Background: Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle invasive urothelial cancer (MIUC) before radical cystectomy (RC) and lymph node dissection in cisplatin-eligible patients (pts). However, many pts are cisplatin-ineligible and while PD-1/PD-L1 inhibitors have had encouraging results in this population, they are not approved for MIUC; new therapies are needed. Enfortumab vedotin (EV), an investigational antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, which is highly expressed in urothelial cancer. In a phase 2 study, EV monotherapy had a confirmed ORR of 44% in 125 heavily pre-treated metastatic urothelial cancer (mUC) pts (Rosenberg JCO 2019). In the present study, an initial analysis of EV combined with the PD-1 inhibitor, pembrolizumab (P) had a confirmed ORR of 71% in 45 cisplatin-ineligible mUC pts in the first-line setting (Hoimes ESMO 2019). These results suggest that EV and EV+P may be suitable for research in MIUC. Methods: Study EV-103 (NCT03288545) mUC cohorts were described previously (Hoimes ASCO 2019). Sequential cohorts were added to test EV alone (Cohort H, n = 20) and EV+P (Cohort J, n = 20) as neoadjuvant therapy in cisplatin-ineligible pts (stage cT2-T4a, N0, M0) with treatment naive MIUC. Eligible pts are ECOG 0-2, have CrCl ≥30 mL/min, and are medically fit for and scheduled for RC. Cohort H pts receive 3 cycles of EV (1.25 mg/kg) on Days 1 and 8 of each 3-week cycle. Cohort J pts receive 3 cycles of EV as described for Cohort H plus P on Day 1 of each cycle. Following EV or EV+P, pts undergo their scheduled RC. Pathological complete response (pCR) rate per local pathology review is the primary endpoint of the MIUC cohorts. Secondary endpoints include assessment of pCR and pathological response (PaR) rate per central pathology review, PaR per local pathology review, PFS and investigator assessed disease-free survival per RECIST v1.1, OS, and assessment of safety and tolerability, including planned surgeries delayed due to treatment-related adverse events. The ongoing study opened Oct 2017 and was amended to include MIUC cohorts Aug 2019. Clinical trial information: NCT03288545