Pharmacovigilance Analysis of Cardiac Toxicities Associated With Targeted Therapies for Metastatic NSCLC

Introduction: Targeted therapies have transformed treatment of driver-mutated metastatic NSCLC. We compared cardiovascular adverse events between and within targeted therapy classes. Methods: We used WHO pharmacovigilance database VigiBase to compare odds of heart failure, conduction disease, QT prolongation, supraventricular tachycardia (SVT), and ventricular arrhythmias between inhibitors of EGFR (erlotinib, gefitinib, afatinib, osimertinib), BRAF (dabrafenib), MEK (trametinib), and ALK and ROS1 (alectinib, brigatinib, ceritinib, crizotinib, lorlatinib). Results: Of 98,765 adverse reactions reported with NSCLC targeted therapies, 1783 (1.8%) were arrhythmias and 1146 (1.2%) were heart failure. ALK and ROS1 inhibitors were associated with increased odds of conduction disease (reporting OR [ROR] = 12.95, 99% confidence interval [CI]: 10.14-16.55) and QT prolongation (ROR = 5.16, 99% CI: 3.92-6.81) relative to BRAF and EGFR inhibitors. Among ALK and ROS1 inhibitors, crizotinib had highest odds of conduction disease (ROR = 1.75, 99% CI: 1.30-2.36) and QT prolongation (ROR = 1.91, 99% CI: 1.22-3.00). Dabrafenib (ROR = 2.24, 99% CI: 1.86-2.70) and trametinib (ROR = 2.44, 99% CI: 2.03-2.92) had higher odds of heart failure than other targeted therapies. Osimertinib was strongly associated with QT prolongation (ROR = 6.13, 99% CI: 4.43-8.48), heart failure (ROR = 3.64, 99% CI: 2.94- 4.50), and SVT (ROR = 1.90, 99% CI: 1.26-2.86) relative to other targeted therapies. Conclusions: ALK and ROS1 inhibitors are associated with higher odds of conduction disease and QT prolongation than other targeted therapies. Osimertinib is strongly associated with QT prolongation, SVT, and heart failure relative to other EGFR inhibitors and targeted therapies. Monitoring for heart failure and arrhythmias should be considered with NSCLC targeted therapies, especially osimertinib.