Real-World Data Highlight Cardiac AEs With Osimertinib

Patrice Wendling

March 17, 2020

Osimertinib (Tagrisso, AstraZeneca) cemented its role as front-line treatment of epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) in last year's FLAURA trial. However, emerging real-world data raise concerns about the increased risk of cardiotoxicity, particularly among patients with cardiac risk factors.

A Japanese study published today in JACC: CardioOncology found that 4.9% of patients treated with osimertinib experienced grade 3 or higher cardiac adverse events. This included acute myocardial infarction in one, heart failure with reduced left ventricular ejection fraction (LVEF) in three, and valvular heart disease in two.

Five of the six cases occurred in patients with preexisting cardiovascular risk factors or disease.

"Physicians, especially oncologists, need to realize cardiovascular risks, such as hypertension, diabetes, high age, and hyperlipidemia, of the patients before treatment and, if necessary, they should consult cardiologists or specialists to improve these problems," study author Toru Oka, MD, PhD, told theheart.org | Medscape Cardiology. Also, "stratification by CV risk may be needed."

The US label for osimertinib already contains safety information on QT prolongation and cardiomyopathy. In Japan, the package insert for osimertinib was updated in December 2019, adding heart failure/cardiac dysfunction as a serious side effect, he noted.

The investigators decided to examine osimertinib-related cardiotoxicity in the real-world setting after a patient suffering from symptomatic heart failure presented to their department, through an oncologist, in December 2018, Oka said. Her LVEF had fallen from 61% to a precarious 28% after 3 months of osimertinib and remained low, at 49%, for 9 months. Gefitinib was started 8 months after the adverse event and the patient remains alive today.  

In all, 123 NSCLC patients with EGFR mutations received osimertinib monotherapy at their institution from 2014 to 2019, of which a quarter received the third-generation tyrosine kinase inhibitor (TKI) as first-line therapy. Hypertension was present in 28.5% of patients, diabetes in 2.4%, dyslipidemia in 9%, and arrhythmia in 5%.

Among 72 patients who underwent serial echocardiography before and after osimertinib, the average corrected QT (QTc) interval was prolonged from 421.9 ms to 442.4 ms (P <.001) over a median 116 days (range 16-851 days). Grade 3 QTc prolongation >501 ms occurred in two patients.

In the subset of 36 patients who underwent ECG before and after osimertinib treatment within a 1-year time period, LVEF declined from 69.4% at baseline to 63.4% with osimertinib therapy (P <.001).

Cancer therapeutics-related cardiac dysfunction, defined as a greater than 10% decline in LVEF from baseline to a value of less than 53%, occurred in four of these patients (mean LVEF 40.3%).

Unpublished data indicate that CV adverse events seem to occur relatively early in osimertinib treatment, within 1 or 3 months, and that pneumonitis induced by osimertinib also occurs during this phase, Oka said.

Combined with the present data, "These observations indicate that awareness of osimertinib-associated adverse events is needed relatively early in the phase of the treatment," he said.

The 4.9% overall rate of cardiac events is similar to that reported by the US Food and Drug Administration but "unexpected higher" than that observed in postmarketing surveillance in Japan, in which grade 3 or higher QTc prolongation was reported in only 0.1% of patients and other serious cardiac events in 0.8%, the authors noted.

QT prolongation was also observed in osimertinib-treated patients in FLAURA, which was published in the New England Journal of Medicine (NEJM) and showed a significant 20% decreased risk for death or progression with osimertinib. Asian patients and those with EGFR L858R mutations, however, did not appear to derive an overall survival benefit from first-line osimertinib.

Five of the six patients in the present study with osimertinib-induced cardiac events carried the L858R mutation. Further data are needed to understand any potential differences in survival between the races, said Oka, who noted that their letter to the NEJM asking about the CV adverse event rate in the Asian subgroup went unanswered.

"A prospective and multi-center is the next step to confirm the result of our study and to evoke more attention to the side effects of osimertinib," Oka said. "Because osimertinib is a very important, key drug for the treatment for NSCLC, cardiologists as well as oncologists should investigate its effect on the heart."

Basic research is also needed to understand the mechanisms of CV adverse events induced by osimertinib, he said.

Myocardial biopsies performed in two patients showed cardiomyocyte hypertrophy and lipofuscin deposition, without typical myocyte degeneration/necrosis with adjacent mononuclear cell infiltration.

The findings suggest that "osimertinib does not result in a pattern of myocyte death seen with anthracyclines nor myocarditis seen with immune checkpoint inhibitors and that cardiac dysfunction associated with osimertinib may result from functional inhibition of myocyte contractility without marked cell death or inflammation," the authors write.

In a linked editorial, Dipesh Uprety, MBBS, and Aaron S. Mansfield, MD, Mayo Clinic Rochester, Minnesota, said that despite the small sample size and lack of standardized electrocardiograms, the study has "many important findings."

Among them that the frequency of cardiotoxicity was higher than reported in the original trials with osimertinib; that patients can develop cardiac toxicity as early as 2 weeks on treatment, "suggesting that cardiotoxicity may not represent a cumulative dose-dependent phenomenon," and that patients who developed cardiotoxicity had cardiovascular disease or a risk factor for it.

The concerns raised by the study, however, should be viewed in the context of the significant survival gains observed with osimertinib and its ability to penetrate the central nervous system, which improves treatment of brain metastases, they said.

"For now, oncologists should counsel patients with cardiac disease or with multiple risk factors for such that there may be heightened risk for cardiotoxicity with this agent. Hopefully more sensitive predictors of cardiotoxicity will be discovered and incorporated into our clinical decision making," Uprety and Mansfield concluded.

Oka was supported by a grant from the Japan Society for the Promotion of Science. Mansfield has received research support from Bristol-Myers Squibb, National Institutes of Health, Novartis, and Verily; remuneration to his institution for participation in advisory boards or other activities from AstraZeneca, Bristol-Myers Squibb, F. Hoffmann-La Roche, AbbVie, and Genentech; travel support from F. Hoffmann-La Roche; and is a nonremunerated director of the Mesothelioma Applied Research Foundation. Uprety has reported no relevant financial relationships.

J Am Coll Cardiol CardioOnc. 2020;2:1-10 and 11-12. Article and Editorial

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