Background: Nectin-4 is a cell adhesion molecule that is highly expressed in a wide variety of cancers and is associated with poor prognosis. SHR-A2102 is a novel ADC consisting of a fully humanized Nectin-4–directed monoclonal antibody, bound to topoisomerase I inhibitor payload via a cleavable linker. We conducted a multi-center, phase 1 trial to evaluate SHRA2102 in advanced solid tumors. Methods: Patients (pts) with Nectin-4 positive, locally advanced unresectable or metastatic solid tumors were enrolled. The study included doseescalation (D-ESC), dose-expansion (D-EXP) and efficacy-expansion (E-EXP) phases. SHRA2102 was given IV at 2–10 mg/kg, Q3W during D-ESC, and at 6 mg/kg and 8 mg/kg Q3W during D-EXP and E-EXP. The primary objectives were to assess safety and tolerability. Results: As of Dec. 20, 2024,369 pts were enrolled and treated (median age, 59 y; ECOG PS 1, 85.6%; $2 lines of prior therapy, 64.0%). During D-ESC, DLT occurred in 1 pt (10 mg/kg; grade 4 decreased platelet count). Overall, grade $3 TRAEs occurred in 167 (45.3%) pts, with the most common ($3%) being decreased neutrophil count (25.5%), decreased white blood cell count (16.3%), anaemia (11.7%), decreased lymphocyte count (8.7%), decreased platelet count (4.9%), asthenia (3.5%) and nausea (3.3%). 2 (0.5%) pts discontinued treatment due to TRAE. ILD occurred in 1 (0.3%; grade 3) pt. In 304 evaluable pts for response, ORR was 35.2% (95% CI 29.8-40.9) and DCR was 84.2% (95% CI 79.6-88.1). As of data cutoff, 146 (39.6%) pts had disease progression or died; median PFS was 4.7 mo (95% CI 4.3-5.6). Efficacy in selected tumor types is shown in Table. Conclusions: SHR-A2102 demonstrated a manageable safety profile and promising activity across a variety of pretreated advanced solid tumors. Multiple trials are ongoing to further assess SHR-A2102 both as monotherapy and in combination therapy for solid tumors. Clinical trial information: NCT05701709. Research Sponsor: Jiangsu Hengrui Pharmaceuticals.