title: Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer.
abstract: OBJECTIVE
  One third of women with advanced human epidermal growth factor receptor 2 (HER-2)-positive breast cancer develop brain metastases; a subset progress in the CNS despite standard approaches. Medical therapies for refractory brain metastases are neither well-studied nor established. We evaluated the safety and efficacy of lapatinib, an oral inhibitor of epidermal growth factor receptor (EGFR) and HER-2, in patients with HER-2-positive brain metastases.
  
  
  METHODS
  Patients had HER-2-positive breast cancer, progressive brain metastases, prior trastuzumab treatment, and at least one measurable metastatic brain lesion. Patients received lapatinib 750 mg orally twice a day. Tumor response was assessed by magnetic resonance imaging every 8 weeks. The primary end point was objective response (complete response [CR] plus partial response [PR]) in the CNS by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included objective response in non-CNS sites, time to progression, overall survival, and toxicity.
  
  
  RESULTS
  Thirty-nine patients were enrolled. All patients had developed brain metastases while receiving trastuzumab; 37 had progressed after prior radiation. One patient achieved a PR in the brain by RECIST (objective response rate 2.6%, 95% conditional CI, 0.21% to 26%). Seven patients (18%) were progression free in both CNS and non-CNS sites at 16 weeks. Exploratory analyses identified additional patients with some degree of volumetric reduction in brain tumor burden. The most common adverse events (AEs) were diarrhea (grade 3, 21%) and fatigue (grade 3, 15%).
  
  
  CONCLUSIONS
  The study did not meet the predefined criteria for antitumor activity in highly refractory patients with HER-2-positive brain metastases. Because of the volumetric changes observed in our exploratory analysis, further studies are underway utilizing volumetric changes as a primary end point.
authors.affiliation: Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA.
authors.forename: Nancy U
authors.initials: NU
authors.lastname: Lin
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
authors.forename: Minetta C
authors.initials: MC
authors.lastname: Liu
authors.forename: Jerry
authors.initials: J
authors.lastname: Younger
authors.forename: Steven E
authors.initials: SE
authors.lastname: Come
authors.forename: Matthew
authors.initials: M
authors.lastname: Ewend
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Harris
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bullitt
authors.forename: Annick D
authors.initials: AD
authors.lastname: Van den Abbeele
authors.forename: John W
authors.initials: JW
authors.lastname: Henson
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Li
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gelman
authors.forename: Harold J
authors.initials: HJ
authors.lastname: Burstein
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kasparian
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
authors.forename: Ann
authors.initials: A
authors.lastname: Crawford
authors.forename: Fred
authors.initials: F
authors.lastname: Hochberg
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases