Background: The current standard of care for patients (pts) with newly diagnosed MIBC is neoadjuvant cisplatin (cis)-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection (RC+PLND). For the 20-50% pts who are cis-ineligible, the current standard of care is RC+PLND alone (Galsky Future Oncol 2021). Adjuvant therapy is currently recommended for cis-ineligible patients with high-risk features at cystectomy. Due to the high rates of recurrence in cis-ineligible pts with RC+PLND alone, there is a need to develop new therapies in this setting. Enfortumab vedotin (EV), an antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, which is highly expressed in urothelial cancer. In EV-301, a phase 3 study, EV showed an overall survival (OS) benefit vs chemotherapy in pts with locally advanced (la) or metastatic urothelial carcinoma (mUC) who had previously received platinum-based therapy and a PD-1 or PD-L1 inhibitor (Powles NEJM 2021). EV has also demonstrated activity and a tolerable safety profile in cis-ineligible pts with la/mUC (Yu Lancet Oncol 2021). Given the efficacy of EV in la/mUC, it is being evaluated as perioperative therapy in cis-ineligible MIBC in EV-103 cohort L. Methods: Study EV-103 (NCT03288545) la/mUC and MIBC cohorts were described previously (Hoimes ASCO 2019; Hoimes ASCO-GU 2020). Cohort L was added to evaluate EV monotherapy (n = 50) as perioperative therapy in cis-ineligible pts with MIBC (cT2-T4aN0M0 or cT1-T4aN1M0). Eligible pts are previously untreated for MIBC, ECOG 0-2, have CrCl ≥30 mL/min, and are medically fit for and agree to undergo curative intent RC+PLND. Pts with pT1 disease are eligible only if they have N1 disease. Pts receive 3 cycles of neoadjuvant EV (1.25 mg/kg IV) on Days 1 and 8 of each 3-week cycle, followed by RC+PLND and then 6 cycles of adjuvant EV starting 8 weeks post-RC on the same schedule. Pathological complete response rate per central pathology review is the primary endpoint. Secondary endpoints include event-free survival and disease-free survival by blinded independent central review and investigator, pathological downstaging rate per central pathology review, OS, safety and tolerability. Cohort L is currently enrolling pts in the US and Canada. Clinical trial information: NCT03288545.