Real-World incidence and risk factors for osimertinib-associated cardiotoxicity

Introduction

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) inhibitor, has improved survival in metastatic lung cancer, but its real-world cardiotoxicity and associated risk factors remain nuclear.

Aim

To assess the real-world incidence, predictors, reversibility and clinical outcomes of osimertinib-related cardiotoxicity.

Methods

We conducted a retrospective single-center study including patients who started osimertinib from 2020 to 2024. Cardiotoxicity was defined as a >10% reduction in left ventricular ejection fraction (LVEF), new-onset atrial fibrillation/flutter, or any clinically relevant cardiovascular (CV) event. Predictors and outcomes were analyzed using multivariable logistic regression, Cox regression and Kaplan–Meier survival estimates.

Results

A total of 40 patients with lung adenocarcinoma were included (mean age 66 ± 3 years; 35% male). Most had metastatic disease (88%) and 50% received osimertinib as first-line therapy. Baseline mean LVEF was 56 ± 2%, with 2 patients (5%) showing LVEF <50%. During a median follow-up of 31 (IQR 19-37) months, 6 patients (15%) developed cardiotoxicity: 3 (8%) had atrial fibrillation/flutter, 2 (5%) had LVEF decline, and 2 (5%) experienced other CV events. QT prolongation occurred in 6 patients (15%) without associated arrhythmias. Four patients (10%) required treatment discontinuation, with therapy resumed in two.

Cardiotoxicity was significantly associated with baseline LVEF <50% (p=0.019), older age (75 ± 4 vs. 65 ± 2 years, p=0.04) and higher baseline NT-proBNP [531 pg/mL (IQR 476–675) vs. 185 pg/mL (IQR 53–412), p=0.01]. Both patients with LVEF decline discontinued osimertinib and recovered; one resumed therapy. LVEF decline was linked to baseline LVEF <50% (p=0.001) and not to treatment line or prior chemotherapy. New-onset atrial fibrillation/flutter was not associated with left atrial volume or obesity.

CV hospitalization was associated with cardiotoxicity (50% vs. 9%, p=0.03), lower hemoglobin (9.9 ± 0.5 vs. 11 ± 0.3 g/dL, p=0.02) and trended toward higher follow-up NT-proBNP [3769 pg/mL (IQR 989–7195) vs. 200 pg/mL (IQR 119–566), p=0.07]. In survival analysis, cardiotoxicity tended to increase the risk of CV hospitalization (HR 4.4; IC95% 1–22; p=0.07). All-cause mortality was not associated with cardiotoxicity, LVEF decline or CV hospitalization, but was asssociated to lower follow-up hemoglobin (10 ± 0.4 vs. 12 ± 0.4 g/dL p=0.01)

Conclusions

Osimertinib-related cardiotoxicity occurred in 15% of patients and trended toward higher CV hospitalization, without affecting mortality, which was mainly driven by disease progression. Given its long-term use, vigilant monitoring is essential, especially in older patients, those with prior heart failure or elevated baseline NT-proBNP.Baseline CharacteristicsFor image description, please refer to the figure legend and surrounding text.Cardiovascular hospitalizationFor image description, please refer to the figure legend and surrounding text.