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Lancet Oncol. 2014 May;15(6):580-91. doi: 10.1016/S1470-2045(14)70138-X. Epub 2014 Apr 14.

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

Author information

1
Department of Medical Oncology, INSERM Unit U981, Université Paris Sud, Institut Gustave Roussy, Villejuif, France.
2
Winship Cancer Institute of Emory University, Atlanta, GA, USA.
3
Cerrahpasa Medical Faculty, Department of Medicine, Division of Medical Oncology, Istanbul University, Istanbul, Turkey.
4
Kyoto University, Sakyo-ku, Kyoto, Japan.
5
Department of Medical Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Beijing, China.
6
Centre Hospitalier Universitaire du Sart-Tilman, Domaine Universitaire B35, Liège, Belgium.
7
NHO Osaka National Hospital, Chuou-ku, Osaka, Japan.
8
Cancer Care Centers of South Texas, San Antonio, TX, USA.
9
NYU Langone Arena Oncology, Lake Success, NY, USA.
10
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
11
National Cancer Centre Singapore, Singapore.
12
Oncology Department, Military Hospital, Budapest, Hungary.
13
Orszagos Onkologiai Intezet, Budapest, Hungary.
14
Christie Hospital NHS Foundation Trust, Manchester, UK.
15
Sanatorio de la Providencia, Buenos Aires, Argentina.
16
Monash Medical Center, Moorabbin Hospital, Bentleigh East, VIC, Australia; Cabrini Brighton Hospital, Brighton, VIC, Australia.
17
Comprehensive Breast Health Center, RuiJin Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, China.
18
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
19
Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
20
Ospedale San Raffaele Scientific Institute, Milan, Italy. Electronic address: gianni.luca@hsr.it.

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.

PMID:
24742739
DOI:
10.1016/S1470-2045(14)70138-X
[Indexed for MEDLINE]

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