Background: For patients (pts) with MIBC who are cisplatin-ineligible and undergoing radical cystectomy and pelvic lymph node dissection (RC+PLND), no neoadjuvant treatment options have been shown to improve survival. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer. EV, alone and in combination w/ pembrolizumab, has been shown to improve OS vs chemotherapy in pts with previously treated and untreated locally advanced or metastatic urothelial cancer, respectively (Powles NEJM 2021; Powles ESMO 2023). In Cohort H of the EV-103 phase 1b/2 study, promising results for 1-year EFS and antitumor activity, including pathological complete response (pCR) and pathological downstaging (pDS) rates, were achieved in cisplatin-ineligible pts with MIBC after neoadjuvant monotherapy EV treatment (Petrylak ASCO GU 2022; Flaig ASCO 2023). Here we report updated results, including 2-year EFS. Methods: Cohort H of the EV-103 study enrolled cisplatin-ineligible pts with MIBC (T2-T4aN0M0) and ECOG PS ≤2 who were eligible for RC+PLND. Pts received neoadjuvant EV (1.25 mg/kg) on Days 1 and 8 every 21 days for 3 cycles before undergoing RC+PLND. The primary endpoint was pCR rate (ypT0 and N0) by central pathology review. Key secondary endpoints included pDS rate (ypT0, ypTis, ypTa, ypT1, and N0), safety, and EFS per investigator assessment (radiographic progression prior to RC, failure to undergo RC, gross residual disease at time of RC, recurrence, or death). Results: 22 pts (median age 74.5 years) were enrolled and treated; 15 pts (68.2%) remain on study. Pts had stage cT2 (68.2%), cT3 (27.3%), or cT4 (4.5%) disease. 68.2% of pts had urothelial carcinoma only; 31.8% had a mixed histology. 86.4% of pts completed all 3 cycles of EV; the median duration of EV treatment was 2.1 months (range 0.7-2.3). The pCR rate was 36.4% (95% CI, 17.2-59.3) and the pDS rate was 50.0% (95% CI, 28.2-71.8). The EFS rate at 24 months was 62.0% (95% CI, 38.2-78.9). Median EFS has not been reached. All pts underwent surgery with no delays due to EV-related TEAEs. The most common EV-related TEAEs were fatigue (45.5%), dysgeusia (36.4%), and alopecia (31.8%); 18.2% of pts had grade ≥3 EV-related TEAEs. 68.2% of pts had surgery-related TEAEs: the most common were procedural pain (18.2%), anemia (13.6%), and constipation (13.6%). 3 pts died due to AEs unrelated to EV treatment. 36.4% of pts received subsequent cancer-related therapy. Conclusions: Neoadjuvant EV monotherapy treatment showed promising results for antitumor activity and 2-year EFS with a manageable safety profile in cisplatin-ineligible pts with MIBC. These results support ongoing phase 2 and 3 programs in MIBC evaluating EV alone or combined with pembrolizumab (EV-103 Cohort L, KN-905/EV-303, KN-B15/EV-304). Clinical trial information: NCT03288545.