title: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Medical Oncology, INSERM Unit U981, Université Paris Sud, Institut Gustave Roussy, Villejuif, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
authors.affiliation: Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: O'Regan
authors.affiliation: Cerrahpasa Medical Faculty, Department of Medicine, Division of Medical Oncology, Istanbul University, Istanbul, Turkey.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Ozguroglu
authors.affiliation: Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Toi
authors.affiliation: Department of Medical Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Beijing, China.
authors.forename: Binghe
authors.initials: B
authors.lastname: Xu
authors.affiliation: Centre Hospitalier Universitaire du Sart-Tilman, Domaine Universitaire B35, Liège, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Jerusalem
authors.affiliation: NHO Osaka National Hospital, Chuou-ku, Osaka, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Masuda
authors.affiliation: Cancer Care Centers of South Texas, San Antonio, TX, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Wilks
authors.affiliation: NYU Langone Arena Oncology, Lake Success, NY, USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Arena
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Claudine
authors.initials: C
authors.lastname: Isaacs
authors.affiliation: National Cancer Centre Singapore, Singapore.
authors.forename: Yoon-Sim
authors.initials: YS
authors.lastname: Yap
authors.affiliation: Oncology Department, Military Hospital, Budapest, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Papai
authors.affiliation: Orszagos Onkologiai Intezet, Budapest, Hungary.
authors.forename: Istvan
authors.initials: I
authors.lastname: Lang
authors.affiliation: Christie Hospital NHS Foundation Trust, Manchester, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Armstrong
authors.affiliation: Sanatorio de la Providencia, Buenos Aires, Argentina.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Lerzo
authors.affiliation: Monash Medical Center, Moorabbin Hospital, Bentleigh East, VIC, Australia; Cabrini Brighton Hospital, Brighton, VIC, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: White
authors.affiliation: Comprehensive Breast Health Center, RuiJin Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, China.
authors.forename: Kunwei
authors.initials: K
authors.lastname: Shen
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Litton
authors.affiliation: Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: David
authors.initials: D
authors.lastname: Chen
authors.affiliation: Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Yufen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Shyanne
authors.initials: S
authors.lastname: Ali
authors.affiliation: Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Tetiana
authors.initials: T
authors.lastname: Taran
authors.affiliation: Ospedale San Raffaele Scientific Institute, Milan, Italy. Electronic address: gianni.luca@hsr.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D018572:Disease-Free Survival; D004311:Double-Blind Method; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D000068338:Everolimus; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D016016:Proportional Hazards Models; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068338:Everolimus; D000068878:Trastuzumab; D020123:Sirolimus