Background: Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy + pelvic lymph node dissection (RC+PLND) is the standard of care for cisplatin-eligible pts with MIBC; however, up to 50% of pts will experience disease recurrence or progression following treatment. Pembro and EV monotherapies are approved for use in select pts with metastatic urothelial carcinoma (mUC). Furthermore, results of the phase 1/2 KEYNOTE-869/EV-103 study showed encouraging antitumor activity and an acceptable safety profile with first-line combination therapy EV + pembro in cisplatin-ineligible pts with mUC. The open-label, multicenter, phase 3, randomized KEYNOTE-B15/EV-304 study (NCT04700124) will compare the efficacy and safety of perioperative EV + pembro versus neoadjuvant cisplatin-based chemotherapy in cisplatin-eligible pts with MIBC. Methods: Eligible pts will have histologically confirmed UC/MIBC (T2-T4aN0M0 or T1-T4aN1M0) with predominant urothelial histology (≥50%), nonmetastatic disease (N≤1, M0) confirmed by blinded independent central review (BICR), ECOG performance status of 0-1, no prior systemic therapy for MIBC, and agree to undergo curative RC+PLND. Approximately 784 pts will be randomly assigned 1:1 to Arm A (4 cycles of neoadjuvant EV + pembro, followed by RC+PLND, followed by 5 cycles of adjuvant EV + 13 cycles of adjuvant pembro) or Arm B (4 cycles of neoadjuvant chemotherapy [gemcitabine + cisplatin] followed by RC+PLND, followed by observation). Neoadjuvant and adjuvant pembro 200 mg + EV 1.25 mg/kg will be administered intravenously every 3 weeks (Q3W) on day 1 (pembro + EV) and day 8 (EV) of each cycle. Neoadjuvant chemotherapy is gemcitabine 1000 mg/m² + cisplatin 70 mg/m² Q3W on day 1 (gemcitabine + cisplatin) and day 8 (gemcitabine) of each cycle. Stratification factors are disease stage (T2N0 vs T3/T4aN0 vs T1-T4aN1), PD-L1 combined positive score (≥10 vs <10), and geographic region (United States vs European Union vs most of the world). Imaging by CT (preferred) or MRI will be performed ≤6 weeks before cystectomy and 6 weeks after cystectomy. Imaging will occur following cystectomy then Q12W through year 2 and at discontinuation, then Q24W in year 3 and beyond. Adverse events (AEs) will be monitored throughout the study and for 30 days following cessation of treatment (90 days for serious AEs). The primary end points are pathologic complete response rate and event-free survival by BICR. Secondary end points are OS, DFS, pathologic downstaging rate, safety and tolerability, and patient-reported outcomes. KEYNOTE-B15/EV-304 is enrolling in Africa, Asia, Australia, Europe, and North America. © 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting. All rights reserved. Clinical trial information: NCT04700124.