Cardiac Safety Assessment of Lazertinib: Findings From Patients With EGFR Mutation-Positive Advanced NSCLC and Preclinical Studies

Seong Bok Jang; Kyeong Bae Kim; Sujin Sim; Byoung Chul Cho; Myung-Ju Ahn; Ji-Youn Han; Sang-We Kim; Ki Hyeong Lee; Eun Kyung Cho; Nahor Haddish-Berhane; Jaydeep Mehta; Se-Woong Oh

doi:10.1016/j.jtocrr.2021.100224

Cardiac Safety Assessment of Lazertinib: Findings From Patients With EGFR Mutation-Positive Advanced NSCLC and Preclinical Studies

JTO Clin Res Rep. 2021 Sep 8;2(10):100224. doi: 10.1016/j.jtocrr.2021.100224. eCollection 2021 Oct.

Authors

Affiliations

¹ Clinical Development Department, Yuhan Corporation, Seoul, Republic of Korea.
² Yuhan R&D Institute, Yuhan Corporation, Yongin, Republic of Korea.
³ Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
⁴ Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
⁵ Center for Lung Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.
⁶ Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
⁷ Division of Medical Oncology, Department of Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Republic of Korea.
⁸ Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea.
⁹ Janssen R&D, Spring House, Pennsylvania.

Abstract

Introduction: Lazertinib is a potent, irreversible, brain-penetrant, mutant-selective, and wild-type-sparing third-generation EGFR tyrosine kinase inhibitor (TKI), creating a wide therapeutic index. Cardiovascular adverse events (AEs), including QT prolongation, decreased left ventricular ejection fraction (LVEF), and heart failure, have emerged as potential AEs with certain EGFR TKI therapies.

Methods: Cardiac safety of lazertinib was evaluated in TKI-tolerant adults with EGFR mutation-positive locally advanced or metastatic NSCLC receiving lazertinib (20-320 mg/d). QT intervals corrected with Fridericia's formula (QTcF) prolongation, time-matched concentration-QTcF relationship, change of LVEF, and cardiac failure-associated AEs were evaluated. The clinical findings were supplemented by the following three preclinical studies: an in vitro hERG inhibition assay, an ex vivo isolated perfused rabbit heart study, and an in vivo telemetry-instrumented beagle dog study.

Results: Preclinical evaluation revealed little to no physiological effect on the basis of electrocardiogram, electrophysiological, proarrhythmic, and hemodynamic parameters. Clinical evaluation of 181 patients revealed no clinically relevant QTcF prolongation by centralized electrocardiogram in any patient and at any dose level. The predicted magnitude of QTcF value increase at maximum steady-state plasma concentration for the therapeutic dose of lazertinib (240 mg/d) was 2.2 msec (upper bound of the two-sided 90% confidence interval: 3.6 msec). No patient had clinically relevant LVEF decrease (i.e., minimum postbaseline LVEF value of <50% and a maximum decrease in LVEF value from baseline of ≥10 percentage points). Cardiac failure-associated AE occurred in one patient (grade 2 decreased LVEF) and resolved without any dose modifications.

Conclusions: Our first-in-human study, together with preclinical data, indicates that lazertinib is not associated with increased cardiac risk.

Keywords: Cardiac toxicity; Lazertinib; Non–small cell lung cancer; Tyrosine kinase inhibitor.