Phase II study of lazertinib and pemetrexed in patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer with leptomeningeal metastases: the KCSG LU 21-01, LAZARUS study

Abstract

Purpose: Lazertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has demonstrated high blood-brain barrier (BBB) penetration in preclinical studies. Similarly, pemetrexed has shown effective BBB penetration and survival benefit in EGFR-mutant non-small cell lung cancer (NSCLC) with leptomeningeal carcinomatosis (LM). This study evaluated the efficacy and safety of lazertinib plus pemetrexed in patients with EGFR-mutant NSCLC and LM. Methods: This prospective, phase II, single-arm, multi-center study enrolled patients with NSCLC and EGFR mutations and cytologically confirmed LM across six hospitals in Korea. Patients received lazertinib (240 mg daily) and pemetrexed (500 mg/m2 every three weeks). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), cerebrospinal fluid (CSF) cytology conversion rate, quality of life, and safety. Pharmacokinetics were evaluated through CSF and plasma sampling. Results: Among 36 patients treated with lazertinib plus pemetrexed, the overall response and disease control rates were 24.1 % and 96.6 %, respectively. Median PFS and OS were 9.3 and 9.9 months, respectively. CSF cytology conversion rates were 9.4 % and 11.5 % at the second and third cycles, respectively. OS and CSF/plasma concentration ratios demonstrated significant correlation in cycle 3. Adverse events occurred in 66.7 % of patients, with peripheral neuropathy (33.3 %) and cutaneous reactions (33.3 %) being the most common. Significant improvements in quality of life and neurological symptoms were noted. Conclusions: Lazertinib plus pemetrexed demonstrated promising intracranial efficacy, OS benefits, and improved quality of life, highlighting its potential as a treatment option for EGFR-mutant NSCLC and LM, particularly in previously treated patients.