Effectiveness of high-dose third-generation EGFR-tyrosine kinase inhibitors in treating EGFR-mutated non-small cell lung cancer patients with leptomeningeal metastasis

Background: Leptomeningeal metastasis (LM) is associated with an extremely poor prognosis in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). The third-generation EGFR-tyrosine kinase inhibitors (TKIs), currently the preferred drug of choice, have significantly improved treatment outcomes in these patients. However, the optimal dose of third-generation EGFR-TKIs for clinical use remains undetermined in NSCLC patients with LM. Methods: We retrospectively analyzed the clinical characteristics and treatment outcomes of 105 patients with EGFR-mutated NSCLC and cytologically confirmed LM who had received third-generation EGFR-TKI treatment after LM diagnosis. Patients were stratified into high- and standard-dose groups based on the treatment dose of third-generation EGFR-TKI. Subsequent treatments for LM were collected, particularly the efficacy of different doses of third-generation EGFR-targeted drugs. Results: The median follow-up period was 28.7 months (range 0.6-40.2) at the cut-off date of August 27, 2023. The 105 included patients who received third-generation EGFR-TKI treatment had a clinical response rate (CRR) of 54.3 % (57/105), and the median overall survival (OS) from LM diagnosis was 12.3 months (95 % confidence interval [CI] = 10.0-15.0). Among them, 46 (43.8 %) patients received a high-dose regimen, and the remaining 59 (56.2 %) patients were treated with standard-dose drugs. Patients treated with high-dose third-generation EGFR-TKIs showed a higher CRR and longer OS than those treated with standard-dose therapy (65.2 % vs. 45.8 %, p = 0.047; 15.0 vs. 10.2 months, p = 0.014). Importantly, high-dose third-generation EGFR-TKI showed superior OS than standard-dose treatment in all subgroups (prior first-/second-generation EGFR-TKI resistance group, 19.5 vs. 9.8 months, p = 0.047; third-generation EGFR-TKI resistance group, 10.0 vs. 4.3 months, p = 0.045; EGFR-TKI naive group, not reach vs. 15.6 months, p = 0.031). Multivariate analysis revealed that highdose third-generation EGFR-TKIs, intrathecal chemotherapy, previous TKI treatment history, and Karnofsky Performance Status score were independent predictors of OS (all p < 0.05). Conclusions: High-dose third-generation EGFR-TKIs are effective treatments for NSCLC patients with EGFR mutations and LM, regardless of previous EGFR-TKI exposure.