What the Efficacy Data from KEYNOTE-B15/EV-304 Revealed

In this video, Joshua J. Meeks, MD, PhD, the Edward M. Schaeffer, MD, PhD Professor of Urology and associate professor of urology, biochemistry, and molecular genetics at Northwestern University Feinberg School of Medicine in Chicago, Illinois, traces the evolution of systemic therapy for muscle-invasive bladder cancer (MIBC), noting that surgery alone cures only about half of patients, since micrometastatic disease—now trackable through ctDNA—often persists despite a technically successful operation.

Meeks recounts how platinum-based regimens became standard starting with the SWOG 8710 trial in the late 1980s, progressing from MVAC to gemcitabine-cisplatin and eventually to the gemcitabine-cisplatin-durvalumab (Imfinzi) regimen studied in the NIAGARA trial. But he emphasizes that roughly half of patients with MIBC could never tolerate platinum, and even eligible patients often couldn't complete a full course because of its effects on kidney function and overall health.

Meeks then reviews the KEYNOTE-B15/EV-304 trial, which randomly assigned 808 patients 1:1 to gemcitabine-cisplatin or 4 cycles of enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) before surgery. Event-free survival reached 79% with the combination vs 66% with chemotherapy, an HR of 0.53, whereas overall survival improved from 81% to 86%, an HR of 0.63.

Meeks calls out the pathologic response data as especially compelling: Standard transurethral resection alone clears cancer in roughly 17% of cases, platinum-based chemotherapy achieves complete pathologic response around 32% to 33% of the time, and the combination regimen reached 56% overall and 64% among those who went on to cystectomy—effectively doubling the cure rate at the bladder level. Meeks describes this as the first nonplatinum regimen in approximately 25 years to outperform cisplatin-based chemotherapy in cisplatin-eligible patients, and attributes the benefit to 2 factors: broader eligibility, since kidney function and comorbidities matter less, and better tolerability, since the antibody-drug conjugate delivers its payload in a targeted way rather than exposing the whole body to chemotherapy.

In the next episode, "MIBC Treatment Timeline and Skin Toxicity: What Urologists Should Know," Meeks shifts to the practical side of care, mapping out the treatment timeline patients can expect and the adverse events urologists should watch for.