Enfortumab Vedotin Combo Boosts MIBC Survival Outcomes in EV-304 Trial

Findings from the phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124) revealed significant improvements in event-free survival (EFS), overall survival (OS), and pathological complete responses (pCR) with perioperative enfortumab vedotin-ejfv (EV; Padcev) plus pembrolizumab (Keytruda) among those with muscle-invasive bladder cancer (MIBC) eligible for cisplatin-based therapy and radical cystectomy, according to a presentation at the 2026 ASCO Genitourinary Cancers Symposium.

Key Findings

EFS, the primary end point, was significantly longer for patients who received EV/pembrolizumab compared with cisplatin and gemcitabine. Specifically, the median EFS was not reached in the EV/pembrolizumab arm vs 48.5 months for the cisplatin and gemcitabine arm. At 24-months, the EFS rate was 79.4% for EV/pembrolizumab vs 66.2% for cisplatin/gemcitabine (HR, 0.53; 95% CI, 0.41-0.70); P < .001).

The effect of EV/pembrolizumab on EFS was generally consistent among all key study subgroups, as well, which was observed regardless of PD-L1 status, clinical stage, and geeographic region.

The secondary end point of OS was also consistently longer for patients in the EV/pembrolizumab arm vs the cisplatin and gemcitabine arm. The median OS was not reached for either arm; at 24-months, the OS rate was 86.9% in the EV/pembrolizumab arm vs 81.3% is the cisplatin and gemcitabine arm (HR, 0.65; 95% CI, 0.48-0.89; P = .0029)

Another secondary end point, pCR, favored the experimental arm at 55.8% vs 32.5% for the control arm. This represents an estimated difference of 23.4% (95% CI, 16.7-29.8; P < .001). Among patients who underwent cystectomy, the pCR on the EV/pembrolizumab arm was 64.4% vs 36.3% in the cisplatin and gemcitabine arm.

“This is a pivotal moment. For the first time in almost 25 years, since we first saw that cisplatin-based neoadjuvant therapy could improve outcomes in muscle-invasive bladder cancer, a non-platinum regimen has now surpassed it,” Matthew Galsky, MD, professor of medicine and deputy director of the Mount Sinai Tisch Cancer Center, New York, New York, said.

Treatment by design was longer on the EV/pembrolizumab arm vs the cisplatin and gemcitabine arm. Patients on the EV/pembrolizumab arm received a median of 10.2 months of treatment vs 3.5 months on the cisplatin and gemcitabine arm. Among patients starting neoadjuvant therapy, the median number of cycles administered was 4 on both arms. Among patients on the EV/pembrolizumab arm initiating the adjuvant phase, the median number of cycles of EV administered was 5, and of pembrolizumab was 13, which was the planned duration.

The median age of patients on both arms was 66 years, and most had an ECOG performance status of 0. Baseline clinical stage was assessed centrally, and approximately 80% of patients on both arms had clinical T3 disease or higher. Notably, baseline clinical stage was also assessed locally, and on local assessment, approximately 70% of patients were deemed to have clinical T2 disease.

Safety

Grade 3 or higher treatment-emergent adverse events (TRAEs) occurred in 75.7% of patients on the EV/pembrolizumab arm and 67.2% of patients on the cisplatin and gemcitabine arm. TRAEs leading to death occurred in 2 patients on the experimental arm and in 1 patient on the gem/cis arm.

The safety profile of the agents in both arms were consistent with prior observations. Patients on the EV/pembrolizumab arm experienced more pruritus, diarrhea, alopecia, and rash. Patients on the cisplatin and gemcitabine arm experienced more neutropenia, thrombocytopenia, anemia, and nausea. Treatment-emergent AEs during the surgical phase of the study were similar on both study arms.

Regarding AEs of special interest, the most common with EV were skin reactions, peripheral neuropathy, and ocular disorders. The most common with pembrolizumab were skin reactions, hypothyroidism, and pneumonitis.

Background

The study enrolled patients with clinically localized, muscle-invasive urothelial cancer of the bladder who were eligible for cisplatin-based chemotherapy and radical cystectomy. A total of 808 patients were randomly assigned 1:1 between May 2021 and December 2023.

KEYNOTE-B15 study compared 1.25 mg/kg enfortumab vedotin plus pembrolizumab (n = 405) vs 70 mg/m² cisplatin and 1000 mg/m² gemcitabine (n = 403). Patients underwent 4 cycles for each arm, which was followed by radical cystectomy. Patients who were randomly assigned to the EV/pembrolizumab arm initially continued to receive EV for 5 cycles and pembrolizumab for 13 cycles. Patients in the control arm were observed following cystectomy.

“These results support neoadjuvant and adjuvant EV-pembrolizumab as a novel treatment option for patients with muscle-invasive bladder cancer, regardless of their cisplatin eligibility,” Galsky concluded.

DISCLOSURES

Dr Galsky has served in a consulting or advisory role to Abbvie; Bristol-Myers Squibb; EMD Serono; Gilead Sciences; Janssen; Merck; and Pfizer. He has received research funding from AstraZeneca (Inst); Bristol-Myers Squibb (Inst); Dendreon (Inst); Genentech/Roche (Inst); Janssen Oncology (Inst); Merck (Inst); and Novartis (Inst).

Reference

Galsky MD, Valderrama BP, Maruzzo M, et al. Neoadjuvant and adjuvant enfortumab vedotin (EV) plus pembrolizumab (pembro) for participants with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin: Randomized, open-label, phase 3 KEYNOTE-B15 study. J Clin Oncol. 2026;44(suppl 7):LBA630. doi: 10.1200/JCO.2026.44.7_suppl.LBA630