Intrathecal pemetrexed improves survival outcomes in previously treated EGFR-mutant advanced non-small-cell lung cancer with leptomeningeal metastases

Objective: This study assessed the impact of intrathecal pemetrexed (IP) in managing leptomeningeal metastases (LM) in previously treated patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC).

Methods: We analyzed the clinical and survival outcomes of 50 patients with LM who received 50 mg IP after disease progression with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment between September 2021 and September 2023 at the Hunan Cancer Hospital. Treatment response was evaluated based on improvement in neurological symptoms/signs and Karnofsky Performance Status (KPS) scores. We also evaluated the overall survival (OS), intracranial progression-free survival (I-PFS), and extracranial progression-free survival (E-PFS). Next generation sequencing (NGS) was employed to explore the underlying mechanisms of LM after EGFR-TKIs resistance.

Results: IP treatment was associated with a 64 % clinical response rate, median I-PFS of 5.3 months (95 % confidence intervals [CI], 1.4-9.2), E-PFS of 8.0 months (95 % CI, 2.2-13.8), and OS of 12.0 months (95 % CI, 9.6-14.4). Compared with non-responders, responders to IP demonstrated significantly prolonged I-PFS (11.2 months vs. 1.0 month; hazard ratio [HR]: 0.15, 95 % CI: 0.06-0.39), E-PFS (11.2 months vs. 3.0 months; HR: 0.24, 95 % CI: 0.10-0.57), and OS (15.5 months vs. 3.8 months; HR: 0.22, 95 % CI: 0.08-0.58) (all P < 0.001). Adverse events(AEs) primarily consisted of myelosuppression (54 %) and hepatic damage (24 %), but were manageable and did not result in any deaths. EGFR mutations were consistent between cerebrospinal fluid (CSF) and primary tumors in 100 % of cases. CSF also exhibited genetic variations such as EGFR mutations/amplifications and alterations in TP53, CDKN2A, MET, and CDK6.

Conclusion: IP represents a potentially viable treatment option for managing LM in patients with EGFR-TKI-resistant EGFR-mutant advanced NSCLC. Clinical responses as measured by the improvement of neurological symptoms/signs and KPS scores were associated with favorable survival outcomes.