Phase 3 Data Back a New Perioperative Standard for Cisplatin-Eligible Muscle-Invasive Bladder Cancer

For patients with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin-based chemotherapy, neoadjuvant gemcitabine plus cisplatin followed by radical cystectomy has long been the standard perioperative approach. Results from the randomized phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124) now challenge that paradigm, demonstrating that perioperative enfortumab vedotin (EV, Padcev; Astellas Pharma US, Inc/Pfizer Inc) plus pembrolizumab (Keytruda; Merck) delivers superior outcomes across every key end point.

The data were presented at the 2026 American Society of Clinical Oncology Annual Meeting in Chicago.

Understanding the MIBC Treatment Landscape

Each year, over 614,000 people worldwide are diagnosed with bladder cancer, making it the ninth most common cancer globally. In the MIBC setting specifically, approximately 117,500 patients received treatment under the established standard of care in 2024––neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy.¹

However, significant gaps remain. As many as half of all patients with MIBC are unable to tolerate cisplatin-based therapy, leaving a substantial portion of the population without access to the most established treatment pathway. Even among those who do undergo radical cystectomy, recurrence remains a persistent threat, occurring in approximately 50% of patients and underscoring the urgent need for more effective perioperative strategies.¹

EV represents a clinically promising advancement in the treatment of MIBC. An antibody-drug conjugate, EV targets Nectin-4, a molecule responsible for cell adhesion. Research shows that Nectin-4 overexpression may contribute to tumor cell growth and proliferation. By targeting this molecule, EV induces cell-cycle arrest and apoptosis.²

Testing EV

Patients with clinical stage T2–T4aN0M0 or T1–T4aN1M0 MIBC who were eligible for cisplatin-based chemotherapy and radical cystectomy plus pelvic lymph node dissection (RC + PLND) were randomly assigned 1:1 to one of 2 treatment arms. The EV plus pembrolizumab arm received 4 cycles of neoadjuvant EV (1.25 mg/kg intravenously [IV], days 1 and 8) plus pembrolizumab (200 mg IV, day 1) every 3 weeks, followed by RC + PLND, then adjuvant EV for 5 cycles and pembrolizumab for 13 cycles. The comparator arm received 4 cycles of neoadjuvant gemcitabine (1000 mg/m² on days 1 and 8) plus cisplatin (70 mg/m² on day 1) every 3 weeks, followed by RC + PLND alone.³

A total of 808 patients were randomly assigned—405 to EV plus pembrolizumab and 403 to gemcitabine plus cisplatin. Baseline characteristics were well balanced between the arms.

The primary end point was event-free survival (EFS) by blinded independent central review. Key secondary end points included pathological complete response (pCR) rate and overall survival (OS).³

EV Shows Promise in Combination Regimens

EV plus pembrolizumab demonstrated statistically significant and clinically meaningful improvements across all 3 primary and key secondary end points. Median EFS was not reached in the EV plus pembrolizumab arm, compared with 48.5 months with gemcitabine plus cisplatin, with 24-month estimated EFS rates of 79.4% vs 66.2% (HR, 0.53; 95% CI, 0.41-0.70; P < .0001). OS also favored EV plus pembrolizumab, with 24-month estimated rates of 86.9% vs 81.3% (HR, 0.65; 95% CI, 0.48-0.89; P = .0029), although median OS had not been reached in either arm.³

The pCR rate was nearly double with EV plus pembrolizumab compared with chemotherapy—55.8% vs 32.5%—a difference of 23.3 percentage points (95% CI, 16.7-29.8; P < .0001), underscoring the regimen’s ability to eradicate disease prior to surgery.³

Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 75.7% of patients in the EV plus pembrolizumab arm and in 67.2% in the chemotherapy arm. The most common grade 3 or higher drug-related AEs of special interest were skin reactions for both EV (14.1%) and pembrolizumab (13.9%). The overall safety profile was consistent with prior experience with the combination.³

Revolutionizing MIBC Care

Across EFS, OS, and pCR rate, perioperative EV plus pembrolizumab outperformed the longstanding chemotherapy standard in cisplatin-eligible patients with MIBC. These results position EV plus pembrolizumab as an effective and practice-changing perioperative treatment option.

REFERENCES

1. Perioperative Imfinzi plus neoadjuvant EV showed statistically significant and clinically meaningful improvements in event-free survival and overall survival in muscle-invasive bladder cancer in the phase III VOLGA trial. Press release. AstraZeneca. May 14, 2026. Accessed May 29, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/imfinzi-ev-improves-efs-os-in-bladder-cancer.html

2. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125-1135. doi:10.1056/NEJMoa2035807

3. Hoimes CJ, Galsky MD, Valderrama BP, et al. Neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab for participants with muscle-invasive bladder cancer who are eligible for cisplatin: randomized, open-label, phase 3 KEYNOTE-B15 study. Presented at: 2026 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract 4614.