Erdafitinib, Potential for Expanding Indications for the Future

It has now been approximately a year and a half since the United States Food and Drug Administration (FDA) granted accelerated approval to erdafitinib for patients with locally advanced or metastatic urothelial carcinoma, with susceptible fibroblast growth factor receptor 3 (FGFR3) or FGFR2 genetic alterations after progression during or following platinum chemotherapy.1 The label is inclusive of patients within 12 months of neoadjuvant or adjuvant platinum chemotherapy. Additionally, the label includes companion diagnostic information for a jointly approved therascreen® FGFR RGQ RT-PCR kit, for this specific therapeutic indication.

The data supporting this accelerated approval was derived from an open-label, Phase II trial that studied the above patient population.2 Prior immunotherapy was allowed. Patients were randomly assigned to receive intermittent or continuous erdafitinib therapy in the initial dose-selection phase of the study. The dose-selection phase of the trial established the dose as 8 mg PO qd in a continuous regimen, and dose escalation to 9 mg PO qd was pharmacodynamically guided by patient toxicity and serum phosphate levels. This approach was introduced by an amendment that allowed dose escalation if no treatment-associated adverse events were noted by day 14 and if the phosphate target level of 5.5 mg per deciliter (1.8 mmol per Liter). This phosphate level was associated with an improved response rate in the Phase I trial.3 The primary endpoint of confirmed objective response rate was met by 40% (3% complete response, 37% partial response) of the 99 patients in the selected-regimen treatment group.  Interestingly, the 22 patients who had received previous immunotherapy had a confirmed objective response rate of 59%. The median overall survival was 13.8 months. Treatment-emergent adverse events were reported in 46% of patients with 13% halting study treatment as a result. Common toxicities, of any grade, noted in the trial included hyperphosphatemia (77%), stomatitis (58%), diarrhea (51%), dry mouth (46%), decreased appetite (38%), dysgeusia (37%), fatigue (32%), and dry skin (32%).

It is important to realize that the population harboring these alterations vary depending on what disease state and what dataset is examined. Rough estimates are that 15-20% of the post-platinum, locally advanced, or metastatic urothelial carcinoma will bear an FGFR alteration necessary for erdafitinib eligibility. Yet, there are multiple opportunities for exploration of erdafitinib for other urothelial carcinoma disease states. Interestingly, activating point mutations of FGFR3 are common (~86%) in low grade and stage bladder tumors.4 This lends support to the concept of testing erdafitinib in nonmuscle-invasive bladder cancer. A neoadjuvant approach is also reasonable for muscle-invasive disease, however, The Cancer Genome Atlas Research Network identified FGFR3 mutations in only 12% of muscle-invasive bladder cancers.5 FGFR3 mutations are, however, very common in upper tract urothelial tumors, especially of the ureter.6

I have previously covered many other FGFR inhibiting small molecular and monoclonal antibody agents in a previous UroToday Clinical Trials Portal article.7  Now that erdafitinib has an accelerated FDA approval, it is only logical that additional clinical trials should test erdafitinib in other urothelial carcinoma disease settings. Below are a few trials that emphasize ongoing attempts with erdafitinib. Specifically, the randomized Phase III trial to gain full FDA approval is still ongoing. Initial combination therapy efforts as well as evaluation in the nonmuscle-invasive bladder cancer setting are ongoing and listed below:

  • Phase II for high-risk nonmuscle-invasive bladder cancer with FGFR mutations or fusions and recurrence after prior Bacillus-Calmette Guérin (BCG) (NCT04172675)
    • Cohort 1 without carcinoma in situ (CIS) – randomize 1:1 to erdafitinib vs. intravesicular gemcitabine or hyperthermic mitomycin C
    • Cohort 2 with CIS – erdafitinib for all
  • Phase Ib/II of erdafitinib in combination with cetrelimab and/or platinum chemotherapy for FGFR altered metastatic bladder cancer (NCT03473743)
    • Phase Ib - erdafitinib + cetrelimab + platinum chemotherapy for chemotherapy-naïve or erdafitinib + cetrelimub for any number of lines of prior therapy
    • Phase II dose-expansion for untreated, cisplatin-ineligible – randomize 1:1 to erdafitinib or the recommended Phase II dose of from Phase Ib for erdafitinib + cetrelimab
  • Phase 3 of erdafitinib for metastatic bladder cancer (NCT03390504)
    • Cohort 1 – randomized erdafitinib vs. vinflunine or docetaxel for post anti PD-(L)1 treated
    • Cohort 2 – randomized erdafitinib vs. pembrolizumab for anti PD-(L)1 untreated

Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington


1. US Food and Drug Administration. "FDA grants accelerated approval to erdafitinib for metastatic urothelial carcinoma." (2019).
2. Loriot, Yohann, Andrea Necchi, Se Hoon Park, Jesus Garcia-Donas, Robert Huddart, Earle Burgess, Mark Fleming et al. "Erdafitinib in locally advanced or metastatic urothelial carcinoma." New England Journal of Medicine 381, no. 4 (2019): 338-348.
3. Tabernero, Josep, Rastislav Bahleda, Rodrigo Dienstmann, Jeffrey R. Infante, Alain Mita, Antoine Italiano, Emiliano Calvo et al. "Phase I dose-escalation study of JNJ-42756493, an oral pan–fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors." Journal of Clinical Oncology 33, no. 30 (2015): 3401-3408.
4. van Rhijn, Bas WG, Rodolfo Montironi, Ellen C. Zwarthoff, Adriaan C. Jöbsis, and Theo H. van der Kwast. "Frequent FGFR3 mutations in urothelial papilloma." The Journal of pathology 198, no. 2 (2002): 245-251.
5. Cancer Genome Atlas Research Network. "Comprehensive molecular characterization of urothelial bladder carcinoma." Nature 507, no. 7492 (2014): 315-322.
6. van Oers, Johanna MM, Ellen C. Zwarthoff, Ishtiaq Rehman, Abdel-Rahmene Azzouzi, Olivier Cussenot, Mark Meuth, Freddie C. Hamdy, and James WF Catto. "FGFR3 mutations indicate better survival in invasive upper urinary tract and bladder tumours." European urology 55, no. 3 (2009): 650-658
7. Yu, Evan. "Fibroblast Growth Factor Receptors, a New Hope for Patients with Urothelial Carcinomas". Urotoday Clinical Trials Portal. December 6, 2017.
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