In the phase III KEYNOTE-B15/EV-304 trial, perioperative enfortumab vedotin-ejfv plus pembrolizumab significantly improved event-free survival, overall survival, and pathologic complete response compared with the long-standing standard approach of neoadjuvant cisplatin plus gemcitabine in cisplatin-eligible muscle-invasive bladder cancer. The trial was reported in The New England Journal of Medicine by Galsky et al.
Study Details
The phase III, open-label, randomized trial was conducted at 158 sites across three geographic regions. It enrolled adults with histologically confirmed muscle-invasive bladder cancer who were eligible for cisplatin-based chemotherapy and curative radical cystectomy with pelvic lymph-node dissection.
A total of 808 patients were randomly assigned 1:1 to receive perioperative enfortumab vedotin plus pembrolizumab or neoadjuvant cisplatin plus gemcitabine. Patients in the investigational group received four cycles of enfortumab vedotin plus pembrolizumab before cystectomy, followed by five additional cycles of enfortumab vedotin and 13 additional cycles of pembrolizumab. Patients in the control group received four cycles of cisplatin plus gemcitabine before cystectomy.
The primary endpoint was event-free survival. Key secondary endpoints included overall survival and pathologic complete response. Safety was assessed in all patients who received at least one dose of trial treatment.
Baseline characteristics were generally balanced between groups. The median age was 66 years, and most patients were men. Cystectomy was performed in 86.7% of patients in the enfortumab vedotin plus pembrolizumab group and 89.6% of patients in the cisplatin plus gemcitabine group.
Key Efficacy Data
At a median follow-up of 33.6 months, the estimated 2-year event-free survival rate was 79.4% with enfortumab vedotin plus pembrolizumab vs 66.2% with cisplatin plus gemcitabine (hazard ratio [HR] = 0.53, P < .001). Median event-free survival was not reached with enfortumab vedotin plus pembrolizumab and was 48.5 months with cisplatin plus gemcitabine.
Overall survival also favored the combination. The estimated 2-year overall survival rate was 86.9% vs 81.3%, respectively (HR = 0.65, P = .006). Death occurred in 17.0% vs 24.6% of patients.
Pathologic complete response was seen in 55.8% of patients receiving the combination and 32.5% of those receiving cisplatin plus gemcitabine (P < .001). Pathologic downstaging occurred in 63.7% vs 45.2% of patients, respectively.
Among patients who were disease-free after cystectomy, recurrence or death occurred in 15.9% of patients in the enfortumab vedotin plus pembrolizumab group and 28.8% of those in the cisplatin plus gemcitabine group. The estimated 2-year disease-free survival rate was 86.1% vs 72.6%, respectively.
Safety Results
Almost all patients in both groups had adverse events, but grade 3 or higher events and serious adverse events were more frequent with the perioperative regimen. Grade 3 or higher adverse events occurred in 75.7% of patients receiving enfortumab vedotin plus pembrolizumab and 67.2% of those receiving cisplatin plus gemcitabine; serious adverse events occurred in 63.3% vs 48.0%, respectively. Adverse events of any cause occurred in 98.0% vs 98.2% of patients.
The adverse event profiles differed between groups. The most frequently reported adverse events with enfortumab vedotin plus pembrolizumab were pruritus and diarrhea, whereas anemia and neutropenia were most frequent with cisplatin plus gemcitabine. Drug-related adverse events led to discontinuation of at least one assigned trial drug in 35.2% vs 11.1% of patients, respectively.
The researchers noted that cystectomy rates and rates of surgical delay were similar between groups, although adverse events were more frequent with enfortumab vedotin plus pembrolizumab. They also pointed to KEYNOTE-905, which evaluated the same perioperative regimen in cisplatin-ineligible patients, as supporting a broader role for the approach.
“The findings of the KEYNOTE-B15 trial, along with those of the KEYNOTE-905 trial, support the role of perioperative [enfortumab vedotin plus pembrolizumab] with radical cystectomy for patients with resectable muscle-invasive bladder cancer irrespective of cisplatin eligibility,” the investigators concluded. “These findings define a new, immunotherapy-based and antibody-drug conjugate–based treatment option in this context.”
Matthew D. Galsky, MD, of the Mount Sinai Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, is the corresponding author for The New England Journal of Medicine article.
DISCLOSURE: The study was supported by Merck Sharp and Dohme, a subsidiary of Merck; Astellas Pharma; and Seagen, which was acquired by Pfizer in December 2023. For full disclosures of the study authors, visit www.nejm.org.
