Targeting EGFR ‐Mutant Non‐Small Cell Lung Cancer in Asia: An Update on Monotherapy and Combination Therapy With EGFR Inhibitors

ABSTRACT EGFR ‐mutant lung cancer represents a major subtype of non‐small cell lung cancer in Asia, with particularly high prevalence in never‐smokers, women, and patients with adenocarcinoma histology. Although this clinicopathologic enrichment has been recognized for more than two decades, the mechanisms underlying the excess frequency of EGFR ‐mutant disease in Asian populations remain only partially understood. Accumulating evidence suggests a multifactorial basis involving host genetic susceptibility and diversity, endogenous mutational processes and exogenous exposures such as ambient particulate matter. In particular, recent genomic and experimental studies support a tumour‐promotion framework in which inflammatory microenvironmental cues may facilitate the outgrowth of pre‐existing oncogenic clones, while mutational signatures provide genomic footprints of these processes. In parallel, the treatment landscape for EGFR ‐mutant non‐small cell lung cancer has evolved substantially with successive generations of EGFR tyrosine kinase inhibitors (EGFR‐TKIs), leading to marked improvements in survival. However, acquired resistance remains inevitable in most patients with advanced disease and is driven by both genetic and non‐genetic mechanisms, including secondary EGFR alterations, bypass pathway activation, TP53 ‐associated genomic instability, adaptive mutagenesis, and drug‐tolerant persister states. These insights have provided a strong rationale for combination strategies beyond EGFR‐TKI monotherapy. In this review, we summarize current understanding of the epidemiology and biological basis of EGFR ‐mutant lung cancer in Asia and discuss the preclinical rationale and emerging clinical evidence supporting combination approaches with chemotherapy, anti‐angiogenic agents, and EGFR/MET‐directed therapies.