Background: DS-1062a is a trophoblast cell-surface antigen 2 (TROP2)-targeting antibody drug conjugate. TROP2 is overexpressed in epithelial cancers, including non-small cell lung cancer (NSCLC), and its overexpression is associated with poor survival in solid tumors. In preclinical studies, DS-1062a showed promising antitumor activity and an acceptable safety profile in TROP2-positive tumors with a long half-life, allowing for every-3-week (Q3W) dosing. This dose escalation (ESC) and dose expansion (EXP) study will investigate DS-1062a in pts with ASTs (NCT03401385). Primary objectives are to determine the maximum tolerated dose and recommended dose for expansion (RDE) based on the dose limiting toxicity (DLT) rate (ESC) and assess safety and tolerability (ESC + EXP). Secondary objectives include pharmacokinetics (PK), antitumor activity and anti-drug antibody (ADA) incidence. Methods: In this multicenter, open-label study in the US and Japan, pts aged ≥18 (US) or ≥20 (Japan) years with unresectable relapsed or refractory advanced NSCLC are eligible regardless of TROP2 expression; other ASTs may be included if safety and efficacy in NSCLC is demonstrated. In ESC, initial intravenous DS-1062a infusion will start at 0.27 mg/kg, followed by 21-day observation. Subsequent doses will be given Q3W. In EXP, pts will receive RDE Q3W. Pts will be treated until unacceptable toxicity, progressive disease, consent withdrawal or death. Endpoints include DLTs, adverse events (safety) and tumor response evaluated using RECIST v1.1 (efficacy). Pre-, on- and post-treatment tumor samples will be evaluated for TROP2 expression and other biomarker analyses. Immunogenicity will be assessed via ADA incidence and titer. Population PK and exposure-response analysis will be conducted. Pts will be enrolled in ESC using a modified continuous reassessment method and dose escalation with overdose control, with at least 3 DLT-evaluable pts per dose level. For EXP, 40 pts with NSCLC and up to 40 pts with other solid tumors will be enrolled. Enrollment is open. Clinical trial information: NCT03401385