Impact of EGFR Mutation Subtypes and TKI Generations on Clinical Outcomes in Lung Adenocarcinoma Patients with Brain Metastases Treated with Gamma Knife Radiosurgery

Background Brain metastases are a common and severe complication in patients with lung adenocarcinoma (ADC) harboring epidermal growth factor receptor (EGFR) mutations. Gamma Knife Radiosurgery (GKRS) is a standard treatment for brain metastases, and its efficacy may be influenced by the type of EGFR mutation and the generation of tyrosine kinase inhibitors (TKIs) used. This retrospective study evaluated the impact of EGFR mutation subtypes (exon 19 deletion vs. exon 21 L858R) and TKI generations on clinical outcomes in patients with lung ADC treated with GKRS. Methods A total of 55 patients and 136 brain metastases were analyzed from January 2017 to December 2023. Tumor response was assessed based on local failure and distant brain failure, defined as tumor progression at the treated site and new brain metastases outside the GKRS-treated regions, respectively. The Kaplan-Meier method and univariate and multivariate analyses using Cox proportional hazard regression models were used to identify prognostic factors for local failure, and distant brain failure. Results The study found that second- and third-generation TKIs, such as afatinib and osimertinib, provided significantly better local control compared to first-generation TKIs (hazard ratio [HR] = 0.12, p = 0.017). Furthermore, tumors with exon 19 deletion demonstrated improved distant brain control compared to those with exon 21 L858R substitution (HR = 2.18, p = 0.048). These findings suggest that mutation type and TKI generation are independent prognostic factors for clinical outcomes following GKRS. Conclusion The superior efficacy of second- and third-generation TKIs is likely attributed to their enhanced blood-brain barrier (BBB) permeability, resulting in better drug delivery to brain lesions. Additionally, the more favorable response in exon 19 deletion tumors may be due to their higher sensitivity to TKIs. Understanding these heterogeneous treatment responses can guide personalized treatment strategies for patients with brain metastases from lung ADCs, potentially improving progression-free and overall survival outcomes.