As reported in The New England Journal of Medicine by Vulsteke et al, the phase III KEYNOTE-905/EV-303 trial has shown improved event-free and overall survival with the addition of perioperative enfortumab vedotin plus pembrolizumab to radical cystectomy in patients with muscle-invasive bladder cancer who declined or were ineligible for cisplatin-based chemotherapy.
Study Details
In the international open-label trial, 344 patients were randomly assigned to receive perioperative enfortumab vedotin plus pembrolizumab and surgery (n = 170) or surgery alone (n = 174). Perioperative systemic therapy consisted of 9 total cycles of enfortumab vedotin (at 1.25 mg/kg on days 1 and 8) plus 17 total cycles of pembrolizumab (at 200 mg on day 1 every 3 weeks), with surgery conducted after 3 cycles of treatment. A total of 84% of patients in the perioperative therapy group and 80% in the control group were cisplatin-ineligible. The primary endpoint of the trial was event-free survival on blinded independent central review in the intention-to-treat population.
Key Findings
At data cutoff, median follow-up was 25.6 months (range = 11.8–53.7 months). Surgery was performed in 87.6% of patients in the perioperative therapy group and 89.7% of those in the control group.
At 2 years, estimated event-free survival was 74.7% in the perioperative therapy group vs 39.4% in the control group (hazard ratio [HR] = 0.40, 95% confidence interval [CI] = 0.28–0.57, P <.001); median event-free survival was not reached (95% CI = 37.3 months to not reached) vs 15.7 months (95% CI = 10.3–20.5 months).
At 2 years, estimated overall survival was 79.7% in the perioperative therapy group vs 63.1% in the control group (HR = 0.50, 95% CI = 0.33–0.74, P < .001); median overall survival was not reached (95% CI = not reached to not reached) vs 41.7 months (95% CI = 31.8 months to not reached).
Pathologic complete response was observed in 57.1% of patients in the perioperative therapy group vs 8.6% of patients in the control group (estimated difference = 48.3 percentage points, 95% CI = 39.5–56.5 percentage points, P <.001).
Grade ≥ 3 adverse events occurred in 71.3% of the perioperative therapy group vs 45.9% of the control group; the most common event in each group was urinary tract infection (12.0% vs 10.7%). Adverse events led to discontinuation of any study drug in 48.5% of the perioperative therapy group. Treatment-related death occurred in two patients in the perioperative therapy group (due to myasthenia gravis and toxic epidermal necrolysis, both occurring during the neoadjuvant phase).
The investigators concluded: “Perioperative enfortumab vedotin plus pembrolizumab and surgery led to significantly better event-free and overall survival outcomes and a greater percentage of participants with pathological complete response than surgery alone in a predominantly cisplatin-ineligible population with muscle-invasive bladder cancer. Safety was also assessed.”
Christof Vulsteke, MD, PhD, of Integrated Cancer Center Ghent, Ghent, Belgium, is the corresponding author for the New England Journal of Medicine article.
DISCLOSURE: The study was funded by Merck Sharp and Dohme, a subsidiary of Merck. For full disclosures of the study authors, visit nejm.com.
