Background: Lung cancer is the leading cause of cancer-related deaths globally, with epidermal growth factor receptor (EGFR) mutations present in approximately 17-39% of non-small cell lung cancer (NSCLC) cases. Osimertinib, a third-generation oral EGFR tyrosine kinase inhibitor (EGFR-TKI), has become a cornerstone in the treatment of EGFR-mutated NSCLC. However, the full scope of its potentially life-threatening adverse effects, particularly cardiomyopathy, remains underexplored. Methods: This retrospective study was conducted using data from a multi-center registry of NSCLC patients with EGFR mutations treated with first-line osimertinib therapy between December 2018 and April 2024. Osimertinib-related cardiotoxicity was defined as a composite of reduced ejection fraction (EF) and cardiac death. Results: The study cohort consisted of 17 patients, and most of the patients had a history of smoking. Cardiac toxicity onset varied from 1 to 28 months following osimertinib initiation, with 70.59% of the patients experiencing symptoms within the first 6 months of treatment. Fourteen patients showed some degree of symptom improvement and EF recovery, although most did not return to baseline EF levels. Comorbidities, including heart failure, hypertension, and dyslipidemia, were prevalent across the cohort. Conclusions: While osimertinib remains an effective treatment for EGFR-mutated NSCLC, its associated cardiac toxicity, particularly in patients with pre-existing conditions, presents a significant challenge. Close monitoring, early intervention, and individualized management strategies are critical in mitigating these risks. Patients with mild cardiac toxicity may be suitable for rechallenge, while those with more severe or persistent toxicity should generally be excluded from further osimertinib treatment.

Department of Pharmacology Faculty of Medicine and Dentistry Palacky University Olomouc Hnevotinska st 976 3 77900 Olomouc Czech Republic

Faculty of Medicine and Dentistry Palacky University Olomouc Hnevotinska st 976 3 77900 Olomouc Czech Republic

Institute of Oncology Chaim Sheba Medical Center Ramat Gan 52600 Israel

Medical School for International Health Faculty of Health Sciences Ben Gurion University of the Negev Beer Sheva 84105 Israel

Oncology Department Bnai Zion Medical Centre Haifa 31048 Israel

School of Medicine Tel Aviv University Tel Aviv 69978 Israel

Sharett Institue of Oncology Hadassah Hebrew University Medical Center Jerusalem 91200 Israel

The Legacy Heritage Cancer Center and Dr Larry Norton Institute Soroka Medical Center Beer Sheva 84105 Israel

Thoracic Cancer Service Davidoff Cancer Centre Beilinson Campus Petah Tikva 49100 Israel

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