As reported in the Journal of Clinical Oncology by Thomas Bachelot, MD, PhD, and colleagues, the phase III UNIRAD trial showed no improvement in disease-free survival with the addition of everolimus to adjuvant endocrine therapy for patients with high-risk hormone receptor–positive, HER2-negative breast cancer.
Thomas Bachelot, MD, PhD
In the double-blind trial, 1,278 patients from sites in France, the United Kingdom, and Belgium were randomly assigned between June 2013 and March 2020 to receive everolimus (n = 637) or placebo (n = 641) for 2 years in combination with standard endocrine therapy. Everolimus was initially administered at 10 mg once daily; due to concerns over toxicity 2 years into the trial, the protocol was amended to allow a starting dose of 5 mg once daily with a possible increase to 10 mg between the first and third month (depending on observed toxicity). Overall, 34% of patients initiated everolimus/placebo at 10 mg and 64% at 5 mg. The most commonly used endocrine therapies were tamoxifen (44%), letrozole (32%), and anastrozole (19%).
The primary endpoint was disease-free survival.
The trial was stopped due to futility at first interim analysis. Median follow-up for the current analysis was 35.7 months (interquartile range = 19.9–47.4 months). At 3 years, disease-free survival rates were 88% (95% confidence interval [CI] = 85%–91%) in the everolimus group vs 89% (95% CI = 86%–91%) in the control group (hazard ratio [HR] = 0.95, 95% CI = 0.69–1.32, P =.77). Overall survival at 3 years was 96% (95% CI = 94%–98%) in the everolimus group vs 96% (95% CI = 94%–97%) in the control group (HR = 1.09, 95% CI = 0.62–1.92).
Grade ≥ 3 adverse events occurred in 29.9% of patients in the everolimus group vs 15.9% of the control group (P < .001); rates were 38.2% among patients starting everolimus at 10 mg and 25.4% among those starting at 5 mg. The most common adverse events in the everolimus group were oral mucositis (7.4%) and hypertriglyceridemia (3.0%). Serious adverse events occurred in 11.8% vs 9.3% of patients (P = .144). Treatment was discontinued early in 53.4% of the everolimus group vs 22.3% of the control group; reasons for discontinuation other than disease progression were adverse events in 35.3% vs 10.0% and patient decision in 15.2% v 7.2%.
The investigators concluded, “Among high-risk patients, everolimus added to adjuvant endocrine therapy did not improve disease-free survival. Tolerability was a concern, with more than half of patients stopping everolimus before study completion. Everolimus cannot be recommended in the adjuvant setting.”
Thomas Bachelot, MD, PhD, of Centre Léon Bérard, Lyon, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the French Ministry of Health, La Ligue contre le Cancer, Cancer Research-UK, Myriad Genetics, and Novartis. For full disclosures of the study authors, visit ascopubs.org.
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