Cancer Drug Development in Never-Smoker Lung Cancer: Targeted and Immune-Based Therapeutic Strategies

Lung cancer in individuals who have never smoked (LCINS) represents a clinically and biologically distinct subset of non–small cell lung cancer, driven predominantly by oncogenic alterations rather than tobacco-related mutagenesis. This review aims to summarize current and emerging targeted and immune-based therapeutic strategies in LCINS individuals. These patients present a molecular profile that differs substantially from tobacco-associated disease and has direct consequences for treatment selection. Evidence published over the past five years has clarified how these molecular features shape treatment response and resistance in this setting. Particular attention is given to tumors with alterations in epidermal growth factor receptor, anaplastic lymphoma kinase, c-ros oncogene 1, rearranged during transfection, Mesenchymal–Epithelial Transition (MET) exon 14 skipping mutation, human epidermal growth factor receptor 2, valine-to-glutamic acid substitution at codon 600 of the BRAF gene (BRAF V600E), and neurotrophic tyrosine receptor kinase, which together comprise the dominant driver landscape in never-smoker lung cancer. Although third-generation tyrosine kinase inhibitors have markedly improved response rates in several of these subgroups, long-term disease control is frequently compromised by acquired resistance, and heterogeneous drug exposure, particularly in the central nervous system. By contrast, immune checkpoint inhibitors have yielded limited benefit, in keeping with the low mutational burden and generally low baseline immune activation observed in most LCINS tumors. As a result, alternative approaches such as antibody–drug conjugates, bispecific antibodies, and adoptive cellular therapies are being evaluated to address gaps left by existing treatments.