Cardiovascular toxicity across epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in <i>EGFR</i> -mutated non–small cell lung cancer: A population-based retrospective cohort study.

12155 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the therapeutic backbone for EGFR -mutated non-small cell lung cancer (NSCLC) and often requiring prolonged exposure. Adverse cardiovascular events limit a long-term treatment and remain a major concern for cancer survivors. Osimertinib, the 3 rd generation EGFR TKI, was associated with cardiac dysfunction. Although Osimertinib is a preferred first-line option, many countries still use first- or second-generation EGFR TKIs upfront; therefore, robust studies are needed to define cardiotoxicity across these earlier-generation EGFR TKIs. Methods: In this retrospective cohort study using a nationwide Health Insurance Claim Database in Korea, patients newly diagnosed with NSCLC between 2010 and 2023 were identified. Patients were classified into three groups: first-generation (1G) EGFR TKIs (gefitinib or erlotinib), second-generation (2G) TKIs (afatinib or dacomitinib), and third-generation (3G) TKI sequence (initial first- or second-generation TKI followed by a switched to osimertinib). The incidence of cardiovascular disease (CVD) during treatment period was compared between groups. CVD included ischemic heart disease, heart failure, atrial tachyarrhythmias, and stroke. For patients with pre-existing CVD, only new-onset CVD were counted as events. Follow-up was completed December 31, 2024. Results: Among the 51,218 patients (58,317 [51%] female; mean [SD] age, 65.5 [10.8] years), 36,335 (70.9%), 8173 (16.0%), 6710 (13.1%) were treated with 1G, 2G and 3G EGFR TKI respectively. Among all patients, 16.7% were receiving medication for diabetes, 52.7% for hypertension, and 19.8% for dyslipidemia. Before lung cancer diagnosis, 1.1% had coronary artery disease and 2.7% had heart failure. In patients treated with 1G EGFR TKIs, the cumulative incidence of CVD at 1, 2, 3, and 5 years was 4.8%, 8.1%, 11.2%, and 16.2%, respectively. In those treated with 2G EGFR TKIs, the corresponding cumulative incidence was 4.2%, 7.0%, 9.4%, and 12.3%. In the group of 3G TKI sequence, the cumulative incidence of CVD at 1, 2, 3, and 5 years was 2.9%, 6.1%, 8.9%, and 14.8%, respectively. There was no statistically significant long-term difference in CVD incidence between the 1G TKI and the 3G TKI group (p = .245). Conclusions: The long-term risk of CVD associated with sustained treatment with 1G EGFR TKIs appears comparable to the risk observed among patients who started with 1G or 2G and switched to 3G EGFR TKI sequence. As long-term survivors with EGFR mutant NSCLC increases in number, ongoing surveillance for cardiotoxicity and proactive risk mitigation are essential.