A cardiac safety analysis of osimertinib, an epidermal growth factor receptor (EGFR) inhibitor, determined that preexisting heart disease, rather than treatment with the drug, was a risk factor for developing cardiac failure, according to a report published in the Journal of Clinical Oncology.1

Osimertinib is a third-generation, irreversible, oral tyrosine kinase inhibitor of EGFR that selectively inhibits activating EGFR mutations, including the EGFR T790M resistance mutation. The US Food and Drug Administration (FDA) approved osimertinib for the treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC) in both adjuvant and first- and subsequent-line metastatic settings.2

The osimertinib package insert includes a warning that heart-rate corrected QT (QTc) interval prolongation can occur in patients treated with the agent.2

Continue Reading

A post-hoc analysis of cardiac-related safety data from clinical studies of first- or second-line osimertinib in patients with advanced/metastatic NSCLC (AURA [ClinicalTrials.gov Identifier: NCT01802632]; AURA2 [ClinicalTrials.gov Identifier: NCT02094261]; AURA3 [ClinicalTrials.gov Identifier: NCT02151981]; FLAURA [ClinicalTrials.gov Identifier: NCT02296125]) was undertaken to evaluate the cardiotoxicity profile of this agent. Analyses of data from the sponsor’s global safety database and reports in the medical literature regarding post-approval cardiac-related adverse events (AEs) associated with osimertinib use were also included.

In the analysis of data from the clinical studies, only those patients with assessments of left ventricular ejection fraction (LVEF) at baseline and between initiation and less than 28 days following cessation of treatment were included. Key findings from the analysis included the following.

From the FLAURA trial, a study of first-line treatment for patients with advanced/metastatic NSCLC with median treatment durations of 16.2 months for osimertinib and 11.5 months for a comparator EGFR inhibitor

  • 3.1% and 1.2% of patients receiving osimertinib and the comparator, respectively, experienced at least a 10 percentage point decrease in LVEF to an absolute LVEF less than 50%
  • 3 of the 8 patients in the osimertinib arm who experienced a drop in LVEF had cardiomyopathy-related risk factors; the LVEF of all 8 patients returned to normal limits while on full-dose osimertinib
  • Rates of cardiac failure-related AEs were 4.3% in the osimertinib arm and 1.8% in the comparator arm, and rates of cardiomyopathy-related AEs were 3.6% and 2.2%, respectively.

From the AURA3 trial, a study of second-line EGFR-directed therapy for patients with advanced/metastatic NSCLC with median treatment durations of 8.1 months in the osimertinib arm and 4.2 months in the chemotherapy arm

  • 5.5% of patients receiving osimertinib and 0% of patients receiving chemotherapy experienced at least a 10 percentage point decrease in LVEF to an absolute LVEF value less than 50%
  • 13 of the 14 patients treated with osimertinib who experienced a drop in LVEF had a history of cardiomyopathy risk factors; for the 13 evaluable patients, 6 experienced LVEF recovery, 2 had no further change in LVEF, 3 continued osimertinib without evidence of causality between osimertinib use and LVEF reduction, and 2 discontinued osimertinib due to an association between LVEF reduction and cardiac failure-related AEs
  • Rates of cardiac failure-related AEs were 3.2% in the osimertinib arm and 0% in the chemotherapy arm, and rates of cardiomyopathy-related AEs were 2.2% and 0%, respectively

In addition, a pooled analysis across all clinical studies showed 3.9% of patients treated with osimertinib experienced LVEF reductions of at least a 10 percentage-point decrease to an absolute LVEF of less than 50%, and the incidence of AEs related to cardiac failure was 2.6%. Of the case reports with sufficient information regarding cardiac-related AEs in patients treated with osimertinib, most identified an alternative etiology.

Limitations of this study included its post-hoc design and the limited follow-up for some patients.

In summarizing the results of this analysis, the study investigators stated, “Our findings indicate that the key factor in the development of cardiac failure is a preexisting cardiac risk factor, rather than the receipt of osimertinib.”

While recommending against routine LVEF surveillance in patients treated with osimertinib without other clinical indications for such assessments, “cardiac monitoring, including LVEF assessment, should be performed at baseline and during treatment [with osimertinib] in patients with cardiac risk factors and in those who develop cardiac signs or symptoms during treatment,” noted the study authors.

They also recommended discontinuing osimertinib in patients with symptomatic congestive heart failure.

Disclosures: Multiple authors declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original article for a full list of disclosures.


  1. Ewer MS, Tekumalla SH, Walding A, Auah KN. Cardiac safety of osimertinib: A review of data.J Clin Oncol. Published online December 23, 2020. doi:10.1200/JCO.20.01171
  2. Tagrisso [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020.