Perioperative Enfortumab Vedotin Plus Pembrolizumab in Bladder Cancer

Key Takeaways

• Perioperative enfortumab vedotin plus pembrolizumab was associated with higher estimated 2-year event-free survival than surgery alone, at 74.7% versus 39.4%.
• Estimated overall survival and pathological complete response were also higher with the perioperative combination than with surgery alone.
• Adverse events, including grade 3 or higher events, were more frequent with the combination, while surgery proceeded at similar rates in both groups.

Perioperative enfortumab vedotin plus pembrolizumab followed by surgery was associated with higher 2-year event-free survival than surgery alone in muscle-invasive bladder cancer among patients ineligible for or declining cisplatin-based chemotherapy. In a NEJM phase 3 trial, estimated 2-year event-free survival was 74.7% with the combination and 39.4% with surgery alone. The comparison tested perioperative systemic therapy plus surgery against surgery alone in a predominantly cisplatin-ineligible population.

This phase 3, open-label trial enrolled participants with muscle-invasive bladder cancer who were ineligible for or declined cisplatin-based chemotherapy. Investigators randomly assigned 344 participants to perioperative enfortumab vedotin plus pembrolizumab and surgery or to surgery alone, with 170 and 174 participants in each group. The perioperative sequence used enfortumab vedotin 1.25 mg per kilogram on days 1 and 8 and pembrolizumab 200 mg on day 1 every 3 weeks. Participants received 9 total cycles of enfortumab vedotin and 17 total cycles of pembrolizumab, with radical cystectomy and pelvic lymph-node dissection after 3 cycles. Event-free survival was the primary end point, and overall survival plus pathological complete response were key secondary end points.

At data cutoff, median follow-up was 25.6 months, ranging from 11.8 to 53.7 months, and 2-year event-free survival was 74.7% versus 39.4%. The hazard ratio for event or death was 0.40, with a 95% confidence interval of 0.28 to 0.57 and a two-sided P value below 0.001. Estimated overall survival was 79.7% versus 63.1%, with a hazard ratio for death of 0.50, a 95% confidence interval of 0.33 to 0.74, and P<0.001. Pathological complete response occurred in 57.1% versus 8.6%, an estimated difference of 48.3 percentage points with a 95% confidence interval of 39.5 to 56.5 and P<0.001. The combination was associated with higher event-free survival, overall survival, and pathological complete response in the randomized population.

Surgery was performed in 87.6% of the treatment group and 89.7% of the control group. Adverse events occurred in all participants receiving the combination and in 64.8% of control participants. Grade 3 or higher adverse events occurred in 71.3% and 45.9%, respectively, and grade 3 or higher drug-related adverse events occurred in 45.5% of the treatment group. The perioperative regimen was accompanied by more frequent adverse events, while surgery rates were similar between groups.

The trial was funded by Merck Sharp and Dohme and conducted in collaboration with Astellas Pharma and Seagen, which was acquired by Pfizer in December 2023. It was published online on February 18, 2026, and appeared in the April 2, 2026, issue.