Clinical Implications of TROP2 Expression and the Importance of Drug Internalization

This segment examines the clinical relevance of TROP2 expression levels in the context of ADC therapy and highlights key biologic factors that influence treatment response. Dr. Santos reviews outcomes from phase 1 and phase 3 clinical trials evaluating TROP2-directed ADCs, including studies of sacituzumab govitecan (EVOKE-01) and datopotamab deruxtecan (TROPION-Lung01). Although TROP2 is broadly expressed across both squamous and non-squamous NSCLC, analyses using conventional IHC-based H-scoring did not demonstrate a clear association between higher expression levels and improved clinical outcomes. These findings suggest that traditional expression-based scoring may not adequately identify patients most likely to benefit from TROP2-targeted therapies.

The discussion shifts to emerging efforts to improve patient selection using more quantitative approaches, such as quantitative continuous scoring (QCS), which has shown early signals of correlation with clinical outcomes and may provide a more informative assessment of target biology.

Dr. Wistuba expands on the mechanistic basis for these observations by emphasizing that TROP2 expression alone does not determine ADC efficacy. Effective treatment depends on several components of ADC function: antibody binding to the cell-surface target, internalization of the antibody–target complex, and intracellular release of the cytotoxic payload. Preclinical studies in NSCLC cell lines demonstrate that higher levels of drug internalization correlate with increased intracellular drug delivery and greater antitumor activity. Importantly, internalization capacity varies across tumors and does not always parallel surface expression levels.

Overall, this segment highlights a critical concept: functional target engagement, particularly internalization, may be more relevant than expression alone, reinforcing the need for more biologically informative biomarkers such as TROP2 normalized membrane ratio (NMR).