Normalized membrane ratio of TROP2 as a predictor of clinical outcomes with datopotamab deruxtecan in non-small-cell lung cancer
Year: 2026
Type: article
Abstract: 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.
Source: Nature Medicine
Authors: Marina C. Garassino, Myung-Ju Ahn, Markus Schick, Ansh Kapil, Luis Paz-Ares, Aaron Lisberg, Melissa L. Johnson, Maurice Pérol, Toshio Shimizu, Rebecca Heist, Alexander Spira, Isamu Okamoto, Nicolas Girard, Robin Cornelissen, Elvire Pons-Tostivint, Min Hee Hong, Ricardo Zwirtes, Rachel Chiaverelli, Marlon Rebelatto, Matthew Sung, Chuyu Deng, James Harper, Danielle Carroll, Hadassah Sade, Jacob Sands
Institutions: University of Chicago, Samsung Medical Center, Sungkyunkwan University, AstraZeneca (Germany), Universidad Complutense de Madrid, Hospital Universitario 12 De Octubre, University of California, Los Angeles, UCLA Jonsson Comprehensive Cancer Center, Sarah Cannon, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Kansai Medical University Hospital, Massachusetts General Hospital, Virginia Cancer Specialists, Kyushu University Hospital, Institut Curie, Erasmus MC Cancer Institute, Centre Hospitalier Universitaire de Nantes, Nantes Université, Severance Hospital, Yonsei Cancer Hospital, Daiichi Sankyo (United States), AstraZeneca (United States), AstraZeneca (United Kingdom), Dana-Farber Cancer Institute
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
OpenAlex ID: W7225784672