David Planchard, Nathalie Cozic, Maria Fernanda Mosele, Noémie Corcos, Loïc Le Bescond, Yoann Pradat, Maria Rosa Ghigna, Ghada Nachabeh, Alexia Alfaro, Cyril Catelain, Bastien Job, Fathia Mami‐Chouaib, Séverine Badel, Stéphanie Corgnac, Françoise Farace, Marianne Oulhen, Patricia Kannouche, Diep Thi Ngoc Tran, Nathalie Droin, Marie Wislez, Christos Chouaid, Hubert Curcio, Sophie Cousin, Celine Mascaux, Jacques Cadranel, Margaux Geier, Rasha Cheikh-Hussin, Pierre Guyader, Nicholas Signolle, Karine Godefroy, Hugues Talbot, Maria Vakalopoulou, Stergios Christodoulidis, Elsa Bernard, Yves Koudou, Valerie Camara, Abdelhafidh Belarkemi, Alexis Klein, Jean Philippe Morretton, Philip East, Rachel Chiaverelli, Ricardo Zwirtes, Stefan Michiels, Fabrice Barlesi, Fabrice André, Guillaume Montagnac, Barbara Pistilli
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.