Normalized membrane ratio of TROP2 as a predictor of clinical outcomes with datopotamab deruxtecan in non-small-cell lung cancer

Datopotamab deruxtecan (Dato-DXd)—a trophoblast cell surface antigen 2 (TROP2)-directed antibody–drug conjugate—has demonstrated efficacy in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) ± actionable genomic alterations. However, TROP2 expression by pathologist assessment using conventional immunohistochemistry with visual scoring does not predict response to TROP2-directed antibody–drug conjugates in NSCLC. We developed TROP2 quantitative continuous scoring (QCS)—a fully supervised computational pathology approach that quantifies TROP2 expression in individual NSCLC cells and subcellular components from immunohistochemistry-stained slides. Using QCS to determine TROP2 expression at the tumor cell membrane and cytoplasm, normalized membrane ratio (NMR) was developed (ratio of membrane relative to membrane + cytoplasmic TROP2) in the biomarker-evaluable population of patients with advanced NSCLC in the TROPION-PanTumor01 study ( n = 115). The TROP2 NMR cut-point was optimized and validated in patients with nonsquamous NSCLC without actionable genomic alterations (primary intended-use population, n = 221) in the biomarker-evaluable population ( n = 352) of the TROPION-Lung01 trial. Association with clinical outcomes was assessed. Progression-free survival was longer in Dato-DXd-treated (median 7.2 versus 4.0 months; hazard ratio 0.40, 95% confidence interval 0.25–0.64) but not docetaxel-treated (median 4.1 versus 4.4 months; hazard ratio 0.94, 95% confidence interval 0.59–1.49) patients with TROP2 NMR-positive versus TROP2 NMR-negative samples (treatment by biomarker status interaction P = 0.0098), indicating that TROP2 NMR may be a predictive biomarker for Dato-DXd.