Summary
A retrospective analysis found that a computational measure of TROP2’s location within tumour cells was associated with longer outcomes from datopotamab deruxtecan in a defined group of patients with non-small-cell lung cancer. Prospective studies are needed to establish its use in treatment selection.
A retrospective analysis published in Nature Medicine reports that the subcellular distribution of TROP2 in tumour cells may help identify patients with a form of non-small-cell lung cancer (NSCLC) more likely to benefit from datopotamab deruxtecan (Dato-DXd). In a biomarker-evaluable subset of a phase 3 trial, a computational score was associated with longer progression-free survival on Dato-DXd, while outcomes on docetaxel were similar across score groups.
Measuring where TROP2 is found in tumour cells
Dato-DXd is an antibody–drug conjugate: an antibody directed at the tumour-associated protein TROP2 is linked to a topoisomerase I inhibitor payload. The treatment is designed to bind TROP2 and deliver the drug payload to cells. The study’s authors note that internalisation of the antibody–target complex is part of the proposed mechanism.
The researchers used quantitative continuous scoring (QCS), a computational pathology method applied to digitised slides stained for TROP2. Its models identify tumour regions, segment individual tumour cells into subcellular compartments, and measure TROP2 staining in the cell membrane and cytoplasm. The resulting normalized membrane ratio (NMR) expresses membrane staining relative to membrane plus cytoplasmic staining. A lower ratio indicates relatively more TROP2 in the cytoplasm.
The team first identified the measure in samples from 115 patients with advanced NSCLC in the phase 1 TROPION-PanTumor01 study. They then selected and assessed a cut-off in a retrospective analysis of TROPION-Lung01, a phase 3 trial comparing Dato-DXd with docetaxel. The primary intended-use group was patients with nonsquamous NSCLC without actionable genomic alterations: 221 biomarker-evaluable patients, of whom 108 received Dato-DXd and 113 docetaxel.
A sample was classed as TROP2 NMR-positive when its 75th-quantile NMR was 0.56 or lower. In practical terms, at least 75% of the tumour cells assessed had an NMR at or below that threshold.
A treatment-specific association in the trial samples
Among Dato-DXd-treated patients in the intended-use group, median progression-free survival was 7.2 months for those with NMR-positive samples and 4.0 months for those with NMR-negative samples (hazard ratio 0.40, 95% confidence interval 0.25–0.64). In the docetaxel group, median progression-free survival was 4.1 and 4.4 months, respectively (hazard ratio 0.94, 95% confidence interval 0.59–1.49). The treatment-by-biomarker interaction had a P value of 0.0098, supporting an association specific to Dato-DXd rather than a general difference in outlook between the biomarker groups.
In the Dato-DXd group, the objective response rate was also higher in NMR-positive than NMR-negative patients (36.8% versus 22.5%). Median overall survival was 17.0 versus 10.8 months (hazard ratio 0.45, 95% confidence interval 0.29–0.74); the interaction between treatment and biomarker status for overall survival had a P value of 0.014.
Laboratory experiments provide a possible biological explanation. Across NSCLC cell lines, lower NMR was associated with greater datopotamab internalisation, and cell lines with lower NMR were more likely to respond to Dato-DXd in a laboratory cytotoxicity assay. These results support a link between TROP2’s cellular location and drug delivery, but they are preclinical evidence, not a direct measurement of drug internalisation in patients.
The findings make TROP2 NMR a candidate biomarker for refining Dato-DXd treatment selection in this particular NSCLC group. The clinical analyses were retrospective and exploratory, so prospective studies are needed to test biomarker-guided treatment. The measure was developed using Dato-DXd datasets; whether it applies to other TROP2-directed drugs or other tumour types remains unsettled.