Background: Globally, HNCs accounted for an estimated 932,000 new cases and 467,000 deaths in 2020. Nectin-4 is expressed in a majority of HNCs. Given the poor prognosis (median survival < 1 y) of recurrent/metastatic disease in patients (pts) with head and neck squamous cell carcinoma, effective treatments are needed. Targeting Nectin-4 with an antibody–drug conjugate (ADC) may be a novel strategy. Enfortumab vedotin (EV) is a Nectin-4 directed ADC approved for treatment of adults with locally advanced or metastatic (la/m) urothelial carcinoma previously treated with platinum-containing chemotherapy and PD-1/L1 inhibitor based on survival benefit shown in the phase 3 EV-301 trial. Use of EV for HNC is investigated in EV-202 (NCT04225117). Methods: In this multicohort, open-label phase 2 study, pts with previously treated la/m solid tumors not amenable to curative-intent treatment and Eastern Cooperative Oncology Group performance status 0–1 were enrolled into tumor-specific cohorts. For the HNC cohort, pts must have progressed/relapsed/discontinued treatment for toxicity after 1 platinum-based therapy for la/m disease and no more than 2 lines of cytotoxic therapy in the la/m setting. Unless contraindicated, pts must have received a programmed cell death protein 1/ligand 1 (PD-1/L1) inhibitor (based on PD-1/L1 expression). Pts received EV 1.25 mg/kg intravenously on days 1, 8, and 15 of a 28-d cycle until disease progression/discontinuation criteria were met. Primary endpoint was confirmed objective response rate (ORR; per RECIST v1.1) per investigator assessment. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety/tolerability. Results: As of April 11, 2022, a total of 46 pts were in the HNC cohort; median follow-up was 9.33 mo. Median age was 65 y, 87% of pts were men, and most had received ≥2 lines of systemic therapy in the metastatic setting. Histology at diagnosis was squamous cell carcinoma for 45 (97.8%) pts and “other” for 1 pt. ORR was 23.9% (n = 11). Median DOR was not reached. DCR was 56.5% (n = 26). Median time to response was 1.74 mo. Median PFS and OS were 3.94 and 5.98 mo, respectively. Common adverse events (AEs) were fatigue, alopecia, and peripheral sensory neuropathy (28.3% for each; n = 13). Grade ≥3 AEs occurring in > 1 pt were anemia (n = 3), decreased neutrophil count (n = 2), and malignant neoplasm progression (disease progression of HNC; n = 2). Of treatment-related AEs of special interest for EV, skin reactions occurred in 45.7% of pts, peripheral neuropathy in 32.6%, and hyperglycemia in 4.3%. Conclusions: In pts with heavily pretreated HNC, antitumor activity of EV monotherapy and tolerability, with manageable adverse events, was observed, consistent with that in previously studied populations with advanced urothelial carcinoma. Further investigation of EV activity in HNC is warranted. Clinical trial information: NCT04225117.