Early Skin Toxicity May Signal Benefit From EV-Pembrolizumab in Retrospective Study

Patients with locally advanced or metastatic urothelial carcinoma who developed skin toxic effects during first-line enfortumab vedotin plus pembrolizumab therapy had longer overall survival than those who did not, according to a retrospective cohort study published in JAMA Network Open.

The investigators noted that skin toxic effects are a common early adverse event of the combination, but that their association with outcomes in first-line treatment has been uncertain. Given the early onset of these events, they hypothesized that skin toxic effects might correlate with treatment benefit.

The single-center study at the University of Texas MD Anderson Cancer Center included 185 patients who began first-line therapy between March 2022 and July 2025. Rash or pruritus occurred in 98 patients (53.0%) a median of 14 days after treatment initiation. To account for immortal-time bias, the researchers modeled skin toxic effects as a time-dependent exposure. At a median follow-up of 17.7 months, skin toxic effects were associated with longer overall survival after adjustment for performance status, starting enfortumab vedotin dose, liver metastases, and laboratory values (hazard ratio, 0.34; 95% CI, 0.20-0.57). The association was consistent across sequential adjustment models and in a prespecified 30-day landmark analysis.

In the landmark analyses, associations with progression-free survival and objective response rate were directionally favorable but attenuated after adjustment. Grade 3 or higher skin toxic effects occurred in 10 patients (5.4%), and skin toxic effects led to dose reductions in 16.8% of patients, treatment holds in 10.8%, and discontinuation of enfortumab vedotin in 4.9%. One patient died of toxic epidermal necrolysis.

The authors noted that patients who developed skin toxic effects had more favorable baseline characteristics, so residual and unmeasured confounding cannot be excluded, and that ascertainment bias may have inflated the association. They said the findings warrant prospective validation of skin toxic effects as an early clinical marker of treatment benefit.

Source: Thomas Z, Jiang CY, Speck PJ, et al. Skin toxic effects and survival with enfortumab vedotin–pembrolizumab in advanced urothelial carcinoma. JAMA Netw Open. 2026;9(10):e2639517. doi:10.1001/jamanetworkopen.2026.39517