Skin Toxic Effects and Survival With Enfortumab Vedotin–Pembrolizumab in Advanced Urothelial Carcinoma

Importance Skin toxic effects are a common early adverse event of enfortumab vedotin plus pembrolizumab (EVP) therapy, but its association with clinical outcomes in patients receiving first-line therapy remains uncertain. Objective To evaluate the association between treatment-emergent skin toxic effects and clinical outcomes among patients receiving first-line EVP. Design, Setting, and Participants This retrospective cohort study was performed at the University of Texas MD Anderson Cancer Center among adults with locally advanced or metastatic urothelial carcinoma receiving first-line EVP therapy between March 3, 2022, and July 31, 2025. Skin toxic effects were used as a time-dependent exposure in Cox proportional hazards regression to account for immortal-time bias. Prespecified sequential adjustment models and 30-day landmark analyses were performed to assess the robustness of the findings. Exposure Treatment-emergent skin toxic effects (rash or pruritus) were identified from medical records. Main Outcomes and Measures Primary outcome was overall survival (OS). Secondary outcomes included progression-free survival and objective response rate (ORR). OS and PFS were measured from EVP therapy initiation to the respective event or last follow-up. ORR was evaluated among patients with a response assessment after the 30-day landmark, according to skin toxic effects status within the first 30 days. Results Among 185 patients (median age, 73 [IQR, 67-79] years; 140 [75.7%] male), skin toxic effects occurred in 98 (53.0%) at a median of 14 (IQR, 7-28) days after EVP therapy initiation. Skin toxic effects of grade 3 or higher occurred in 10 patients (5.4%). Skin toxic effects resulted in EV dose reduction in 31 patients (16.8%), treatment interruption in 20 (10.8%), and treatment discontinuation in 9 (4.9%). At a median follow-up of 17.7 (IQR, 11.3-24.2) months, Simon-Makuch curves demonstrated longer OS and PFS among all patients and longer OS among patients with visceral metastases in the skin toxic effects stratum than in the no toxicity stratum. In adjusted time-dependent Cox proportional hazards regression, skin toxic effects were associated with longer OS (hazard ratio, 0.34 [95% CI, 0.20-0.57]). The association remained consistent across sequential adjustment models and prespecified 30-day landmark analyses. In the 30-day landmark analyses, associations with PFS and ORR remained directionally favorable but were attenuated after multivariable adjustment. Conclusions and Relevance In this cohort study of 185 patients with locally advanced or metastatic urothelial carcinoma receiving first-line EVP therapy, treatment-emergent skin toxic effects were associated with longer OS. These findings support further prospective validation of skin toxic effects as an early clinical marker of treatment benefit and investigation of the biological mechanisms underlying this association.