# The Landscape of Clinical Trials in Never-Smoker Non-Small-Cell Lung Cancer: Registered Evidence and Persistent Gaps

## TL;DR

This paper reviews clinical trials focused on lung cancer in never-smokers, highlighting treatment differences and gaps in research.

## Contribution

The study provides a comprehensive analysis of clinical trial landscapes and identifies specific gaps in research for never-smoker lung cancer patients.

## Key findings

- Many trials for never-smoker lung cancer lack molecular stratification and biomarker-guided designs.
- Therapeutic evidence for never-smokers is often extrapolated from trials primarily involving smokers.
- There is a need for more contemporary platform trials tailored to the unique biology of never-smoker lung cancer.

## Abstract

An increasing number of people are developing lung cancer despite never having smoked. These tumours often behave differently and may carry specific molecular changes that can potentially guide treatment. Yet, much treatment evidence has historically been derived from trials that mainly include smokers, which may not fully represent never-smokers. In this review, we examine registered clinical trials that were specifically designed for never-smokers with lung cancer. We summarize what types of treatments were tested, how patients were selected, whether molecular testing was used to guide enrolment, and how trial activity has evolved over time. We also identify key gaps and propose priorities for future studies so that never-smokers with lung cancer can benefit from evidence generated in trials tailored to their condition. Addressing these gaps is essential to ensure that never-smoker lung cancer patients benefit from evidence truly reflective of their disease biology.

Lung cancer in never-smokers is increasingly recognized as a distinct clinical and biological entity, often enriched for actionable oncogenic alterations and characterized by molecular profiles that differ from tobacco-associated disease. However, therapeutic evidence for this growing patient population has frequently been extrapolated from trials in which smokers predominate, potentially limiting treatment optimization and biomarker-driven decision-making. In this review, we map and critically appraise clinical trials registered in ClinicalTrials.gov that explicitly target never-smokers with lung cancer, focusing on therapeutic strategies, molecular stratification approaches, trial design features, and temporal trends. We discuss how eligibility definitions, histological and genomic enrichment, and endpoints have been handled across studies, and we highlight persistent gaps in dedicated trial activity, particularly in prospective biomarker-guided designs and contemporary platform strategies. Finally, we propose priorities for future trials to better reflect never-smoker lung cancer biology, improve external validity, and accelerate evidence generation for personalized therapeutic approaches in this population.