According to results from the phase 3 KEYNOTE-905/EV-303 trial, perioperative enfortumab vedotin plus pembrolizumab significantly improved survival outcomes compared to surgery alone in patients with muscle-invasive bladder cancer who were ineligible for cisplatin-based chemotherapy. 

These findings were presented by Christof Vulsteke, MD, PhD, Integrated Cancer Centre of Ghent University Hospital, Ghent, Belgium, at the 2025 European Society for Medical Oncology (ESMO) Congress in Berlin, Germany. 

The trial randomized 344 patients 1:1 to receive either 1.25 mg/kg of enfortumab vedotin for 3 cycles on days 1 and 8 plus 200 mg of pembrolizumab once every 3 weeks on day 1 followed by radical cystectomy and pelvic lymph node dissection and an additional 6 cycles of enfortumab vedotin and 14 cycles of pembrolizumab (n = 170) or radical cystectomy and pelvic lymph node dissection alone (n = 174). Patients were treated until disease progression or unacceptable toxicity. 

The primary trial end point was event-free survival (EFS). Key secondary end points included overall survival (OS), pathological complete response (pCR), and safety. 

At a median follow-up of 25.6 months, 87.6% of patients underwent resection in the enfortumab vedotin plus pembrolizumab arm and 89.7% of patients underwent resection in the control arm. The median EFS was not reached in the enfortumab vedotin plus pembrolizumab arm and was 15.7 months in the control arm (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.28 to 0.57; P <.001). OS was not reached in the enfortumab vedotin plus pembrolizumab arm and 41.7 months in the control arm (HR, 0.50; 95% CI, 0.33 to 0.74; P <.001) and pCR rates were 57.1% and 8.6%, respectively P <.001). Grade ≥3 treatment-emergent adverse events occurred in 71.3% of patients in the enfortumab vedotin plus pembrolizumab arm and 64.8% of patients in the control arm. The most frequently reported events included skin reactions. 

“Adding [perioperative enfortumab vedotin and pembrolizumab] to surgery significantly and meaningfully improved EFS, OS, and pCR rate in pts with [muscle invasive bladder cancer] who were predominantly cisplatin-ineligible,” concluded Dr Vulsteke et al. “This is the first [perioperative] regimen to improve outcomes vs [radical cystectomy and pelvic lymph node dissection] in this setting and may be a new standard of care.”

Source: 

Vulsteke C, Kaimakliotis H, Danchavijitr P, et al. Perioperative (periop) enfortumab vedotin (EV) plus pembrolizumab (pembro) in participants (pts) with muscle-invasive bladder cancer (MIBC) who are cisplatin-ineligible: The phase 3 KEYNOTE-905 study. Presented at the 2025 ESMO Congress. October 17-21, 2025; Berlin, Germany. LBA2