title: Adjuvant lapatinib for women with early-stage HER2-positive breast cancer: a randomised, controlled, phase 3 trial.
abstract: BACKGROUND
  Worldwide, many patients with HER2-positive early stage breast cancer do not receive trastuzumab-the standard adjuvant treatment. We investigated the efficacy and safety of adjuvant lapatinib for patients with trastuzumab-naive HER2-positive early-stage breast cancer, started at any time after diagnosis.
  
  
  METHODS
  This study was a placebo-controlled, multicentre, randomised phase 3 trial. Women outpatients from 405 [corrected] centres in 33 countries [corrected] with HER2-positive early-breast cancer who had previously received adjuvant chemotherapy but not trastuzumab were randomly assigned (1:1) to receive daily lapatinib (1500 mg) or daily placebo for 12 months. Randomisation was done with a computer-generated sequence, stratified by time since diagnosis, lymph node involvement at diagnosis, and tumour hormone-receptor status. Investigators, site staff, and patients were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00374322.
  
  
  RESULTS
  Between August, 2006, and May, 2008, 3161 women were enrolled and 3147 were assigned to lapatinib (n=1571) or placebo (n=1576). After a median follow-up of 47·4 months (range 0·4-60·0) in the lapatinib group and 48·3 (0·7-61·3) in the placebo group, 210 (13%) disease-free survival events had occurred in the lapatinib group versus 264 (17%) in the placebo group (hazard ratio [HR] 0·83, 95% CI 0·70-1·00; p=0·053). Central review of HER2 status showed that only 2490 (79%) of the randomised women were HER2-positive. 157 (13%) of 1230 confirmed HER2-positive patients in the lapatinib group and in 208 (17%) of 1260 in the placebo group had a disease-free survival event (HR 0·82, 95% 0·67-1·00; p=0·04). Serious adverse events occurred in 99 (6%) of 1573 patients taking lapatinib and 77 (5%) of 1574 patients taking placebo, with higher incidences of grade 3-4 diarrhoea (97 [6%] vs nine [<1%]), rash (72 [5%] vs three [<1%]), and hepatobiliary disorders (36 [2%] vs one [<1%]).
  
  
  CONCLUSIONS
  Our data show that there was no significant difference in disease-free survival between groups when analysed in the intention-to-treat population. However, exploratory analyses restricted to patients who had HER2-positive disease confirmed by central fluorescence in-situ hybridisation review suggested marginal benefit with lapatinib in terms of disease-free survival. Thus lapatinib might be an option for women with HER2-positive breast cancer who do not or cannot receive adjuvant trastuzumab.
  
  
  BACKGROUND
  GlaxoSmithKline.
authors.affiliation: Massachusetts General Hospital, Boston, MA 02114, USA. pgoss@partners.org
authors.forename: Paul E
authors.initials: PE
authors.lastname: Goss
authors.forename: Ian E
authors.initials: IE
authors.lastname: Smith
authors.forename: Joyce
authors.initials: J
authors.lastname: O'Shaughnessy
authors.forename: Bent
authors.initials: B
authors.lastname: Ejlertsen
authors.forename: Manfred
authors.initials: M
authors.lastname: Kaufmann
authors.forename: Frances
authors.initials: F
authors.lastname: Boyle
authors.forename: Aman U
authors.initials: AU
authors.lastname: Buzdar
authors.forename: Pierre
authors.initials: P
authors.lastname: Fumoleau
authors.forename: William
authors.initials: W
authors.lastname: Gradishar
authors.forename: Miguel
authors.initials: M
authors.lastname: Martin
authors.forename: Beverly
authors.initials: B
authors.lastname: Moy
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart-Gebhart
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pritchard
authors.forename: Deborah
authors.initials: D
authors.lastname: Lindquist
authors.forename: Yanin
authors.initials: Y
authors.lastname: Chavarri-Guerra
authors.forename: Gursel
authors.initials: G
authors.lastname: Aktan
authors.forename: Erica
authors.initials: E
authors.lastname: Rappold
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Williams
authors.forename: Dianne M
authors.initials: DM
authors.lastname: Finkelstein
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008198:Lymph Nodes / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human