Elucidating the Role of EGFR^L858R in Brain Metastasis Among Patients With Advanced NSCLC Undergoing TKI Therapy

Introduction: Brain metastases (BM) are a prevalent and severe complication of non-small cell lung cancer (NSCLC) that significantly affects quality of life. Although several predictive factors for BM have been identified, the influence of EGFR mutation subtypes remains under-explored. Methods: We retrospectively examined patients with advanced NSCLC and EGFR mutations treated with first-line EGFR-TKIs. Our primary endpoint was intracranial progression-free survival (icPFS), defined as the time from the initiation of upfront treatment to the development of BM, the progression of existing brain lesions, or death. Additionally, we evaluated intracranial objective response rates (icORR) and disease control rates (icDCR) for patients with baseline BM. Subgroup and multivariate analyses were performed to adjust for relevant factors. Results: Of the 324 patients analyzed, 40.7% had baseline BM. Overall, the EGFR^L858R mutation was linked to a significantly shorter median icPFS of 13.9 months, compared to 23.4 months for those with EGFR^Δ19 (HR 1.60, P < .0001) For patients without baseline BM, icPFS was 14.3 months for EGFR^L858R versus 26.2 months (HR 1.65, P = .007), while with baseline BM, it was 13.9 versus 18.5 months (HR 1.59, P = .035); icORR was lower for EGFR^L858R (31.2% vs. 58.8%). Multivariate analysis showed EGFR^L858R was independently linked to worse icPFS in patients with (HR 1.634, P = .031) and without BM (HR 1.606, P = .008), and lower icORR (OR 3.511, P = .007) and icDCR (OR 4.443, P = .006). Conclusions: EGFR^L858R mutation significantly impacts BM development, intracranial progression, and response, emphasizing its critical role in therapy selection.