TROP2-directed antibody-drug conjugates (ADCs) challenge of predicting clinical outcome

INTRODUCTION: Trophoblast cell surface antigen 2 (TROP2)-directed antibody-drug conjugates (ADCs), including sacituzumab govitecan (SG), sacituzumab tirumotecan (sac-TMT) and datopotamab deruxtecan (Dato-DXd), have become important treatment options across multiple solid tumor malignancies, yet the relationship between TROP2 expression level and clinical benefit remains incompletely defined. AREAS COVERED: This review synthesizes preclinical and clinical data on TROP2-directed ADCs in non-small cell lung, breast, urothelial and other solid tumors to evaluate whether TROP2 expression predicts response and details the biologic and pharmacologic factors, including payload, linker and resistance mechanisms, that may govern response. Literature was identified through a search of PubMed and Google Scholar through April 2026. EXPERT OPINION: Available data suggest an association between TROP2 expression and clinical benefit, but findings are inconsistent across tumor types and ADC platforms and are confounded by assay variability, narrow ranges of TROP2 expression and agent-specific pharmacology. Standardized, quantitative and routine TROP2 assessment is justified to optimize patient selection and improve the benefit-risk ratio of TROP2-directed ADC therapy.