Abstract 12757: Osimertinib-Associated Cardiotoxicity: Insights Into Echocardiographic Changes and Patients at Increased Risk

Introduction: Osimertinib is a third-generation epidermal growth factor (EGFR) tyrosine kinase inhibitor used in the treatment of EGFR-mutant non-small cell lung cancer (NSCLC). While osimertinib has known cardiotoxicity risks, there is a paucity of detailed transthoracic echocardiographic (TTE) changes and known predictors.

Hypothesis: Osimertinib is associated with TTE changes other than reduced EF in patients with NSCLC; further, those with pre-existing cardiac risk factors may be at increased risk of cardiotoxicity.

Methods: Single-center retrospective analysis of patients with NSCLC with available TTEs after starting osimertinib between 2007-2022. Cardiac event (any grade ≥2 cardiac common terminology criteria for adverse events [CTCAE]) cumulative incidence was estimated and Fine and Gray regressions performed (adjusting for non-cardiac death as a competing risk).

Results: In total, 85 patients were included (mean age was 68 years, 67% female). Median interval between osimertinib initiation and first follow-up TTE was 17.6 months. After a median follow-up of 35 months, 17 patients developed grade ≥2 CTCAE (2-year cumulative incidence, 19.2%; 95% confidence interval [CI]: 11%-29%). These CTCAEs include QTc prolongation (n = 10), EF decline of ≤50% or ≥10% drop from baseline (n = 5), new valvular regurgitation/stenosis on imaging (n = 5), and supraventricular arrhythmia (n = 3). A pre-treatment TTE was available for 38 patients prior to osimertinib initiation. Comparing post- vs pre-osimertinib TTEs, there was significant LVEF decline (58 ± 11% vs 61 ± 8%), increased diastolic dysfunction (40% vs 32%, mitral regurgitation (49% vs 24%), and tricuspid regurgitation (45% vs 24%), all p <0.01. On multivariable analysis, preexisting arrhythmias (hazard ratio [HR] 3.90; 95% CI 1.11-1.13; p = 0.034) and BMI (HR 1.07, 95% CI 1.00-1.14; p = 0.04) were associated with an increased risk of cardiac events.

Conclusions: Osimertinib was associated with a nearly 20% 2-year cumulative incidence of cardiac events and multiple echocardiographic changes. BMI is a potential modifiable risk factor to mitigate Osimertinib-associated cardiac events. These findings highlight the need for close surveillance in these higher cardiac-risk patients with NSCLC.