title: Afatinib alone or afatinib plus vinorelbine versus investigator's choice of treatment for HER2-positive breast cancer with progressive brain metastases after trastuzumab, lapatinib, or both (LUX-Breast 3): a randomised, open-label, multicentre, phase 2 trial.
abstract: BACKGROUND
  Patients with advanced HER2-positive breast cancer frequently develop CNS metastases. The metastases that progress after brain radiotherapy and HER2-targeted systemic therapy are a difficult therapeutic challenge. We aimed to assess the efficacy and safety of afatinib, an irreversible blocker of the ErbB protein family, alone or combined with vinorelbine, compared with treatment of the investigator's choice in women with HER2-positive breast cancer with progressive brain metastases during or after treatment with trastuzumab, lapatinib, or both.
  
  
  METHODS
  We did this randomised, open-label, multicentre, phase 2 trial in 40 hospitals in Canada, Finland, France, Germany, Italy, Spain, South Korea, and the USA. Women older than 18 years with histologically confirmed HER2-overexpressing breast cancer and CNS recurrence or progression as determined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) during or after treatment with trastuzumab, lapatinib, or both, were eligible. We randomly assigned patients (1:1:1) centrally to afatinib 40 mg orally once per day, afatinib 40 mg per day plus intravenous vinorelbine 25 mg/m(2) once per week, or investigator's choice of treatment in cycles of 3 weeks until disease progression, patient withdrawal, or unacceptable toxicity. Treatment assignment was not masked for clinicians or patients, but the trial team was masked until database lock to reduce bias. The primary endpoint, assessed in the intention-to-treat population, was patient benefit at 12 weeks, defined by an absence of CNS or extra-CNS disease progression, no tumour-related worsening of neurological signs or symptoms, and no increase in corticosteroid dose. Safety was assessed in all patients who received at least one dose of a study drug. This completed trial is registered with ClinicalTrials.gov, number NCT01441596.
  
  
  RESULTS
  Between Dec 22, 2011, and Feb 12, 2013, we screened 132 patients, of whom 121 were eligible and randomly assigned to treatment: 40 to afatinib alone, 38 to afatinib plus vinorelbine, and 43 to investigator's choice. All patients discontinued study treatment before the data collection cutoff on Oct 16, 2014. Patient benefit was achieved in 12 (30·0%; 95% CI 16·6-46·5) patients given afatinib alone (difference vs investigator's choice: -11·9% [95% CI -32·9 to 9·7], p=0·37), 13 (34·2%; 19·6-51·4) given afatinib plus vinorelbine (difference vs investigator's choice: -7·6% [-28·9 to 14·2], p=0·63), and 18 (41·9%; 27·0-57·9) given investigator's choice. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (seven [18%] of 40 patients in the afatinib only group vs nine [24%] of 37 patients in the afatinib plus vinorelbine group vs two [5%] of 42 patients in the investigator's choice group) and neutropenia (none vs 14 [38%] vs four [10%]).
  
  
  CONCLUSIONS
  Patient benefit with afatinib-containing treatments was not different from that in patients given investigator's choice of treatments; however, adverse events were frequent and afatinib-containing treatments seemed to be less well tolerated. No further development of afatinib for HER2-positive breast cancer is currently planned.
  
  
  BACKGROUND
  Boehringer Ingelheim.
authors.affiliation: Vall d'Hebron Institute of Oncology, Barcelona, Spain and Ramon y Cajal University Hospital, Madrid, Spain. Electronic address: jacortes@vhio.net.
authors.forename: Javier
authors.initials: J
authors.lastname: Cortés
authors.affiliation: Institut Curie, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dieras
authors.affiliation: National Cancer Center, Goyang-si, Republic of Korea.
authors.forename: Jungsil
authors.initials: J
authors.lastname: Ro
authors.affiliation: Centre Antoine Lacassagne, Nice, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Barriere
authors.affiliation: Centre Léon Bérard, Lyon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelot
authors.affiliation: University of California, Los Angeles, CA, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Hurvitz
authors.affiliation: Centre Oscar Lambret, Lille, France; University Hospital, Lille, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Le Rhun
authors.affiliation: Hôpital Saint-Louis, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Espié
authors.affiliation: Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Sung-Bae
authors.initials: SB
authors.lastname: Kim
authors.affiliation: National Center for Tumor Diseases, University Hospital, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schneeweiss
authors.affiliation: Severance Hospital, Sinchon-dong, Seodaemun-gu, Seoul, South Korea.
authors.forename: Joo Hyuk
authors.initials: JH
authors.lastname: Sohn
authors.affiliation: Centre Jean Perrin, Clermont-Ferrand, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Nabholtz
authors.affiliation: Tampere University Hospital and University of Tampere, Tampere, Finland.
authors.forename: Pirkko-Liisa
authors.initials: PL
authors.lastname: Kellokumpu-Lehtinen
authors.affiliation: Sansum Clinic, Santa Barbara, CA, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Taguchi
authors.affiliation: Università di Modena e Reggio Emilia, Modena, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Piacentini
authors.affiliation: Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Ciruelos
authors.affiliation: Comprehensive Cancer Center, Helsinki University Hospital, and University of Helsinki, Helsinki, Finland.
authors.forename: Petri
authors.initials: P
authors.lastname: Bono
authors.affiliation: Boehringer Ingelheim, Paris, France.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Ould-Kaci
authors.affiliation: Boehringer Ingelheim, Reims, France.
authors.forename: Flavien
authors.initials: F
authors.lastname: Roux
authors.affiliation: Comprehensive Cancer Center, Helsinki University Hospital, and University of Helsinki, Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
mesh_terms: D000328:Adult; D000077716:Afatinib; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000037:antagonists & inhibitors*; D001932:Brain Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002170:Canada; D018450:Disease Progression; D018572:Disease-Free Survival; D005060:Europe; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077341:Lapatinib; D008875:Middle Aged; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors*; D056910:Republic of Korea; D012307:Risk Factors; D013997:Time Factors; D000068878:Trastuzumab / Q000627:therapeutic use; D016896:Treatment Outcome; D014481:United States; D014747:Vinblastine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000077235:Vinorelbine
chemical_list: D000077716:Afatinib; D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D014747:Vinblastine; D000077235:Vinorelbine; C508053:ERBB2 protein, human