Jonathan N Le ¹ Jordan O Gasho ² Olivia Peony ³ Asneh Singh ³ Katrina D Silos ³ Sungjin Kim ² Anthony T Nguyen ⁴ Mitchell Kamrava ⁴ Amin Mirhadi ⁴ Behrooz Hakimian ⁵ Karen L Reckamp ⁵ Kamya Sankar ⁵ Raymond H Mak ⁶ Andriana P Nikolova ⁷ Katelyn M Atkins ^4,8*

• ¹ Department of Medicine, Cedars Sinai Medical Center, Los Angeles, United States
• ² Biostatistics Research Center, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, California, United States
• ³ Cedars Sinai Medical Center, Los Angeles, United States
• ⁴ Department of Radiation Oncology, Cedars Sinai Medical Center, Los Angeles, California, United States
• ⁵ Division of Medical Oncology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, United States
• ⁶ Department of Radiation Oncology, Dana–Farber Cancer Institute, Boston, Massachusetts, United States
• ⁷ Department of Cardiology, Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California, United States
• ⁸ Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California, United States

Osimertinib is first-line treatment for epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC) and has been associated with cardiotoxicity. However, the nature of cardiac remodeling and associated risk factors remains incompletely understood. Retrospective analysis of NSCLC patients with ≥1 echocardiogram post-osimertinib between 2007-2022 was performed. The cumulative incidence of grade ≥2 cardiac common terminology criteria for adverse events (CTCAE) was estimated and Fine and Gray regressions performed (non-cardiac death as competing risk). Eighty-five patients (mean [interquartile range, IQR], 68 [60-75] years; 67% female; 12% with pre-existing heart conditions) met inclusion criteria. With a median follow up of 34.7 months, the 2-year cumulative incidence of grade ≥2 and grade ≥3 cardiac events were 19.2% and 8.5%, respectively. There was an increased risk of grade ≥2 cardiac CTCAE with pre-existing arrhythmia (hazard ratio[HR] 3.90, 95%CI, 1.11-13.72; p=0.034) and higher body mass index (HR 1.07, 95%CI, 1.00-1.14; p=0.04). Following osimertinib (vs baseline), the median QTc was prolonged (451 vs 437 ms; p<0.001) and LVEF ≤50% was more common (10.6% vs. 5.3%; p=.046). Osimertinib treatment was associated with QTc prolongation and reduced LVEF. BMI was identified as a potentially modifiable risk factor for osimertinib-associated cardiotoxicity, worthy of further study.