Enfortumab Vedotin/Pembrolizumab Redefines Neoadjuvant Therapy for MIBC

Neoadjuvant and adjuvant enfortumab vedotin-ejfv (EV; Padcev) and pembrolizumab (Keytruda) significantly and meaningfully improved event-free survival (EFS), overall survival (OS), and pathological complete response (pCR) vs neoadjuvant cisplatin plus gemcitabine in patients with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin-containing therapy and radical cystectomy, according to results from the KEYNOTE-B15/EV-304 trial (NCT04700124). Results from the phase 3 trial were delivered during the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium.

Key Findings

EFS, the primary end point, was significantly longer in patients who received EV/pembrolizumab than in those who received cisplatin and gemcitabine. Specifically, the median EFS was not reached in the EV/pembrolizumab arm vs 48.5 months for the cisplatin/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 across all key study subgroups, regardless of PD-L1 status, clinical stage, or geographic region.

The secondary end point of OS was also consistently longer in patients in the EV/pembrolizumab arm vs the cisplatin/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% in the cisplatin/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, pCR was 64.4% in the EV/pembrolizumab arm vs 36.3% in the cisplatin/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 nonplatinum regimen has now surpassed it,” Matthew Galsky said during the presentation. Galsky is a professor of medicine, director of genitourinary medical oncology, and deputy director of the Mount Sinai Tisch Cancer Center in New York, New York.

By design, treatment was longer on the EV/pembrolizumab arm vs the cisplatin/gemcitabine arm. Patients on the EV/pembrolizumab arm received a median of 10.2 months of treatment vs 3.5 months for those on the cisplatin/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 who initiated the adjuvant phase, the median number of EV cycles administered was 5, and the median number of pembrolizumab cycles administered 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 centrally assessed, and approximately 80% of patients on both arms had clinical T3 or higher disease. 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-related adverse events (TRAEs) occurred in 75.7% of patients on the EV/pembrolizumab arm and 67.2% of patients on the cisplatin/gemcitabine arm. TRAEs leading to death occurred in 2 patients on the experimental arm and in 1 patient on the cisplatin/gemcitabine arm.

The safety profile of the agents in both arms was consistent with prior observations. Patients on the EV/pembrolizumab arm experienced more pruritus, diarrhea, alopecia, and rash. Patients on the cisplatin/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 AEs 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 of enfortumab vedotin plus pembrolizumab (n = 405) vs 70 mg/m² of cisplatin and 1000 mg/m² of gemcitabine (n = 403). Patients underwent 4 cycles for each arm, followed by radical cystectomy. Patients assigned to the EV/pembrolizumab arm initially received 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: 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