Everolimus/Letrozole Provides Survival Benefit in HR-Positive/ERBB2-Negative Advanced Breast Cancer


Combination everolimus/letrozole yielded a higher progression-free survival over letrozole alone in a population of patients with hormone receptor (HR)–positive, ERBB2-negative advanced breast cancer.

The addition of everolimus (Afinitor) to letrozole (Femara) provided a greater survival benefit over letrozole alone in patients with hormone receptor (HR)–positive, ERBB2-negative advanced breast cancer, according to findings from the phase 2 MIRACLE trial (NCT02313051).

Investigators reported that patients in the intent-to-treat population who were treated with everolimus and letrozole experienced a median progression-free survival (PFS) of 19.4 months (95% CI, 16.3-22.0) vs 12.9 months (95% CI, 7.6-15.7) among those who received letrozole alone (HR, 0.64; 95% CI, 0.46-0.89; P = .008). Patients who crossed over from the control arm to the experimental arm following disease progression (n = 53) experienced further survival benefit, with an additional 5.5 months PFS (95% CI, 3.8-8.2).

“The MIRACLE trial included premenopausal patients with breast cancer receiving first-line treatment. To our knowledge, this trial represents the first evaluation of everolimus added to first-line endocrine treatment of premenopausal women, with the exception of a trial from Korea22 that was reported at the European Society of Medical Oncology Congress in 2019,” investigators wrote.

The national, multicenter, open-label trial enrolled adult women above the age of 18 who were premenopausal at the time of enrollment. Patients were required to have histologically confirmed HR-positive, ERBB2-negative breast cancer, as well as an ECOG performance status of 0 or 1.

Patients were randomized 1:1 to receive either 2.5 mg of oral letrozole once daily alone or in combination with 10 mg of oral everolimus. Additionally, patients received 3.6 mg of goserelin (Zoladex) on day 1 of each 28-day cycle.

The primary end point of the study was PFS, with key secondary end points consisting of objective response rate (ORR) and clinical benefit rate.

A total of 199 patients enrolled on the study, 101 of whom received the combination and 98 received the monotherapy. The median patient age was 44.3 years. Additionally, 2.5% of patients had stage IV disease upon being diagnosed, 57.8% had visceral disease, 27.1% had bone-only lesions, and 39.7% had cancer at 2 sites or more.

Disease-free intervals of 2 or more years occurred in 67.8% of patients. A total of 7 patients were enrolled in a second-line endocrine therapy and 15 patients were considered to be endocrine sensitive.

The ORR in the everolimus plus letrozole arm was 50.0% and 39.3% in the letrozole arm (P = .23). Additionally, the experimental arm had a greater clinical benefit rate (72.7%) compared with the control group (47.5%; P = .004). Those who crossed over to receive the combination therapy experienced a clinical benefit rate of 58.5%. The median durations of response between the combination and single agent arms were 18.7 months and 14.8 months, respectively.

Additional data from the study indicated that the median overall survival had not been reached at the data cutoff, as the data were still immature. At the data cut off, 25 patients in the combination group and 27 patients in the monotherapy group had died (HR, 0.76; 95% CI, 0.44-1.32).

Subgroup analyses indicated that the PFS benefit of everolimus and letrozole was comparable to the benefit observed in the intent-to-treat group among those with secondary endocrine resistance (19.0 vs 10.9 months; HR, 0.50; 95% CI, 0.32-0.79; P = .02). Among patients with primary endocrine resistance, those who were treated with the combination achieved a median PFS of 13.9 months (95% CI, 7.2-19.3) compared with 5.2 months (95% CI, 1.8-14.2) in the letrozole group.

In terms of safety, the most common adverse effects (AEs) that occurred in the everolimus/letrozole cohort included stomatitis, hypertriglyceridemia, and elevated alanine aminotransferase and aspartate aminotransferase. Additionally, 33.7% of patients experienced AEs that led to dose reduction, 53.5% had AEs leading to treatment delays, and 8.9% had AEs leading to treatment discontinuation.


Fan Y, Sun T, Shao Z, et al. Effectiveness of adding everolimus to the first-line treatment of advanced breast cancer in premenopausal women who experienced disease progression while receiving selective estrogen receptor modulators. JAMA Oncol. Published online August 26, 2021. doi:10.1001/jamaoncol.2021.3428

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