title: Ganitumab with either exemestane or fulvestrant for postmenopausal women with advanced, hormone-receptor-positive breast cancer: a randomised, controlled, double-blind, phase 2 trial.
abstract: BACKGROUND
  Insulin-like growth factors (IGF-1 and IGF-2) bind to the IGF-1 receptor (IGF-1R), increasing cell proliferation and survival. Ganitumab is a monoclonal IgG1 antibody that blocks IGF-1R. We tested the efficacy and safety of adding ganitumab to endocrine treatment for patients with hormone-receptor-positive breast cancer.
  
  
  METHODS
  We did this phase 2 trial in outpatient clinics and hospitals. We enrolled postmenopausal women with hormone-receptor-positive, locally advanced or metastatic breast cancer previously treated with endocrine treatment. They were randomly assigned (2:1) with a central randomisation schedule to receive intravenous ganitumab 12 mg per kg bodyweight or placebo in combination with open-label intramuscular fulvestrant (500 mg on day 1, then 250 mg on days 15, 29, and every 28 days) or oral exemestane (25 mg once daily) on a 28-day cycle. Patients, investigators, study monitors, and the sponsor staff were masked to treatment allocation. Response was assessed every 8 weeks. The primary endpoint was median progression-free survival in the intention-to-treat population. We analysed overall survival as one of our secondary endpoints. The study is registered at ClinicalTrials.gov, number NCT00626106.
  
  
  RESULTS
  We screened 189 patients and enrolled 156 (106 in the ganitumab group and 50 in the placebo group). Median progression-free survival did not differ significantly between the ganitumab and placebo groups (3·9 months, 80% CI 3·6-5·3 vs 5·7 months, 4·4-7·4; hazard ratio [HR] 1·17, 80% CI 0·91-1·50; p=0·44). However, overall survival was worse in the the ganitumab group than in the placebo group (HR 1·78, 80% CI 1·27-2·50; p=0·025). With the exception of hyperglycaemia, adverse events were generally similar between groups. The most common grade 3 or higher adverse event was neutropenia-reported by six of 106 (6%) patients in the ganitumab group and one of 49 (2%) in the placebo group. Hyperglycaemia was reported by 12 of 106 (11%) patients in the ganitumab group (with six patients having grade 3 or 4 hyperglycaemia) and none of 49 in the placebo group. Serious adverse events were reported by 27 of 106 (25%) patients in the ganitumab group and nine of 49 (18%) patients in the placebo group.
  
  
  CONCLUSIONS
  Addition of ganitumab to endocrine treatment in women with previously treated hormone-receptor-positive locally advanced or metastatic breast cancer did not improve outcomes. Our results do not support further study of ganitumab in this subgroup of patients.
  
  
  BACKGROUND
  Amgen.
authors: Royal Derby Hospital, Derby, UK. john.robertson@nottingham.ac.uk
authors: John Fr
authors: JF
authors: Robertson
authors: Jean-Marc
authors: JM
authors: Ferrero
authors: Hugues
authors: H
authors: Bourgeois
authors: Hagen
authors: H
authors: Kennecke
authors: Richard H
authors: RH
authors: de Boer
authors: William
authors: W
authors: Jacot
authors: Jesse
authors: J
authors: McGreivy
authors: Samuel
authors: S
authors: Suzuki
authors: Min
authors: M
authors: Zhu
authors: Ian
authors: I
authors: McCaffery
authors: Elwyn
authors: E
authors: Loh
authors: Jennifer L
authors: JL
authors: Gansert
authors: Peter A
authors: PA
authors: Kaufman
mesh_terms: D000368:Aged; D000730:Androstadienes / Q000008:administration & dosage / Q000009:adverse effects; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004958:Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017698:Postmenopause; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics
chemical_list: D000730:Androstadienes; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004958:Estradiol; D000077267:Fulvestrant; D018719:Erb-b2 Receptor Tyrosine Kinases; C545764:ganitumab; C508053:ERBB2 protein, human; C056516:exemestane