Multicenter phase 2 trial of datopotamab deruxtecan in advanced non-small cell lung cancer: efficacy, safety, and biomarker analysis

Antibody-drug conjugates (ADCs) are rapidly transforming the treatment landscape of advanced non-small cell lung cancer (aNSCLC), yet validated predictive biomarkers to guide their use are lacking. The multicenter phase 2 ICARUS-LUNG01 trial in France was designed to integrate clinical outcomes with longitudinal translational analyses. The trial included 100 pretreated patients with aNSCLC who received the TROP2-directed ADC datopotamab deruxtecan (Dato-DXd). The clinical outcomes were objective response rate 26% (95% CI 17.7-35.7), clinical benefit rate 37% (27-6-47.2), median duration of response 7.0 months (5.5-11.9), median progression-free survival 3,6 months (2.9-6.1) with a longer PFS in patients with non-squamous compared to squamous histology, and median overall survival 11.9 months (7.5-14.6). Baseline and on-treatment tumor analyses suggested that resistance to Dato-DXd could be associated with a lack of TROP2 cytoplasmic staining and the early activation of DNA repair pathways. Conversely, the activation of immune-related pathways was associated with treatment response. The authors conclude that validation of these findings in phase 3 studies will be essential to define biomarkers, ultimately enabling more precise identification of patients most likely to benefit from Dato-DXd.