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.
| Original language | English |
|---|---|
| Article number | 100224 |
| Journal | JTO Clinical and Research Reports |
| Volume | 2 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 2021 Oct |
Bibliographical note
Funding Information:Disclosure: Jang is an employee of Yuhan Corporation. Kim is an employee of Yuhan Corporation and has a patent pending for salt composition and a patent for combination use. Sim is an employee of Yuhan Corporation and holds stocks in Yuhan Corporation. Cho reports receiving research funding from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan Corporation, Ono, Dizal Pharma, Merck Sharp & Dohme, AbbVie, Medpacto, GIInnovation, Eli Lilly, Blueprint Medicines, and Interpark Bio Convergence Corp.; receiving royalties from Champions Oncology; serving as a consultant for Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Ono, Yuhan Corporation, Pfizer, Eli Lilly, Janssen, Takeda, Merck Sharp & Dohme, Medpacto, and Blueprint Medicines; serving on the scientific advisory boards of KANAPH Therapeutic Inc., Bridgebio Therapeutics, Cyrus Therapeutics, Guardant Health, and Oscotec Inc.; serving as a member of the board of directors of Interpark Bio Convergence Corp.; holding stocks in TheraCanVac Inc., Gencurix Inc., Bridgebio Therapeutics, KANAPH Therapeutic Inc., Cyrus Therapeutics, and Interpark Bio Convergence Corp.; and being the founder of DAAN Biotherapeutics. Ahn reports receiving research funding from AstraZeneca; serving as a consultant for AstraZeneca, Merck Sharp & Dohme, Novartis, Takeda, Eli Lilly, Ono, Roche, Yuhan Corporation, and Alpha Pharmaceuticals; receiving honoraria from AstraZeneca, Merck Sharp & Dohme, Novartis, Takeda, Eli Lilly, Ono, Roche, Yuhan Corporation, Amgen, Merck, Beigen, and Alpha Pharmaceuticals; and serving on the scientific advisory boards of AstraZeneca, Merck Sharp & Dohme, Novartis, Takeda, Eli Lilly, Ono, Roche, Yuhan Corporation, Amgen, Merck, Beigen, and Alpha Pharmaceuticals. Han reports receiving research grants from Roche, Pfizer, Ono, and Takeda; receiving honoraria from Roche, AstraZeneca, and Takeda; and serving on the scientific advisory boards of AstraZeneca, Eli Lilly, Merck Sharp & Dohme, Bristol-Myers Squibb, Pfizer, and Medpacto. Lee reports receiving honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Pfizer, and Eli Lilly. Haddish-Berhane is an employee of Janssen and holds stocks in Janssen. Mehta is an employee of Janssen and holds stocks in Janssen. Oh is an employee of Yuhan Corporation; holds stocks in Yuhan Corporation; and has a patent pending for salt composition and a patent for combination use. The remaining authors declare no conflict of interest.
Funding Information:
Medical writing and editorial support were funded by Yuhan Corporation and provided by Tech Observer Asia Pacific Pte. Ltd.
Publisher Copyright:
© 2021 The Authors
All Science Journal Classification (ASJC) codes
- Oncology
- Pulmonary and Respiratory Medicine