TROP2 and Dato-DXd in EGFRm Non–Small Cell Lung Cancer: Evolving Biomarkers and Treatment Strategies

This video segment discusses the emerging role of TROP2-targeted antibody-drug conjugates (ADCs), specifically datopotamab deruxtecan (dato-DXd), in treating EGFR-mutated non–small cell lung cancer and the challenges of precision selection without established biomarkers. Like HER3-DXd, this represents another precision therapy being used in a less precise manner due to the absence of reliable predictive biomarkers, contrasting with the established HER2 ADC paradigm, where HER2 expression directly guides treatment decisions.

The discussion highlights ongoing efforts to develop more sophisticated biomarker strategies for TROP2 ADCs, including digital pathology approaches. While basic TROP2 protein expression hasn’t proven useful as a predictive biomarker, researchers have developed more nuanced scoring systems, such as the SHCs score, using digital pathology-based approaches. These methods aim to refine pathology-based biomarkers that could help identify patients most likely to benefit from treatment. However, these approaches remain in early stages and require prospective validation, with practical implementation questions around feasibility, real-time availability, and tissue requirements for routine pathology labs.

Currently, datopotamab deruxtecan is positioned as an alternative to traditional chemotherapy options like docetaxel in later-line settings for patients with EGFR-mutated lung cancer. Given docetaxel’s modest response rates of 10% to 15% and significant adverse effects including hair loss, dato-DXd offers a potentially more effective and better-tolerated option after patients have progressed through EGFR TKIs and platinum-based chemotherapy. The treatment positioning may evolve depending on whether amivantamab continues to be used primarily in frontline settings or moves to later-line therapy, which would influence the overall sequencing strategy for these ADCs in the treatment paradigm.