Impact of Smoking on Immune Checkpoint Inhibitor Treatment Outcomes in Patients with Non-Squamous Non-Small Cell Lung Cancer with High PD-L1 Expression: A Real-World Observational Study

Background Smoking history is increasingly recognized as a potential prognostic indicator for immune checkpoint inhibitor (ICI) efficacy in metastatic non-small-cell lung cancer (NSCLC). However, the findings of most studies have not reached statistical significance. Furthermore, no studies have evaluated the impact of smoking specifically on non-squamous cell NSCLC with high programmed cell death-ligand 1 (PD-L1) expression (≥ 50%). Materials and Methods Patients with stage IIIB to IV non-squamous cell NSCLC without epidermal growth factor receptor/anaplastic lymphoma kinase mutations and ≥ 50% PD-L1 expression were retrospectively recruited from August 2017 to December 2022. The enrolled patients were categorized into two groups based on their smoking status: smokers or nonsmokers. Results The final analysis included 53 patients, comprising 36 smokers and 17 nonsmokers. The partial response rates to ICI treatment were significantly higher in smokers (75.0%) than in nonsmokers (17.6%; p  < 0.001). The median progression-free survival (PFS) was not reached in smokers, which is longer than the 1.4 months in nonsmokers ( p  < 0.001). Smokers also had a longer overall survival (OS) than nonsmokers (not reached vs. 8.1 months, p  = 0.006). Multivariate regression analysis demonstrated that smoking independently predicted better PFS ( p  < 0.001) and OS ( p  = 0.003) in patients with non-squamous NSCLC with high PD-L1 expression receiving ICI therapy. Conclusions Our findings underscore the significant role of smoking in treatment outcomes among patients with non-squamous NSCLC with high PD-L1 expression undergoing ICI therapies. Smoking serves as an independent predictor of improved PFS and OS.