Osimertinib-Induced Cardiotoxicity: A Retrospective Review of the FDA Adverse Events Reporting System (FAERS)

Abstract

Objectives: The goal of this study was to compare the risk of cardiotoxicity with osimertinib versus all other drugs and versus epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) (erlotinib, afatinib, and gefitinib) in the U.S. Food and Drug Administration Adverse Events Reporting System (FAERS), a pharmacovigilance database.

Background: Osimertinib has been shown to improve outcomes in T790M-positive non-small cell lung cancer patients who progress on EGFR-TKI therapy and in the frontline setting in EGFR mutated non-small cell lung cancer. In pivotal trials, osimertinib was associated with higher rates of cardiotoxicity compared with the control arm.

Methods: FAERS was queried for "Cardiac failure," "Electrocardiogram QT-prolonged," "Atrial Fibrillation (AF)," "Myocardial Infarction (MI)," and "Pericardial Effusion" secondary to "Osimertinib," "Erlotinib," "Afatinib," "Gefitinib," and all other drugs from 2016 to 2018. Disproportionality signal analysis was performed by calculating the reporting odds ratio (ROR) with its 95% confidence interval (CI). The ROR was considered significant when the lower limit of the 95% CI was >1.0.

Results: The ROR (95% CI) for cardiac failure, atrial fibrillation (AF), QT prolongation, myocardial infarction, and pericardial effusion due to osimertinib versus all other drugs in FAERS was 5.4 (4.2 to 7.1), 4.0 (2.8 to 5.8), 11.2 (7.9 to 15.8), 1.6 (0.9 to 2.6), and 8.2 (4.8 to 14), respectively. The ROR (95% CI) for cardiac failure, AF, QT prolongation, myocardial infarction, and pericardial effusion in comparing osimertinib versus other EGFR-TKIs was 2.2 (1.5 to 3.2), 2.1 (1.3 to 3.5), 6.6 (3.4 to 12.8), 1.2 (0.6 to 2.3), and 1.6 (0.8 to 3.3).

Conclusions: The RORs for cardiac failure, AF, and QT prolongation were higher due to osimertinib compared with other TKIs. Electrocardiographic monitoring for QT prolongation and monitoring for signs and symptoms of heart failure should be considered in patients taking osimertinib.

Keywords: AF, atrial fibrillation; CI, confidence interval; EGFR mutation; EGFR, epidermal growth factor receptor; FAERS, U.S. Food and Drug Administration Adverse Events Reporting System; FDA, U.S. Food and Drug Administration; LVEF, left ventricular ejection fraction; NSCLC, non–small cell lung cancer; QT prolongation; ROR, reporting odds ratio; TKI, tyrosine kinase inhibitor; cardiotoxicity; non–small cell lung cancer; osimertinib.

Graphical abstract

Figure 1

Disproportionality Signal Analysis Calculated by Using the ROR The reporting odds ratio (ROR) was calculated for osimertinib versus all drugs and osimertinib versus other tyrosine kinase inhibitors (TKIs). Compared with all other drugs in the U.S. Food and Drug Administration Adverse Events Reporting System database, osimertinib was associated with increased cardiac failure, atrial fibrillation, QT prolongation, and pericardial effusion. RORs for osimertinib versus other TKIs were elevated for cardiac failure, atrial fibrillation, and QT prolongation. CI = confidence interval.

Central Illustration

Cardiotoxicity Associated With Osimertinib Osimertinib has improved outcomes for epidermal growth factor receptor (EGFR)-mutated lung cancer. In pivotal studies, osimertinib has been linked to an increased risk of QT prolongation and cardiac failure. We performed a retrospective study of the U.S. Food and Drug Administration Adverse Events Reporting System database and found that osimertinib increased the reporting odds ratio (ROR) for QT prolongation, cardiac failure, and atrial fibrillation compared with standard EGFR–tyrosine kinase inhibitors (TKIs) (erlotinib, gefitinib, or afatinib). CI = confidence interval.