Cardiac adverse event profiles of EGFR tyrosine kinase inhibitors: a disproportionality analysis using eudravigilance

Background/Introduction

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are widely used in EGFR-mutated non-small-cell lung cancer, a population with high baseline cardiovascular vulnerability. Although cardiac adverse events have been reported, evidence is largely limited to case reports or electrocardiographic outcomes, with limited focus on heart failure phenotypes. European pharmacovigilance data remain sparse.

Purpose

To assess and compare cardiac adverse event reporting patterns, with a focus on heart failure phenotypes, among EGFR-TKIs using European pharmacovigilance data.

Methods

A retrospective disproportionality analysis was conducted using aggregated adverse event reports from the EudraVigilance database. Osimertinib, gefitinib, erlotinib, afatinib, and dacomitinib were included. Cardiac adverse events were identified using MedDRA Preferred Terms. Reporting odds ratios (RORs) with 95% confidence intervals were calculated by comparing each EGFR-TKI with all other EGFR-TKIs combined. Robust signals were defined as at least five reports and a lower 95% confidence interval greater than one.

Results

Using conservative criteria (≥ 5 reports; lower 95% CI > 1), osimertinib demonstrated 13 robust cardiac signals. The strongest signal was QT prolongation (287 reports; ROR 1353, 95% CI 84–21,687). Additional QT-related signals included long QT syndrome (20; ROR 15.4, 4.6–51.8) and Torsades de Pointes (23; ROR 8.9, 3.6–21.8).

Heart failure phenotypes were prominent, including cardiac failure (367; ROR 7.1, 5.8–8.7), acute cardiac failure (29; ROR 7.4, 3.5–15.7), congestive cardiac failure (85; ROR 4.2, 2.9–6.0), chronic cardiac failure (13; ROR 6.0, 2.1–16.8), heart failure with reduced ejection fraction (24; ROR 55.4, 7.5–409.9), and left ventricular failure (11; ROR 12.7, 2.8–57.3).

Arrhythmic events included atrial fibrillation (84; ROR 2.4, 1.8–3.3) and arrhythmia (29; ROR 3.5, 2.0–6.3). Gefitinib exhibited two robust signals: QT prolongation (21; ROR 47.9, 11.2–204.4) and atrioventricular block (9; ROR 2.4, 1.1–5.4). No robust cardiac signals were identified for erlotinib or afatinib, and available dacomitinib data were too sparse for analysis.

Conclusion(s)

This disproportionality analysis using the European EudraVigilance database confirms previously reported cardiac safety concerns associated with osimertinib and extends them by demonstrating a consistent pattern of heart failure–related reporting across multiple clinically relevant phenotypes. In contrast, other EGFR-TKIs showed limited or no robust heart failure signals under the same analytical criteria, indicating heterogeneity in cardiac reporting within the drug class. These findings provide European real-world pharmacovigilance support for osimertinib-associated cardiotoxicity and underscore the importance of heart failure–focused monitoring in patients treated with higher-signal EGFR-TKIs.For image description, please refer to the figure legend and surrounding text.