Differential Treatment Effects by Smoking Status for NSCLC Therapies (2010-2023): A Meta-Analysis

NSCLC, largely linked to smoking, remains a global health challenge with poor prognosis despite therapeutic advances. Understanding how smoking status affects treatment response is essential for optimizing therapies, yet comprehensive analyses are lacking.

This study evaluates outcome differences by smoking status, assesses smoking rates in trials leading to Food and Drug Administration approval for NSCLC, and estimates overall outcome disparities between smoking status by treatment type. Trials supporting drug approvals for NSCLC in adults between January 2010 and December 2023 were identified from Food and Drug Administration archives. Non-comparative studies, biosimilar studies, and those without a time-to-event end point were excluded. Outcome data based on smoking status subgroups were collected, focusing on progression-free survival (PFS), overall survival (OS), and disease-free or event-free survival for pooled analyses. A trial-level pairwise comparison and random effects meta-analysis assessed outcome differences by smoking status (current/former versus never), with p less than 0.05 for significance.

The final cohort comprised 33 trials including 19,660 patients, 74% of whom were smokers, compared with an estimated 87% from U.S. NSCLC population data. No effect modification from smoking status was found across all treatment types. However, differences emerged evaluating specific treatment subtypes: small molecule therapies favored nonsmokers in PFS (n = 11, hazard ratio 1.22, 95% confidence interval 1.03-1.45, p = 0.025), whereas immunotherapy favored smokers in OS (n = 10, hazard ratio 0.76, 95% confidence interval 0.57-1.00, p = 0.05).

Our analysis supports smokers' improved OS from immunotherapy in NSCLC, contrasting with nonsmokers' improved PFS with small molecule therapies, possibly due to differences in tumor mutations and immune microenvironment induced by smoking.