Transforming MIBC Therapy: Phase 3 Results of Enfortumab Vedotin Plus Pembrolizumab

Article Impact Level: HIGH
Data Quality: STRONG
Summary of  New England Journal of Medicine https://doi.org/10.1056/NEJMoa2601486 
Dr., Valderrama Galsky  et al.

Points

Muscle-invasive bladder cancer accounts for roughly a quarter of all bladder cancer diagnoses and carries a exceptionally high risk of recurrence and systemic spread.
The phase 3 KEYNOTE-B15/EV-304 trial evaluated perioperative enfortumab vedotin plus pembrolizumab against standard neoadjuvant cisplatin-based chemotherapy in 808 global patients.
Patients receiving the targeted combination achieved a 47% reduction in the risk of disease progression recurrence or death compared with standard chemotherapy.
More than half of the patients treated with enfortumab vedotin and pembrolizumab showed no detectable cancer tissue at the time of surgery.
On July 10 2026 the FDA expanded approval for this perioperative regimen to include all cystectomy-eligible muscle-invasive bladder cancer patients regardless of cisplatin eligibility

Summary

This randomized, open-label, phase 3 trial (KEYNOTE-B15/EV-304) evaluated the efficacy and safety of perioperative enfortumab vedotin—a Nectin-4-directed antibody-drug conjugate—combined with pembrolizumab, a programmed death 1 (PD-1) inhibitor, compared with standard neoadjuvant cisplatin-based chemotherapy in 808 patients with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy. Approximately 25% of the estimated 85,000 annual US bladder cancer cases present as muscle-invasive disease. Led by Matthew D. Galsky, MD, the global study accrued participants across 158 sites to determine if this novel, targeted perioperative approach could outperform the established, decades-old neoadjuvant standard.

Primary and key secondary endpoints demonstrated statistically significant and clinically meaningful improvements with the perioperative combination. At a median follow-up of 33.6 months, the treatment arm yielded a 47% reduction in the risk of disease progression, recurrence, or death compared with neoadjuvant chemotherapy (HR, 0.53; 95% CI, 0.41–0.70; 1-sided P < .0001), with 24-month event-free survival rates of 79.4% versus 66.2%. Additionally, the risk of death was reduced by 35% (HR, 0.65; 95% CI, 0.48–0.89; 1-sided P = .0029), with 24-month overall survival rates reaching 86.9% versus 81.3%. Pathologic complete response rates at surgery were 55.8% for the experimental combination versus 32.5% for standard chemotherapy.

While treatment-emergent adverse events of grade 3 or higher occurred more frequently in the combination group (75.7% vs. 67.2%), the safety profile remained manageable and consistent with prior reports for these agents. Based on these robust efficacy data, on July 10, 2026, the Food and Drug Administration expanded the approved label of pembrolizumab plus enfortumab vedotin to include perioperative treatment for all patients with MIBC eligible for cystectomy. These findings challenge the 20-year neoadjuvant platinum paradigm, establishing perioperative enfortumab vedotin plus pembrolizumab as a new global standard of care.

Link to the article: https://www.nejm.org/doi/10.1056/NEJMoa2601486

References

Galsky, M. D., Valderrama, B. P., Maruzzo, M., Font, A., Ciuleanu, T., Chatzkel, J., Koie, T., Hoimes, C. J., Puente, J., Zakharia, Y., Rosenbaum, E., Boehm, K., Loriot, Y., Bedke, J., Powles, T. B., Necchi, A., Wiechno, P., Álvarez-Fernández, C., Kim, T.-H., … Gómez De Liaño, A. (2026). Enfortumab vedotin and pembrolizumab in cisplatin-eligible bladder cancer. New England Journal of Medicine, 395(4), 338–348. https://doi.org/10.1056/NEJMoa2601486