Perioperative enfortumab vedotin combined with pembrolizumab significantly improved event-free survival, overall survival, and pathological complete response compared with neoadjuvant cisplatin–gemcitabine in patients with cisplatin-eligible muscle-invasive bladder cancer.
The findings from the phase 3 KEYNOTE-B15/EV-304 trial were published in The New England Journal of Medicine on July 23, 2026.
Challenging a Long-Standing Perioperative Standard
Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy has long been a standard treatment approach for eligible patients with muscle-invasive bladder cancer.
However, recurrence remains a major clinical concern, and the role of newer systemic combinations in the curative perioperative setting has remained uncertain.
The KEYNOTE-B15/EV-304 trial evaluated whether enfortumab vedotin, an antibody–drug conjugate, combined with the immune checkpoint inhibitor pembrolizumab could provide better outcomes than conventional cisplatin–gemcitabine chemotherapy.
How Was the KEYNOTE-B15/EV-304 Trial Designed?
The phase 3, open-label, randomized trial included adults with muscle-invasive bladder cancer who were eligible to receive cisplatin-based chemotherapy and undergo radical cystectomy with pelvic lymph-node dissection.
A total of 808 participants were randomly assigned to one of two treatment groups.
In the experimental group, 405 participants received four neoadjuvant cycles of enfortumab vedotin plus pembrolizumab. Enfortumab vedotin was administered at a dose of 1.25 mg per kilogram on days 1 and 8, while pembrolizumab was administered at a dose of 200 mg on day 1 of each three-week cycle.
Following surgery, participants were scheduled to receive five additional cycles of enfortumab vedotin and 13 cycles of pembrolizumab as adjuvant therapy.
In the control group, 403 participants received four neoadjuvant cycles of cisplatin–gemcitabine. Cisplatin was administered at a dose of 70 mg per square meter on day 1, and gemcitabine was administered at a dose of 1000 mg per square meter on days 1 and 8 of each three-week cycle. Participants subsequently underwent cystectomy without the study-specified adjuvant regimen used in the experimental group.
The primary endpoint was event-free survival. Key secondary endpoints included overall survival and pathological complete response.
Event-Free Survival Favored Enfortumab Vedotin–Pembrolizumab
After a median follow-up of 33.6 months, the estimated two-year event-free survival rate was 79.4% with perioperative enfortumab vedotin–pembrolizumab and 66.2% with neoadjuvant cisplatin–gemcitabine.
This corresponded to a 47% reduction in the risk of an event or death with enfortumab vedotin–pembrolizumab.
The hazard ratio for an event or death was 0.53 (95% confidence interval [CI], 0.41–0.70; P<0.001).
The median time from randomization to the data-cutoff date was 33.6 months, with a range of 22.5 to 53.6 months.
An Overall Survival Benefit Emerges
The trial also demonstrated a statistically significant improvement in overall survival.
At two years, the estimated overall survival rate was 86.9% in the enfortumab vedotin–pembrolizumab group and 81.3% in the cisplatin–gemcitabine group.
The hazard ratio for death was 0.65 (95% CI, 0.48–0.89; two-sided P=0.006), representing a 35% reduction in the risk of death with the perioperative combination.
The overall survival result is particularly notable because the trial compared the experimental regimen with an established cisplatin-based neoadjuvant treatment in a population considered eligible for standard chemotherapy.
Pathological Complete Response Nearly Doubled
A pathological complete response was observed in 55.8% of participants treated with enfortumab vedotin–pembrolizumab, compared with 32.5% of those treated with cisplatin–gemcitabine.
The difference was statistically significant (P<0.001).
A pathological complete response indicates that no residual invasive cancer is detected in the surgical specimen following neoadjuvant treatment. In muscle-invasive bladder cancer, this endpoint provides an early measure of the depth of treatment response before longer-term survival outcomes fully mature.
Most Participants Proceeded to Cystectomy
Radical cystectomy was completed in 86.7% of participants assigned to enfortumab vedotin–pembrolizumab and 89.6% of those assigned to cisplatin–gemcitabine.
These findings show that most participants in both treatment groups were able to proceed to definitive surgery following neoadjuvant therapy.
The slightly lower cystectomy rate in the experimental group must be considered alongside the regimen’s higher pathological complete response rate and improved event-free and overall survival outcomes.
Greater Efficacy Came With More High-Grade Adverse Events
The improvement in efficacy was accompanied by a higher incidence of severe adverse events.
Grade 3 or higher adverse events from any cause occurred in 75.7% of participants receiving enfortumab vedotin–pembrolizumab and 67.2% of those receiving cisplatin–gemcitabine.
The safety findings emphasize the importance of careful patient selection, close toxicity monitoring, and coordinated perioperative management when administering the combination.
The treatment burden also differed between the two groups. Participants in the experimental arm received both neoadjuvant and adjuvant systemic therapy, while those in the control arm received four cycles of neoadjuvant cisplatin–gemcitabine before surgery.
A New Direction for Curative-Intent Bladder Cancer Treatment
The KEYNOTE-B15/EV-304 findings demonstrate that perioperative enfortumab vedotin–pembrolizumab can improve outcomes beyond those achieved with neoadjuvant cisplatin–gemcitabine in cisplatin-eligible muscle-invasive bladder cancer.
The combination produced significant improvements across all three major efficacy endpoints: event-free survival, overall survival, and pathological complete response.
At two years, nearly four in five participants treated with enfortumab vedotin–pembrolizumab remained free from an event, while the pathological complete response rate exceeded 55%.
These results extend the clinical development of enfortumab vedotin–pembrolizumab beyond advanced urothelial cancer and into the perioperative treatment of localized muscle-invasive disease.
The benefits, however, must be weighed against the higher rate of grade 3 or greater adverse events and the longer perioperative treatment course.
KEYNOTE-B15/EV-304: Key Results
- Participants: 808
- Enfortumab vedotin–pembrolizumab group: 405
- Cisplatin–gemcitabine group: 403
- Median follow-up: 33.6 months
- Two-year event-free survival: 79.4% vs 66.2%
- Hazard ratio for an event or death: 0.53
- Two-year overall survival: 86.9% vs 81.3%
- Hazard ratio for death: 0.65
- Pathological complete response: 55.8% vs 32.5%
- Grade 3 or higher adverse events: 75.7% vs 67.2%
- Cystectomy completed: 86.7% vs 89.6%
Written by Nare Hovhannisyan, MD
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