Background: Up to 25% of all pts diagnosed with urothelial cancer present with muscle-invasive disease for whom the risk of progression or metastasis is substantial. Neoadjuvant chemotherapy prior to radical cystectomy and pelvic lymph node dissection (RC+PLND) has been shown to prolong overall survival for patients who are cisplatin (cis) eligible. The standard of care for cis-ineligible pts undergoing surgery does not include neoadjuvant therapy. Therefore, safe, and effective neoadjuvant therapies are an unmet need for cis-ineligible pts with MIBC. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer, and has been shown to benefit locally advanced or metastatic urothelial cancer pts in Phase II and III trials, including cis-ineligible pts. Methods: Cohort H of the EV-103 phase 1b/2 trial (NCT03288545) enrolled pts with cis-ineligible cT2-T4aN0M0 MIBC who were eligible for RC+PLND and had an ECOG of 0-2. Pts received 3 cycles of neoadjuvant EV (1.25 mg/kg) on Days 1 and 8 of every 3-week cycle prior to RC+PLND. The primary endpoint of the study was pathological complete response rate (pCRR; ypT0N0) by central review. Key secondary endpoints included pathological downstaging (pDS) rate (yp T0,Tis,Ta,T1,N0) and safety. Results from a preliminary analysis are presented. Results: 22 pts were treated. Pts had cT2 (68.2%), cT3 (27.3%), and cT4 (4.5%) tumors. 68.2% pts had predominant urothelial cancer; 31.8% had a mixed histology. 19 pts completed all 3 cycles of EV. 21 underwent RC+PLND, and 1 had a partial cystectomy. 36.4% pts had a pCR. pDS was seen in 50.0% pts, with 1 case pending central pathology review. The most common EV treatment-related adverse events (TRAEs) were fatigue (45.5%), alopecia (36.4%), and dysgeusia (36.4%). 18.2% pts had Grade ≥3 EV TRAEs. No surgeries were delayed due to EV administration. 3 pts had Grade 5 AEs while on study that were unrelated to EV; in 2 pts these AEs occurred > 30 days after RC+PLND. Conclusions: Observed pCRR after neoadjuvant EV showed promising activity in cis-ineligible pts with MIBC who have a high unmet need. Adverse events were consistent with the known safety profile of EV. This first disclosure of data supports the ongoing Phase II and III programs evaluating EV in MIBC. Clinical trial information: NCT03288545.