Addition of Everolimus to Letrozole in Premenopausal Women With Advanced HR-Positive, HER2-Negative Breast Cancer

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In the Chinese phase II MIRACLE trial reported in JAMA Oncology, Fan et al found that the addition of everolimus to letrozole significantly improved progression-free survival among premenopausal women with advanced hormone receptor (HR)-positive, HER2-negative breast cancer whose disease had progressed on adjuvant treatment with selective estrogen receptor modulators (SERMs).

Study Details

In the open-label multicenter trial, 199 women were randomly assigned between December 2014 and September 2018 to receive everolimus at 10 mg once daily plus letrozole at 2.5 mg once daily (n = 101) or letrozole at 2.5 mg once daily (n = 98). Both groups received goserelin at 3.6 mg on day 1 of each 28-day cycle.

Patients in the letrozole group were permitted to cross over to receive everolimus at disease progression. The primary endpoint was progression-free survival.

Progression-Free Survival

Median progression-free survival was 19.4 months (95% confidence interval [CI] = 16.3–22.0 months) in the everolimus/letrozole group vs 12.9 months (95% CI = 7.6–15.7 months) in the letrozole group (hazard ratio [HR] = 0.64, 95% CI = 0.46–0.89, P = .008). Among 56 patients in the letrozole group (57.1%) who crossed over to receive everolimus, median progression-free survival after crossover was 5.5 months (95% CI = 3.8–8.2 months).


  • The addition of everolimus to letrozole significantly improved progression-free survival.
  • Patients crossing over to receive everolimus after progression had second progression-free survival of 5.5 months.

Overall survival data were immature at data cutoff. Death had occurred in 25 patients in the everolimus/letrozole group and in 27 patients in the letrozole group (HR = 0.76, 95% CI = 0.44–1.32, P = .33). Among patients with measurable disease, objective response was observed in 33 (50.0%) of 66 in the everolimus/letrozole group vs 24 (39.3%) of 61 in the letrozole group (P = .23), with complete response in 1 patient in each group. Median duration of response was 18.7 months (95% CI = 7.6–28.6 months) vs 14.8 months (95% CI = 9.2–20.5 months).

Adverse Events

Adverse events of any grade reported more frequently in the everolimus/letrozole group included stomatitis, hypertriglyceridemia, elevated alanine aminotransferase and aspartate aminotransferase, infection, hypercholesterolemia, rash, leukopenia and neutropenia, diarrhea, headache, anemia, pneumonitis, and fatigue. Adverse events led to dose reduction in 33.7% vs 1.1% of patients, treatment delay in 53.5% vs 4.3%, and treatment discontinuation in 8.9% vs 0%.

The investigators concluded, “In this randomized clinical trial, progression-free survival was significantly longer among premenopausal patients with HR-positive/HER2-negative advanced breast cancer who received everolimus plus letrozole than among those who received letrozole alone. The results revealed that everolimus was effective even among patients receiving treatment with the same endocrine agent after disease progression.”

Binghe Xu, MD, PhD, of the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by Novartis Oncology China. For full disclosures of the study authors, visit

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