title: Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer.
abstract: OBJECTIVE
  Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine.
  
  
  METHODS
  Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as >or=50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease.
  
  
  RESULTS
  Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a >or=20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a >or=20% volumetric reduction in their CNS lesions.
  
  
  CONCLUSIONS
  This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Nancy U
authors.initials: NU
authors.lastname: Lin
authors.forename: Véronique
authors.initials: V
authors.lastname: Diéras
authors.forename: Devchand
authors.initials: D
authors.lastname: Paul
authors.forename: Dominique
authors.initials: D
authors.lastname: Lossignol
authors.forename: Christos
authors.initials: C
authors.lastname: Christodoulou
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Stemmler
authors.forename: Henri
authors.initials: H
authors.lastname: Roché
authors.forename: Minetta C
authors.initials: MC
authors.lastname: Liu
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
authors.forename: Eva
authors.initials: E
authors.lastname: Ciruelos
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
authors.forename: Stefania
authors.initials: S
authors.lastname: Gori
authors.forename: Andrew
authors.initials: A
authors.lastname: Wardley
authors.forename: Denise
authors.initials: D
authors.lastname: Yardley
authors.forename: Adam
authors.initials: A
authors.lastname: Brufsky
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Blum
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Rubin
authors.forename: Bernie
authors.initials: B
authors.lastname: Dharan
authors.forename: Klaudia
authors.initials: K
authors.lastname: Steplewski
authors.forename: Denise
authors.initials: D
authors.lastname: Zembryki
authors.forename: Cristina
authors.initials: C
authors.lastname: Oliva
authors.forename: Debasish
authors.initials: D
authors.lastname: Roychowdhury
authors.forename: Paolo
authors.initials: P
authors.lastname: Paoletti
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis* / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D000069287:Capecitabine; D003841:Deoxycytidine; D005472:Fluorouracil; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human