Skin toxicity and effectiveness of first-line enfortumab vedotin plus pembrolizumab for urothelial carcinoma: a prospective multicenter real-world study in Japan

Background Skin toxicity is a common adverse event associated with enfortumab vedotin plus pembrolizumab (EVP) but its association with treatment outcomes remains unclear. We aimed to evaluate this association in patients with locally advanced or metastatic urothelial carcinoma (la/mUC). Patients and methods This prospective multicenter observational study conducted in Japan enrolled patients receiving first-line EVP. Skin toxicity incidence, onset, and management were evaluated. Objective response rates (ORRs) were compared according to the development of skin toxicity within 42 days. Progression-free survival (PFS) was assessed using a prespecified 42-day landmark analysis and a time-dependent Cox model to account for immortal time bias. Results Among 163 assessable patients, 94 (57.7%) developed skin toxicity at a median of 13 days, of whom 81 (86.2%) recovered. Patients with skin toxicity within 42 days had a higher ORR than those without (70.1% versus 44.2%, P < 0.001). In the landmark cohort ( n = 144), skin toxicity was associated with longer PFS [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.22-0.84, log-rank P = 0.011]. In multivariable time-dependent Cox analysis, skin toxicity remained independently associated with longer PFS (HR 0.44, 95% CI 0.23-0.83, P = 0.011). Conclusion Skin toxicity associated with first-line EVP was frequent, occurred early, and was generally manageable. Its development was associated with a higher ORR and its association with longer PFS persisted after accounting for immortal time bias. Skin toxicity may serve as a potential on-treatment prognostic indicator of favorable outcomes, although further validation is warranted.