Article ; Online: Cardiac Safety Assessment of Lazertinib: Findings From Patients With
JTO clinical and research reports
2021 Volume 2, Issue 10, Page(s) 100224
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 ... ...
| 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 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. |
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| Language | English |
| Publishing date | 2021-09-08 |
| Publishing country | United States |
| Document type | Journal Article |
| ISSN | 2666-3643 |
| ISSN (online) | 2666-3643 |
| DOI | 10.1016/j.jtocrr.2021.100224 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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