medwireNews: A review of data from the osimertinib clinical trials program has not identified a causal relationship between the use of the EGFR–tyrosine kinase inhibitor and cardiotoxicity among patients with advanced non-small-cell lung cancer.
“Our findings indicate that the key factor in the development of cardiac failure is a pre-existing cardiac risk factor, rather than the receipt of osimertinib,” write the researchers in the Journal of Clinical Oncology.
“Therefore, in line with standard practice, cardiac monitoring, including assessment of left ventricular ejection fraction [LVEF], is advised in patients with cardiac risk factors.”
Michael Ewer (The University of Texas MD Anderson Cancer Center, Houston, USA) and co-authors conducted a post-hoc analysis of the phase 3 FLAURA and AURA3 trials, as well as a pooled dataset of patients who received osimertinib 80 mg/day across the five clinical trials of the program.
Of the 257 osimertinib-treated FLAURA participants with available LVEF assessments at baseline and follow-up, 3.1% experienced a decrease of at least 10 percentage points to an absolute value below 50%, as did 5.5% of 255 osimertinib-treated AURA3 participants and 3.9% of 908 patients in the pooled dataset with available LVEF measurements.
The incidence of LVEF declines was 1.2% among the 253 FLAURA patients who received the comparator EGFR–TKI and 0.0% for the 92 AURA3 patients who instead received chemotherapy.
Cardiac failure-related adverse events (AEs) among individuals given osimertinib occurred at rates of 4.3%, 3.2%, and 2.6% in FLAURA, AURA3, and the pooled population, respectively, while the rates were a respective 1.8% and 0.0% in the control groups of the FLAURA and AURA3 studies.
Ewer and colleagues highlight that “the majority of cardiac failure-related AEs were asymptomatic EF decreases that resolved without dose modification of osimertinib.”
And they note that symptomatic events primarily occurred in patients with cardiac medical histories.
Moreover, “pharmacokinetic or pharmacodynamic analysis did not indicate a relationship between exposure to osimertinib and decreases in LVEF from baseline,” and an analysis of the sponsor’s global safety database did not reveal any “specific trend or pattern for cardiac failure-related AEs in patients receiving osimertinib,” say the study authors.
They therefore write: “These data do not suggest a causal relationship between osimertinib and cardiac failure.”
The investigators believe that in light of their findings “routine LVEF surveillance in the absence of clinical indications is not indicated.”
But the team adds: “[A]s stated in the osimertinib-prescribing information, cardiac monitoring, including LVEF assessment, should be performed at baseline and during treatment in patients with cardiac risk factors and in those who develop cardiac signs or symptoms during treatment; osimertinib should be discontinued in the case of symptomatic [congestive heart failure].
Commenting on the findings, Charu Aggarwal, MD, MPH, Leslye M Heisler Associate Professor of Lung Cancer Excellence (University of Pennsylvania, Philadelphia, USA), told medwireNews that “[b]ased on these observations, baseline echocardiogram and serial monitoring is advised.”
But she said that several questions remain unanswered, such as how best to apply these results in the clinic, whether all patients need to be screened, and whether treatment should be discontinued in those without symptoms.
She believes that “[a] risk predictor, to select patients for monitoring would be useful,” and that the “systematic integration of cardio-oncologists is essential to appropriately manage cardiac effects of novel immunotherapy and targeted agents.”
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J Clin Oncol 2020; doi:10.1200/JCO.20.01171