Everolimus Fails to Show DFS Benefit in Aromatase Inhibitor–Resistant Metastatic Breast Cancer

Disease-free survival in patients with metastatic breast cancer did not differ between treatment with everolimus or placebo.

The oral mTOR inhibitor everolimus (Afinitor) in combination with endocrine therapy (ET) did not improve disease-free survival (DFS) compared with placebo for postmenopausal patients with aromatase inhibitor–resistant metastatic breast cancer, according to findings from a phase 3 study (NCT01805271).1

Patients who received adjuvant everolimus plus ET (n = 637) had a 3-year DFS rate of 88% (95% CI, 85%-91%) compared with 89% (95% CI, 86%-91%) among 641 patients who were treated with placebo plus ET (HR, 0.95; 95% CI, 0.69-1.32; P = .77). The 3-year overall survival (OS) rates were 96% (95% CI, 94%-98%) vs 96% (95% CI, 94%-97%), respectively (HR, 1.09; 95% CI, 0.62-1.92; P = .75).

“This first phase 3 clinical trial of adjuvant everolimus in combination to standard hormone therapy for patients with estrogen receptor–-positive, HER2-negative early breast cancer failed to show improvement in DFS and was stopped after the initial interim analysis for futility,” study authors wrote. “Added toxicity was significant, and early treatment discontinuation may be in part responsible for the lack of observed benefit. Follow-up will continue to evaluate long-term outcomes. At the present time, everolimus cannot be recommended in the adjuvant setting.”

The double-blind, multicenter trial enrolled adult patients with estrogen receptor–positive, HER2-negative early breast cancer who were at high risk of relapse. Eligible patients must have undergone a complete resection of their primary tumor with no clinically or radiologically detectable metastases at the time of inclusion. Patients also must have undergone at least 1 year but no more than 4 years of prior ET and have an ECOG performance status of 1 or less.

Eligible patients were randomly assigned 1:1 to be treated with 2 years of placebo or 2 years of everolimus, added to ongoing ET. Stratification was performed based on ET agent, previous adjuvant vs neoadjuvant chemotherapy or ET, progesterone receptor status, duration of ET, and lymph node involvement.

Initially, investigators administered everolimus at a dose of 10 mg daily. However, 2 years into the trial, toxicity was identified as an issue and the study protocol was modified to allow to a starting dose of 5 mg daily with the option to increase to 10 mg daily between the first and third month depending on toxicity. Patients remained on the investigational arm for a maximum of 2 years.

Treatment with everolimus was halted until toxicity resolved if grade 2/3 toxicity occurred, then it was resumed. If the starting dose was 10 mg daily, the resumed dose was 5 mg daily and if the starting dose had been 5 mg daily, the new dose was 5 mg every 2 days. If grade 2/3 toxicities recurred, treatment was interrupted and resumed at 5 mg every 2 days for patients who were receiving 5 mg daily and permanently discontinued for those who were already receiving 5 mg once every 2 days. In the case of a third recurrence, treatment with everolimus was permanently discontinued.

The primary end point was DFS from the date of randomization. Secondary end points included OS, event-free survival, distant metastasis-free survival, and toxicity.

Baseline patient characteristics were well-balanced between the placebo arm and the everolimus arm; the median age was 53.5 years (IQR, 48.3-62.7) and 53.8 years (range, 47.8-62.6), respectively. Most patients in both arms had an ECOG performance status of 0 (89.2% vs 89.8%), were postmenopausal (65.6% vs 66.0%), and underwent adjuvant chemotherapy (76.3% vs 78.4%). The median duration of treatment with ET at randomization was 14.6 months (IQR, 4.9-28.9) for those who received everolimus compared with 15.2 months (IQR, 4.9-30.3) for those who received placebo.

On study, the median duration of treatment with everolimus was 9.2 months (IQR, 2.1-23.4) vs 22.5 months (IQR, 9.7-23.9) with placebo. Dose reduction occurred more frequently among patients treated with everolimus compared with those who received placebo, 34.2% vs 11.7%, respectively. Most patients in the investigational arm (53.4%) were eventually forced to permanently cease treatment compared with 22.3% of patients in the placebo arm.

Additional findings from the trial showed that at a median follow-up of 35.7 months (range, 0.7-85) patients who received tamoxifen in the everolimus arm (n = 252) experienced a 3-year DFS rate of 91% (95% CI, 86%-94%) compared with 86% (95% CI, 81%-90%) in the placebo arm (n = 253; HR, 0.62; 95% CI, 0.37-1.06). Patients who received an aromatase inhibitor in the investigational arm (n = 388) achieved a 3-year DFS rate of 87% (95% CI, 82%-90%) vs 91% (95% CI, 87%-93%) in the placebo arm (n = 385; HR, 1.25; 95% CI, 0.83-1.90). Investigators noted that the biology of premenopausal patients vs postmenopausal patients was a potentially confounding factor.

In terms of safety, patients in the everolimus safety population (n = 625) experienced an any-grade adverse event (AE) at a rate of 98.1% compared with 96.5% in the 634-patient placebo safety population. Serious AEs occurred at a rate of 10.6% vs 9.3%, respectively (P = .144). Treatment withdrawal due to grade 3 or greater AEs occurred at a rate of 29.6% vs 9.1%, respectively (P < .001), and 1 treatment-related death was reported in the everolimus arm due to septic shock because of streptococcus septicemia.

The most common any grade AEs in the everolimus arm included oral mucositis (66.7%), fatigue (54.2%), and high cholesterol (35.0%). Grade 3 or greater AEs in this arm consisted of oral mucositis (7.4%), hypertriglyceridemia (3.0%), and hepatic alanine transaminase/aspartate aminotransferase/gamma-glutamyl transferase increase (2.2%), among others.

In the placebo arm, the most common AEs of any grade included fatigue (48.1%), oral mucositis (32.5%), and arthralgia (28.7%). AEs that were of grade 3 or higher in this arm included hepatic ALT/AST/GGT increase (1.7%), fatigue (1.3%), and decreased lymphocyte count (0.6%).


Bachelot T, Cottu P, Chabaud S, et al. Everolimus added to adjuvant endocrine therapy in patients with high-risk hormone receptor–positive, human epidermal growth factor receptor 2–negative primary breast cancer. J Clin Oncol. 2022;40(32):3699-3708. doi:10.1200/JCO.21.02179

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