title: Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy.
abstract: BACKGROUND
  Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor with clinical activity in patients with ErbB2/HER2-positive breast cancer.
  
  
  METHODS
  Phase I of this open-label, phase I/II study investigated the maximum tolerated dose (MTD) of oral neratinib (160 or 240 mg/day) plus vinorelbine (25 mg/m2; days 1 and 8 of each 21-day cycle) in patients with solid tumors. Phase II assessed the safety, clinical activity, and pharmacokinetics of the combination in patients with HER2-positive metastatic breast cancer; the primary efficacy end point was objective response (OR).
  
  
  RESULTS
  In phase I (n=12), neratinib (240 mg) plus vinorelbine (25 mg/m2) was established as the MTD. In phase II, 79 patients with HER2-positive metastatic breast cancer were treated at the MTD. The most common treatment-related adverse events were diarrhea (96%), neutropenia (54%), and nausea (50%). Three patients discontinued treatment due to diarrhea. No clinically important skin side-effects were observed. The OR rate in assessable phase II patients was 41% (no prior lapatinib) and 8% (prior lapatinib). There was no evidence of pharmacokinetic interaction between neratinib and vinorelbine.
  
  
  CONCLUSIONS
  Neratinib plus vinorelbine showed promising antitumor activity and no unexpected toxic effects in HER2-positive metastatic breast cancer patients. Trial registration ClinicalTrials.gov #NCT00706030.
authors.affiliation: Medical Oncology Clinic, Jules Bordet Institute, Brussels University, Brussels. ahmad.awada@bordet.be
authors.forename: A
authors.initials: A
authors.lastname: Awada
authors.forename: L
authors.initials: L
authors.lastname: Dirix
authors.forename: L
authors.initials: L
authors.lastname: Manso Sanchez
authors.forename: B
authors.initials: B
authors.lastname: Xu
authors.forename: T
authors.initials: T
authors.lastname: Luu
authors.forename: V
authors.initials: V
authors.lastname: Diéras
authors.forename: D L
authors.initials: DL
authors.lastname: Hershman
authors.forename: V
authors.initials: V
authors.lastname: Agrapart
authors.forename: R
authors.initials: R
authors.lastname: Ananthakrishnan
authors.forename: E
authors.initials: E
authors.lastname: Staroslawska
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077235:Vinorelbine
chemical_list: D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D014747:Vinblastine; D000077235:Vinorelbine; C508053:ERBB2 protein, human; C487932:neratinib