Clinical usability of an explainable AI decision support tool and evaluation of multimodal models in NSCLC

Despite a decade in, immunotherapy (IO) treatment selection in non-small cell lung cancer (NSCLC) remains largely guided by subgroup analyses and imperfect programmed death ligand 1 (PD-L1) and clinical scores. To our knowledge, I³LUNG ( NCT05537922 ) is currently the largest international, real-world, multimodal, artificial intelligence (AI)-based study, enrolling 2,396 patients. We integrated real-world clinical and blood (CB) data, computed tomography (CT) images, digital pathology (DP), and genomics into machine learning early fusion (MLEF) and deep learning intermediate fusion (DLIF) models. Machine learning (ML) and deep learning (DL) CB-only models achieved consistent performance across outcomes with area under the curve (AUC) up to 0.77 in the test (TEST) set. Performance drop in external validation (EXVAL) likely reflects population differences (AUC range: 0.55-0.72). AI models significantly surpassed PD-L1, Eastern Cooperative Oncology Group performance status (ECOG PS), neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH) and Lung Immune Prognostic Index (LIPI) score in the independent TEST set. The clinical usability study showed that lung expert and nonexpert physicians improved their prediction with the explainable AI (XAI) ML CB-only based tool. Although multimodal integration with MLEF (CB+CT+DP) was associated with higher performance, its incremental benefit remains uncertain, not translated in TEST and EXVAL. The I³LUNG project is a pioneering framework showing the clinical usefulness of AI tools. A prospective validation of the decision support system (both CB and multimodal) is currently undergoing in more than 2,000 patients.