Exciting developments in the management of muscle-invasive bladder cancer (MIBC) may reshape treatment strategies for patients who are ineligible for cisplatin-based chemotherapy. A phase 3 study has revealed that combining perioperative enfortumab vedotin, an antibody–drug conjugate targeting nectin-4, with the immune checkpoint inhibitor pembrolizumab significantly improves survival outcomes and tumor clearance when paired with surgery.

The trial evaluated 344 participants, randomly assigned to either surgery alone or a treatment regimen featuring enfortumab vedotin and pembrolizumab, followed by surgery. After a median follow-up of 25.6 months, the data showed striking advantages for the combination therapy group. At 2 years, event-free survival was nearly double that of the control group, with rates of 74.7% versus 39.4%, respectively. Similarly, overall survival climbed to 79.7% compared with 63.1% in the surgery-alone cohort.

Perhaps the most remarkable finding was the rate of pathological complete response (ie, the absence of a viable tumor post-surgery) which reached 57.1% in the combination therapy group, compared with just 8.6% among patients undergoing surgery alone. These results underscore the potential of enfortumab vedotin and pembrolizumab as a game-changing duo for patients unable to tolerate cisplatin-based regimens.

The safety profile of the combination therapy was also carefully assessed. While adverse events (AEs) were reported in all participants receiving enfortumab vedotin and pembrolizumab, the majority were manageable. Grade ≥3 AEs occurred in 71.3% of patients in the treatment group, with 45.5% deemed drug-related, compared with 45.9% in the control group. Common side effects included fatigue, peripheral neuropathy, and rash, but these were addressed effectively through dose adjustments and supportive care measures.

For oncology teams, this study provides actionable insights into addressing the unmet needs of patients with cisplatin-ineligible MIB. The dual approach of enfortumab vedotin and pembrolizumab offers a viable pathway to improving survival rates while achieving greater tumor clearance prior to surgery. Early identification and management of AEs can ensure patients remain on treatment and achieve optimal outcomes.

As practices explore innovative approaches for challenging cancer populations, the findings from this trial represent an important step forward. By embracing this promising perioperative strategy, oncology teams can deliver more effective, personalized care that gives patients with cisplatin-ineligible bladder cancer a better chance at long-term survival and improved quality of life.

Source: Vulsteke C, Adra N, Danchaivijitr P, et al. Perioperative enfortumab vedotin and pembrolizumab in bladder cancer. N Engl J Med. 2026;394:1257-1269.