Perioperative Enfortumab Vedotin Plus Pembrolizumab Outperforms Cisplatin Plus Gemcitabine in Muscle-Invasive Bladder Cancer

Clinical Summary: 

• Design/Population: The phase 3 KEYNOTE-B15/EV-304 trial evaluated perioperative enfortumab vedotin plus pembrolizumab compared with standard neoadjuvant cisplatin plus gemcitabine in patients with cisplatin-eligible muscle-invasive bladder cancer.
• Key Outcomes: Perioperative enfortumab vedotin plus pembrolizumab improved 2-year event-free survival (79.4% vs 66.2%), 2-year overall survival (86.9% vs 81.3%), and pathologic complete response (55.8% vs 32.5%) compared with cisplatin plus gemcitabine.
• Clinical Relevance: Perioperative enfortumab vedotin plus pembrolizumab reduced the risks of disease recurrence or death and death alone compared with standard neoadjuvant cisplatin-based chemotherapy, supporting a potential shift in perioperative treatment for cisplatin-eligible muscle-invasive bladder cancer despite increased high-grade toxicity.

Results from the phase 3 KEYNOTE-B15/EV-304 trial showed that perioperative enfortumab vedotin plus pembrolizumab significantly improved event-free survival (EFS), overall survival (OS), and pathologic complete response (pCR) compared with standard neoadjuvant cisplatin plus gemcitabine in patients with cisplatin-eligible muscle-invasive bladder cancer.

In this open-label trial, 808 patients eligible for cisplatin-based chemotherapy and radical cystectomy with pelvic lymph-node dissection were randomized to receive either perioperative enfortumab vedotin plus pembrolizumab (n = 405) or standard neoadjuvant cisplatin plus gemcitabine (n = 403). Patients in the investigational arm received 4 neoadjuvant cycles of 1.25 mg/kg of enfortumab vedotin on days 1 and 8 plus 200 mg of pembrolizumab on day 1 every 3 weeks, followed by cystectomy and 5 cycles of adjuvant enfortumab vedotin and 13 cycles of pembrolizumab. Patients in the comparator arm received 4 neoadjuvant cycles of 70 mg/m² of cisplatin on day 1 plus 1000 mg/m² of gemcitabine on days 1 and 8 every 3 weeks, followed by cystectomy.

The primary end point was EFS, with OS and pCR serving as key secondary end points. At a median of 33.6 months from randomization to data cutoff, 86.7% of patients in the enfortumab vedotin plus pembrolizumab arm and 89.6% in the cisplatin plus gemcitabine arm had undergone cystectomy.

At 2 years, estimated EFS was 79.4% with enfortumab vedotin plus pembrolizumab and 66.2% with cisplatin plus gemcitabine, corresponding to a 47% reduction in the risk of an event or death (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.41 to 0.70; P < .001).

An OS benefit was also observed, with estimated 2-year OS rates of 86.9% and 81.3%, respectively, corresponding to a 35% reduction in the risk of death (HR, 0.65; 95% CI, 0.48 to 0.89; P = .006). The pCR rate was also significantly higher with enfortumab vedotin plus pembrolizumab (55.8% vs 32.5%; P < .001). 

The efficacy gains were accompanied by increased high-grade toxicity. Grade ≥3 adverse events of any cause occurred in 75.7% of patients receiving enfortumab vedotin plus pembrolizumab compared with 67.2% of patients receiving cisplatin plus gemcitabine.

Source: 

Galsky MD, Valderrama BP, Maruzzo M, et al. Enfortumab vedotin and pembrolizumab in cisplatin-eligible bladder cancer. N Engl J Med. Published online: July 22, 2026. doi: 10.1056/NEJMoa2601486