title: A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses.
abstract: OBJECTIVE
  Lapatinib is a small molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor type 2 (HER2). Initial results of a phase III trial demonstrated that lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that progressed following prior therapy including trastuzumab. Updated efficacy and initial biomarker results from this trial are reported.
  
  
  METHODS
  Women with HER2-positive, locally advanced or metastatic breast cancer previously treated with anthracycline-, taxane-, and trastuzumab-containing regimens were randomized to lapatinib 1,250 mg/day continuously plus capecitabine 2,000 mg/m(2) days 1-14 of a 21-day cycle or capecitabine 2,500 mg/m(2) on the same schedule. The primary endpoint was time to progression (TTP) as determined by an independent review panel. Relationship between progression-free survival (PFS) and tumor HER2 expression and serum levels of HER2 extracellular domain (ECD) were assessed.
  
  
  RESULTS
  399 women were randomized. The addition of lapatinib prolonged TTP with a hazard ratio (HR) of 0.57 (95% CI, 0.43-0.77; P < 0.001) and provided a trend toward improved overall survival (HR: 0.78, 95% CI: 0.55-1.12, P = 0.177), and fewer cases with CNS involvement at first progression (4 vs. 13, P = 0.045). Baseline serum HER2 ECD did not predict for benefit from lapatinib.
  
  
  CONCLUSIONS
  The addition of lapatinib to capecitabine provides superior efficacy for women with HER2-positive, advanced breast cancer progressing after treatment with anthracycline-, taxane-, and trastuzumab-based therapy. Biomarker studies could not identify a subgroup of patients who failed to benefit from the addition of lapatinib to capecitabine.
authors.affiliation: University of Leeds, Leeds, England, UK. d.cameron@ncrn.org.uk
authors.forename: David
authors.initials: D
authors.lastname: Cameron
authors.forename: Michelle
authors.initials: M
authors.lastname: Casey
authors.forename: Michael
authors.initials: M
authors.lastname: Press
authors.forename: Deborah
authors.initials: D
authors.lastname: Lindquist
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Pienkowski
authors.forename: C Gilles
authors.initials: CG
authors.lastname: Romieu
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Jagiello-Gruszfeld
authors.forename: Bella
authors.initials: B
authors.lastname: Kaufman
authors.forename: John
authors.initials: J
authors.lastname: Crown
authors.forename: Arlene
authors.initials: A
authors.lastname: Chan
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.forename: Patrice
authors.initials: P
authors.lastname: Viens
authors.forename: Neville
authors.initials: N
authors.lastname: Davidson
authors.forename: Vera
authors.initials: V
authors.lastname: Gorbounova
authors.forename: Johannes Isaac
authors.initials: JI
authors.lastname: Raats
authors.forename: Dimosthenis
authors.initials: D
authors.lastname: Skarlos
authors.forename: Beth
authors.initials: B
authors.lastname: Newstat
authors.forename: Debasish
authors.initials: D
authors.lastname: Roychowdhury
authors.forename: Paolo
authors.initials: P
authors.lastname: Paoletti
authors.forename: Cristina
authors.initials: C
authors.lastname: Oliva
authors.forename: Stephen
authors.initials: S
authors.lastname: Rubin
authors.forename: Steven
authors.initials: S
authors.lastname: Stein
authors.forename: Charles E
authors.initials: CE
authors.lastname: Geyer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy*; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018450:Disease Progression; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000008:administration & dosage*; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D011799:Quinazolines; D000077341:Lapatinib; D003841:Deoxycytidine; D000069287:Capecitabine; D011505:Protein-Tyrosine Kinases; D000068878:Trastuzumab; D005472:Fluorouracil