FDA Expands Perioperative Pembrolizumab Plus Enfortumab Vedotin to All Eligible Patients With Muscle-Invasive Bladder Cancer

Clinical Summary:

• The FDA approved perioperative pembrolizumab or pembrolizumab and berahyaluronidase alfa in combination with enfortumab vedotin for adults with muscle-invasive bladder cancer undergoing cystectomy based on findings from the phase 3 KEYNOTE-B15/EV-304 trial.
• Perioperative pembrolizumab plus enfortumab vedotin significantly improved event-free survival and overall survival compared with neoadjuvant gemcitabine plus cisplatin. The safety profile was consistent with previous studies of the combination in urothelial cancer.
• The approval expands the indication for perioperative pembrolizumab plus enfortumab vedotin from cisplatin-ineligible patients to all eligible adults with muscle-invasive bladder cancer undergoing cystectomy.

On July 10, 2026, the US Food and Drug Administration (FDA) approved pembrolizumab (Keytruda, Merck) or pembrolizumab and berahyaluronidase (Keytruda Qlex, Merck), each in combination with enfortumab vedotin (Padcev, Astellas Pharma), for perioperative treatment of patients with muscle-invasive bladder cancer. This approval was based on results from the KEYNOTE-B15/EV-304 trial.

The approval expands the previous indication from patients who are ineligible for cisplatin-based chemotherapy to all patients with muscle-invasive bladder cancer who are candidates for cystectomy.

In this open-label, active-controlled trial, 808 previously untreated patients who were eligible for cisplatin-based chemotherapy and radical cystectomy with pelvic lymph node dissection were randomized 1:1 to receive perioperative pembrolizumab plus enfortumab vedotin or neoadjuvant gemcitabine plus cisplatin followed by surgery. The primary end point was event-free survival (EFS), as assessed by blinded independent central review. A key secondary end point was overall survival (OS). 

At analysis, median EFS was not reached in the pembrolizumab plus enfortumab vedotin arm and 48.5 months in the gemcitabine plus cisplatin arm (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.41 to 0.70; P < .0001). Median OS was not reached in either arm, with pembrolizumab plus enfortumab vedotin reducing the risk of death by 35% compared with chemotherapy (HR, 0.65; 95% CI, 0.48 to 0.89; P = .0029). 

For cisplatin-eligible patients, the recommended neoadjuvant regimen consists of 200 mg of pembrolizumab once every 3 weeks or 400 mg once every 6 weeks in combination with 1.25 mg/kg of enfortumab vedotin (maximum 125 mg for patients weighing ≥100 kg) on days 1 and 8 of each 21-day cycle for four cycles. 

Following cystectomy, patients receive adjuvant pembrolizumab plus enfortumab vedotin followed by pembrolizumab monotherapy according to the prescribing information. When administered on the same day, pembrolizumab should be given after enfortumab vedotin.

The prescribing information for pembrolizumab includes warnings and precautions regarding immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity. The prescribing information for enfortumab vedotin includes warnings and precautions for skin reactions, hyperglycemia, pneumonitis/interstitial lung disease, peripheral neuropathy, ocular disorders, infusion site extravasation, and embryo-fetal toxicity.

Source:

US Food and Drug Administration. FDA approves pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph each with enfortumab vedotin-ejfv for muscle invasive bladder cancer. Accessed July 10, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-or-pembrolizumab-and-berahyaluronidase-alfa-pmph-each-enfortumab-vedotin