title: Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study.
abstract: BACKGROUND
  Brain metastases occur in 30-50% of patients with metastatic HER2-positive breast cancer. In the case of diffuse brain metastases, treatment is based on whole brain radiotherapy (WBRT). Few systemic options are available. We aimed to investigate the combination of lapatinib plus capecitabine for the treatment of previously untreated brain metastases from HER2-positive breast cancer.
  
  
  METHODS
  In this single-arm phase 2, open-label, multicentre study, eligible patients had HER2-positive metastatic breast cancer with brain metastases not previously treated with WBRT, capecitabine, or lapatinib. Tretament was given in 21 day cycles: patients received lapatinib (1250 mg, orally) every day and capecitabine (2000 mg/m(2), orally) from day 1 to day 14. The primary endpoint was the proportion of patients with an objective CNS response, defined as a 50% or greater volumetric reduction of CNS lesions in the absence of increased steroid use, progressive neurological symptoms, and progressive extra-CNS disease. All responses had to be confirmed 4 weeks after initial response. Efficacy analyses included all patients who received the study drugs and were assessable for efficacy criteria. This trial is registered with ClinicalTrials.gov, number NCT00967031.
  
  
  RESULTS
  Between April 15, 2009, to Aug 2, 2010, we enrolled 45 patients, 44 (98%) of whom were assessable for efficacy, with a median follow-up of 21·2 months (range 2·2-27·6). 29 patients had an objective CNS response (65·9%, 95% CI 50·1-79·5); all were partial responses. Of all 45 treated patients, 22 (49%) had grade 3 or grade 4 treatment-related adverse events, of which the most common were diarrhoea in nine (20%) patients and hand-foot syndrome in nine (20%) patients. 14 (31%) patients had at least one severe adverse event; treatment was discontinued because of toxicity in four patients. No toxic deaths occurred.
  
  
  CONCLUSIONS
  The combination of lapatinib and capecitabine is active as first-line treatment of brain metastases from HER2-positive breast cancer. A phase 3 trial is warranted.
  
  
  BACKGROUND
  GlaxoSmithKline-France and UNICANCER.
authors.affiliation: Department of Medical Oncology and Léon-Bérard Centre, Lyon, France. thomas.bachelot@lyon.unicancer.fr
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelot
authors.forename: Gilles
authors.initials: G
authors.lastname: Romieu
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.forename: Véronique
authors.initials: V
authors.lastname: Diéras
authors.forename: Claire
authors.initials: C
authors.lastname: Cropet
authors.forename: Florence
authors.initials: F
authors.lastname: Dalenc
authors.forename: Marta
authors.initials: M
authors.lastname: Jimenez
authors.forename: Emilie
authors.initials: E
authors.lastname: Le Rhun
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Pierga
authors.forename: Anthony
authors.initials: A
authors.lastname: Gonçalves
authors.forename: Marianne
authors.initials: M
authors.lastname: Leheurteur
authors.forename: Julien
authors.initials: J
authors.lastname: Domont
authors.forename: Maya
authors.initials: M
authors.lastname: Gutierrez
authors.forename: Hervé
authors.initials: H
authors.lastname: Curé
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Ferrero
authors.forename: Catherine
authors.initials: C
authors.lastname: Labbe-Devilliers
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000069287:Capecitabine; D002490:Central Nervous System / Q000187:drug effects / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced / Q000145:classification / Q000473:pathology; D023381:Endpoint Determination; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D009367:Neoplasm Staging; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
chemical_list: D000069287:Capecitabine; D003841:Deoxycytidine; D005472:Fluorouracil; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human