At a recent international medical congress, Dr. Steffen Rausch from the University Hospital Tübingen presented the latest analysis of pathological outcomes and disease-free survival (DFS) from the KEYNOTE-905 study. This randomized, open-label Phase III trial evaluates the efficacy and safety of perioperative enfortumab vedotin (EV) combined with pembrolizumab in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy.01. Study Design and Objectives
KEYNOTE-905 enrolled patients with clinically staged T2–T4aN0M0 MIBC with at least a 50% urothelial histology component. Participants were required to be cisplatin-ineligible or to have declined cisplatin-based chemotherapy.
A total of 344 patients were randomized 1:1 into two arms:
• EV + Pembro Arm (n=170): Received 3 cycles of neoadjuvant EV plus pembrolizumab, followed by radical cystectomy and pelvic lymph node dissection (PLND), and subsequently 6 cycles of adjuvant EV plus pembrolizumab followed by 14 cycles of pembrolizumab monotherapy.
• Control Arm (n=174): Received radical cystectomy and PLND followed by observation. (Note: Adjuvant nivolumab was permitted later in the trial for the control group).
The primary endpoints were event-free survival (EFS) and overall survival (OS) by Blinded Independent Central Review (BICR). This update focused on secondary endpoints: pathological complete response (pCR), pathological downstaging (pDS), and DFS.
02. Pathological Outcomes: Substantial Tumor Clearance
Based on BICR assessment in the intention-to-treat (ITT) population, the EV plus pembrolizumab regimen demonstrated superior pathological efficacy:
• pCR Rate (ypT0N0): 57.0% in the EV + Pembro arm compared to 8.6% in the control arm. The estimated difference of 48.3% was both clinically meaningful and statistically significant.
• pDS Rate (<ypT2N0): 65.9% in the EV + Pembro arm versus 12.6% in the control arm.
• Surgical Quality: Negative surgical margin rates were 92.6% in the EV + Pembro group compared to 78.8% in the control group.
Subgroup analyses confirmed that the benefit of EV plus pembrolizumab remained consistent regardless of clinical stage (T2 vs. T3/T4) or other pre-defined clinical stratification factors.
03. Disease-Free Survival: 63% Reduction in Risk
DFS was defined as the time from the post-surgery scan to local/distant recurrence or death. At a median follow-up of 25.6 months:
• Median DFS: Not reached (NR) for the EV + Pembro arm versus 23.6 months for the control arm.
• Hazard Ratio (HR): 0.37, indicating a 63% reduction in the risk of recurrence or death compared to surgery alone.
• Kaplan-Meier Curves: The survival curves showed an early and sustained separation favoring the combination therapy.
04. Safety and Clinical Implications
Dr. Rausch noted that the safety profile of the perioperative regimen was manageable and consistent with previous reports of EV plus pembrolizumab in the locally advanced or metastatic urothelial carcinoma (la/mUC) setting (e.g., KEYNOTE-A39/EV-302). No new safety signals were identified.
Given that MIBC patients are often elderly with significant comorbidities, the ability of the EV + Pembro regimen to dramatically improve pathological outcomes and DFS without compromising surgical feasibility addresses a critical unmet medical need for those ineligible for cisplatin.
05. Conclusion and Future Outlook
The results from KEYNOTE-905 establish perioperative EV plus pembrolizumab as a powerful, potential new standard of care for cisplatin-ineligible MIBC. Dr. Rausch concluded his presentation by announcing that the primary manuscript has been accepted for publication in The New England Journal of Medicine (NEJM), underscoring the practice-changing nature of these data.
