Osimertinib was associated with a 4.9% incidence of severe cardiac adverse events (AEs) in a Japanese population with advanced non-small cell lung cancer (NSCLC) with EGFR mutations, according to a retrospective study.1
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) that has become the standard of care for patients with advanced NSCLC with EGFR mutations, including patients whose disease harbors the EGFR T790M mutation after progressing on prior EGFR TKI treatment. Although common AEs associated with osimertinib include diarrhea, rash, nausea, and decreased appetite, AEs of special concern include interstitial lung disease and QTc prolongation.
Large, international clinical trials reported incidents of 1% for grade 3 or higher QTc prolongation, 4% for any cardiac failure, and 3% for reduced left ventricular ejection fraction (LVEF) >10% from baseline and to <50%. A large postmarketing surveillance study of Japanese patients found a lower rate of QTc prolongation of 0.1% and severe cardiac AEs of 0.8%. The purpose of this study was to conduct a detailed retrospective analysis of osimertinib-associated cardiac AEs in a real-world setting.
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The single-center, retrospective study included 123 patients with advanced NSCLC with EGFR mutations who received osimertinib between 2014 and 2019 at the Osaka International Cancer Institute in Japan. Patients had histologically and cytologically confirmed, clinical stage IIIB-IV NSCLC and a sensitizing, activating EGFR mutation. A cardiologist adjudicated all AEs by a detailed medical record review.
Among the 123 patients, the median age was 69 years, 67.5% were female, and 28.5% were former or current tobacco smokers. Nearly all patients had adenocarcinoma, and 26.8% and 26% received osimertinib in the first or second line, respectively. Hypertension was present in 28.5%, dyslipidemia in 8.9%, arrythmia in 4.9%, valvular disease in 3.3%, and diabetes mellitus in 2.4% of patients.
Severe cardiac AEs, defined as grade 3 or higher, occurred in 6 patients, or 4.9%, with a time to event range of 2 weeks to 9 months. Five of the patients had preexisting cardiovascular history or risk factors, including hypertension, or aortic or mitral valve regurgitation. The cardiac AEs included acute myocardial infarction, heart failure with reduced LVEF, and valvular heart disease.
QTc prolongation was evaluated among 72 patients who underwent serial electrocardiogram before and after receiving osimertinib. Overall, during a median of 116 days, there was a significant prolongation in QTc from 421.9 ± 23.0 ms to 442.4 ± 33.2 ms (p<.001). However, grade 3 QTc prolongation, defined as >501 ms, occurred in 2 patients. Another 18 patients experienced grade 1 or 2 QTc prolongation. There were no reports of fatal arrythmias.
In addition, 36 patients with serial echocardiography before and after osimertinib treatment were assessed for changes in LVEF. There was a small, but significant, reduction in LVEF from 69.4 ± 4.2% at baseline to 63.5 ± 10.5% (P <.001). Grade 3 LVEF reduction developed in 4 patients.
The authors stated that the rate of observed severe cardiac AEs in this study was similar to the rate reported by the US Food and Drug Administration, but was higher than the rates reported by larger retrospective analyses. They noted several limitations of their study, including small sample size and the lack of a standardized protocol for cardiovascular follow-up and monitoring.
The authors concluded, “Further investigations are necessary to further understand the associations between osimertinib and cardiac AEs … including defining the predictors, natural history, and potential mechanisms of toxicity.”
Reference
Kunimasa K, Kamada R, Oka T, et al. Cardiac adverse events in EGFR-mutated non-small cell lung cancer treated with osimertinib. J Am Coll Cardiol CardioOnc. 2020;2:1-10.
