Researchers have uncovered that TROP2 expression as measured by quantitative continuous scoring may be a predictor of clinical outcomes in patients with advanced or metastatic non–small cell lung cancer (NSCLC) treated with the TROP2-directed antibody-drug conjugate datopotamab deruxtecan, according to recent findings presented by Garassino et al at the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer (Abstract PL02.11).
Background
Datopotamab deruxtecan is designed with a plasma-stable linker that necessitates active internalization for effective payload release.
Traditional methods of assessing TROP2 expression through visual scoring of immunohistochemical assays have not been found to be predictive of responses to TROP2-directed antibody-drug conjugates in patients with NSCLC. Quantitative continuous scoring is a computational pathology approach. The researchers hypothesized that a more precise, quantitative measurement of TROP2 expression both on the cell membrane and in the cytoplasm could better predict therapeutic responses to datopotamab deruxtecan in this patient population.
Study Methods and Results
In the study, the researchers used digitalized TROP2 immunohistochemical-stained whole-slide images from patients with NSCLC to develop the quantitative continuous scoring model. The deep learning algorithm, trained using pathologists’ annotations, was capable of identifying tumor areas and cellular compartments (membrane and cytoplasm) within the whole-slide images. The quantitative continuous scoring model calculated TROP2 expression in the membrane relative to the cytoplasm of tumor cells, producing a normalized membrane ratio. Tumors were then classified as TROP2 quantitative continuous scoring–normalized membrane ratio–positive if most of the tumor cells exhibited a normalized membrane ratio below a predetermined value.
The quantitative continuous scoring–normalized membrane ratio was optimized for progression-free survival in the biomarker-evaluable subgroup of patients with nonsquamous NSCLC without actionable genomic alterations.
The phase III TROPION-Lung01 trial compared datopotamab deruxtecan with docetaxel in second-line or later advanced or metastatic NSCLC. Clinical outcomes were assessed across all biomarker-evaluable patients.
Among the 604 patients who participated in the trial, 352 of them were biomarker-evaluable—with 221 of them in the nonsquamous NSCLC without actionable genomic alterations subgroup. The baseline characteristics were consistent between randomly assigned and biomarker-evaluable populations, showing similar overall progression-free survival outcomes. Among the evaluable patients, 63% of them were classified as TROP2 quantitative continuous scoring–normalized membrane ratio–positive. The highest prevalence of TROP2 quantitative continuous scoring–normalized membrane-ratio positivity was observed in the nonsquamous NSCLC with actionable genomic alterations subgroup (75%), followed by the nonsquamous NSCLC without actionable genomic alterations (63%) and squamous (43%) subgroups.
Additionally, the researchers discovered that the objective response rate was higher and median progression-free survival was longer with datopotamab deruxtecan compared with docetaxel in the TROP2 quantitative continuous scoring–normalized membrane ratio–positive subgroups. The rates of overall and grade 3 or higher adverse events were similar regardless of TROP2 quantitative continuous scoring–normalized membrane ratio status.
Conclusions
“It is important that research identifies how to optimize treatment options for patients with NSCLC. This exploratory analysis is going in this direction and reveals that [datopotamab deruxtecan] exhibits robust efficacy in patients with TROP2 [quantitative continuous scoring–normalized membrane ratio–positive] advanced [NSCLC], in the nonsquamous, [without actionable genomic alterations] subgroup,” underscored lead study author Marina Chiara Garassino, MD, of the University of Chicago.
The quantitative continuous scoring–measured TROP2 normalized membrane ratio showed the potential to be used as a predictive biomarker for datopotamab deruxtecan response. Further studies are currently underway to validate this biomarker in the first-line advanced or metastatic NSCLC setting.
Disclosure: For full disclosures of the study authors, visit cattendee.abstractsonline.com.
