title: Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
abstract: BACKGROUND
  Neratinib, an irreversible tyrosine-kinase inhibitor of HER1, HER2, and HER4, has clinical activity in patients with HER2-positive metastatic breast cancer. We aimed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer.
  
  
  METHODS
  We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 495 centres in Europe, Asia, Australia, New Zealand, and North and South America. Eligible women (aged ≥18 years, or ≥20 years in Japan) had stage 1-3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before randomisation. Inclusion criteria were amended on Feb 25, 2010, to include patients with stage 2-3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously. Patients were randomly assigned (1:1) to receive oral neratinib 240 mg per day or matching placebo. The randomisation sequence was generated with permuted blocks stratified by hormone receptor status (hormone receptor-positive [oestrogen or progesterone receptor-positive or both] vs hormone receptor-negative [oestrogen and progesterone receptor-negative]), nodal status (0, 1-3, or ≥4), and trastuzumab adjuvant regimen (sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system. Patients, investigators, and trial sponsors were masked to treatment allocation. The primary outcome was invasive disease-free survival, as defined in the original protocol, at 2 years after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00878709.
  
  
  RESULTS
  Between July 9, 2009, and Oct 24, 2011, we randomly assigned 2840 women to receive neratinib (n=1420) or placebo (n=1420). Median follow-up time was 24 months (IQR 20-25) in the neratinib group and 24 months (22-25) in the placebo group. At 2 year follow-up, 70 invasive disease-free survival events had occurred in patients in the neratinib group versus 109 events in those in the placebo group (stratified hazard ratio 0·67, 95% CI 0·50-0·91; p=0·0091). The 2-year invasive disease-free survival rate was 93·9% (95% CI 92·4-95·2) in the neratinib group and 91·6% (90·0-93·0) in the placebo group. The most common grade 3-4 adverse events in patients in the neratinib group were diarrhoea (grade 3, n=561 [40%] and grade 4, n=1 [<1%] vs grade 3, n=23 [2%] in the placebo group), vomiting (grade 3, n=47 [3%] vs n=5 [<1%]), and nausea (grade 3, n=26 [2%] vs n=2 [<1%]). QT prolongation occurred in 49 (3%) patients given neratinib and 93 (7%) patients given placebo, and decreases in left ventricular ejection fraction (≥grade 2) in 19 (1%) and 15 (1%) patients, respectively. We recorded serious adverse events in 103 (7%) patients in the neratinib group and 85 (6%) patients in the placebo group. Seven (<1%) deaths (four patients in the neratinib group and three patients in the placebo group) unrelated to disease progression occurred after study drug discontinuation. The causes of death in the neratinib group were unknown (n=2), a second primary brain tumour (n=1), and acute myeloid leukaemia (n=1), and in the placebo group were a brain haemorrhage (n=1), myocardial infarction (n=1), and gastric cancer (n=1). None of the deaths were attributed to study treatment in either group.
  
  
  CONCLUSIONS
  Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer. Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained.
  
  
  BACKGROUND
  Wyeth, Pfizer, Puma Biotechnology.
authors.affiliation: Breast Cancer Research Centre-Western Australia and Curtin University, Perth, WA, Australia. Electronic address: arlenechan@me.com.
authors.forename: Arlene
authors.initials: A
authors.lastname: Chan
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Suzette
authors.initials: S
authors.lastname: Delaloge
authors.affiliation: Texas Oncology, Houston, TX, USA.
authors.forename: Frankie A
authors.initials: FA
authors.lastname: Holmes
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA, USA.
authors.forename: Beverly
authors.initials: B
authors.lastname: Moy
authors.affiliation: Aichi Cancer Center, Chikusa-ku, Nagoya, Japan.
authors.forename: Hiroji
authors.initials: H
authors.lastname: Iwata
authors.affiliation: Auckland Hospital, Auckland, New Zealand.
authors.forename: Vernon J
authors.initials: VJ
authors.lastname: Harvey
authors.affiliation: Virginia Cancer Specialists, The US Oncology Network, Fairfax, VA, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Robert
authors.affiliation: University Hospital For Tumors, University Hospital Center "Sestre Milosrdnice", Zagreb, Croatia.
authors.forename: Tajana
authors.initials: T
authors.lastname: Silovski
authors.affiliation: Ege University Faculty of Medicine, Izmir, Turkey.
authors.forename: Erhan
authors.initials: E
authors.lastname: Gokmen
authors.affiliation: Luisenkrankenhaus, German Breast Group Forschungs GmbH, Düsseldorf, Neu-lsenburg, Germany.
authors.forename: Gunter
authors.initials: G
authors.lastname: von Minckwitz
authors.affiliation: Rigshospitalet, Copenhagen, Denmark.
authors.forename: Bent
authors.initials: B
authors.lastname: Ejlertsen
authors.affiliation: BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Stephen K L
authors.initials: SKL
authors.lastname: Chia
authors.affiliation: Guy's and St Thomas' NHS Foundation Trust and Biomedical Research Centre, King's College London, London, UK.
authors.forename: Janine
authors.initials: J
authors.lastname: Mansi
authors.affiliation: Pontifical Catholic University of Rio Grande do Sul School of Medicine, Porto Alegre, Brazil.
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Barrios
authors.affiliation: Department of Surgery and Comprehensive Cancer Centre, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Gnant
authors.affiliation: International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Buyse
authors.affiliation: Alabama Oncology, Birmingham, AL, USA.
authors.forename: Ira
authors.initials: I
authors.lastname: Gore
authors.affiliation: Northwest Cancer Specialists, Vancouver, VA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Smith
authors.affiliation: Utah Cancer Specialists, Salt Lake City, UT, USA.
authors.forename: Graydon
authors.initials: G
authors.lastname: Harker
authors.affiliation: National Hospital Organization Osaka National Hospital, Chuou-ku, Osaka, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Masuda
authors.affiliation: Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors.forename: Katarina
authors.initials: K
authors.lastname: Petrakova
authors.affiliation: Instituto Valenciano de Oncologia, València, Spain.
authors.forename: Angel Guerrero
authors.initials: AG
authors.lastname: Zotano
authors.affiliation: Hematology Oncology Associates of Treasure Coast, Port Saint Lucie, FL, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Iannotti
authors.affiliation: South Texas Oncology and Hematology, San Antonio, TX, USA.
authors.forename: Gladys
authors.initials: G
authors.lastname: Rodriguez
authors.affiliation: Magna Graecia University, Catanzaro, Italy.
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
authors.affiliation: Puma Biotechnology, Los Angeles, CA, USA.
authors.forename: Alvin
authors.initials: A
authors.lastname: Wong
authors.affiliation: Puma Biotechnology, Los Angeles, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Bryce
authors.affiliation: Puma Biotechnology, Los Angeles, CA, USA.
authors.forename: Yining
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Puma Biotechnology, Los Angeles, CA, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Yao
authors.affiliation: Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Martin
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D038622:Internationality; D053208:Kaplan-Meier Estimate; D008408:Mastectomy / Q000379:methods; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D016019:Survival Analysis; D000068878:Trastuzumab / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C487932:neratinib