Background: Standard of care for MIBC is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection (RC+PLND); however, in time, patients experience disease recurrence or progression. Enfortumab vedotin (EV) is a Nectin-4–directed antibody–drug conjugate comprising a fully human, monoclonal antibody and the microtubule-disrupting agent monomethyl auristatin E. The KEYNOTE-869/EV-103 phase 1/2 study (NCT03288545) showed that the PD-1 inhibitor pembrolizumab + EV had encouraging antitumor activity and acceptable safety as first-line treatment for cisplatin-ineligible patients with metastatic urothelial cancer (Rosenberg JE et al. J Clin Oncol. 2020;38[15 suppl]:5044). Based on these data, investigating EV + pembrolizumab in an earlier setting such as MIBC and in a perioperative fashion is appropriate. KEYNOTE-B15/EV-304 (NCT04700124) is a randomized, open-label, phase 3 study to evaluate the efficacy and safety of perioperative EV + pembrolizumab versus neoadjuvant chemotherapy using gemcitabine/cisplatin in cisplatin-eligible patients with MIBC. Methods: Patients must have histologically confirmed urothelial cancer/MIBC (clinical stage T2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology, have nonmetastatic disease (≥N2 disease and/or M1 excluded) confirmed by blinded independent central review (BICR), have ECOG PS 0 or 1, and not have previously received systemic therapy for MIBC. Approximately 784 patients will be randomly assigned 1:1 to receive either 4 cycles of neoadjuvant EV + pembrolizumab followed by 5 cycles of adjuvant EV + 13 cycles of adjuvant pembrolizumab after RC+PLND or 4 cycles of neoadjuvant cisplatin-based chemotherapy followed by observation after RC+PLND. Neoadjuvant and adjuvant pembrolizumab 200 mg + EV 1.25 mg/kg will be administered intravenously every 3 weeks (Q3W), and neoadjuvant chemotherapy will consist of gemcitabine 1000 mg/m² + cisplatin 70 mg/m² Q3W. Randomization will be stratified by centrally determined (pathology or imaging) initial T and N stage (T2N0 or T3/T4aN0 or T1-T4aN1), PD-L1 combined positive score (CPS ≥10 or CPS < 10), and geographic region (United States or Europe or most of world). Imaging (CT or MRI) will be performed ≤6 weeks before cystectomy and 6 weeks after cystectomy. After postcystectomy imaging, additional imaging will be performed Q12W up to the end of year 2 (week 96) and at discontinuation. In year 3 and beyond, imaging will be performed Q24W. Primary end points are pathological complete response and event-free survival by BICR. Secondary end points are overall survival, disease-free survival, pathological downstaging, and safety and tolerability. Clinical trial information: NCT04700124