As reported in the Journal of Clinical Oncology by Michael S. Ewer, MD, JD, PhD, and colleagues, an analysis of data from clinical trials of osimertinib suggests the absence of a “causal relationship” between osimertinib and cardiac failure.
Study Details
The study involved a post hoc assessment of cardiac data from the FLAURA trial (osimertinib, n = 279; comparator EGFR tyrosine kinase inhibitor [TKI], n = 277) and the AURA3 trial (osimertinib, n = 279; comparator chemotherapy, n = 140) in advanced non–small cell lung cancer and a pooled data set from patients treated with 80 mg of osimertinib across the clinical trial program (n = 1,142). Outcomes of interest were left-ventricular ejection fraction reductions and cardiac failure–related adverse events.
Michael S. Ewer, MD, JD, PhD
Key Findings
Among all patients in the analysis, the majority of cardiac failure adverse events were asymptomatic left-ventricular ejection fraction decreases that resolved without dose modification.
In FLAURA, for the osimertinib vs comparator TKI group, reductions in left-ventricular ejection fraction from baseline of ≥ 10 percentage points to an absolute value of < 50% were observed in 3.1% vs 1.2% of patients; cardiac failure adverse events were reported in 4.3% (3.6% left-ventricular ejection fraction reductions) vs 1.8%; and cardiomyopathy adverse events were reported in 3.6% (all left-ventricular ejection fraction reductions) vs 2.2%.
All left-ventricular ejection fraction events in patients treated with osimertinib in FLAURA were asymptomatic, and none required dose modification. Among the eight patients treated with osimertinib with left-ventricular ejection fraction reductions, three had cardiomyopathy risk factors.
In AURA3, for the osimertinib group vs the chemotherapy group, such reductions in left-ventricular ejection fraction were reported in 5.5% vs 0% of patients, cardiac failure adverse events were reported in 3.2% (2.2% left-ventricular ejection fraction reductions) vs 0%, and cardiomyopathy adverse events were reported in 2.2% (all left-ventricular ejection fraction reductions) vs 0%.
Left-ventricular ejection fraction events were symptomatic in two patients treated with osimertinib in AURA3 and required discontinuation of treatment in both. The majority of the 14 patients with left-ventricular ejection fraction reductions had cardiomyopathy risk factors.
In the pooled data set, such decreases in left-ventricular ejection fraction were reported in 3.9% of patients and cardiac failure adverse events in 2.6%.
Pharmacokinetic/pharmacodynamic analysis did not indicate a relationship between osimertinib exposure and left-ventricular ejection fraction reductions.
The investigators concluded, “These data do not suggest a causal relationship between osimertinib and cardiac failure. However, because of left-ventricular ejection fraction decreases that were observed in patients with cardiac risk factors before osimertinib treatment, cardiac monitoring, including an assessment of left-ventricular ejection fraction at baseline and during osimertinib treatment, is advised.”
Dr. Ewer, of the Department of Cardiology, The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by AstraZeneca. For full disclosures of the study authors, visit ascopubs.org.
