Stephen Liu, Chief of Division of Hematology and Oncology at Georgetown Lombardi Comprehensive Cancer Center, shared on X:
“Normalized membrane ratio (NMR) of TROP2 by quantitative continuous scoring (QCS) as a predictor for Dato-DXd (TROP2 ADC) in NSCLC in Nature Medicine.
Computational pathology approach using digital pathology to assess internalization, not just expression.
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Datopotamab deruxtecan (Dato-DXd) is an effective therapy for advanced non-small-cell lung cancer (NSCLC), yet traditional pathologist visual scoring of TROP2 expression fails to predict which patients will respond. To solve this, researchers developed Quantitative Continuous Scoring (QCS), a digital pathology tool that measures TROP2 levels inside individual tumor cells by separating membrane and cytoplasmic compartments.
Analyzing tumor samples from the phase 1 TROPION-PanTumor01 trial identified the TROP2 Normalized Membrane Ratio (NMR) as the strongest predictive metric. Lower NMR values, which reflect higher or comparable TROP2 levels inside the cytoplasm relative to the cell surface, were strongly linked to better responses and longer progression-free survival (PFS). Lab experiments on lung cancer cells confirmed why: a lower NMR directly corresponded with more efficient internalization of the antibody, a critical step required for Dato-DXd to deliver its cytotoxic payload inside the tumor cell.
Researchers validated this cutoff in the phase 3 TROPION-Lung01 trial among patients wit NSCLC without actionable genomic alterations, defining a tumor as TROP2 NMR-positive if at least 75% of cells had an NMR of 0.56 or lower.
Within this group, TROP2 NMR-positive patients treated with Dato-DXd achieved significantly better outcomes than NMR-negative patients, including:
- longer median PFS (7.2 versus 4.0 months),
- longer overall survival (17.0 versus 10.8 months),
- higher response rates (36.8% versus 22.5%).
Conversely, TROP2 NMR status showed no predictive value in standard chemotherapy or immunotherapy cohorts (docetaxel, NEPTUNE, and POSEIDON), proving that the biomarker specifically predicts Dato-DXd efficacy rather than general prognosis.
Safety profiles remained consistent across biomarker groups, and the companion diagnostic device integrating this algorithm has received US FDA Breakthrough Device Designation, supporting its ongoing prospective validation in phase 3 clinical trials.”
Title: Normalized membrane ratio of TROP2 as a predictor of clinical outcomes with datopotamab deruxtecan in non-small-cell lung cancer
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.
You can also read: Dato-DXd in Lung Cancer: International Experts Define New Strategies to Manage ADC Toxicities
