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

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.