Real‐World Evidence That Non‐Smokers With High PD ‐ L1 Non‐Squamous NSCLC Have Poorer Outcomes With Immune Checkpoint Inhibitors

ABSTRACT Background Immune checkpoint inhibitors (ICIs) improve outcomes in non‐small cell lung cancer (NSCLC) with high PD‐L1 expression, but biomarkers beyond PD‐L1 are limited. Smoking‐related immune activation may enhance ICI efficacy, yet evidence in non‐squamous NSCLC, especially among non‐smokers, is sparse. Methods We retrospectively analyzed 74 patients with Stage IIIB – IV non‐squamous NSCLC , PD ‐ L1 ≥ 50%, and no EGFR / ALK / ROS1 mutations, treated at a tertiary center in Taiwan (2017–2023). Patients were stratified by smoking status. Treatment responses, progression‐free survival ( PFS ), and overall survival ( OS ) were evaluated using RECIST v1.1, Kaplan–Meier, and Cox regression. Results Among 74 patients, 54 (72.9%) were smokers and 20 (27.1%) were non‐smokers. Compared with non‐smokers, smokers had a higher partial response rate (66.7% vs. 25.0%, p  = 0.001), longer median PFS (12.8 vs. 1.4 months, p  = 0.001), and improved OS (47.1 vs. 10.0 months, p  = 0.011). In the non‐smoker subgroup, chemoimmunotherapy significantly prolonged PFS compared with ICI monotherapy (not reached vs. 1.4 months, p  = 0.034). In multivariate analysis, smoking independently predicted better PFS (HR = 0.234, p  = 0.001) and OS (HR = 0.229, p  = 0.011). Conclusion Non‐smokers with PD‐L1‐high non‐squamous NSCLC showed significantly poorer outcomes with ICI monotherapy. Chemoimmunotherapy may be preferred in this group. Smoking history may provide a simple and clinically relevant stratification factor when considering ICI‐based treatment.