Perioperative Enfortumab Vedotin and Pembrolizumab in Bladder Cancer
Clinical Snapshot
PICO Framework
| P — Population | Adults with muscle-invasive bladder cancer who were ineligible for or declined cisplatin-based chemotherapy (n=344) |
| I — Intervention | Perioperative enfortumab vedotin (1.25 mg/kg days 1,8) plus pembrolizumab (200 mg day 1 every 3 weeks) for 9 and 17 cycles respectively, with surgery after 3 cycles |
| C — Comparator | Surgery alone (radical cystectomy with pelvic lymph-node dissection) |
| O — Outcomes | Primary: event-free survival. Secondary: overall survival, pathological complete response, safety |
Bottom Line
This phase 3 trial demonstrates substantial clinical benefit from perioperative enfortumab vedotin plus pembrolizumab in cisplatin-ineligible muscle-invasive bladder cancer patients. The combination nearly doubled 2-year event-free survival (74.7% vs 39.4%) and overall survival (79.7% vs 63.1%) compared to surgery alone, with impressive pathological complete response rates (57.1% vs 8.6%). However, the open-label design and high toxicity burden (71.3% grade ≥3 adverse events) require careful consideration. The NNT of approximately 3 suggests strong clinical utility, but implementation requires robust supportive care infrastructure and careful patient selection. These results likely represent a new standard of care for this challenging patient population, pending regulatory approval and cost-effectiveness evaluation in the Australian healthcare system.
Key Findings
P Value: P<0.001 for both primary and key secondary endpoints
Effect Size: Hazard ratio 0.40 for event-free survival, 0.50 for overall survival
Primary Outcome: Event-free survival at 2 years: 74.7% vs 39.4%
Nnt Or Sensitivity: NNT approximately 3 for preventing one event at 2 years (based on 35.3% absolute risk reduction)
Confidence Interval: Event-free survival HR 0.40 (95% CI 0.28-0.57), Overall survival HR 0.50 (95% CI 0.33-0.74)
Clinical Application
Requires access to enfortumab vedotin and pembrolizumab, specialised oncology and urology services, intensive monitoring for toxicity Pembrolizumab PBS-listed for various indications. Enfortumab vedotin TGA-approved but PBS access limited. Would require multidisciplinary uro-oncology teams available in major centres Adults with muscle-invasive bladder cancer ineligible for or declining cisplatin-based chemotherapy
Abstract
BACKGROUND: Patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy proceed directly to radical cystectomy with pelvic lymph-node dissection. Perioperative therapy may improve outcomes in this population. METHODS: In this phase 3, open-label trial, participants with muscle-invasive bladder cancer who were ineligible for or declined cisplatin-based chemotherapy were randomly assigned to perioperative (neoadjuvant and adjuvant) enfortumab vedotin, an antibody-drug conjugate directed at nectin-4, plus pembrolizumab and surgery (9 total cycles of enfortumab vedotin [1.25 mg per kilogram of body weight on days 1 and 8] plus 17 total cycles of pembrolizumab [200 mg on day 1 every 3 weeks], with surgery after 3 cycles) or surgery alone (control). The primary end point was event-free survival. Key secondary end points were overall survival and pathological complete response (absence of viable tumor after surgical resection). Other secondary end points included safety. RESULTS: A total of 344 participants underwent randomization (170 in the enfortumab vedotin-pembrolizumab group and 174 in the control group). At data cutoff, median follow-up was 25.6 months (range, 11.8 to 53.7). Surgery was performed in 87.6% of participants in the enfortumab vedotin-pembrolizumab group and in 89.7% in the control group. At 2 years, estimated event-free survival was 74.7% in the enfortumab vedotin-pembrolizumab group and 39.4% in the control group (hazard ratio for an event or death, 0.40; 95% confidence interval [CI], 0.28 to 0.57; two-sided P<0.001); estimated overall survival was 79.7% and 63.1% (hazard ratio for death, 0.50; 95% CI, 0.33 to 0.74; two-sided P<0.001). A pathological complete response had occurred in 57.1% and 8.6% of the participants (estimated difference, 48.3 percentage points; 95% CI, 39.5 to 56.5; two-sided P<0.001). Adverse events occurred in all participants in the enfortumab vedotin-pembrolizumab group (grade ≥3, 71.3%; grade ≥3 drug-related, 45.5%) and in 64.8% in the control group (grade ≥3, 45.9%). CONCLUSIONS: 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. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-905 ClinicalTrials.gov number, NCT03924895.).
References
- 1.Vulsteke, C., Adra, N., Danchaivijitr, P., Sabadash, M., Rodriguez-Vida, A., Zhang, Z., Atduev, V., Göger, Y. E., Rausch, S., Kang, S.-H., Loriot, Y., Bedke, J., Galsky, M. D., O'Donnell, P. H., von Amsberg, G., Alimohamed, N., Sulimka, G., Gupta, S., Paramonov, V., ... Ullén, A. (2026). Perioperative enfortumab vedotin and pembrolizumab in bladder cancer. *New England Journal of Medicine*. https://doi.org/10.1056/NEJMoa2511674
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