Abstract 1338P
Background
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).
Methods
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.
Results
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.
Conclusions
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.
Clinical trial identification
KCT0005919.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Yuhan, Korean Cancer Study Group.
Disclosure
B. Keam: Financial Interests, Personal, Invited Speaker: Merck, Lily; Financial Interests, Personal, Advisory Board: Handok, TrialInformatics, ImmunOncia, NeoImmunetech, Beigen; Financial Interests, Personal, Coordinating PI: MSD Oncology, AstraZeneca, Ono Pharmaceutical. T.M. Kim: Financial Interests, Personal, Advisory Board: AstraZeneca, Janssen, Novartis, Takeda, Samsung Bioepis, Regeneron; Financial Interests, Personal, Research Grant: AstraZeneca-KHIDI; Non-Financial Interests, Principal Investigator: AstraZeneca/MedImmune, Boryung, Hanmi, Janssen, Boehringer Ingelheim, Novartis, Takeda, Sanofi, Roche/Genentech, Merck Sharp & Dohme Corp, Merck Serono, Regeneron, Genmab, Bayer, Rapt Therapeutics, Blueprint Medicines Corporation, Black Diamond Therapeutics, AbbVie, Amgen, BeyondBio Inc, Fore Biotherapeutics, Dizal Pharmaceutical, Incyte Corporation. S. Lee: Financial Interests, Personal, Advisory Board: AstraZeneca/MedImmune, Roche, Merck, Pfizer, Lilly, BMS/Ono, Takeda, Janssen, IMBdx; Financial Interests, Personal, Invited Speaker: AstraZeneca/MedImmune, Roche, Merck, Lilly, Amgen; Financial Interests, Institutional, Research Grant: Merck, AstraZeneca, Lunit. D. Kim: Financial Interests, Personal, Invited Speaker: Korean Cancer Association, Korean Society of Medical Oncology, Korean Association for Lung Cancer, Taiwan Lung Cancer Society, Japan Cancer Association; Financial Interests, Personal, Other, Scientific Advisor: Health Insurance Review & Assessment Service, Korea; Financial Interests, Personal, Writing Engagement, Medical writing assistance: Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Chong Keun Dang, Daiichi Sankyo, GSK, Pfizer, MSD, Merck, Novartis, Roche, Takeda, Yuhan; Financial Interests, Institutional, Local PI, Clinical Trial Funding: Hanmi, Alpha Biopharma, Amgen, AstraZeneca/Medimmune, Boehringer Ingelheim, Daiichi Sankyo, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Bridge BioTherapeutics, GSK; Financial Interests, Institutional, Coordinating PI, Clinical Trial Funding: Chong Keun Dang; Financial Interests, Institutional, Research Grant, Laboratory research funding to my institution: InnoN; Non-Financial Interests, Advisory Role: Amgen, BMS / Ono Pharmaceuticals, Daiichi Sankyo, Janssen, GSK, Pfizer, AstraZeneca, SK Biopharm, Takeda, Yuhan; Non-Financial Interests, Member of Board of Directors: Korean Cancer Association, Korean Society of Medical Oncology, Korean Association for Lung Cancer, Asian Thoracic Oncology Research Group; Other, Travel support for advisory board meeting attendance: Amgen, Daiichi Sankyo; Other, Clinical trial research funding to my institution: Asian Thoracic Oncology Research Group. M. Ahn: Financial Interests, Personal, Advisory Board: AstraZeneca, Takeda, MSD, Yuhan, Amgen, Alpha Pharmaceutical, Janssen, BMS, Roche, Daiichi Sankyo, Merck, Boronoi. All other authors have declared no conflicts of interest.
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