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Management of Fibroblast Growth Factor Inhibitor Treatment–emergent Adverse Events of Interest in Patients with Locally Advanced or Metastatic Urothelial Carcinoma
Erdafitinib is indicated for the treatment of adults with locally advanced/metastatic urothelial carcinoma and susceptible FGFR3/2 alterations progressing on/after one or more lines of prior platinum-based chemotherapy.
Objective
To better understand the frequency and management of select treatment-emergent adverse events (TEAEs) to enable optimal fibroblast growth factor receptor inhibitor (FGFRi) treatment.
Design, setting, and participants
Longer-term efficacy and safety results of the BLC2001 (NCT02365597) trial in patients with locally advanced and unresectable or metastatic urothelial carcinoma were studied.
Intervention
Erdafitinib schedule of 8 mg/d continuous in 28-d cycles, with uptitration to 9 mg/d if serum phosphate level was <5.5 mg/dl and no significant TEAEs occurred.
Outcome measurements and statistical analysis
Adverse events were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The Kaplan-Meier methodology was used for the cumulative incidence of the first onset of TEAEs by grade. Time to resolution of TEAEs was summarized descriptively.
Results and limitations
At data cutoff, the median treatment duration was 5.4 mo among 101 patients receiving erdafitinib. Select TEAEs (total; grade 3) were hyperphosphatemia (78%; 2.0%), stomatitis (59%; 14%), nail events (59%; 15%), non–central serous retinopathy (non-CSR) eye disorders (56%; 5.0%), skin events (55%; 7.9%), diarrhea (55%; 4.0%), and CSR (27%; 4.0%). Select TEAEs were mostly of grade 1 or 2, and were managed effectively with dose modifications, including dose reductions or interruptions, and/or supportive concomitant therapies, resulting in few events leading to treatment discontinuation. Further work is needed to determine whether management is generalizable to the nonprotocol/general population.
Conclusions
Identification of select TEAEs and appropriate management with dose modification and/or concomitant therapies resulted in improvement or resolution of most TEAEs in patients, allowing for continuation of FGFRi treatment to ensure maximum benefit.
Patient summary
Early identification and proactive management are warranted to mitigate or possibly prevent erdafitinib side effects to allow for maximum drug benefit in patients with locally advanced or metastatic bladder cancer.
], is indicated for the treatment of adults with locally advanced or metastatic urothelial carcinoma (UC) and susceptible FGFR3/2 alterations who have progressed on/after one or more prior lines of platinum-based chemotherapy [
]. This leads to specific toxicities distinct from those observed with broader tyrosine kinase inhibition, including hyperphosphatemia, alopecia, dry skin, stomatitis, nail disorders (onycholysis, nail loss, and paronychia), and eye disorders including central serous retinopathy (CSR) detected with and without routine optical coherence tomography (OCT) testing [
]. Any-grade toxicity rates with erdafitinib and other FGFRis across trials in patients with UC and cholangiocarcinoma (CCA) were reported to be 31–77% for hyperphosphatemia, 7–58% for stomatitis, 15–61% for diarrhea, 18% for nail events, 21–23% for palmar-plantar erythrodysesthesia, and 13–41% for ocular events [
]. Here, we further examine long-term safety, focusing on the frequency and management of select treatment-emergent adverse events (TEAEs; ie, most common and FGFRi class-effect TEAEs) to enable optimal erdafitinib treatment.
2. Patients and methods
2.1 Study design
Longer-term efficacy and safety results of the BLC2001 (NCT02365597) trial in patients with locally advanced and unresectable or metastatic UC were described recently [
]. Briefly, eligible adult patients had measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1, one or more FGFR3 mutations or FGFR2/3 fusions per prespecified panel by central laboratory testing, had a history of disease progression during or after one or more lines of systemic chemotherapy or within 12 mo after neoadjuvant/adjuvant chemotherapy or were cisplatin ineligible and chemotherapy naïve, had Eastern Cooperative Oncology Group performance status ≤2, and had adequate bone marrow, liver, and kidney function (creatinine clearance, ≥40 ml/min/1.73 m2).
2.2 Treatment
Patients received 8 mg/d oral erdafitinib, with uptitration to 9 mg/d permitted on day 15 of cycle 1 for those without adverse events (AEs) considered to be related to treatment by the investigator, if they had not reached the target serum phosphate level of 5.5 mg/dl (1.8 mmol/l). Patients continued erdafitinib treatment at 8 mg/d if their serum phosphate levels on day 14 were within 5.5–<7.0 mg/dl (1.8–2.3 mmol/l; target range). Patients continued to receive erdafitinib until disease progression or unacceptable AEs, as determined by the investigator. At the discretion of the investigator and the sponsor, patients with investigator-assessed disease progression could continue erdafitinib treatment.
2.3 Assessments and statistical methods
Safety was assessed in treated patients (safety population) through clinical laboratory testing and physical and ophthalmological examinations as of the August 9, 2019, data cutoff. Investigators assessed and graded AEs using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Select TEAEs (ie, the most common and FGFRi class-effect TEAEs) identified for this analysis were hyperphosphatemia, nail events, skin events, CSR events, non-CSR eye disorders, stomatitis, and diarrhea. The most significant dose modification action taken for a TEAE was recorded; thus, TEAEs that led to interruption followed by reduction were reported as reductions. Events that recurred within 3 d of each other were considered a single, continuous event, with the entire duration included in the time-to-resolution calculation. Time to resolution was defined as the time from the day of the onset of a TEAE of any grade, through changes in grade, to the day of the event’s resolution (with recurrence ≤3 d). Events that changed in grade, per patient, were reported independently in the Kaplan-Meier analysis for each respective grade. Patients without a corresponding event of a particular grade are censored in the time-to-event analysis for that grade at the last dose date plus 30 d, data cutoff, or the end of study date, whichever was first. Patients may have had more than one TEAE in the higher-level categories of nail events, skin events, non-CSR eye disorders, and CSR, which comprise multiple preferred terms. Resolution data are presented only for the most common preferred terms in these higher-level categories to accurately reflect patient experience for each TEAE preferred term. Concomitant medication duration was reported by class of agents used to treat select TEAEs, with missing end dates imputed with respective nonmissing TEAE end dates; records with both missing concomitant medication and TEAE end dates were excluded.
3. Results
3.1 Patient characteristics
A total of 101 patients were treated with the 8 mg/d uptitration regimen, which reflects the safety data reported herein (Supplementary Fig. 1). At the data cutoff date (August 9, 2019), the median treatment duration was 5.4 mo among 101 patients who received erdafitinib 8 mg/d uptitration, and the median follow-up (estimated based on the time from the first dose date to the censoring date for progression-free survival) [
] was 24.0 mo. Progressive disease was the primary reason for treatment discontinuation (n = 76). Seventeen patients discontinued due to AEs, and five continued treatment. Patient demographic and baseline characteristics, as reported previously [
]. The most common select TEAEs were hyperphosphatemia (78%), stomatitis (59%), and nail events (59%; Table 1). The median onset time, frequencies of dose reduction, interruption, discontinuation, and median time treatment was withheld for select TEAEs are shown in Table 2. The incidence of the first onset of select TEAEs displays a temporal sequence with either an acute peak onset (eg, hyperphosphatemia or diarrhea) or a delayed peak onset (eg, CSR or nail events; Fig. 1).
The three most frequently occurring TEAEs in each of the categories, grouped by higher-level terms, were onycholysis (19%), paronychia (19%), and nail dystrophy (17%) for nail events; dry eye (28%), vision blurred (18%), and conjunctivitis (13%) for non-CSR eye disorders; dry skin (34%), palmar-plantar erythrodysesthesia syndrome (25%), and erythema (7.9%) for skin events; and chorioretinopathy (7.9%), retinal detachment (5.9%), and vitreous detachment (5.9%) for CSR events.
The three most frequently occurring TEAEs in each of the categories, grouped by higher-level terms, were onycholysis (19%), paronychia (19%), and nail dystrophy (17%) for nail events; dry eye (28%), vision blurred (18%), and conjunctivitis (13%) for non-CSR eye disorders; dry skin (34%), palmar-plantar erythrodysesthesia syndrome (25%), and erythema (7.9%) for skin events; and chorioretinopathy (7.9%), retinal detachment (5.9%), and vitreous detachment (5.9%) for CSR events.
The three most frequently occurring TEAEs in each of the categories, grouped by higher-level terms, were onycholysis (19%), paronychia (19%), and nail dystrophy (17%) for nail events; dry eye (28%), vision blurred (18%), and conjunctivitis (13%) for non-CSR eye disorders; dry skin (34%), palmar-plantar erythrodysesthesia syndrome (25%), and erythema (7.9%) for skin events; and chorioretinopathy (7.9%), retinal detachment (5.9%), and vitreous detachment (5.9%) for CSR events.
a The three most frequently occurring TEAEs in each of the categories, grouped by higher-level terms, were onycholysis (19%), paronychia (19%), and nail dystrophy (17%) for nail events; dry eye (28%), vision blurred (18%), and conjunctivitis (13%) for non-CSR eye disorders; dry skin (34%), palmar-plantar erythrodysesthesia syndrome (25%), and erythema (7.9%) for skin events; and chorioretinopathy (7.9%), retinal detachment (5.9%), and vitreous detachment (5.9%) for CSR events.
b One grade 4 TEAE occurred: cataract (grade 1 cataract was present at baseline). No other grade 4 or grade 5 TEAEs occurred.
The most significant dose modification action taken for a TEAE was recorded; thus, TEAEs that led to interruption followed by reduction were reported as reductions.
Dose reduction
11/79 (14)
19/60 (32)
20/60 (33)
15/57 (26)
11/55 (20)
0
13/27 (48)
Dose interruption
24/79 (30)
27/60 (45)
17/60 (28)
10/57 (18)
13/55 (24)
6/55 (11)
8/27 (30)
Discontinuation
1/79 (1.3)
2/60 (3.3)
1/60 (1.7)
3/57 (5.3)
3/55 (5.5)
1/55 (1.8)
3/27 (11)
Received treatment for select TEAE, n/N with TEAE (%)
31/79 (39)
44/60 (73)
34/60 (57)
34/57 (60)
31/55 (56)
30/55 (55)
5/27 (19)
Time treatment was withheld for select TEAE (d), median (IQR)
Data for chorioretinopathy (other CSR-related TEAEs are shown in Supplementary Table 4).
CSR = central serous retinopathy; IQR = interquartile range; NA = not available; TEAE = treatment-emergent adverse event.
a The most significant dose modification action taken for a TEAE was recorded; thus, TEAEs that led to interruption followed by reduction were reported as reductions.
b For each of the subsequent rows, data for the select TEAEs grouped by higher-level terms are the most common events.
c Data for nail events represent two separate preferred terms (onycholysis [top] and paronychia [bottom]).
d Data for skin events represent two separate terms (dry skin [top] and palmar-plantar erythrodysesthesia [bottom]).
e Data for chorioretinopathy (other CSR-related TEAEs are shown in Supplementary Table 4).
f Data for non-CSR eye disorders represent the preferred term of dry eye.
Fig. 1Incidence of the first onset of select treatment-emergent adverse events. CSR = central serous retinopathy; TEAE = treatment-emergent adverse event.
Serum phosphate levels were monitored over the course of treatment (Supplementary Fig. 2), with the mean values peaking 6 wk after the start of treatment and generally decreasing thereafter.
Seventy-nine (78%) patients developed hyperphosphatemia, with a median time to onset of 20 (interquartile range [IQR], 14–29) d; of these patients, 77 (76%) had grade 1 or 2 events (Table 1, Table 2; cumulative incidence, Fig. 2). The median phosphate values for dose interruption and dose reduction due to hyperphosphatemia were 7.16 (IQR, 7.00–7.70) and 7.30 (IQR, 6.50–8.50) mg/dl, respectively. The most common therapy for hyperphosphatemia among the 31 (39%) of 79 patients with hyperphosphatemia was the use of various phosphate binders (94%; median duration 72 [IQR, 44–121] d; Supplementary Table 2). By data cutoff, resolution of one or more hyperphosphatemia events was observed in 74 (94%) patients. The median time to resolution of hyperphosphatemia was 17 (IQR, 9–37) d.
Fig. 2Cumulative incidence of the first onset of hyperphosphatemia by grade using the Kaplan-Meier method.
The incidence of any TEAEs considered potential sequelae of prolonged hyperphosphatemia was similar in patients with prolonged hyperphosphatemia (≥5.5 mg/dl for >1 mo; seven of 21 [33%]) and those without (29 of 80 [36%]; Supplementary Table 3). Patients with prolonged hyperphosphatemia had a higher incidence of anemia (29% vs 20%) and renal impairment (14% vs 6.3%) than those without prolonged hyperphosphatemia, and a lower incidence of hypotension (4.8% vs 7.5%). The incidence of all other TEAEs that were considered potential sequelae of prolonged hyperphosphatemia was nonexistent for patients with prolonged hyperphosphatemia versus those without: hyperparathyroidism (0 vs 2.5%), hypocalcemia (0 vs 5.0%), and renal failure (0 vs 2.5%). No events of calcinosis or calciphylaxis were reported. Cumulative incidence curves of the first onset of TEAEs considered potential sequelae of prolonged hyperphosphatemia, by grade, are shown in Supplementary Figure 3.
3.5 Dermatological events
3.5.1 Nail events
Sixty (59%) patients developed nail events, with a median time to onset of 69 (IQR, 50–89) d; of these patients, 45 (45%) had grade 1 or 2 events (Table 1, Table 2; cumulative incidence, Fig. 3A). Among the 34 (57%) of 60 patients with nail events receiving concomitant medications, the most common therapies were systemic antibacterials (38%; median duration 15 [IQR, 11–24] d) and dermatological antifungals (35%; median duration 59 [IQR, 35–214] d). The most commonly reported nail events were onycholysis and paronychia (n = 19, 19% for each). The median time treatment was withheld for onycholysis (n = 2 with dose interruption) and paronychia (n = 6 with dose interruption) was 14 (IQR, 14–14) and 18 (IQR, 12–21) d, respectively. By data cutoff, resolution of one or more onycholysis events was observed in six (32%) patients, and resolution of one or more paronychia events was observed in 11 (58%) patients. The median time to resolution of onycholysis and paronychia was 122 (IQR, 100–237) and 75 (IQR, 16–138) d, respectively.
Fig. 3Cumulative incidence of the first onset of (A) nail and (B) skin events by grade using the Kaplan-Meier method.
Fifty-five (55%) patients developed skin events, with a median time to onset of 42 (IQR, 22–83) d; of these patients, 47 (47%) had grade 1 or 2 events (Table 1, Table 2; cumulative incidence, Fig. 3B). Among the 31 (56%) of 55 patients with skin events receiving concomitant medications, the most common therapies were emollients and protective agents (45%; median duration 111 [IQR, 65–156] d) and systemic corticosteroids (29%; median duration 63 [IQR, 21–74] d). The most commonly reported skin event was dry skin (n = 34, 34%) followed by palmar-plantar erythrodysesthesia (n = 25, 25%). The median time treatment was withheld for palmar-plantar erythrodysesthesia (n = 9 with dose interruption) was 25 (IQR, 15–35) d. By data cutoff, resolution of one or more palmar-plantar erythrodysesthesia events was observed in 12 (48%) patients. The median time to resolution of palmar-plantar erythrodysesthesia was 93 (IQR, 41–121) d.
3.6 Central serous retinopathy
Twenty-seven (27%) patients developed CSR, with a median time to onset of 53 (IQR, 32–100) d; of these patients, 23 (23%) had grade 1 or 2 events (Table 1, Table 2; cumulative incidence, Fig. 4). Among the five (19%) of 27 patients with CSR receiving concomitant medications, the most common therapy was the use of ophthalmologicals (60%, mostly artificial tears; median duration 112 [IQR, 23–113] d). The most commonly reported CSR event was chorioretinopathy (CR; n = 8, 8%). The median time treatment was withheld for CR (n = 3 with dose interruption) was 22 (IQR, 21–24) d. By data cutoff, resolution of one or more CR events was observed in six (75%) patients. The median time to resolution of CR was 27 (IQR, 17–133) d. In addition to CR, CSR encompasses several TEAEs that could potentially overlap in an individual patient (eg, retinal detachment and vitreous detachment). Supplementary Table 4 provides a summary of their frequency of occurrence and resolution.
Fig. 4Cumulative incidence of the first onset of central serous retinopathy (CSR) by grade using the Kaplan-Meier method.
Fifty-seven (56%) patients developed non-CSR eye disorders, with a median time to onset of 50 (IQR, 28–80) d; of these patients, 51 (50%) had grade 1 or 2 events (Table 1, Table 2; cumulative incidence, Supplementary Fig. 4). Among the 34 (60%) of 57 patients with non-CSR eye disorders receiving concomitant medications, the most common therapy was the use of ophthalmologicals (85%, mostly eye lubricants/artificial tears; median duration 51 [IQR, 30–143] d). The most commonly reported non-CSR eye event was dry eye (n = 28, 28%). By data cutoff, resolution of one or more dry eye events was observed in 21 (75%) of 28 patients. The median time to resolution of dry eye was 44 (IQR, 29–91) d.
3.8 Gastrointestinal TEAEs
3.8.1 Stomatitis
Sixty (59%) patients developed stomatitis, with a median time to onset of 32 (IQR, 18–85) d; of these patients, 46 (46%) had grade 1 or 2 events (Table 1, Table 2; cumulative incidence, Supplementary Fig. 5A). Among the 44 (73%) of 60 patients with stomatitis receiving concomitant medications, the most common therapy was the use of stomatological preparations (45%; median duration 65 [IQR, 27–137] d), including magic mouthwash (9%) and systemic corticosteroids (30%). By data cutoff, resolution of one or more stomatitis events was observed in 48 (80%) patients. The median time to resolution of stomatitis was 34 (IQR, 22–75) d.
3.8.2 Diarrhea
Fifty-five (55%) patients developed diarrhea, with a median time to onset of 14 (IQR, 8–23) d; of these patients, 51 (50%) had grade 1 or 2 events (Table 1, Table 2; cumulative incidence, Supplementary Fig. 5B). Among the 30 (55%) of 55 patients with diarrhea receiving concomitant medications, the most common therapies included antidiarrheals (97%; median duration 29 [IQR, 12–91] d), primarily loperamide hydrochloride/loperamide (87%). Resolution of one or more diarrhea events by data cutoff was observed in 50 (91%) patients. The median time to resolution of diarrhea was 20 d (IQR, 7–34).
4. Discussion
Patients treated with erdafitinib in the BLC2001 study exhibited common class-effect TEAEs known to be associated with FGFRi. Dose interruption and reduction guidelines were provided to investigators as guidance during the conduct of the study and are provided here (Supplementary Table 5), as they may be beneficial for the general care of patients being treated with FGFRi. Overall, the select TEAEs were managed effectively with erdafitinib dose modifications, including reductions or interruptions, and/or supportive concomitant therapies, resulting in few events leading to treatment discontinuation. Additionally, low-grade events occur earlier than more severe grade 3 events. These data suggest that identification of the select TEAEs and appropriate management with dose modification and concomitant therapies resulted in resolution of most TEAEs, may avoid more severe events, and may have prevented treatment discontinuation thereby ensuring maximum benefit with erdafitinib.
Hyperphosphatemia is a known class effect of FGFRi mediated by blockade of FGF23 inhibition of phosphate reabsorption [
]. Based on this off-tumor physiology, serum phosphate is carefully monitored as a pharmacokinetic/pharmacodynamic marker for erdafitinib and infigratinib [
]. The lower rate of hyperphosphatemia observed in patients who had uptitration may be explained by lower phosphate levels on erdafitinib due to lower FGFR target engagement than the group that did not require uptitration. Treatment with continuous erdafitinib was well tolerated, with a decrease in phosphate levels over time, and allows for improved clinical activity in patients. Further, hyperphosphatemia is seen in patients with chronic kidney disease, due to a decreased ability to excrete excess phosphate, acid, and potassium [
]. As adequate kidney function was an inclusion criterion for BLC2001, the risks of hyperphosphatemia associated with FGFRi treatment in patients with chronic kidney disease were not assessed in the study, so caution should be practiced in this setting.
Events of calcinosis and calciphylaxis were not reported in this study, but cases have been reported with FGFRi treatment [
]. There are also other underlying clinical risk factors that can contribute to the development of calciphylaxis and calcinosis, including but not limited to female sex, obesity, and diabetes [
]. Therefore, clinicians should consider a patient’s underlying risk factors for calciphylaxis and calcinosis, and counsel patients accordingly.
CSR developed in 27% of patients, with most commonly reported events of CR, retinal detachment, and vitreous detachment. Additional FGFRis have shown similar findings of CSR. Rogaratinib treatment led to a serious treatment-related adverse event of retinopathy in one patient with UC (2%) on routine OCT testing [
]. Different degrees of reported retinopathy may be related to variability in monitoring across clinical trials (ie, routine OCTs vs OCT in response to clinical symptoms or abnormal Amsler grid test). There may also be age-related differences in CSR occurrence. For example, patients in our study were on average 10 yr older than CCA cohorts, and that could impact TEAEs. The underlying mechanism of CSR in patients treated with FGFRi is unclear, but other inhibitors of the MEK/MAP kinase pathways have been associated with CSR, such as transient MEK inhibitor–associated grade 1/2 bilateral retinopathies (40–65%) in patients with metastatic melanoma [
Nail disorders are the most concerning TEAEs that arise during long-term erdafitinib dosing. Treatments for symptom management of grade 2/3 nail onycholysis or onychodystrophy include over-the-counter nail strengthener/nail lacquer and silver nitrate application weekly, and topical antibiotics and vinegar soaks. For signs of infection (periungal edema/erythema/tenderness or discharge), bacterial cultures should be obtained with initiation of oral antibiotics (cefadroxil 500 mg twice daily, ciprofloxacin 500 mg twice daily, or sulfamethoxazole/trimethoprim twice daily) for 2 wk. For cases of severe or refractory infection, intravenous antibiotics should be considered, along with dermatological or surgical evaluation.
A potential study limitation is generalizability to the nonprotocol/general population given the sample size. This safety analysis does not include any description of potential correlation between the select TEAEs and efficacy. Additionally, the absence of dosing details for concomitant medications, the small number of patients who received specific therapies or supportive measures, and investigator discretion in the management of TEAEs limit the ability to precisely assess the efficacy of such interventions for the management of erdafitinib-related toxicities.
5. Conclusions
Erdafitinib is being studied in a phase 3 randomized, controlled trial (NCT03390504) in patients with previously treated advanced UC as monotherapy versus an immune checkpoint inhibitor (programmed cell death protein 1) or chemotherapy. Erdafitinib is also being investigated in a randomized phase 1/2 trial in the first-line cisplatin-ineligible metastatic UC setting in combination with the programmed cell death protein 1 inhibitor cetrelimab (NCT03473743) and as monotherapy versus intravesical chemotherapy in a randomized phase 2 trial (NCT04172675) in high-risk, non–muscle-invasive bladder cancer recurring after treatment with bacillus Calmette-Guérin. These additional studies and ongoing studies with other FGFRi will continue to inform optimal management of FGFRi TEAEs with dose modification and concomitant therapies in different patient populations and settings. Pending such additional information from clinical studies, multidisciplinary management may be recommended to manage select higher-grade TEAEs in metastatic UC patients with FGFRi to prevent the onset, or minimize the severity, of the select TEAEs and optimize patient compliance and outcome.
Author contributions: Arlene O. Siefker-Radtke had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Siefker-Radtke, Rezazadeh Kalebasty, O’Hagan.
Acquisition of data: All authors.
Analysis and interpretation of data: All authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Qi, Akapame.
Obtaining funding: Triantos.
Administrative, technical, or material support: Triantos.
Supervision: Akapame, Triantos, O’Hagan.
Other: None.
Financial disclosures: Arlene O. Siefker-Radtke certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Arlene O. Siefker-Radtke has received support from the National Institutes of Health, Michael and Sherry Sutton Fund for Urothelial Cancer, Janssen, Takeda, Bristol Myers Squibb, BioClin Therapeutics, Nektar, Merck Sharp & Dohme, and Basilea; consulting fees from Janssen, Merck, National Comprehensive Cancer Network, Bristol Myers Squibb, AstraZeneca, Bavarian Nordic, Seattle Genetics, Nektar, Genentech, EMD Serono, Mirati Therapeutics, and Basilia; and has patents planned, issued, or pending related to molecular testing in muscle invasive bladder cancer, outside of the submitted work. Andrea Necchi received personal fees from Bayer during the conduct of the study; and has received consulting fees from Merck Sharp & Dohme, Roche, Bayer, AstraZeneca, Clovis Oncology, Janssen, Seattle Genetics/Astellas, Bristol Myers Squibb, GlaxoSmithKline, and Ferring; honoraria from Roche, Merck, AstraZeneca, Janssen, Foundation Medicine, and Bristol Myers Squibb; support for attending meetings or travel from Roche, Merck, Sharp & Dohme, AstraZeneca, Janssen, and Rainier Therapeutics; stocks or stock options for an immediate family member from Bayer; and other financial or nonfinancial interests from Merck Sharp & Dohme, AstraZeneca, and Ipsen, outside of the submitted work. Se Hoon Park has no disclosures to report. Jesús García-Donas has received consulting fees from Bristol Myers Squibb and Clovis Oncology; honoraria from Roche, Bristol Myers Squibb, AstraZeneca, PharmaMar, GlaxoSmithKline, Amgen, Clovis Oncology, and Janssen-Cilag; and other financial or nonfinancial interests from Pfizer, Bristol Myers Squibb, Roche, AstraZeneca, Merck, GamaMabs Pharma, and InvitroCue, outside of the submitted work. Robert A. Huddart received personal fees from Aspen Parkside Hospital during the conduct of the study; has received consulting fees from Bristol Myers Squibb, Roche, Merck Sharp & Dohme, Janssen Oncology, Nektar, and Bayer; has received honoraria from Janssen Oncology; support for attending meetings or travel from Janssen Oncology, Roche/Genentech, MSD Oncology, and Nektar; has other financial or nonfinancial interests from Merck Sharp & Dohme, Roche, Bristol Myers Squibb, and Janssen; and has a leadership or fiduciary role at Cancer Clinic London Limited Liability Partnership, outside of the submitted work. Earle F. Burgess has received grants or contracts from Pfizer and Astellas Pharma; honoraria from Exelixis and Bayer; and stocks or stock options from Exelixis, Becton Dickinson, Gilead Sciences, Medtronic, and Macrogenics, outside of the submitted work. Mark T. Fleming has received consulting fees from Janssen Oncology; has received honoraria from Genentech and Janssen Oncology; and has been reimbursed for travel, accommodations, or expenses from Medivation/Astellas and Genentech, outside of the submitted work. Arash Rezazadeh Kalebasty has served in a consulting or advisory role with AstraZeneca, Bayer, Bristol Myers Squibb, EMB Serono, Exelixis, Genentech, Gilead Sciences, Immunomedics, Novartis, and Pfizer; has served on speakers’ bureau for Amgen, Astellas Medivation, AstraZeneca, AVEO, Bristol Myers Squibb, EMD Serono, Eisai, Exelixis, Genentech/Roche, Gilead Sciences, Janssen, Merck, Myovant Sciences, Novartis, Pfizer, Sanofi, and Seattle Genetics/Astellas; has received institutional research funding from AstraZeneca, Bavarian Nordic, Bayer, BeyondSpring, BioClin Therapeutics, Bristol Myers Squibb, Clovis Oncology, Eisai, Epizyme, Exelixis, Genentech, Immunomedics, Janssen, Macrogenics, and Seattle Genetics; has received travel, accommodations, and expenses support from Astellas Medivation, AstraZeneca, Bayer, Eisai, Exelixis, Genentech, Janssen, Novartis, Pfizer, and Prometheus Laboratories; and has stock and other ownership interests with ECOM Medical. Begoña Mellado has received consulting fees from Pfizer, Roche, AstraZeneca, Bayer, Astellas Pharma, and Janssen, and for an immediate family member from Roche, Pfizer, and Amgen; support for attending meetings or travel from Janssen-Cilag and for an immediate family member from Roche; and other financial or nonfinancial interests from Roche, Janssen, and Bayer, outside of the submitted work. Sergei Varlamov has no disclosures to report. Monika Joshi has received personal fees for serving on advisory boards for Sanofi and Seagen; has received institutional research funds from AstraZeneca and Pfizer; and received free drug to institution for research from Eisai. Ignacio Duran has been an invited speaker/served on an advisory board for Astellas, Bristol Myers Squibb, Ipsen, and MSD; has been an invited speaker for Eusa Pharma, Janssen, and Novartis; has served on an advisory board for Merck; has served on advisory board/received a research grant with institutional support for Roche Genentech; has received a research grant with institutional support from AstraZeneca; has served on a steering committee for Immunomedics, Inc.; and reports the following nonfinancial interests: ASEICA (Board of Directors member); GO NORTE (leadership role). Scott T. Tagawa has received consulting fees from Medivation, Astellas Pharma, Dendreon, Janssen, Bayer, Genentech, Endocyte, Immunomedics, Karyopharm Therapeutics, Abbvie, Tolmar, QED Therapeutics, Amgen, Sanofi, Pfizer, Clovis Oncology, Novartis, Genomic Health, and Point Biopharma; support for attending meetings or travel from Sanofi, Immunomedics, and Amgen; and other financial or nonfinancial interests from Lilly, Sanofi, Janssen, Astellas Pharma, Progenics, Millenium, Amgen, Bristol Myers Squibb, Dendreon, Rexahn Pharmaceuticals, Bayer, Genentech Newlink Genetics, Inovio Pharmaceuticals, AstraZeneca, Immunomedics, Novartis, Aveo, Boehringer Ingelheim, Merck, Stem CentRx, Karyopharm Therapeutics, Abbvie, Medivation, Endocyte, Exelixis, and Clovis Oncology, outside of the submitted work. Yousef Zakharia has served on advisory boards for Amgen, Array, Aveo, Bayer, Bristol Myers Squibb, Castle Bioscience, Clovis, Eisai, EMD Serono, Exelixis, Janssen, Novartis, Pfizer, and Roche Diagnostics; has received consultant honorarium from Novartis and Pfizer; has received institutional grant/research support from Eisai, Exelixis, and Pfizer; and has served on a data safety monitoring committee for Janssen Research & Development.
Keqin Qi is an employee of Janssen. Sydney Akapame, Spyros Triantos, and Anne O’Hagan are employees of Janssen. Yohann Loriot has received consulting fees from Janssen, Astellas Pharma, Roche, AstraZeneca, MSD Oncology, Clovis Oncology, Seattle Genetics, and Bristol Myers Squibb; and has been reimbursed for accommodations or expenses from Astellas Pharma, Janssen Oncology, Roche, AstraZeneca, MSD Oncology, Clovis Oncology, Seattle Genetics, and Bristol Myers Squibb, outside of the submitted work.
Funding/support and role of sponsor: This study was funded by Janssen Research & Development, LLC. The sponsor was involved in the design and conduct of the study; analysis and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. Funding for editorial assistance was provided by Janssen Global Services, LLC.
Data sharing: Janssen Pharmaceutical Companies of Johnson & Johnson’s data sharing policy is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for study data access can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.
Acknowledgments: This paper was presented in part at the Genitourinary Cancers Symposium, February 11–13, 2021, Virtual (abstract 426). Erdafitinib (JNJ-42756493) was discovered in collaboration with Astex Pharmaceuticals. We thank the patients who volunteered to participate in this study and the investigators and staff who cared for them, as well as the BLC2001 study team. Writing assistance was provided by Ira Mills, PhD, of Parexel, and was funded by Janssen Global Services, LLC.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
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