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: Jain Rohit K. , Ong Faustine , Faltas Bishoy Morris , Tagawa Scott T. , Jiang Di Maria , Heiligh Jazlyn , Naqvi Syeda Mahrukh Hussnain , Kim Youngchul , Pelosof Lorraine Cheryl , Yang Yuanquan , Graham Laura , Arafat Waddah , Synold Timothy Walter , Chatwal Monica Sheila , Zhang Jingsong , Chadha Jus , Sonpavde Guru P. 
Published: February 2025

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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