Background: Patients with MIBC who are ineligible for neoadjuvant cisplatin-based chemotherapy receive the standard-of-care treatment of radical cystectomy (RC) and pelvic lymph node dissection (PLND); however, RC + PLND alone is associated with high rates of recurrence and relatively poor overall survival (OS). The PURE-01 study (NCT02736266) demonstrated a pathologic complete response (pCR) rate of 37% (95% CI, 28%-36%) with neoadjuvant pembrolizumab in MIBC (Necchi, Eur Urol, 2020). The combination of pembrolizumab plus EV demonstrated encouraging antitumor activity in metastatic urothelial cancer (Rosenberg, ASCO GU, 2020). KEYNOTE-905/EV-303 (NCT03924895) is a randomized, multinational phase 3 study that will assess efficacy and safety of perioperative pembrolizumab plus RC + PLND versus perioperative EV with pembrolizumab plus RC + PLDN versus RC + PLND alone for patients with MIBC. Methods: Approximately 836 patients will be randomly assigned 1:1:1 to 3 cycles of neoadjuvant pembrolizumab followed by RC + PLND and 14 cycles of adjuvant pembrolizumab or 3 cycles of neoadjuvant EV and pembrolizumab followed by RC+PLND and 6 cycles of adjuvant EV and pembrolizumab and then 8 cycles of adjuvant pembrolizumab or RC + PLND alone. Neoadjuvant or adjuvant pembrolizumab 200 mg will be administered intravenously every 3 weeks (Q3W). Neoadjuvant or adjuvant EV 1.25 mg/kg will be administered on days 1 and 8 Q3W. Stratification factors will be PD-L1 status (combined positive score [CPS] ≥10 vs < 10), disease stage (T2N0 vs T3/T4N0 vs T1-T4aN1), and region (United States vs European Union vs most of the world). Adults with histologically confirmed MIBC (T2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology will be enrolled. These patients must also be previously untreated with systemic therapies for MIBC, be ineligible for cisplatin, have Eastern Cooperative Oncology Group performance status of 0-2, and have tumor tissue for histology and PD-L1 analysis. Imaging (CT or MRI) will be performed 5 weeks or fewer before cystectomy and at 6 weeks after cystectomy. Scans will then be performed every 12 weeks up to year 2 after cystectomy and at discontinuation. At year 3 and beyond imaging will be every 24 weeks. Coprimary end points are pCR and event-free survival (EFS) (expressing PD-L1 [CPS ≥10] and all patients regardless of CPS). Secondary end points are OS, disease-free survival, pathologic downstaging, safety, and patient-reported outcomes. Adverse events graded according to Common Terminology Criteria for Adverse Events v4.0 will be monitored from randomization through 30 days after last dose of study drug (90 days for serious adverse events). KEYNOTE-905/EV-303 is ongoing or planned in 25 countries across Asia, Australia, Europe, and North America. Clinical trial information: NCT03924895