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

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.

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Journal
Nature Medicine
Published
2026-11-11
DOI
https://doi.org/10.1038/s41591-026-04716-9
Primary Topic
Lung Cancer Treatments and Mutations
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article
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article

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

Elvire Pons‐Tostivint, Min Hee Hong, Hadassah Sade, Markus Schick et al.
Nature Medicine
Lung Cancer Treatments and Mutations
article

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

Elvire Pons‐Tostivint, Min Hee Hong, Hadassah Sade, Markus Schick, Rachel A. Chiaverelli, Matthew S. Sung, Chuyu Deng, Myung‐Ju Ahn, Maurice Pérol, Danielle K. Carroll, Melissa Lynne Johnson, Robin Cornelissen, Luis G Paz-Ares, Jacob M. Sands, Rebecca Suk Heist, Ansh Kapil, Aaron Elliott Lisberg, Ricardo F. Zwirtes, Nicolas M Girard, Marina Chiara Garassino, James A. Harper, Marlon Cezar Rebelatto, Isamu Okamoto, Alexander I. Spira, Toshio Shimizu
article en

Abstract

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.

Nature Medicine
AstraZeneca (United Kingdom) (GB), Universidad Complutense de Madrid (ES), University of California, Los Angeles (US), Severance Hospital (KR), Samsung Medical Center (KR), Centre Hospitalier Universitaire de Nantes (FR), University of Chicago (US), Massachusetts General Hospital (US), Kyushu University Hospital (JP), Sarah Cannon (US), Hospital Universitario 12 De Octubre (ES), Centre Léon Bérard (FR), Dana-Farber Cancer Institute (US), Virginia Cancer Specialists (US), Centre de Recherche en Cancérologie de Lyon (FR), Erasmus MC Cancer Institute (NL), AstraZeneca (United States) (US), AstraZeneca (Germany) (DE), Daiichi Sankyo (United States) (US), UCLA Jonsson Comprehensive Cancer Center (US), Yonsei Cancer Hospital (KR), Kansai Medical University Hospital (JP), Institut Curie (FR), Sungkyunkwan University (KR), Nantes Université (FR)
Lung Cancer Treatments and Mutations
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