Furmonertinib-based triplet therapy improves survival in EGFR-mutant NSCLC with leptomeningeal metastases: a large-scale multicenter retrospective study (FURMO-LM)

BACKGROUND: Leptomeningeal metastases (LM) in epidermal growth factor receptor mutant (EGFRm) non-small-cell lung cancer (NSCLC) represent a major therapeutic challenge. Despite the improved central nervous system penetration of third-generation EGFR tyrosine kinase inhibitors (TKIs), key uncertainties persist regarding the efficacy of combination regimens with antiangiogenic therapy and intrathecal chemotherapy and optimal dosing because of the limited evidence. PATIENTS AND METHODS: In this large-scale, multicenter, retrospective study, 618 patients with EGFRm NSCLC and LM who were treated with furmonertinib-based regimens between March 2021 and December 2024 were enrolled. The primary endpoint was overall survival (OS). Secondary endpoints included OS from LM diagnosis (LMOS), time to treatment failure (TTF), clinical response rate (CRR), LM-specific objective response rate (ORR-LM), and treatment-related adverse events (TRAEs). RESULTS: The median OS was 14.19 months [95% confidence interval (CI) 13.04-16.79], median LMOS was 17.05 months (95% CI 14.81-19.22), and median TTF was 11.23 months (95% CI 10.23-12.13). Triple therapy (furmonertinib plus antiangiogenic therapy and chemotherapy) was associated with longer median OS than mono or dual regimens (17.91 versus 10.31-14.19 months, P < 0.001). Notably, among patients with prior third-generation EGFR-TKI exposure, triplet therapy achieved a median OS of 17.18 months. In patients with poor performance status (Eastern Cooperative Oncology Group score 3-4), triplet therapy showed markedly improved OS compared with other regimens (17.31 versus 9.02-12.81 months, P = 0.003). Regarding furmonertinib dosing, 80 mg/day and 160 mg/day were associated with longer OS than 240 mg/day (16.79/14.68 versus 11.39 months, P = 0.002). The CRR was 66.7%, and the ORR-LM was 40.6%. TRAEs occurred in 59.2% of patients, with grade 3-4 events reported in 7.9%. CONCLUSIONS: This large real-world study suggests that furmonertinib-based therapy, particularly the triplet regimen with antiangiogenic agent and chemotherapy, is associated with meaningful clinical outcomes over mono or dual therapy in patients with EGFRm NSCLC and LM, including those with prior third-generation TKI resistance or poor performance status.