Multiple combination therapy based on intrathecal pemetrexed in non-small cell lung cancer patients with refractory leptomeningeal metastasis.

Abstract

Leptomeningeal metastasis (LM) is a fatal complication, and its incidence is increasing in non-small cell lung cancer (NSCLC). Refractory LM (rLM) has become problematic due to the lack of uniform definition and standardized treatment guidelines. In this study, we assessed the efficacy and safety of multiple therapy based on intrathecal pemetrexed (IP) in patients with rLM in NSCLC. From March 2019 to June 2020, patients with cytologically confirmed rLM who received IP and systemic salvage therapy were retrospectively analyzed. Our objectives were to assess progression-free survival (PFS), overall survival (OS), clinical response, and safety. Clinical response was assessed by an investigator according to the Response Assessment in Neuro-Oncology (RANO) proposal criteria. We performed next generation sequencing (NGS) of cerebrospinal fluid (CSF) to explore the gene profile of rLM. A total of 23 patients were enrolled, and the genetic status of the primary tissue was 16 epidermal growth factor receptor (EGFR) mutations (69.6%), two anaplastic lymphoma kinase (ALK) fusions (8.7%), one ROS proto-oncogene 1 (ROS1) fusion (4.3%), one Erb-B2 receptor tyrosine kinase 2 (ERBB2) mutation (4.3%), and three wild-type (13.0%). On the basis of IP therapy, 19 patients were rechallenged with tyrosine-kinase inhibitors (TKIs), 10 patients were treated with systemic chemotherapy, 10 patients were treated with antivascular therapy, one patient was treated with immunotherapy, and one patient was treated with whole-brain radiotherapy (WBRT). Thirteen patients received two or more of the aforementioned combination treatment modes. The median PFS (mPFS) was 9.6 months [95% confidence interval (CI): 3.4-15.8 months]. OS was not mature at the final follow-up. The clinical assessment was: response in eight patients (34.8%), stable in 11 patients (47.8%), worse in two patients (8.7%), and non-evaluable in two patients (8.7%). Adverse events (AEs) related to any component occurred in 14 patients (60.9%). The driver mutation status was highly consistent between the CSF and primary tumor samples (14/14), but we detected EGFR mutations in the CSF of two patients whose primary tumor samples tested wild-type. IP-based multimodal therapy has significant efficacy and a controlled safety profile in patients with rLM in NCSLC.