title: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial.
abstract: BACKGROUND
  The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer. We argue that the two anti-HER2 agents given together would be better than single-agent therapy.
  
  
  METHODS
  In this parallel groups, randomised, open-label, phase 3 study undertaken between Jan 5, 2008, and May 27, 2010, women from 23 countries with HER2-positive primary breast cancer with tumours greater than 2 cm in diameter were randomly assigned to oral lapatinib (1500 mg), intravenous trastuzumab (loading dose 4 mg/kg [DOSAGE ERROR CORRECTED], subsequent doses 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab. Treatment allocation was by stratified, permuted blocks randomisation, with four stratification factors. Anti-HER2 therapy alone was given for the first 6 weeks; weekly paclitaxel (80 mg/m(2)) was then added to the regimen for a further 12 weeks, before definitive surgery was undertaken. After surgery, patients received adjuvant chemotherapy followed by the same targeted therapy as in the neoadjuvant phase to 52 weeks. The primary endpoint was the rate of pathological complete response (pCR), analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00553358.
  
  
  RESULTS
  154 patients received lapatinib, 149 trastuzumab, and 152 the combination. pCR rate was significantly higher in the group given lapatinib and trastuzumab (78 of 152 patients [51·3%; 95% CI 43·1-59·5]) than in the group given trastuzumab alone (44 of 149 patients [29·5%; 22·4-37·5]; difference 21·1%, 9·1-34·2, p=0·0001). We recorded no significant difference in pCR between the lapatinib (38 of 154 patients [24·7%, 18·1-32·3]) and the trastuzumab (difference -4·8%, -17·6 to 8·2, p=0·34) groups. No major cardiac dysfunctions occurred. Frequency of grade 3 diarrhoea was higher with lapatinib (36 patients [23·4%]) and lapatinib plus trastuzumab (32 [21·1%]) than with trastuzumab (three [2·0%]). Similarly, grade 3 liver-enzyme alterations were more frequent with lapatinib (27 [17·5%]) and lapatinib plus trastuzumab (15 [9·9%]) than with trastuzumab (11 [7·4%]).
  
  
  CONCLUSIONS
  Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting.
  
  
  BACKGROUND
  GlaxoSmithKline.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA. jbaselga@partners.org
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Ian
authors.initials: I
authors.lastname: Bradbury
authors.forename: Holger
authors.initials: H
authors.lastname: Eidtmann
authors.forename: Serena
authors.initials: S
authors.lastname: Di Cosimo
authors.forename: Evandro
authors.initials: E
authors.lastname: de Azambuja
authors.forename: Claudia
authors.initials: C
authors.lastname: Aura
authors.forename: Henry
authors.initials: H
authors.lastname: Gómez
authors.forename: Phuong
authors.initials: P
authors.lastname: Dinh
authors.forename: Karine
authors.initials: K
authors.lastname: Fauria
authors.forename: Veerle
authors.initials: V
authors.lastname: Van Dooren
authors.forename: Gursel
authors.initials: G
authors.lastname: Aktan
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
authors.forename: Tsai-Wang
authors.initials: TW
authors.lastname: Chang
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Horváth
authors.forename: Maria
authors.initials: M
authors.lastname: Coccia-Portugal
authors.forename: Julien
authors.initials: J
authors.lastname: Domont
authors.forename: Ling-Min
authors.initials: LM
authors.lastname: Tseng
authors.forename: Georg
authors.initials: G
authors.lastname: Kunz
authors.forename: Joo Hyuk
authors.initials: JH
authors.lastname: Sohn
authors.forename: Vladimir
authors.initials: V
authors.lastname: Semiglazov
authors.forename: Guillermo
authors.initials: G
authors.lastname: Lerzo
authors.forename: Marketa
authors.initials: M
authors.lastname: Palacova
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Probachai
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.forename: Michael
authors.initials: M
authors.lastname: Untch
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gelber
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart-Gebhart
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D000077341:Lapatinib; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors*; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D000077341:Lapatinib; D017239:Paclitaxel; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab