# Real-World Safety and Early Effectiveness of First-Line Enfortumab Vedotin Plus Pembrolizumab with Routine Dexamethasone Premedication in Advanced Urothelial Carcinoma

## TL;DR

This study shows that adding dexamethasone to a cancer treatment for urothelial carcinoma is safe and effective in real-world settings, even for older or less healthy patients.

## Contribution

The study provides real-world evidence on the safety and effectiveness of enfortumab vedotin plus pembrolizumab with dexamethasone premedication in routine clinical practice.

## Key findings

- Severe skin reactions were uncommon with dexamethasone premedication.
- Early disease control was maintained across different patient risk groups.
- Objective response rate was 73.0% with 6-month progression-free survival at 73.9%.

## Abstract

Enfortumab vedotin combined with pembrolizumab has become a new first-line treatment for advanced urothelial carcinoma, but it is frequently associated with skin reactions and other side effects. In pivotal clinical trials, routine use of systemic corticosteroids such as dexamethasone was not permitted, and therefore the safety of this supportive strategy in everyday practice has not been well studied in routine practice. In this multicenter real-world study in Japan, we evaluated the safety and early treatment outcomes of this combination when dexamethasone was routinely administered as a premedication. Many patients were elderly or would not have qualified for clinical trials. Severe skin reactions were uncommon, and early disease control was maintained across risk groups. These findings provide practical evidence that this approach is feasible in routine clinical settings and support further prospective studies to clarify its long-term impact.

Background: Enfortumab vedotin plus pembrolizumab (EVP) has become a first-line standard for metastatic or unresectable urothelial carcinoma. However, EVP is associated with distinct toxicities, particularly cutaneous adverse events, and prophylactic systemic corticosteroids were not permitted in pivotal trials. Therefore, the safety and early effectiveness of EVP with routine dexamethasone premedication in real-world practice remain unclear. Methods: This multicenter retrospective study included consecutive patients with metastatic or unresectable urothelial carcinoma who received first-line EVP at five institutions in Japan between September 2024 and September 2025. All patients received routine intravenous dexamethasone premedication before enfortumab vedotin administration. Safety and early clinical outcomes were evaluated, with exploratory subgroup analyses according to clinical trial eligibility and EVITA criteria. Results: Seventy-seven patients were included, with a median age of 75 years, and more than half would have been ineligible for pivotal clinical trials. Cutaneous toxicity was the most frequent adverse event (52.0%), whereas grade ≥3 skin reactions were uncommon (3.9%). With a median follow-up of 6.7 months, the objective response rate was 73.0%. The 6-month progression-free survival and overall survival rates were 73.9% and 78.7%, respectively. Early progression-free survival was generally maintained across subgroups stratified by clinical trial eligibility and EVITA category, with no evidence of excess early progression. Conclusions: In this real-world multicenter cohort, first-line EVP with routine dexamethasone premedication was feasible, with manageable toxicity and encouraging early clinical activity, including in patients with comorbidities commonly encountered in routine clinical practice. Longer follow-up and prospective comparative studies are warranted to clarify long-term outcomes and the impact of dexamethasone on efficacy and toxicity.