Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial.

Abstract

BACKGROUND:

Disease progression in patients with HER2-positive breast cancer receiving trastuzumab might be associated with activation of the PI3K/Akt/mTOR intracellular signalling pathway. We aimed to assess whether the addition of the mTOR inhibitor everolimus to trastuzumab might restore sensitivity to trastuzumab.

METHODS:

In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited women with HER2-positive, trastuzumab-resistant, advanced breast carcinoma who had previously received taxane therapy. Eligible patients were randomly assigned (1:1) using a central patient screening and randomisation system to daily everolimus (5 mg/day) plus weekly trastuzumab (2 mg/kg) and vinorelbine (25 mg/m(2)) or to placebo plus trastuzumab plus vinorelbine, in 3-week cycles, stratified by previous lapatinib use. The primary endpoint was progression-free survival (PFS) by local assessment in the intention-to-treat population. We report the final analysis for PFS; overall survival follow-up is still in progress. This trial is registered with ClinicalTrials.gov, number NCT01007942.

FINDINGS:

Between Oct 26, 2009, and May 23, 2012, 569 patients were randomly assigned to everolimus (n=284) or placebo (n=285). Median follow-up at the time of analysis was 20.2 months (IQR 15.0-27.1). Median PFS was 7.00 months (95% CI 6.74-8.18) with everolimus and 5.78 months (5.49-6.90) with placebo (hazard ratio 0.78 [95% CI 0.65-0.95]; p=0.0067). The most common grade 3-4 adverse events were neutropenia (204 [73%] of 280 patients in the everolimus group vs 175 [62%] of 282 patients in the placebo group), leucopenia (106 [38%] vs 82 [29%]), anaemia (53 [19%] vs 17 [6%]), febrile neutropenia (44 [16%] vs ten [4%]), stomatitis (37 [13%] vs four [1%]), and fatigue (34 [12%] vs 11 [4%]). Serious adverse events were reported in 117 (42%) patients in the everolimus group and 55 (20%) in the placebo group; two on-treatment deaths due to adverse events occurred in each group.

INTERPRETATION:

The addition of everolimus to trastuzumab plus vinorelbine significantly prolongs PFS in patients with trastuzumab-resistant and taxane-pretreated, HER2-positive, advanced breast cancer. The clinical benefit should be considered in the context of the adverse event profile in this population.

• Authors: Fabrice André, Ruth O'Regan, Mustafa Ozguroglu, Masakazu Toi, Binghe Xu, Guy Jerusalem, Norikazu Masuda, Sharon Wilks, Francis Arena, Claudine Isaacs, Yoon-Sim Yap, Zsuzsanna Papai, Istvan Lang, Anne Armstrong, Guillermo Lerzo, Michelle White, Kunwei Shen, Jennifer Litton, David Chen, Yufen Zhang, Shyanne Ali, Tetiana Taran, Luca Gianni
• Journal: The Lancet. Oncology (Lancet Oncol) Vol. 15 Issue 6 Pg. 580-91 (May 2014) ISSN: 1474-5488 [Electronic] England
• PMID: 24742739 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Antibodies, Monoclonal, Humanized
• Everolimus
• Trastuzumab
• Sirolimus

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Breast Neoplasms (drug therapy, genetics, mortality)
• Disease-Free Survival
• Double-Blind Method
• Drug Resistance, Neoplasm (drug effects)
• Everolimus
• Female
• Genes, erbB-2
• Humans
• Kaplan-Meier Estimate
• Middle Aged
• Proportional Hazards Models
• Sirolimus (analogs & derivatives, therapeutic use)
• Trastuzumab
• Treatment Outcome