Abstract Background Up to 15% of non-small-cell lung cancer (NSCLC) cases occur in never-smokers, and a smaller subset occurs in light smokers. Data from the Middle East are limited. This study examined the clinical characteristics and survival outcomes of never- and light-smokers with stage IV NSCLC. Methods A retrospective review of patients diagnosed between 2015 and 2023 was performed. Never-smokers were defined as having smoked 100 cigarettes in their lifetime, and light smokers were defined as having smoked 5 pack-years. Clinicopathological data and molecular results (EGFR, ALK, ROS1, KRAS, and PD-L1) were collected. Survival was analyzed using Kaplan-Meier and Cox regression methods, with significance set at p 0.05. Results Of the 190 patients (median age 54 years), 159 (83.7%) were never smokers and 31 (16.3%) were light smokers. Never-smokers were predominantly female (69.8%), whereas light smokers were predominantly male (58.1%). Brain metastases occurred in 55.8% of patients. EGFR mutations were more frequent in light smokers (80.6%) than in never-smokers (58.5%). PD-L1 expression ≥50% was detected in 30% of both groups. One-year overall survival (OS) was 61% for never-smokers and 54.8% for light-smokers. EGFR-negative tumors showed superior 3- and 5-year OS compared with EGFR-positive tumors in both smoking strata. Younger patients (≤46 years) and those with ECOG 0 status demonstrated the best long-term survival, whereas patients ≥60 years had markedly poor outcomes. Treatment with EGFR, ALK, or ROS1 tyrosine kinase inhibitors was more effective than that with chemotherapy. However, resistance mutations (T790M in 30.4% of patients) were common. No variables reached statistical significance in the univariate Cox models. Conclusion Never and light smokers with stage IV NSCLC display distinct molecular and clinical profiles. The high prevalence of EGFR mutations underscores the necessity of routine comprehensive molecular testing. Despite the availability of targeted therapy, EGFR-positive tumors show earlier progression, highlighting the urgent need for next-generation inhibitors and resistance-modifying strategies. These findings provide a foundation for future prospective multicenter studies to inform precision oncology in non-traditional risk groups. This abstract is funded by: None
Kharabsheh et al. (Fri,) studied this question.