10 below.

Table E7: Summary of Assay Performance

*WT and Mutation: Based on the defined 4 SNVs and 5 Fusions included in the Therascreen® RT-PCR assay (FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3_V1, FGFR3-TACC3_V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7)

**Samples (107) were selected from the matched urine and tissue sample set for measuring the assay performance.

*** Comparison between Therascreen® RT-PCR vs PredicineCARE™ Tissue gDNA NGS

Allele frequency (AF) cut-off of the reportable range for urine NGS (SNV and indels): 0.3% (hot spot: 0.1%)

Allele frequency (AF) cut-off of the reportable range for tissue (“FFPE”) NGS (SNV and indels): 5% (hot spot: 2%)

Allele frequency (AF) cut-off of the reportable range for fusion: urine (0.1%) and tissue (1%)

Table E8: Concordance Results between PredicineCARE™ Urine NGS and Qiagen

Therascreen® Tissue FGFR RT-PCR kit

Note: FGFR+ and FGFR- are based on the previously defined 4 SNVs and 5 Fusions included in the Qiagen therascreen® FGFR RGQ RT-PCR kit

Table E9: Concordance Results between PredicineCARE™ Urine NGS and Qiagen

Therascreen® Tissue FGFR RT-PCR kit

PPA, positive percent agreement; NPA, negative percent agreement; OPA, overall percent agreement. Table E10: Concordance Results between PredicineCARE™ Urine NGS and Qiagen

Therascreen® Tissue EGER RT-PCR

PPA, positive percent agreement; NPA, negative percent agreement; OPA, overall percent agreement.

[0636] Three tissue FGFR negative (FGFR-) samples by RT-PCR were FGFR positive (FGFR+) by urine NGS testing, while 0 urine NGS FGFR negative samples were FGFR positive by tissue RT-PCR (Table E8). Discrepant samples (i.e., samples that were tissue FGFR WT or invalid but urine positive for FGFR mutations) were further analyzed and confirmed positive by independent orthogonal droplet digital PCR (Bio-Rad ddPCR Mutations Detection Assay), suggesting that discordance between the urine and tissue results is often caused by reduced sensitivity of the tissue FGFR RT-PCR test.

[0637] A heat map of the identified genetic alterations for matched urine NGS and FFPE tissue RT-PCR samples is shown in FIG. 21. A scatter plot for the variant allele frequency (VAF) between matched urine NGS (X-axis) and tissue (“FFPE”) RT-PCR (Y-axis) variants is shown for all identified genetic alterations including somatic and germline variants (FIG. 22A) and for somatic FGFR3 alterations (FIG. 22B).

[0638] These results showed high concordance between FGFR alterations detected with the FDA approved tissue companion diagnostic (CDx) assay and the urine cfDNA NGS assay. This demonstrates applicability of a non-invasive urine-based test for molecular diagnosis testing to identify biomarkers in bladder cancer, alleviating the need for a tissue based test.

Example 4: Urine-Based Testing for Patient Selection and Genomic Characterization of Patients with FGFR Alterations-Positive Non-Muscle Invasive Bladder Cancer (NMIBC) Treated with an erdafitinib Intravesical Drug Delivery System (TAR-210) [0639] This example describes a non-invasive urine-based test for identifying bladder cancer patients that may respond to intravesical delivery of erdafitinib. In this Example, the urine-based test was evaluated for use in enrollment in the clinical trial described in Example 1. This example demonstrates that the urine-based test is accurate, and all patients enrolled by urine analysis showed clinical activity when treated with the intravesical drug delivery system comprising erdafitinib. [0640] To overcome tissue-based challenges in identifying FGFR alterations (FGFRalt), including insufficient sample, sample integrity, and sample extraction from a single tumor, a urine cell-free DNA diagnostic test (PredicineCARE™) was used to select patients for treatment with the intravesical drug delivery system comprising erdafitinib (TAR-210).

[0641] Validation of the urine test to detect FGFRalt was previously demonstrated using contemporaneous tissue and urine samples (Kim et al. J Clin Oncol. 2023;41 :6:565).

Reported in this example are the preliminary results of the urine test to detect FGFRalt to enable study enrollment, early efficacy data based on urine testing, and the characterization of the urine-defined genomic landscape.

Methods

[0642] First-in-human study enrollment (reference is made to Example 1) was based on detection of prespecified FGFRalt from either tumor tissue obtained from previous biopsies (Qiagen Therascreen® FGFR RT-PCR assay) or urine samples obtained prior to enrollment (PredicineCARE™ next-generation sequencing test). These tumor tissue and urine sample testing were centrally performed. Alternatively, FGFRalt testing on tumor tissue sample was done by existing local PCR or NGS tests performed in CLIA-certified or equivalent laboratories, or results from commercially available NGS tests may also be used to enroll participants.

Results - Part A

Screening

[0643] As of June 20, 2023, urine test performance was compared to the tissue test from all screened patients with NMIBC (N=178) (FIG. 23). The proportions of samples that yielded evaluable results were 58% and 60% from urine and tissue, respectively. FGFRalt detection rates in the subsets that yielded positive results were 42% from urine and 62% from tissue. FGFR3 S249C was the most frequent alteration detected in both urine (61%) and tissue (48%) (Table Ell). For 36% of urine samples in which FGFRalt were detected, there was no corresponding tissue result. In all instances, the same FGFRalt were detected in both urine and tissue.

Table Ell: Type and Prevalence of FGERalt Identified by Urine and Tissue Tests

Efficacy Based on Urine Testing

[0644] Of the disease-evaluable patients with HR-NMIBC (N=l 1) in Cohort 1 or IR-

NMIBC (N=15) in Cohort 3, as described in Example 1, 46% (5/11) and 20% (3/15), respectively, were enrolled based on both urine and tissue testing. 18% (2/11) of disease- evaluable patients in Cohort 1 and 33% (5/15) in Cohort 3 were enrolled based on urine testing alone due to no sample or insufficient tumor tissue. In Cohort 1, 82% of patients were recurrence-free at the first disease evaluation (FIG. 24A), and in Cohort 3, 87% achieved a complete response at the first disease evaluation (FIG. 24B). All patients (Cohort 1, N=2, and Cohort 3, N=5) enrolled by “urine only” were recurrence-free or achieved a complete response. Further, urine-based testing reliably captured the spectrum of genomic alterations that were similar to those observed in tissue-based genomic landscape assessments of bladder cancer (FIG. 25)

Conclusions - Part A

[0645] These results demonstrated that implementing a urine-based test expanded the molecular testing methods to identify 7 (27%) additional bladder cancer patients that may respond to the intravesical drug delivery system comprising erdafitinib. The spectrum of genomic alterations detected using the urine test was similar to that described in prior studies using tissue-based testing. These data highlight that the complex genomic landscape in bladder cancer can be assessed from urine.

Results - Part B

[0646] As of March 2024, urine test performance was compared to the tissue test from screened patients with HR-NMIBC and IR-NMIBC. The FGFFalt prevalence and type detected in tissue and urine samples from screened patients with HR-NMIBC or IR-NMIBC are shown below in Table E12.

Table E12: Type and Prevalence of FGFRait Identified by Urine and Tissue Tests in screened patients for HR-NMIBC and IR-NMIBC patients

[0647] The results demonstrate that the FGFRah+ rates and frequency of type of alteration identified by urine is generally comparable with those identified by tissue. For HR- NMIBC patients, 36.5% of tissue and 32.3% of urine samples yielded an FGFRalt+ result. For IR-NMIBC patients, 71.8% of tissue and 55.1% of urine samples yielded an FGFRalt+ result. The most prevalent FGFRalt detected across both HR-NMIBC and IR-NMIBC and sample types was FGFR3 S249C.

[0648] As of March 2024, a total of 21 patients with HR-NMIBC and 31 patients with

IR-NMIBC were efficacy evaluable. Among those enrolled, 6 of 21 (28.6%) patients with HR-NMIBC and 9 of 31 (29.0%) patients with IR-NMIBC were enrolled based on urine samples only (FIG. 33). 7 of 21 (33.3%) patients with HR-NMIBC and 14 of 31 (45.2%) patients with IR-NMIBC were enrolled based on tissue samples only (FIG. 33). 8 of 21 (38.1%) patients with HR-NMIBC and 8 of 31 (25.8%) patients with IR-NMIBC were enrolled based on both urine and tissue samples (FIG. 33).

[0649] Of the enrolled HR-NMIBC patients, 19 of 21 (90.5%) patients were recurrence- free at data cutoff (FIG. 34A). All 6 (100%) HR-NMIBC patients enrolled based on urine sample only were recurrence-free at data cutoff (FIG. 34A). 7 of 8 (87.5%) HR-NMIBC patients enrolled based on both urine and tissue samples were recurrence-free at data cutoff (FIG. 34A) 6 of 7 (85.7%) HR-NMIBC patients enrolled based on tissue sample only were recurrence-free at data cutoff (FIG. 34A).

[0650] Of the enrolled IR-NMIBC patients, 28 of 31 (90.3%) patients had a complete response at the three-month evaluation (FIG. 34B). All 9 (100%) IR-NMIBC patients enrolled based on urine sample only had a complete response at the three-month evaluation (FIG. 34B) 6 of 8 (75.0%) IR-NMIBC patients enrolled based on both urine and tissue samples had a complete response at the three-month evaluation (FIG. 34B). 13 of 14 (92.9%) IR-NMIBC patients enrolled based on tissue sample only had a complete response at the three-month evaluation (FIG. 34B).

Conclusions - Part B

[0651] These results demonstrated that urine testing can be used to identify additional NMIBC patients who may respond to erdafitinib, which can be especially valuable when the parallel tissue sample submitted does not return a result. Rates of FGFRalts, overall and specific type of alt, identified in urine were generally comparable with those of FGFRalts identified in tissue. All patients identified through urine samples were recurrence-free (HR- NMIBC) or achieved a complete response (IR-NMIBC) at the data cutoff. These findings support urine testing for patient selection in the recently initiated Phase III study (MoonRISe- 1, referred to above as Example 2).

[0652] Many modifications and other implementations of the disclosure set forth herein will be apparent having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosure is not to be limited to the specific implementations disclosed and that modifications and other implementations are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. [0653] In the descriptions provided herein, the terms “includes,” “is,” “containing,” “having,” and “comprises” are used in an open-ended fashion, and thus should be interpreted to mean “including, but not limited to.” When methods, compositions, or apparatuses are claimed or described in terms of “comprising” various steps or components, then the methods, composition, or apparatuses can also “consist essentially of’ or “consist of’ the various steps or components, unless stated otherwise. In the case of chemical compounds or compositions, the use of "consisting essentially of' means that only those further components not materially affecting the essential characteristics of the specified compound or composition may be present.

Claims

CLAIMS What is claimed is:

1. A drug delivery system, comprising: a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 2.5 mg/day to about 3.5 mg/day, and wherein the two interface edges are disposed at an arc angle of about 125 to about 145 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure.

2. A drug delivery system, comprising: a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent one another at two interface edges and together form a tube, wherein the drug delivery system is configured to release the erdafitinib at an average rate of about 3 mg/day and wherein the two interface edges are disposed at an arc angle of about 135 degrees of a circumference of the tube in a cross section normal to a longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure.

3. The drug delivery system of claim 1 or claim 2, comprising 42-46 erdafitinib mini tablets.

4. The drug delivery system of claim 3, comprising 43 erdafitinib minitablets.

5. The drug delivery system of any one of claims 1-4, wherein the first material comprises AC-4075A and the second material comprises EG-80-A, optionally wherein the first material comprises AC-4075A-B20.

6. The drug delivery system of any one of claims 1-5, wherein the drug formulation comprises:

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(g) colloidal silicon dioxide in a concentration of 0.25 wt% of the drug formulation; (h) hydroxypropyl methylcellulose in a concentration of 1.5 wt% of the drug formulation; and

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose;

(f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide;

(h) hydroxypropyl methylcellulose; and

(i) magnesium stearate.

7. The drug delivery system of any one of claims 1-5, wherein the drug formulation comprises:

(h) magnesium stearate in a concentration of 1.5 wt% of the drug formulation; or (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(l-methylethyl)-N-[3-(l-methyl- l//- pyrazol-4-yl)quinoxalin-6-yl]ethane-l,2-diamine) in a concentration of 50 wt% of the drug formulation;

(b) hydroxypropyl -beta-cyclodextrin;

(c) microcrystalline cellulose;

(d) silicified microcrystalline cellulose;

(e) vinylpyrrolidone-vinyl acetate copolymer;

(f) colloidal silicon dioxide;

(g) hydroxypropyl methylcellulose; and

(h) magnesium stearate.

8. The drug delivery system of any one of claims 1-5, wherein the drug formulation comprises:

(c) meglumine in a concentration of 1 wt% of the drug formulation;

(h) magnesium stearate in a concentration of 2 wt% of the drug formulation; or

(b) hydroxypropyl -beta-cyclodextrin;

(c) meglumine;

(d) microcrystalline cellulose;

(e) silicified microcrystalline cellulose; (f) vinylpyrrolidone-vinyl acetate copolymer;

(g) colloidal silicon dioxide; and

(h) magnesium stearate.

9. The drug delivery system of any one of claims 1-8, wherein the first wall structure and the second wall structure have a thickness between about 0.2 mm to about 1.0 mm.

10. The drug delivery system of any one of claims 1-9, wherein the second wall structure has a thickness, wherein the thickness of the second wall structure is from about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib.

11. The drug delivery system of any one of claims 1-10, wherein the drug formulation comprises minitablets, wherein each minitablet has a weight that is between about 22 mg and about 24 mg.

12. The drug delivery system of any one of claims 1-11, wherein the drug formulation comprises minitablets, wherein each minitablet has a weight that is about 23 mg.

13. The drug delivery system of any one of claims 1-12, wherein the drug formulation comprises minitablets, wherein each minitablet has a thickness that is between about 3.0 mm and about 3.4 mm.

14. The drug delivery system of any one of claims 1-13, wherein the drug formulation comprises minitablets, wherein each minitablet has a thickness that is about 3.2 mm.

15. The drug delivery system of any one of claims 1-14, wherein the drug formulation comprises minitablets, wherein each minitablet has a diameter is that between about 2.60 mm to about 2.66 mm.

16. The drug delivery system of any one of claims 1-15, wherein the drug formulation comprises minitablets, wherein each minitablet has a diameter that is about 2.63 mm.

17. The drug delivery system of any one of claims 1-16, wherein the housing has a first end and a second end and defines a length between the first end and the second end, wherein the length is about 17 cm.

18. The drug delivery system of any one of claims 1-17, wherein the housing of the drug delivery system comprises a retention frame lumen and a wireform disposed in the retention frame lumen.

19. The drug delivery system of claim 18, wherein the wireform has a diameter that is about 0.305 mm and a length that is about 156 mm.

20. The drug delivery system of claim 18 or 19, wherein the wireform is a nitinol wire.

21. The drug delivery system of any one of claims 1-20, comprising a plurality of the minitablets arranged in series and defining a drug core length between a first face of a first minitablet and an opposed second face of a last minitablet.

22. The drug delivery system of claim 21, wherein the drug core length is about 15 cm.

23. The drug delivery system of any one of claims 1-22, wherein the second material of the drug delivery system defines a wall thickness extending along the diameter of the drug reservoir lumen that is 0.2 ± 0.04 mm.

24. The drug delivery system of any one of claims 1-23, wherein the drug reservoir lumen defines an inner diameter that is 2.64 ± 0.05 mm.

25. The drug delivery system of any one of claims 1-24, wherein the drug delivery system is elastically deformable between a coiled retention shape and a relatively straightened insertion shape.

26. The drug delivery system of claim 25, wherein the coiled retention shape comprises a bi-oval shape.

27. The drug delivery system of claim 25 or 26, wherein, when in the coiled retention shape, the drug delivery system has a maximum dimension in any direction that is equal to or less than about 6 cm.

28. The drug delivery system of any one of claims 25-27, wherein, when in the coiled retention shape, the drug delivery system has a maximum dimension in any direction that is equal to or less than about 5.5 cm.

29. The drug delivery system of any one of claims 25-28, wherein, when in the coiled retention shape, the drug delivery system fits within an envelope of 5.5 cm by 4.5 cm.

30. The drug delivery system of any one of claims 1-29, wherein the erdafitinib is erdafitinib free base.

31. The drug delivery system of any one of claims 1-30, wherein both the first wall structure and the second wall structure are permeable to water.

32. A method of treating non-muscle invasive bladder cancer in a patient comprising: deploying the drug delivery system according to any one of claims 1-31 to the bladder of the patient; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; and removing the drug delivery system at least about 90 days later.

33. The method of claim 32, wherein the cancer is intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC).

34. The method of claim 32, wherein the cancer is newly diagnosed intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC).

35. The method of claim 32, wherein the cancer is recurrent intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC).

36. The method of any one of claims 32 to 35, wherein the cancer harbors an FGFR alteration.

37. The method of claim 35, wherein the FGFR alteration is a FGFR2 alteration or a FGFR3 alteration.

38. The method of claim 36 or 37, wherein the FGFR alteration is a FGFR3 alteration, in particular a FGFR3 mutation or a FGFR3 fusion.

39. The method of claim 38, wherein the FGFR3 alteration is at least one of FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, in particular FGFR3-TACC3 variant 1 (FGFR3-TACC3 VI) or FGFR3-TACC3 variant 3 (FGFR3- TACC3 V3), FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

40. The method of any one of claims 32-39, wherein the patient did not receive recent bacillus Calmette-Guerin (BCG) treatment.

41. The method of any one of claims 32-40, wherein the patient has 1 or more of the following risk factors: multiple low grade (LG) tumors, solitary LG tumor >3 cm, early recurrence of LG tumor (<1 year), frequent recurrence (> 1 per year), or recurrence after prior intravesical chemotherapy.

42. The method of any one of claims 32-41, wherein such treatment results in a median duration of response of at least 12 months, or is about 12 months.

43. The method of any one of claims 33-40, wherein such treatment results in a complete response rate of about 90% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, the complete response rate assessed at 12 weeks.

44. The method of any one of claims 33-40, wherein such treatment results in a complete response rate of about 85% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, the complete response rate assessed at 12 weeks.

45. The method of claim 32, wherein the cancer is high-risk non-muscle invasive bladder cancer (HR.-NMIBC).

46. The method of claim 45, wherein the cancer harbors an FGFR alteration.

47. The method of claim 46, wherein the FGFR alteration is a FGFR2 alteration or a FGFR3 alteration.

48. The method of claim 46 or 47, wherein the FGFR alteration is a FGFR3 alteration, in particular a FGFR3 mutation or a FGFR3 fusion.

49. The method of claim 48, wherein the FGFR3 alteration is at least one of FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, in particular FGFR3-TACC3 variant 1 (FGFR3-TACC3 VI) or FGFR3-TACC3 variant 3 (FGFR3- TACC3 V3), FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

50. The method of any one of claims 45-49, wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib, and in particular the 12-month RFS rate, is about 90%.

51. The method of any one of claims 45-49, wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib, and in particular the 12-month RFS rate, is about 75% or about 79% or about 80%.

52. A method of treating intermediate-risk non-muscle invasive bladder cancer (IR- NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein: i) the patient is newly diagnosed or recurrent IR-NMIBC; ii) the patient is determined to have intermediate risk of recurrence or progression; iii) the patient has select FGFR genetic alterations; iv) the patient is without prior bacillus Calmette-Guerin (BCG) treatment; and v) the patient comprises one or more of the following risk factors selected from the list consisting of: a) multiple low grade (LG) tumors, b) solitary LG tumor >3 cm, c) frequent recurrence (> 1 per year), and d) recurrence after prior intravesical chemotherapy.

53. The method of claim 52, wherein the patient and/or population of patients have histologically confirmed diagnosis of IR-NMIBC with at least one of the following disease characterizations: i) Ta LG/G1 : recurrent; ii) Ta LG/G1 : primary & (multifocal or > 3 cm); and/or iii) Ta G2: primary or recurrent.

54. A method of treating recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein such treatment results in an at least 50% complete response rate in a population of patients receiving such treatment.

55. A method of treating recurrent, intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient comprising: deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; and removing the drug delivery system at least about 90 days later; wherein such treatment results in an at least 50% complete response rate in a population of patients receiving such treatment.

56. The method of any one of claims 52-55, wherein such treatment results in a median duration of response of at least 12 months, or is about 12 months.

57. The method of any one of claims 52-56, wherein such treatment results in a complete response rate of about 90% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, the complete response rate assessed at 12 weeks.

58. The method of any one of claims 52-57, wherein such treatment results in a complete response rate of about 85% in the population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, the complete response rate assessed at 12 weeks.

59. The method of any one of claims 52-58, comprising administering about 2.5 mg/day to about 3.5 mg/day of erdafitinib to the patient.

60. The method of any one of claims 52-59, comprising administering about 3 mg/day of erdafitinib to the patient.

61. A method of treating recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising administering about 2 mg/day to about 4 mg/day of erdafitinib locally to the bladder of the patient for at least about 90 days, wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment.

62. A method of treating recurrent bacillus Calmette-Guerin (BCG)-experienced high risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient comprising deploying an intravesical drug delivery system to the bladder of a patient, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed in the closed drug reservoir lumen, wherein the drug reservoir lumen is formed of a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being joined to one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are disposed at an arc angle of 45 degrees to 270 degrees of a circumference of the tube in cross-section normal to the longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure; releasing the erdafitinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; removing the drug delivery system at least about 90 days later; wherein such treatment results in a recurrence-free rate of at least 50% in a population of patients receiving such treatment.

63. The method of any one of claim 61 or 62, wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib, and in particular the 12-month RFS rate, is about 90%.

64. The method of any one of claim 61 or 62, wherein the recurrence-free survival (RFS) rate in a population of patients treated with about 2 mg/day to about 4 mg/day of erdafitinib, in particular about 3 mg/day of erdafitinib, and in particular the 12-month RFS rate, is about 75% or about 79% or about 80%.

65. The method of any one of claims 61-64, comprising administering about 2.5 mg/day to about 3.5 mg/day of erdafitinib to the patient.

66. The method of any one of claims 61-65, comprising administering about 3 mg/day of erdafitinib to the patient.

67. The method of any one of claims 52-66, wherein the method further comprises using a urine sample assay to select patients for treatment.

68. The method of claim 67, wherein the urine sample assay is a urine sample NGS or PCR assay, in particular a urine sample NGS assay.

69. The method of claim 67 or 68, wherein the urine sample assay detects the presence of at least one FGFR2 genetic alteration and/or FGFR3 genetic alteration.

70. The method of claim 69, wherein the FGFR2 genetic alteration and/or the FGFR3 genetic alteration comprises an activating tumor FGFR2 or FGFR3 mutation or fusion.

71. The method of claim 69 or 70, wherein the FGFR2 genetic alteration and/or the FGFR3 genetic alteration is selected from FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, in particular FGFR3-TACC3 VI or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof, in particular wherein the FGFR2 genetic alteration and/or the FGFR3 genetic alteration is selected from FGFR3-TACC3 variant 1 (FGFR3-TACC3 VI) , FGFR3 G370C, FGFR3 S249C, FGFR3 Y373C, and FGFR3 R248C.

72. The method of any one of claims 67-71, wherein at least 50%, 60%, 70%, 80%, or 90% of treated patients selected by the urine sample assay were recurrence-free or achieved a complete response.

73. The method of any one of claims 67-71, wherein at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% of treated patients selected by the urine sample assay were recurrence-free or achieved a complete response.

74. The method of claim 55 or 62, wherein the drug formulation comprises about 480 mg to about 510 mg of erdafitinib, optionally wherein the erdafitinib is erdafitinib free base.