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

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.

Lazertinib versus Gefitinib as First-Line Treatment for EGFR-mutated Locally Advanced or Metastatic NSCLC: LASER301 Korean Subset

“…ILD was reported in two patients in each treatment group. Consistent with safety assessments in previous studies [ 17 , 18 , 30 ], which showed that lazertinib had no clinically relevant effects on QT interval, no severe QTc prolongation was observed in patients receiving lazertinib. Off-target inhibition of human epidermal growth factor receptor 2 (HER2) has been suggested as a possible underlying mechanism for EGFR TKI–associated cardiotoxicity.…”

Successful treatment of a patient with advanced lung adenocarcinoma (EGFR-T790M and C797S cis) with lazertinib: A case report and literature review

“…This study confirmed that lazertinib is effective in treating patients with non-small cell lung cancer and is more efficient in patients with T790M mutations. In a study exploring the cardiac safety of lazertinib, a total of 181 patients with EGFR mutation-positive advanced NSCLC treated with lazertinib were enrolled, and the result showed that lazertinib did not cause serious cardiotoxicity ( 16 ). The above findings suggest that lazertinib is effective in the treatment of NSCLC patients with the T790M mutation without serious toxic effects.…”

Lazertinib: on the Way to Its Throne

“…Consistent with this background, lazertinib has been found to exert minimal effects on cardiac function in both preclinical and clinical studies. 46 No patients experienced clinically significant QT prolongation or decreased left ventricular ejection fraction. Considering that lazertinib demonstrated comparable anti-tumor efficacy to osimertinib, it may be considered a relatively safer option in terms of cardiotoxicity.…”

“…Meanwhile, researchers have shown that lazertinib selectivity for HER2 over EGFR was 275-fold, compared to 6.7-fold for osimertinib, which implies that lazertinib has lower cardiotoxicity. 46 …”