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The non-small cell lung cancer (NSCLC) drug osimertinib (Tagrisso) was associated with an increased risk of therapy-related cardiovascular (CV) events compared with older EGFR inhibitors, a retrospective cohort study from Taiwan found.

In a matched analysis of 401 patients with EGFR-mutant NSCLC, therapy-related CV events occurred in 14.9% of those who received the third-generation EGFR inhibitor over nearly 2 years of median follow-up, as compared with 4.4% of those treated with earlier-generation agents, reported Chien-Chung Lin, MD, PhD, of National Cheng Kung University in Tainan, Taiwan, and colleagues.

The researchers found a fourfold higher risk of therapy-related CV events in the osimertinib-treated group (adjusted subdistribution hazard ratio [sHR] 4.00, 95% CI 1.81-8.85, P<0.001) after accounting for mortality as a competing risk and adjusting for CV risk factors and other variables.

While prior research has linked osimertinib-related heart events to preexisting CV disease or risk factors, the higher risk observed in the current study was observed even among the lower-risk patients (14.3% vs 1.7%; adjusted sHR 8.78, 95% CI 1.65-46.70, P=0.01), according to the findings in .

"This highlights the need for careful monitoring of cardiac adverse effects, even in patients without preexisting cardiovascular conditions or risk factors," wrote Lin and co-authors.

Furthermore, the therapy-related CV events were independently associated with overall survival (OS; HR 4.02, 95% CI 2.44-6.63, P<0.001), "underscoring the necessity for vigilant cardiac monitoring in this patient population," the researchers wrote.

Osimertinib is now the standard first-line option for EGFR-mutant NSCLC, as established by the FLAURA trial, which demonstrated improved progression-free survival and OS compared with earlier-generation EGFR inhibitors.

"Despite the extended survival observed in patients with EGFR variations treated with osimertinib compared with gefitinib [Iressa] or erlotinib [Tarceva], long-term outcomes may be compromised by significant cardiac risks, particularly given the high prevalence of EGFR variants (about 50%) in Asian populations," according to the study authors.

In an , Nicholas Wilcox, MD, MHS, and Michael Fradley, MD, both of the Thalheimer Center for Cardio-Oncology at the Abramson Cancer Center in Philadelphia, said that in order "to optimize the CV health of patients with cancer and to minimize disruption to their oncologic therapy, understanding the relationship between osimertinib and CV toxicity risk is critical."

The researchers included the incidence of new arrhythmias, myocardial infarction (MI), heart failure, and moderate or greater valvular heart disease in their composite of therapy-related CV events, but the increased risk appeared driven by arrhythmias (sHR 3.17, 95% CI 1.32-7.59, P=0.01) and potentially heart failure (sHR 3.87, 95% CI 0.80-18.67, P=0.09). Few valvular heart disease events or MIs occurred, limiting statistical comparison.

The findings, Wilcox and Fradley noted, add to suggesting a link between osimertinib and CV risks, including heart failure, atrial fibrillation, QT prolongation, and supraventricular tachycardia. In a of FLAURA, researchers found that a higher proportion of patients on osimertinib had meaningful decreases in left ventricular ejection fraction compared with the control group (3.1% vs 1.2%).

"Taken together, these data have important implications for the surveillance and management of an increasing number of patients with NSCLC treated with osimertinib," wrote Wilcox and Fradley. "There is an urgent need for clinical studies to address appropriate monitoring strategies emphasizing both patient safety and cost-effectiveness."

Lin and colleagues' cohort study examined data on EGFR-mutant NSCLC patients treated at a single center from September 2019 through July 2022. The analysis involved 401 matched patients (63% female, mean 69 years): 195 beginning treatment with osimertinib and 206 treated with other EGFR inhibitors.

Over a median follow-up of 23.2 months, 29 cardiac events occurred in the osimertinib-treated group, including 19 newly emerging arrhythmias, eight cases of heart failure, one case of valvular heart disease, and one MI. Among the nine cardiac events in the control group, there were six newly emerging arrhythmias, two cases of heart failure, and one MI.

Analyses adjusted for age, sex, smoking, alcohol consumption, body mass index, CV comorbidities, thoracic radiotherapy, and use of CV medications.

Patients considered to be lower-risk included those with two or fewer CV risk factors or preexisting CV disease. A significant difference in therapy-related CV events was not observed among those with three or more such factors, though the risk remained numerically elevated in the osimertinib-treated patients (15.8% vs 8%; adjusted sHR 2.33, 95% CI 0.65-8.40, P=0.20).

Study limitations, said Lin and colleagues, included its retrospective design, the inconsistent availability of routine echocardiogram monitoring, and that the limited number of cardiac events "might restrict definitive conclusions."

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