Background
Phase 3, open-label, randomized trial. N=808 adults with muscle-invasive bladder cancer (cT2–T4aN0M0, predominantly urothelial) eligible for cisplatin-based chemotherapy and radical cystectomy with pelvic lymph-node dissection. Tests whether perioperative (neoadjuvant + adjuvant) enfortumab vedotin (Nectin-4–directed antibody–drug conjugate) plus pembrolizumab (anti–PD-1) should replace neoadjuvant cisplatin-based chemotherapy as the standard of care in the cisplatin-eligible setting.
Results
Interventions and follow up: Arm A: neoadjuvant enfortumab vedotin 1.25 mg/kg (days 1, 8) + pembrolizumab 200 mg (day 1) q3w × 4 cycles → radical cystectomy → adjuvant enfortumab vedotin × 5 cycles + pembrolizumab × 13 cycles (n=405).
Arm B: neoadjuvant cisplatin 70 mg/m² (day 1) + gemcitabine 1000 mg/m² (days 1, 8) q3w × 4 cycles → radical cystectomy (n=403).
Primary endpoint: event-free survival (EFS).
Key secondary: overall survival (OS), pathological complete response (pCR).
mFollow up: 33.6 months.
Results: EFS: median NR vs 48.5 mo; 2-yr 79.4% vs 66.2%; HR 0.53 (95% CI 0.41–0.70); P<.001.
OS: 2-yr 86.9% vs 81.3%; HR 0.65 (95% CI 0.48–0.89); P=.006.
pCR: 55.8% vs 32.5% (absolute difference 23.4%); P<.001.
Arm B: neoadjuvant cisplatin 70 mg/m² (day 1) + gemcitabine 1000 mg/m² (days 1, 8) q3w × 4 cycles → radical cystectomy (n=403).
Primary endpoint: event-free survival (EFS).
Key secondary: overall survival (OS), pathological complete response (pCR).
mFollow up: 33.6 months.
Results: EFS: median NR vs 48.5 mo; 2-yr 79.4% vs 66.2%; HR 0.53 (95% CI 0.41–0.70); P<.001.
OS: 2-yr 86.9% vs 81.3%; HR 0.65 (95% CI 0.48–0.89); P=.006.
pCR: 55.8% vs 32.5% (absolute difference 23.4%); P<.001.
Adverse events
Grade ≥3 (any cause): 75.7% vs 67.2%.
EV events of special interest: skin reactions, peripheral neuropathy, ocular disorders; grade ≥3 skin reactions prominent.
Immune-mediated (pembrolizumab): consistent with prior EV+pembro experience; no new safety signals.
Discontinuation: NR.
EV events of special interest: skin reactions, peripheral neuropathy, ocular disorders; grade ≥3 skin reactions prominent.
Immune-mediated (pembrolizumab): consistent with prior EV+pembro experience; no new safety signals.
Discontinuation: NR.
Conclusions
Perioperative enfortumab vedotin plus pembrolizumab significantly improved EFS, OS, and pCR versus neoadjuvant cisplatin–gemcitabine in cisplatin-eligible MIBC, nearly halving the risk of an event or death (HR 0.53) with a manageable, expected toxicity profile. This is the first regimen to beat cisplatin-based neoadjuvant chemotherapy in cisplatin-eligible MIBC and defines a new perioperative standard of care.
Key Limitations
Open-label design with investigator-assessed primary EFS; OS follow-up remains early (2-yr landmark, medians not reached). Higher grade ≥3 toxicity and a more intensive ~1-year adjuvant schedule versus 4 neoadjuvant chemotherapy cycles. The trial cannot separate the contribution of the neoadjuvant vs adjuvant phases, or of enfortumab vedotin vs pembrolizumab individually. Control arm did not incorporate adjuvant nivolumab (CheckMate-274) or perioperative durvalumab (NIAGARA), the emerging comparators.
Clinical Context
FDA approved perioperative pembrolizumab + enfortumab vedotin for cisplatin-eligible MIBC in July 2026 (priority review), extending the EV+pembro combination already standard in first-line metastatic urothelial carcinoma (EV-302). NCCN, ASCO, and ESMO had recommended neoadjuvant cisplatin-based chemotherapy as the only level-1 standard for cisplatin-eligible MIBC; KEYNOTE-B15 is the first trial to displace it. Contrasts with perioperative durvalumab + chemotherapy (NIAGARA), which added immunotherapy to — rather than replaced — cisplatin-based chemotherapy.