Efficacy, safety, and biomarker analysis of datopotamab deruxtecan in advanced non-small cell lung cancer: ICARUS-LUNG01 phase 2 study.

Antibody-drug conjugates (ADCs) are rapidly transforming the treatment landscape of advanced non-small cell lung cancer (NSCLC), yet validated predictive biomarkers to guide their use remain lacking. ICARUS-LUNG01 is a prospective, phase II study designed to integrate clinical outcomes with longitudinal translational analyses. In this multicenter trial, 100 pretreated patients with advanced NSCLC received the TROP2-directed ADC datopotamab deruxtecan (Dato-DXd). The study reported an objective response rate (ORR) of 26.0%, with a median progression-free survival (PFS) of 3.6 months, and a greater benefit observed in non-squamous tumors. 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. Validation of these findings in phase III studies will be essential to define biomarkers, ultimately enabling more precise identification of patients most likely to benefit from Dato-DXd.