Integrating clinical outcomes with molecular simulations to guide the selection of non-classical EGFR-TKIs: A comprehensive analysis and development of treatment strategies.

Non-classical EGFR mutations in non-small cell lung cancer (NSCLC) are uncommon and heterogeneous, and the optimal EGFR-tyrosine kinase inhibitor (TKI) strategy remains uncertain. This retrospective study analyzed 31 patients with advanced/metastatic, recurrent or post-resection NSCLC harboring non-classical EGFR mutations who were treated at the Chinese Academy of Medical Sciences Cancer Hospital (Beijing, China) between 2013 and 2020, with follow-up updated to June 30, 2024. EGFR mutation status was obtained from routine clinical molecular pathology reports based on clinically validated targeted next-generation sequencing and/or amplification refractory mutation system PCR. Molecular docking and Prime Molecular Mechanics Generalized Born Surface Area (MM-GBSA) calculations were used to evaluate drug-mutant EGFR binding. Clinical outcomes varied by mutation subtype and EGFR-TKI regimen; relatively favorable progression-free survival (PFS) was observed with dacomitinib in L861Q and with afatinib- or dacomitinib-based treatment in selected S768I compound mutations. Exploratory Spearman analysis suggested that lower docking scores and more negative MM-GBSA ∆G_bind values were associated with longer PFS. These findings provide hypothesis-generating evidence that molecular simulation may help inform personalized EGFR-TKI selection for non-classical EGFR mutations, although validation in larger, consecutive and prospective multicenter cohorts is required.