Outcomes and Management of Dermatologic Toxicity Following Enfortumab Vedotin Rechallenge in Patients With Metastatic Urothelial Carcinoma: A Retrospective Single‐Center Study

BACKGROUND: Enfortumab vedotin (EV) has demonstrated clinical benefits as a third-line monotherapy after chemotherapy and immune checkpoint inhibitors and is currently established, in combination with pembrolizumab, as a first-line standard therapy for metastatic urothelial carcinoma (mUC). However, dermatologic adverse events (DAEs) are common and may necessitate treatment interruption. While EV rechallenge is often considered, evidence regarding the recurrence and management of DAEs after rechallenge is limited. AIMS: To analyze the incidence, timing, and severity of DAEs following EV rechallenge and assess the impact of dose modifications and initial inpatient versus outpatient management on clinical outcomes. METHODS AND RESULTS: This retrospective observational study included patients with mUC who received EV at a single institution between January 2022 and December 2024. Of the 48 patients treated with EV, 36 (75.0%) developed DAEs, with a median onset of 11 days. Twenty patients resumed EV after interruption due to DAEs; 13 (65%) experienced recurrence. Recurrent DAEs tended to be of lower grade than the initial events and to be similar to the initial episode in terms of the type of DAEs. Early-onset (≤ 7 days) DAEs were more likely to progress to grade ≥ 3. Although inpatient management enabled earlier detection and intervention, it did not reduce the incidence of severe toxicity compared to outpatient care. CONCLUSION: DAEs frequently recur after EV rechallenge but are typically less severe than the initial episode. Early-onset DAEs may predict severe toxicity, underscoring the need for close monitoring and proactive management. Prospective studies are warranted to optimize rechallenge strategies and improve the safety of EV therapy.