Epidermal growth factor receptor (EGFR) atypical mutations in non-small-cell lung cancer (NSCLC): 'Where the streets have no name'.

Atypical Epidermal Growth Factor Receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) account for approximately 12% of all EGFR alterations. In contrast to classical mutations (exon 19 deletions and exon 21 L858R) and exon 20 insertions, for which therapeutic strategies have significantly evolved, relatively little progress has been achieved in the management of patients with atypical EGFR-mutated NSCLC. To date, afatinib remains the only approved agent specifically indicated for tumors harboring selected atypical variants-namely S768I, L861Q, and G719X-based on regulatory approvals by the FDA and EMA in 2018. For the wide spectrum of these and other atypical mutations, treatment recommendations remain undefined, and clinical decision-making is often extrapolated from strategies validated in classical EGFR-mutant disease or relies on conventional chemotherapy. In this context, we conducted a comprehensive review of all available clinical studies addressing patients with atypical EGFR mutations, encompassing therapeutic outcomes from first-generation TKIs through to newer therapeutical approaches. The objective of this review is to delineate the clinical characteristics of this heterogeneous population and to clarify the therapeutic activity and limitations of current treatment approaches. Specifically, we will examine the efficacy of first-, second-, and third-generation EGFR TKIs in this subgroup, discuss the mechanisms underlying resistance, and highlight the clinical implications of the recently proposed structure-function-based classification of EGFR mutations. Finally, we will review emerging evidence from ongoing clinical trials of novel therapeutic agents, including bispecific antibodies and next-generation inhibitors, which may offer new opportunities for patients with atypical EGFR-mutant NSCLC.