Efficacy and Safety of Intrathecal Pemetrexed Combined With Dexamethasone for Treating Tyrosine Kinase Inhibitor-Failed Leptomeningeal Metastases From EGFR-Mutant NSCLC—a Prospective, Open-Label, Single-Arm Phase 1/2 Clinical Trial (Unique Identifier: ChiCTR1800016615)

Introduction: We aimed to evaluate the efficacy and safety of intrathecal pemetrexed (IP) for treating EGFR-mutant leptomeningeal metastases (LMs) from EGFR-mutant NSCLC. Methods: Patients with EGFR-mutant NSCLC with LM who had failed tyrosine kinase inhibitors were recruited. The dose of IP was escalated from 15 mg to 80 mg using an accelerated titration design in a phase 1 study. The recommended dose (RD) determined in phase 1 was used in the phase 2 study. The primary end point was treatment efficacy measured as the clinical response rate. Overall survival and adverse events (AEs) were evaluated as secondary end points. Results: The RD observed in the phase 1 study was 50 mg pemetrexed. A total of 30 cases of LM-NSCLC were enrolled in the phase 2 study, including 14 males and 16 females. Four patients did not survive for 4 weeks and could not be evaluated for efficacy. The clinical response rate was 84.6% (22 of 26). The median overall survival of all patients was 9.0 months (n = 30, 95% confidence interval: 6.6-11.4 mo). Most AEs were mild, and the most frequent AE of any grade was myelosuppression (n = 9, 30%), which returned to normal after symptomatic treatment. Conclusions: This study revealed that 50 mg pemetrexed is the RD which results in few AEs and a good response rate. IP is an effective treatment for patients with EGFRmutant NSCLC-LM who had failed on tyrosine kinase inhibitor. (c) 2021 Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer.