Abstract
Lung cancer in never-smokers is increasingly recognized as a distinct clinical and biological entity, often enriched for actionable oncogenic alterations and characterized by molecular profiles that differ from tobacco-associated disease. However, therapeutic evidence for this growing patient population has frequently been extrapolated from trials in which smokers predominate, potentially limiting treatment optimization and biomarker-driven decision-making. In this review, we map and critically appraise clinical trials registered in ClinicalTrials.gov that explicitly target never-smokers with lung cancer, focusing on therapeutic strategies, molecular stratification approaches, trial design features, and temporal trends. We discuss how eligibility definitions, histological and genomic enrichment, and endpoints have been handled across studies, and we highlight persistent gaps in dedicated trial activity, particularly in prospective biomarker-guided designs and contemporary platform strategies. Finally, we propose priorities for future trials to better reflect never-smoker lung cancer biology, improve external validity, and accelerate evidence generation for personalized therapeutic approaches in this population.