Enfortumab Vedotin Plus Pembrolizumab Improves Survival in Muscle-Invasive Bladder Cancer

The phase III KEYNOTE-B15 trial met its primary endpoint, demonstrating that enfortumab vedotin plus pembrolizumab administered both before and after cystectomy significantly improved event-free survival compared with standard gemcitabine plus cisplatin neoadjuvant chemotherapy in patients with cisplatin-eligible muscle-invasive bladder cancer (MIBC). This represents the first phase III trial demonstrating superiority of a non-platinum regimen over cisplatin-based neoadjuvant chemotherapy in MIBC.

KEYNOTE-B15 was a randomized, open-label phase III trial enrolling 808 patients with cisplatin-eligible MIBC scheduled for radical cystectomy. Patients were randomized to receive enfortumab vedotin plus pembrolizumab administered both before and after cystectomy, or standard gemcitabine plus cisplatin neoadjuvant chemotherapy, followed by cystectomy and observation. The primary endpoint was event-free survival assessed by blinded independent central review. Key secondary endpoints included overall survival and pathologic complete response.

Median event-free survival was not reached with enfortumab vedotin plus pembrolizumab compared with 48.5 months with cisplatin plus gemcitabine, with a hazard ratio of 0.53 (95% CI 0.41–0.70; P < 0.0001). This corresponds to a 47% reduction in recurrence, progression, or death. Landmark event-free survival rates were 86.0% vs 75.4% at 12 months and 79.4% vs 66.2% at 24 months. Benefit was consistent across major clinical subgroups, including PD-L1 status, age, sex, and geographic region.

A major improvement was observed in surgical outcomes. The pathologic complete response rate was 55.8% with enfortumab vedotin plus pembrolizumab compared with 32.5% with chemotherapy (P < 0.0001). Among patients undergoing surgery, the rates were 64.4% vs 36.3%, respectively. These findings suggest substantially deeper tumor eradication prior to cystectomy.

Treatment-emergent adverse events occurred in nearly all patients in both groups. Grade ≥3 adverse events occurred in 75.7% with enfortumab vedotin plus pembrolizumab compared with 67.2% with chemotherapy. Key toxicities included enfortumab vedotin-related skin reactions (63.5%), peripheral neuropathy (36%), hyperglycemia (13.2%), immune-related hypothyroidism (12.2%), and pneumonitis (6.9%). No unexpected safety signals were identified, confirming feasibility of prolonged perioperative therapy.

For more than two decades, cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy has represented the standard treatment for muscle-invasive bladder cancer. Despite this approach, nearly 50% of patients ultimately develop metastatic recurrence, highlighting persistent unmet need for more effective perioperative strategies. Antibody–drug conjugates and immune checkpoint inhibitors have independently demonstrated substantial activity in advanced urothelial carcinoma.

This study introduces a perioperative immune-ADC strategy that improves event-free survival and overall survival, nearly doubles pathologic complete response rates, and moves treatment beyond chemotherapy dependence. The results support the emergence of a cisplatin-chemotherapy–free curative pathway, integrating systemic immune activation and targeted cytotoxic delivery. The findings position enfortumab vedotin plus pembrolizumab as a potential new standard of care for eligible patients undergoing radical cystectomy.