1338P Cerebrospinal fluid pharmacokinetic study of lazertinib and pemetrexed in patients with EGFR-mutant non-small cell lung cancer with leptomeningeal metastases: KCSG21-01 LAZARUS trial

Lazertinib, an irreversible third-generation EGFR tyrosine kinase inhibitor (TKI), has shown high blood-brain barrier (BBB) penetration in preclinical studies. In this study, we present cerebrospinal fluid (CSF) pharmacokinetic (PK) study from a phase II trial investigating lazertinib and pemetrexed in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) patients with leptomeningeal metastases (LMs). This is a single-arm, phase II study that enrolled patients with cytologically confirmed LM and EGFR-mutation. Patients were administered lazertinib at a daily dose of 240mg along with pemetrexed at a dose of 500mg/m2 every 3weeks. The primary endpoint was post-LM overall survival (OS). Secondary endpoint included PK studies. To evaluate the through concentration of lazertinib, plasma and CSF samples were collected serially before the start of the 2nd and 3rd cycles. The concentration ratio of CSF to free plasma (FP) was analyzed. CSF and plasma PK samples were available from 32 patients. All the patients had previously failed treatment with 1st or 2nd generation EGFR TKIs. At the second cycle, the median CSF concentration was 1.05 ng/ml (range, 0.13-17.8 ng/ml), and the median plasma concentration was 213.2 ng/ml (range, 59.0-934.1 ng/ml). There was a correlation between the concentration of lazertinib in CSF and FP (r=0.38; P=0.032), with a mean CSF/FP concentration of 0.77 and a median CSF/FP concentration ratio of 0.5 (range: 0.09-6.0). At the third cycle, the median CSF concentration was 1.04 ng/ml (range, 0.07-139.0ng/ml), and the median plasma concentration was 212.3 ng/ml (range, 48.3-803.7 ng/ml). The mean CSF/FP concentration was 0.71, and the median CSF/FP concentration ratio was 0.45 (range: 0.09-4.28) at the third cycle. Due to short follow-up time, there was no significant difference in CSF/FP concentration ratio and survival. These results suggest that lazertinib had a promising CSF/FP concentration ratio in patients with EGFR-mutant NSCLC with LMs. Given its high potency for penetrating the BBB, lazertinib may be a therapeutic option for LMs from a pharmacokinetic perspective.