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

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.