Background: Nectin-4, a transmembrane cell adhesion protein, is highly expressed in urothelial carcinoma (UC), breast cancer (BC), non-small cell lung cancer (NSCLC), and gastroesophageal cancers (GEC); targeting Nectin-4 on these tumors may provide a novel treatment approach. Enfortumab vedotin (EV), an investigational human monoclonal antibody-drug conjugate, binds to Nectin-4 and upon internalization releases MMAE resulting in cell cycle arrest and cell death. Recently, EV received accelerated approval by the FDA for the treatment of adults with locally advanced/metastatic UC who previously received a PD-1 or PD-L1 inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. Use of EV in this study is investigational. Methods: This open-label phase 2 study (NCT04225117) will assess the efficacy and safety/tolerability of EV in patients (pts) with previously treated locally advanced/metastatic malignant solid tumors. Adult pts (~240) with histologically or cytologically confirmed disease and an ECOG ≤1 will be enrolled into 1 of 6 tumor-specific cohorts (Table), with ~40 pts each. While Nectin-4 expression is not required for enrollment, it is being tested retrospectively. Patients with active CNS metastases, grade ≥2 preexisting sensory or motor neuropathy, grade ≥3 immunotherapy-related hypothyroidism or panhypopituitarism, ongoing grade >3 immunotherapy-related AEs requiring high-dose steroids, or a history of uncontrolled diabetes mellitus within 3 months of the study will be excluded. All pts will receive EV 1.25 mg/kg IV on Days 1, 8, and 15 of each 28-day cycle until treatment discontinuation criteria are met; dose reductions/interruptions will be permitted. For all cohorts, the primary endpoint is investigator-assessed confirmed objective response rate (RECIST v1.1); secondary endpoints include duration of response, disease control rate, progression-free and overall survival, and safety/tolerability of EV. This study is recruiting as of February 2020. Clinical trial information: NCT04225117.