title: Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): an open-label, randomised, phase 3 trial.
abstract: BACKGROUND
  Trastuzumab resistance is a key therapeutic challenge in metastatic breast cancer. We postulated that broader inhibition of ErbB receptors with afatinib would improve clinical outcomes compared with HER2 inhibition alone in patients who had progressed on previous trastuzumab treatment. LUX-Breast 1 compared afatinib plus vinorelbine with trastuzumab plus vinorelbine for such patients with HER2-positive metastatic breast cancer.
  
  
  METHODS
  We did this open-label trial at 350 hospitals in 41 countries worldwide. We enrolled female patients with HER2-overexpressing metastatic breast cancer who had progressed on or following adjuvant trastuzumab or first-line treatment of metastatic disease with trastuzumab. Participants were randomly assigned (2:1) to receive oral afatinib (40 mg/day) plus intravenous vinorelbine (25 mg/m(2) per week) or intravenous trastuzumab (2 mg/kg per week after 4 mg/kg loading dose) plus vinorelbine. Randomisation was done centrally and stratified by previous trastuzumab treatment (adjuvant vs first-line treatment), hormone receptor status (oestrogen receptor and progesterone receptor positive vs others), and region. The primary endpoint was progression-free survival, assessed in the intention-to-treat population. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT01125566.
  
  
  RESULTS
  Between Aug 26, 2010, and April 26, 2013, we enrolled 508 patients: 339 assigned to the afatinib group and 169 assigned to the trastuzumab group. Recruitment was stopped on April 26, 2013, after a benefit-risk assessment by the independent data monitoring committee was unfavourable for the afatinib group. Patients on afatinib plus vinorelbine had to switch to trastuzumab plus vinorelbine, afatinib monotherapy, vinorelbine monotherapy, or receive treatment outside of the trial. Median follow-up was 9·3 months (IQR 3·7-16·0). Median progression-free survival was 5·5 months (95% CI 5·4-5·6) in the afatinib group and 5·6 months (5·3-7·3) in the trastuzumab group (hazard ratio 1·10 95% CI 0·86-1·41; p=0·43). The most common drug-related adverse events of grade 3 or higher were neutropenia (190 [56%] of 337 patients in the afatinib group vs 102 [60%] of 169 patients in the trastuzumab group), leucopenia (64 [19%] vs 34 [20%]), and diarrhoea (60 [18%] vs none).
  
  
  CONCLUSIONS
  Trastuzumab-based therapy remains the treatment of choice for patients with HER2-positive metastatic breast cancer who had progressed on trastuzumab.
  
  
  BACKGROUND
  Boehringer Ingelheim.
authors.affiliation: Brustzentrum der Universität München and Comprehensive Cancer Center of the Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.affiliation: National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Taiwan Breast Cancer Consortium, Taipei, Taiwan.
authors.forename: Chiun-Sheng
authors.initials: CS
authors.lastname: Huang
authors.affiliation: University of California, Los Angeles, Los Angeles, CA, USA; Translational Research in Oncology, Los Angeles, CA, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Hurvitz
authors.affiliation: Taiwan Breast Cancer Consortium, Taipei, Taiwan; Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Dah-Cherng
authors.initials: DC
authors.lastname: Yeh
authors.affiliation: Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.affiliation: Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Kyung Hae
authors.initials: KH
authors.lastname: Jung
authors.affiliation: Comprehensive Breast Health Center, Rui Jin Hospital, Shanghai, China.
authors.forename: Kunwei
authors.initials: K
authors.lastname: Shen
authors.affiliation: National Cancer Center, Goyang, South Korea.
authors.forename: Jungsil
authors.initials: J
authors.lastname: Ro
authors.affiliation: Medical University, Gdansk, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Jassem
authors.affiliation: Cancer Hospital of Harbin Medical University, Harbin, China.
authors.forename: Qingyuan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Samsung Medical Center, Seoul, South Korea.
authors.forename: Young-Hyuck
authors.initials: YH
authors.lastname: Im
authors.affiliation: Comprehensive Cancer Centre, Medical University, Bialystok, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Wojtukiewicz
authors.affiliation: Peking Union Medical College Hospital, Beijing, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Taiwan Breast Cancer Consortium, Taipei, Taiwan; Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Shin-Cheh
authors.initials: SC
authors.lastname: Chen
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany.
authors.forename: Rainer-Georg
authors.initials: RG
authors.lastname: Goeldner
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Uttenreuther-Fischer
authors.affiliation: Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Peking Union Medical College, Beijing, China. Electronic address: bhxu@hotmail.com.
authors.forename: Binghe
authors.initials: B
authors.lastname: Xu
authors.affiliation: Institut Jules Bordet, Brussels, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart-Gebhart
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008408:Mastectomy / Q000379:methods; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D018570:Risk Assessment; D016019:Survival Analysis; D000068878:Trastuzumab / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000077235:Vinorelbine
chemical_list: D000077716:Afatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D014747:Vinblastine; D000077235:Vinorelbine