2028 - Comparative Efficacy of Whole-Brain Radiotherapy Combined with EGFR-TKI vs. EGFR-TKI Monotherapy in EGFR-Mutant NSCLC with Leptomeningeal Metastasis

Purpose/Objective(s): This study aimed to evaluate whether combining whole-brain radiotherapy (WBRT) with third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improves survival outcomes compared with EGFR-TKI monotherapy in EGFR-mutant non-small cell lung cancer (NSCLC) patients with leptomeningeal metastasis (LM).

Materials/Methods: A total of 70 patients with EGFR-mutant NSCLC and leptomeningeal metastasis (confirmed by cerebrospinal fluid cytology) were retrospectively recruited between January 2017 and June 2025. All patients received third-generation EGFR-TKI as first-line therapy and were stratified into two groups based on the administration of concurrent WBRT: the combination group (n=32) and the EGFR-TKI monotherapy group (n=38). The primary endpoint was overall survival (OS) rate, while the secondary endpoints included intracranial progression-free survival (iPFS) and progression-free survival (PFS). Survival analysis was performed using the Kaplan-Meier method followed by the log-rank test, and multivariate prognostic analysis was conducted using the Cox proportional hazards regression model.

Results: The median follow-up period was 20.8 months (IQR: 12.3–29.5 months). The 1-year and 2-year OS rates were 60.6% and 32.8% in the EGFR-TKI monotherapy group, and 66.1% and 45.8% in the combination group, respectively (HR=0.762, 95%CI: 0.401–1.450, P=0.408). Compared with the monotherapy group, the combination group exhibited a 9.59-month prolongation in median iPFS (16.69 months vs. 7.10 months), though this difference did not reach statistical significance (HR=0.701, 95%CI: 0.384–1.280, P=0.248). The combination group showed a 10.55-month prolongation in median PFS compared with the monotherapy group (16.69 vs. 6.14 months), though the difference was not statistically significant (HR=0.592, 95%CI: 0.328–1.071, P=0.083). Subgroup analysis indicated that patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 (P=0.035) and those harboring the L858R mutation (P=0.047) obtained more significant PFS benefits from the combined regimen. Multivariate Cox regression analysis demonstrated that combination group (P=0.047) and extracranial lesion control (P=0.002) were independent prognostic factors for PFS. No statistically significant prognostic factors associated with OS were identified.

Conclusion: For patients with EGFR-mutant NSCLC and leptomeningeal metastasis, WBRT combined with third-generation EGFR-TKI can significantly prolong PFS, particularly for L858R-positive patients and good performance status (ECOG 0–1). While OS differences were not statistically significant, the observed survival trends and subgroup benefits warrant further prospective validation to optimize therapeutic strategies.