Evaluating datopotamab deruxtecan (Dato-DXd) as a novel treatment option for EGFR-mutated non-small cell lung cancer.

Datopotamab deruxtecan (Dato-DXd) is a TROP2-directed antibody-drug conjugate (ADC) that has received accelerated approval in the US for adults with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) after progression on EGFR-directed therapy and platinum chemotherapy. In pooled analyses from TROPION-Lung01 and TROPION-Lung05, Dato-DXd achieved an objective response rate of ~45% and a median duration of response of 6.5 months, which compares favorably with historical outcomes with docetaxel. Dato-DXd is being evaluated in combination with osimertinib in the first-line and post-osimertinib settings, following encouraging activity in the phase II ORCHARD platform trial evaluating therapeutic strategies for EGFR-TKI-resistant disease. Importantly, Dato-DXd demonstrates a favorable safety profile and has lower rates of grade ≥3 adverse events and less hematologic toxicity than docetaxel. Adverse events of special interest include mucositis, interstitial lung disease, and ocular surface events. While these toxicities are generally manageable, they require prophylaxis, monitoring, and early intervention. Current research aims to elucidate the mechanisms underlying these toxicities and to identify modifiable risk factors to further improve tolerability. The biological mechanisms contributing to the differential efficacy of Dato-DXd are also under investigation and may further inform its clinical role.