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

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 ZhangShyanne Ali, Tetiana Taran, Luca Gianni

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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/m2) 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. Funding: Novartis Pharmaceuticals Corporation.

Original languageEnglish
Pages (from-to)580-591
Number of pages12
JournalThe Lancet Oncology
Volume15
Issue number6
DOIs
Publication statusPublished - May 2014

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ASJC Scopus subject areas

  • Oncology

Cite this

André, F., O'Regan, R., Ozguroglu, M., Toi, M., Xu, B., Jerusalem, G., Masuda, N., Wilks, S., Arena, F., Isaacs, C., Yap, Y. S., Papai, Z., Lang, I., Armstrong, A., Lerzo, G., White, M., Shen, K., Litton, J., Chen, D., ... Gianni, L. (2014). Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): A randomised, double-blind, placebo-controlled phase 3 trial. The Lancet Oncology, 15(6), 580-591. https://doi.org/10.1016/S1470-2045(14)70138-X