KEYNOTE-B15 data on enfortumab vedotin plus pembrolizumab in MIBC published in NEJM

Data from the KEYNOTE-B15/EV-304 trial (NCT04700124) have been published in the New England Journal of Medicine, showing that the combination of enfortumab vedotin-ejfv (Padcev; EV) plus pembrolizumab (Keytruda) as perioperative treatment led to significant improvements in event-free survival (EFS), overall survival (OS), and pathological complete response (pCR) rate vs neoadjuvant cisplatin-gemcitabine in patients with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin-based chemotherapy.¹

This publication comes on the heels of the FDA approval of the regimen for all patients with MIBC, regardless of cisplatin eligibility, in July 2026.²

Related: FDA approves enfortumab vedotin plus pembrolizumab for MIBC

“Over the past 30 years, there's been 3 major advances [in MIBC]: cisplatin-based chemotherapy, the introduction of immune checkpoint blockade, and [now] EV–pembro,” said lead author Matthew D. Galsky, MD, in an interview with Urology Times®. “This is a major step forward for the treatment of patients with muscle invasive bladder cancer.”

About the KEYNOTE-B15 study

The phase 3, open-label KEYNOTE-B15 trial enrolled 808 patients with previously untreated MIBC who were randomly assigned 1:1 to receive perioperative EV plus pembrolizumab and radical cystectomy with pelvic lymph node dissection (n = 405), or to standard neoadjuvant gemcitabine plus cisplatin (n = 403) followed by surgery. The experimental arm received 4 neoadjuvant cycles of EV plus pembrolizumab, followed by 5 adjuvant cycles of EV and 13 adjuvant cycles of pembrolizumab. The control arm underwent 4 cycles of neoadjuvant cisplatin plus gemcitabine, followed by cystectomy and observation.

The primary end point was EFS, with OS, pCR, and safety as secondary end points. The median follow-up was 33.6 months. Among all patients, 86.7% in the EV–pembrolizumab arm and 89.6% of patients in the cisplatin–gemcitabine arm underwent cystectomy.

The trial met its primary end point of EFS. The median EFS was not reached in the EV–pembrolizumab arm vs 48.5 months in the gemcitabine–cisplatin arm (HR, 0.53; 95% CI, 0.41 to 0.70; P < .001). At 2 years, the estimated EFS rate was 79.4% with EV–pembrolizumab vs 66.2% in the control arm. Overall survival (OS) was also significantly improved, with a 35% reduction in the risk of death (HR, 0.65; 95% CI, 0.48 to 0.89; two-sided P = .006) and a 24-month estimated OS rate of 86.9% in the EV–pembrolizumab arm vs 81.3% in the control arm.

The pathologic complete response (pCR) rate at surgery was 55.8% with EV–pembrolizumab vs 32.5% with gemcitabine–cisplatin—a difference of 23.4 percentage points (95% CI, 16.7 to 29.8; P < .001). Pathological downstaging (tumor stage below pT2N0) occurred 63.7% (95% CI, 58.8 to 68.4) in the EV–pembrolizumab group and 45.2% (95% CI, 40.2 to 50.2) in the cisplatin–gemcitabine group (estimated difference, 18.6 percentage points; 95% CI, 11.8 to 25.2). Among patients who were disease-free following cystectomy, recurrence or death occurred in 15.9% and 28.8% of patients, respectively.

At the time of data report, 14.1% of patients in the EV–pembrolizumab arm and 28.3% of patients in the cisplatin–gemcitabine arm had received subsequent therapy.

Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 75.7% of patients in the EV–pembrolizumab arm vs 67.2% in the gemcitabine–cisplatin arm. In the treatment arm, the most common drug-related AEs of special interest were skin reactions (63.5%) and peripheral neuropathy (36%) with enfortumab vedotin and skin reactions (17.1%) and hypothyroidism (12.2%) with pembrolizumab.

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