Clinical trialPhase 3Breast cancer

Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

N Engl J Med · 2012724 patients

Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, et al. N Engl J Med. 2012. 366:520-529

Study type: Clinical trial
Study name: BOLERO-2
Phase: Phase 3
Design: Randomised phase 3 trial with 2:1 allocation (everolimus plus exemestane versus placebo plus exemestane)
Sample size: 724 patients
Source: N Engl J Med · 2012
Trial registration: NCT00863655

In plain words

In this study, postmenopausal women with advanced hormone-sensitive breast cancer whose earlier hormone treatment had stopped working received either everolimus with exemestane or a placebo (dummy pill) with exemestane. Adding everolimus clearly lengthened the time the cancer stayed under control without growing. On the other hand, side effects such as mouth sores, anaemia, shortness of breath, high blood sugar, tiredness and lung inflammation were more common in the everolimus group.

Key results

6.9 months vs 2.8 months

Median progression-free survival (local investigator assessment)

HR 0.43; 95% CI 0.35–0.54; P<0.001

10.6 months vs 4.1 months

Median progression-free survival (central assessment)

HR 0.36; 95% CI 0.27–0.47; P<0.001

Drugs in this study:Everolimus (Afinitor)Exemestane (Aromasin)

Dose and schedule cards

Exemestane + everolimus (BOLERO-2)

Postmenopausal women with advanced HR-positive/HER2-negative disease after failure of letrozole or anastrozoleCycle length: ContinuousOn the page “Breast cancer” · Advanced hormone receptor-positive / HER2-negative disease

Postmenopausal women with advanced HR-positive/HER2-negative disease after failure of letrozole or anastrozole

Drug	Dose	Route	Schedule
Everolimus	10 mg once daily	Oral	Continuous
Exemestane	25 mg once daily after a meal	Oral	Continuous

Cycle length: Continuous
Duration: Until progression or unacceptable toxicity

From the first day, an alcohol-free dexamethasone mouthwash (swish and spit) to reduce stomatitis; avoid mouthwashes containing alcohol, hydrogen peroxide, iodine or thyme. Monitor for noninfectious pneumonitis and infections; blood glucose and lipids, renal function and blood counts before starting and periodically.

On the page “Breast cancer” · Advanced hormone receptor-positive / HER2-negative disease

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Everolimus plus exemestane

Everolimus 10 mg (two 5 mg tablets) orally once daily continuously, with exemestane 25 mg orally daily (2:1 allocation).

2Placebo plus exemestane

Matching placebo (two tablets daily) with exemestane 25 mg orally daily.

Source of the regimen details: ClinicalTrials.gov NCT00863655 and the FDA label for Afinitor (DailyMed)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with hormone receptor-positive advanced breast cancer whose disease had recurred or progressed during prior therapy with a nonsteroidal aromatase inhibitor (in the adjuvant setting, for advanced disease, or both). Median age was 62 years; 56% had visceral involvement and 84% had hormone-sensitive disease. Prior therapies included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%) and chemotherapy (68%).

Endpoints

Primary endpoint: progression-free survival. Secondary endpoints: survival, response rate and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 359 progression-free survival events had been observed.

Safety and side effects

The most common grade 3 or 4 adverse events (everolimus + exemestane vs placebo + exemestane): stomatitis 8% vs 1%, anaemia 6% vs less than 1%, dyspnoea 4% vs 1%, hyperglycaemia 4% vs less than 1%, fatigue 4% vs 1%, and pneumonitis 3% vs 0%.

Clinical significance and place in guidelines

According to the abstract, adding everolimus to aromatase inhibitor endocrine therapy improved progression-free survival in patients with hormone receptor-positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. The status of drug approvals and clinical guideline recommendations should be checked separately.

Limitations

The reported results come from a preplanned interim analysis. Overall survival is not reported in the abstract. The study was funded by Novartis. The higher rate of grade 3 or 4 adverse events in the everolimus group must be considered in treatment decisions.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.