ETCTN 10483: Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma (mUC) with FGFR3/2 genetic alterations (GAs).
Authors: Rohit K. Jain, Faustine Ong, Bishoy Morris Faltas, Scott T. Tagawa, Di Maria Jiang, Jazlyn Heiligh, Syeda Mahrukh Hussnain Naqvi, Youngchul Kim, Lorraine Cheryl Pelosof, Yuanquan Yang, Laura Graham, Waddah Arafat, Timothy Walter Synold, Monica Sheila Chatwal, Jingsong Zhang, Jus Chadha, Guru P. Sonpavde
Journal: Journal of Clinical Oncology (2025)

808 Background: Erdafitinib (E) is an approved treatment in patients with mUCwith FGFR 3 GAs after progression on platinum-based chemotherapy (PBC). Enfortumab Vedotin (EV) is approved to treat patients with mUC following prior PBC and PD1/L1 inhibitors or as First-line therapy in combination with pembrolizumab. Retrospective studies suggest that the activity of EV is not compromised by FGFR 3/2 GAs. EV and erdafitinib have different mechanisms of activity and toxicities are mostly non-overlapping. Hence, there is rationale to evaluate the feasibility of combination EV and E, to overcome the difficulties of resistance and sequencing agents in mUC patients with FGFR 3/2 GAs. Methods: This is an ongoing, single arm, multicenter, Phase I, 3+3 design dose-escalation and expansion study of E+ EV combination evaluating the safety, tolerability, PK, and antitumor activity in patients with mUC harboring FGFR3/2 GAs who have progressed after platinum and/or PD1/L1 inhibitor therapies. Dose escalation phase aims to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of EV in combination with fixed dose of E at 8 mg/day (table). Results: As of data cutoff, 9 patients were enrolled and completed dose limiting toxicity (DLT) period (1 st cycle) in the dose-escalation phase. Six patients were enrolled at DL1 with 1 DLT (skin rash) and 3 at DL2 (no DLT). The most common all grade treatment-related adverse events (TRAEs) included hyperphosphatemia (88%), mucositis (88%), high AST (88%), hypercalcemia (75%), palmar plantar erythrodysesthesia (75%), peripheral neuropathy (75%), alopecia (63%), diarrhea (63%), hypoalbuminemia (63%) and hypomagnesemia (63%). 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. PK data are available for all 6 patients in DL1. The average steady-state Cmin of E and MMAE was 1430 ± 639 ng/mL and 1.4 ± 0.9 ng/ml, respectively, and the average Cmax of MMAE was 3.9 ± 0.9 ng/mL at DL1. All 9 patients are evaluable with 100% best objective rate, including 8 partial responses (PRs) and 1 complete response (CR). The mOS was NR (95% 17.1 months-NR), mPFS was 7.52 months (95% CT 5.55-NR) with median follow up of 22.7 months. The mDOR is 5.49 months. The RP2D of EV is 1.25 mg/kg in combination with E at 8 mg/day. Conclusions: E+EV combination is feasible and preliminarily exhibits promising antitumor activity. Dose expansion is ongoing at RP2D dose of EV with E. Clinical trial information: NCT04963153 . Dose Level (DL) Dose Cycle Length E EV Level -1 8 mg PO QD 0.75 mg/kg IV (maximum dose 75 mg) D1,8,15 28 days Level 1 8 mg PO QD 1 mg/kg IV (maximum dose 100 mg) D1,8,15 Level 2 8 mg PO QD 1.25 mg/kg IV (maximum dose 125 mg) D1,8,15