Trial results for NCT03924895 were posted on 2026-06-30, evaluating perioperative pembrolizumab and enfortumab vedotin in muscle-invasive bladder cancer. The study demonstrated that the combination of enfortumab vedotin plus pembrolizumab with surgery significantly increased the pathologic complete response (pCR) rate to 57.1% compared to 8.6% for surgery alone.
Background
Pembrolizumab (Keytruda) is an immune checkpoint inhibitor. This study investigates its use in muscle-invasive bladder cancer (MIBC), a condition where cancer has spread into the muscle layer of the bladder wall. Enfortumab vedotin is an antibody-drug conjugate.
Trial design
The PHASE3 study, KEYNOTE-905/EV-303 (NCT03924895), enrolled 595 participants with muscle-invasive bladder cancer who were cisplatin-ineligible or declined cisplatin. The trial's primary hypothesis was that perioperative pembrolizumab plus radical cystectomy (RC) and pelvic lymph node dissection (PLND), and perioperative enfortumab vedotin in combination with pembrolizumab plus RC+PLND, would achieve superior event-free survival (EFS) compared with RC+PLND alone. The key comparisons detailed in the results focused on Arm C (enfortumab vedotin + pembrolizumab + surgery) versus Arm B (surgery alone).
Key results
Results from the comparison of Arm C (enfortumab vedotin + pembrolizumab + surgery) versus Arm B (surgery alone) showed significant improvements across several endpoints. For event-free survival (EFS), the median EFS for Arm B was 15.7 Months, while the median for Arm C was not provided. A key analysis indicated a hazard ratio (HR) of 0.4 (95% CI: 0.28, 0.57) with a p-value of 0.0001, favoring the combination arm. The pathologic complete response (pCR) rate was 57.1 Percentage of Participants in Arm C, significantly higher than 8.6 Percentage of Participants in Arm B. This represented a difference of 48.3 Percentage (95% CI: 39.5, 56.5) with a p-value of 1e-06. Similarly, the pathologic downstaging (pDS) rate was 65.9 Percentage of Participants in Arm C, compared to 12.6 Percentage of Participants in Arm B, showing a difference of 53.1 Percentage (95% CI: 44.0, 61.2) and a p-value of 1e-06.
What this means
The substantial increases in pathologic complete response and downstaging rates observed with the perioperative combination of enfortumab vedotin and pembrolizumab plus surgery suggest a meaningful clinical benefit for patients with muscle-invasive bladder cancer who are cisplatin-ineligible or decline cisplatin. The favorable hazard ratio for event-free survival further supports the potential of this regimen to improve outcomes in this patient population. Clinicians may consider these results when evaluating treatment strategies for MIBC, particularly for patients with limited options due to cisplatin ineligibility.
Source
The trial results were posted on 2026-06-30 on ClinicalTrials.gov, an official database of clinical studies maintained by the U.S. National Library of Medicine (NLM). The full details are available on clinicaltrials.gov under study identifier NCT03924895.