Erdafitinib Plus Enfortumab Vedotin Shows Promise in FGFR-Altered Metastatic Urothelial Carcinoma

At the American Society of Clinical Oncology 2025 Genitourinary Cancers Symposium, Rohit Jain, MD, of Weill Cornell Medicine, presented the results of a study on the use of erdafitinib with enfortumab vedotin (EV) after platinum and programmed cell death 1/programmed cell death ligand 1 (PD-1/L1) inhibitors for patients with metastatic urothelial carcinoma (mUC) with FGFR3/2 alterations.

EV is an approved treatment for patients with mUC after prior platinum-based chemotherapy (PBC) and PD-1/L1 inhibitors or as a first-line therapy in combination with pembrolizumab. Erdafitinib is also approved for patients with mUC with FGFR3 alterations after progression during PBC.

It has been suggested that the activity of EV is not compromised by FGFR3/2 alterations, and EV and erdafitinib have different mechanisms of activity with nonoverlapping toxicities. Because of this, there is reason to evaluate the feasibility of combining EV and erdafitinib to overcome the difficulties of resistance and sequencing agents in patients with mUC and FGFR3/2 alterations.

The ongoing single-arm study evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of EV with erdafitinib in patients with mUC and FGFR3/2 alterations who experienced disease progression after platinum and/or PD-1/L1 inhibitor therapies. A dose-escalation phase will determine the maximum tolerated dose (MTD) of the combination and recommend a phase II dose of EV with a fixed dose of erdafitinib at 8 mg/ day.

A total of nine patients were enrolled in the trial as of data cutoff. Each patient completed a dose-limiting toxicity (DLT) period (first cycle) in the dose-escalation phase. Six patients were enrolled at DL1 with one DLT (skin rash), and three were enrolled at DL2 (no DLT).

The most common all-grade treatment-related adverse events (TRAEs) included hyperphosphatemia (88%), mucositis (88%), high aspartate aminotransferase (88%), hypercalcemia (75%), and palmar plantar erythrodysesthesia (75%). Grade 3 TRAEs included palmar plantar erythrodysesthesia (50%), anemia (17%), rash (17%), anorexia (17%), and paronychia (17%). One patient developed grade 4 Stevens-Johnson syndrome related to EV, which subsequently improved.

The mean steady-state minimum concentration for erdafitinib and monomethyl auristatin E (MMAE) was 1430 ± 639 ng/mL and 1.4 ± 0.9 ng/mL, respectively, and the mean maximum concentration of MMAE at DL1 was 3.9 ± 0.9 ng/mL. All nine patients were evaluable, achieving a 100% objective response rate, including eight partial responses and one complete response. The median overall survival was not reached (NR) (95% CI, 17.1 months-NR), and the median progression-free survival was 7.52 months (95% CI, 5.55-NR), with a median follow-up of 22.7 months. The median duration of response was 5.49 months. The recommended phase II dose for EV is 1.25 mg/kg in combination with erdafitinib at 8 mg/day.

EV with erdafitinib is a feasible combination with the ability to provide promising antitumor activity. The dose-expansion stage is ongoing at the recommended phase II dose of the combination.