TY - JOUR
T1 - Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3)
T2 - A randomised, double-blind, placebo-controlled phase 3 trial
AU - André, Fabrice
AU - O'Regan, Ruth
AU - Ozguroglu, Mustafa
AU - Toi, Masakazu
AU - Xu, Binghe
AU - Jerusalem, Guy
AU - Masuda, Norikazu
AU - Wilks, Sharon
AU - Arena, Francis
AU - Isaacs, Claudine
AU - Yap, Yoon Sim
AU - Papai, Zsuzsanna
AU - Lang, Istvan
AU - Armstrong, Anne
AU - Lerzo, Guillermo
AU - White, Michelle
AU - Shen, Kunwei
AU - Litton, Jennifer
AU - Chen, David
AU - Zhang, Yufen
AU - Ali, Shyanne
AU - Taran, Tetiana
AU - Gianni, Luca
N1 - Funding Information:
We thank all the patients, investigators, and their institutions for the time and effort put into this study. Douglas Robinson did the statistical analysis of biomarker data. Editorial support was provided by Susan DePetris and James Street of Phase Five Communications Inc. (New York, NY, USA), and was supported by Novartis Pharmaceuticals Corporation.
Funding Information:
FA is a consultant for Novartis Pharmaceuticals Corporation, and has received honorarium from Novartis. RO'R is an adviser and consultant for Novartis Pharmaceuticals Corporation, and has received research support from Genentech and Novartis. MO has received honoraria for expert testimony from Novartis Pharmaceuticals Corporation and Sanofi. MT has received research funding, honoraria, and consultancy fees from Novartis Pharmaceuticals Corporation. GJ is an advisory board member and consultant for Novartis Pharmaceuticals Corporation, and has received lecture fees, a research grant, and a travel grant from Novartis. FA has received a study grant for this trial and has been paid as expert witness by Novartis Pharmaceuticals Corporation. CI has received honoraria from Novartis Pharmaceuticals Corporation. Y-SY has received honoraria and a travel grant from Novartis Pharmaceuticals Corporation. AA has received travel grants and honoraria from Roche. MW is an advisory board member for Novartis Australia. JL is institutional principal investigator for BOLERO studies done by Novartis Pharmaceuticals Corporation (no compensation received). DC is an employee and stock holder of Novartis Pharmaceuticals Corporation. YZ is an employee of Novartis Pharmaceuticals Corporation. SA is an employee of Novartis Pharmaceuticals Corporation, and receives stock awards from Novartis. TT is an employee and stock holder of Novartis Pharmaceuticals Corporation. LG is a consultant or advisory board member for Roche, Genentech, GlaxoSmithKline, Novartis Pharmaceuticals Corporation, Pfizer, Boehringer lngelheim, Celgene, and Tahio. BX, NM, SW, ZP, IL, GL, and KS declare that they have no competing interests.
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84899992665&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(14)70138-X
DO - 10.1016/S1470-2045(14)70138-X
M3 - Article
C2 - 24742739
AN - SCOPUS:84899992665
SN - 1470-2045
VL - 15
SP - 580
EP - 591
JO - The Lancet Oncology
JF - The Lancet Oncology
IS - 6
ER -