title: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response.
abstract: BACKGROUND
  Findings from the randomised phase 3 NeoALTTO trial in women with HER2-positive early breast cancer showed that the combination of lapatinib and trastuzumab significantly improved rates of pathological complete response compared with either drug alone. Here, we report data for the prespecified secondary endpoints of event-free and overall survival, and assess the association between these outcomes and pathological complete response.
  
  
  METHODS
  We enrolled women with HER2-positive early breast cancer and randomly assigned them to receive oral lapatinib (1500 mg), intravenous trastuzumab (4 mg/kg loading dose followed by 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab (same dose as for single agent) in combination for 6 weeks, followed by an additional 12 weeks of the assigned anti-HER2 therapy in combination with weekly paclitaxel (80 mg/m(2)). Definitive surgery was done 4 weeks after the last dose of paclitaxel. After surgery, women received three cycles of FEC (fluorouracil 500 mg/m(2) plus epirubicin 100 mg/m(2) plus cyclophosphamide 500 mg/m(2)) given intravenously every 3 weeks, followed by 34 weeks of the same assigned neoadjuvant anti-HER2 therapy. The primary endpoint was pathological complete response. Secondary endpoints included event-free and overall survival (intention-to-treat analysis), and the association between pathological complete response and event-free or overall survival (analysed by landmark analysis at 30 weeks after randomisation). Follow-up is ongoing, and the trial is registered with ClinicalTrials.gov, number NCT00553358.
  
  
  RESULTS
  455 patients were enrolled: 154 (34%) were assigned to the lapatinib group, 149 (33%) to the trastuzumab group, and 152 (33%) to the lapatinib plus trastuzumab group. At an event follow-up of 3·77 years (IQR 3·50-4·22), 3-year event-free survival was 78% (95% CI 70-84) in the lapatinib group, 76% (68-82) in the trastuzumab group, and 84% (77-89) in the combination group. Event-free survival did not differ between the lapatinib and trastuzumab groups (HR 1·06, 95% CI 0·66-1·69, p=0·81), nor between the combination and trastuzumab groups (0·78, 0·47-1·28, p=0·33). Median survival follow-up was 3·84 years (IQR 3·60-4·24), and 3-year overall survival was 93% (95% CI 87-96) for lapatinib, 90% (84-94) for trastuzumab, and 95% (90-98) for combination therapy. Overall survival did not significantly differ between the lapatinib and trastuzumab groups (HR 0·86, 95% CI 0·45-1·63, p=0·65), nor between the combination and trastuzumab groups (0·62, 0·30-1·25, p=0·19). Landmark analyses showed that 3-year event-free survival was significantly improved for women who achieved pathological complete response compared with those who did not (HR 0·38, 95% CI 0·22-0·63, p=0·0003), as was 3-year overall survival (0·35, 0·15-0·70, p=0·005). Adverse events occurred in 149 (99%) patients receiving lapatinib, 142 (96%) patients receiving trastuzumab, and 147 (99%) patients receiving combination therapy. The most common adverse events were diarrhoea, rash or erythema, hepatic adverse events, and neutropenia (not related to FEC administration), and were consistent with known safety profiles of lapatinib and trastuzumab. Three primary and eight secondary cardiac events occurred, with no significant difference in incidence between treatment groups for primary or any cardiac events.
  
  
  CONCLUSIONS
  Although event-free survival or overall survival did not differ between treatment groups, findings from our study confirm that patients who achieve pathological complete response after neoadjuvant anti-HER2 therapy have longer event-free and overall survival than do patients without pathological complete response.
  
  
  BACKGROUND
  GlaxoSmithKline.
authors.affiliation: Institut Jules Bordet and Breast European Adjuvant Study Team, Brussels, Belgium. Electronic address: evandro.azambuja@bordet.be.
authors.forename: Evandro
authors.initials: E
authors.lastname: de Azambuja
authors.affiliation: Frontier Science (Scotland) Ltd, Grampian View, Kincraig, Kingussie, UK.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Holmes
authors.affiliation: Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart-Gebhart
authors.affiliation: Frontier Science (Scotland) Ltd, Grampian View, Kincraig, Kingussie, UK.
authors.forename: Eileen
authors.initials: E
authors.lastname: Holmes
authors.affiliation: Istituto Nazionale del Tumori, Milan, Italy; SOLTI Breast Cancer Research Group, Spain.
authors.forename: Serena
authors.initials: S
authors.lastname: Di Cosimo
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Ramona F
authors.initials: RF
authors.lastname: Swaby
authors.affiliation: Clinic for Gynaecology, Gynaecologic Oncology and Obstetrics and Breast Cancer Centre, HELIOS Klinikum Berlin, Buch, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Untch
authors.affiliation: Sana Klinikum Offenbach, Offenbach, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Jackisch
authors.affiliation: National Institute of Oncology, Budapest, Hungary.
authors.forename: Istvan
authors.initials: I
authors.lastname: Lang
authors.affiliation: Royal Marsden Hospital, London, UK; Institute of Cancer Research, London, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Smith
authors.affiliation: Patricia Ritchie Centre for Cancer Care and Research, The University of Sydney, Mater Hospital, North Sydney, NSW, Australia.
authors.forename: Frances
authors.initials: F
authors.lastname: Boyle
authors.affiliation: Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Binghe
authors.initials: B
authors.lastname: Xu
authors.affiliation: PUC-RS School of Medicine, Porto Alegre, Brazil.
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Barrios
authors.affiliation: Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
authors.affiliation: Institut Jules Bordet and Breast European Adjuvant Study Team, Brussels, Belgium.
authors.forename: Hatem A
authors.initials: HA
authors.lastname: Azim
authors.affiliation: Asian Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Sung-Bae
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Kliniken Essen-Mitte, Essen, Germany.
authors.forename: Sherko
authors.initials: S
authors.lastname: Kuemmel
authors.affiliation: National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chiun-Sheng
authors.initials: CS
authors.lastname: Huang
authors.affiliation: Clinique St-Elisabeth, Namur, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Vuylsteke
authors.affiliation: Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Ruey-Kuen
authors.initials: RK
authors.lastname: Hsieh
authors.affiliation: Kashirskoye Shosse, Moscow, Russia.
authors.forename: Vera
authors.initials: V
authors.lastname: Gorbunova
authors.affiliation: Cancer Institute "Prof Dr Ion Chiricuta", Cluj-Napoca, Romania.
authors.forename: Alexandru
authors.initials: A
authors.lastname: Eniu
authors.affiliation: Department of Medical Oncology, University of Pretoria, Pretoria, South Africa.
authors.forename: Lydia
authors.initials: L
authors.lastname: Dreosti
authors.affiliation: Odessa Oncology Centre, Odessa, Ukraine.
authors.forename: Natalia
authors.initials: N
authors.lastname: Tavartkiladze
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Frontier Science and Technology Research Foundation, Boston, MA, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gelber
authors.affiliation: University Hospital Kiel, Kiel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Eidtmann
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D017024:Chemotherapy, Adjuvant; D016001:Confidence Intervals; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D000077341:Lapatinib; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D016019:Survival Analysis; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab