title: Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial.
abstract: BACKGROUND
  We compared the efficacy and safety of the addition of lapatinib versus trastuzumab to anthracycline-taxane-based neoadjuvant chemotherapy.
  
  
  METHODS
  In the GeparQuinto randomised phase 3 trial, patients with untreated HER2-positive operable or locally advanced breast cancer were enrolled between Nov 7, 2007, and July 9, 2010. Patients were eligible if their tumours were classified as cT3/4a-d, or hormone receptor (HR)-negative, HR-positive with clinically node-positive and cT2 disease (cT2 cN+), or HR-positive and pathologically node-positive in the sentinel lymph node for those with cT1 disease (cT1 pN(SLN+)). Patients were randomly assigned in a 1:1 ratio to receive neoadjuvant treatment with four cycles of EC (epirubicin [90 mg/m(2) intravenously] plus cyclophosphamide [600 mg/m(2) intravenously], every 3 weeks), and four cycles of docetaxel (100 mg/m(2) intravenously every 3 weeks) with either trastuzumab (6 mg/kg intravenously, with a starting loading dose of 8 mg/kg, for eight cycles, every 3 weeks) or lapatinib (1000-1250 mg per day orally) throughout all cycles before surgery. Randomisation was done by dynamic allocation with the minimisation method of Pocock and patients were stratified by participating site, HR status, and extent of disease (cT1-3 cN0-2 vs T4 or N3). The primary endpoint was pathological complete response (defined as ypT0 and ypN0) and was analysed in all patients who received at least one cycle of EC. Participants and investigators were not masked to treatment assignment. Pathologists in centres assessing surgery outcomes were masked to group assignment. This trial is registered with ClinicalTrials.gov, number NCT00567554.
  
  
  RESULTS
  Of 620 eligible patients, 309 were randomly assigned to chemotherapy with trastuzumab (ECH-TH group) and 311 to chemotherapy with lapatinib (ECL-TL group). Two patients in the ECH-TH group and three patients in the ECL-TL group did not start treatment because of withdrawal of consent or immediate surgery. 93 (30·3%) of 307 patients in the ECH-TH group and 70 (22·7%) of 308 patients in the ECL-TL group had a pathological complete response (odds ratio [OR] 0·68 [95%CI 0·47-0·97]; p=0·04). Chemotherapy with trastuzumab was associated with more oedema (119 [39·1%] vs 88 [28·7%]) and dyspnoea (90 [29·6%] vs 66 [21·4%]), and ECL-TL with more diarrhoea (231 [75·0%] vs 144 [47·4%]) and skin rash (169 [54·9%] vs 97 [31·9%]). 43 (14·0%) patients discontinued in the ECH-TH group and 102 (33·1%) in the ECL-TL group. 70 serious adverse events were reported in the ECH-TH group and 87 in the ECL-TL group.
  
  
  CONCLUSIONS
  This direct comparison of trastuzumab and lapatinib showed that pathological complete response rate with chemotherapy and lapatinib was significantly lower than that with chemotherapy and trastuzumab. Unless long-term outcome data show different results, lapatinib should not be used outside of clinical trials as single anti-HER2-treatment in combination with neoadjuvant chemotherapy.
  
  
  BACKGROUND
  GlaxoSmithKline, Roche, and Sanofi-Aventis.
authors.affiliation: Helios-Klinikum, Berlin-Buch, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Untch
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
authors.forename: Joachim
authors.initials: J
authors.lastname: Bischoff
authors.forename: Holger
authors.initials: H
authors.lastname: Eidtmann
authors.forename: Manfred
authors.initials: M
authors.lastname: Kaufmann
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Blohmer
authors.forename: Jörn
authors.initials: J
authors.lastname: Hilfrich
authors.forename: Dirk
authors.initials: D
authors.lastname: Strumberg
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.forename: Rolf
authors.initials: R
authors.lastname: Kreienberg
authors.forename: Hans
authors.initials: H
authors.lastname: Tesch
authors.forename: Claus
authors.initials: C
authors.lastname: Hanusch
authors.forename: Bernd
authors.initials: B
authors.lastname: Gerber
authors.forename: Mahdi
authors.initials: M
authors.lastname: Rezai
authors.forename: Christian
authors.initials: C
authors.lastname: Jackisch
authors.forename: Jens
authors.initials: J
authors.lastname: Huober
authors.forename: Thorsten
authors.initials: T
authors.lastname: Kühn
authors.forename: Valentina
authors.initials: V
authors.lastname: Nekljudova
authors.forename: Gunter
authors.initials: G
authors.lastname: von Minckwitz
mesh_terms: D000368:Aged; D018943:Anthracyclines / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D001952:Bridged-Ring Compounds / Q000627:therapeutic use; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D043823:Taxoids / Q000627:therapeutic use; D000068878:Trastuzumab; D055815:Young Adult
chemical_list: D018943:Anthracyclines; D061067:Antibodies, Monoclonal, Humanized; D001952:Bridged-Ring Compounds; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C080625:taxane; C508053:ERBB2 protein, human