Enfortumab Vedotin Plus Pembrolizumab Sets New Standard for Cisplatin-Ineligible Bladder Cancer, NEJM Study Finds
A recent phase 3, randomized trial has found a potent perioperative combination of enfortumab vedotin and pembrolizumab that redefines outcomes in muscle-invasive bladder cancer by achieving a landmark 74.7% two-year event-free survival rate, as detailed in a recent study published in the New England Journal of Medicine in February 2026.
Traditionally, patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy proceed directly to radical cystectomy with pelvic lymph-node dissection; however, the lack of effective systemic options for this population has long represented a critical clinical gap that previous research has struggled to address. To solve this, lead investigator Christof Vulsteke and the KEYNOTE-905/EV-303 research group initiated the investigation to determine if a perioperative approach could significantly improve the standard of care for these high-risk patients.
Therefore, the phase 3, open-label, randomized trial enrolled 344 participants who were either ineligible for or declined cisplatin, assigning them to receive either surgery alone or a combination of surgery and perioperative enfortumab vedotin (EV) plus pembrolizumab (P). The experimental arm received nine total cycles of EV at 1.25 mg per kilogram and seventeen cycles of P at 200 mg every three weeks, with surgery performed after three neoadjuvant cycles. Researchers tracked primary and secondary endpoints—including event-free survival (EFS), overall survival (OS), and pathological complete response (pCR), defined as the absence of viable tumor—to evaluate the efficacy and safety of this systemic approach.
Key Clinical Findings of the Study Include:
• Survival Efficacy: This study demonstrated that the combination therapy group achieved a 74.7% estimated EFS at two years, compared to 39.4% in the control group (hazard ratio, 0.40).
• Mortality Benefit: Mortality risks were halved for participants receiving the investigative regimen in this study, with an estimated two-year OS of 79.7% versus 63.1% in the surgery-only cohort (hazard ratio, 0.50).
• Complete Response: A striking pCR was observed in 57.1% of patients in the EV-P group during this study, contrasted with only 8.6% in the control arm, marking a difference of 48.3 percentage points.
• Safety Profile: While adverse events were documented in all participants in the investigative group—with 71.3% experiencing grade 3 or higher complications—the study provides essential safety data for clinicians managing the toxicities associated with these potent agents.
The results suggest that for the predominantly cisplatin-ineligible population with muscle-invasive bladder cancer, adding perioperative enfortumab vedotin and pembrolizumab to surgical resection leads to significantly improved survival and a much higher likelihood of achieving a pathological complete response. These data demonstrate that the experimental regimen effectively doubles the two-year event-free survival rate compared to the current standard of surgery alone.
Thus, the study concludes that the inclusion of this perioperative combination therapy could represent a transformative shift in clinical practice for managing cisplatin-ineligible patients with bladder cancer.
While these outcomes are highly encouraging, the study notes that managing treatment-related toxicities is necessary, and future research should focus on the long-term durability of these responses to further refine perioperative protocols.
Reference
Vulsteke C, Adra N, Danchaivijitr P, et al. Perioperative Enfortumab Vedotin and Pembrolizumab in Bladder Cancer. N Engl J Med. 2026;394(13):1257-1269.
