title: Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial.
abstract: BACKGROUND
  Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) progressing after first-line platinum regimens have a poor prognosis and few treatment options. Afatinib, an irreversible ERBB family blocker, has shown efficacy in a phase 2 study in this setting. We aimed to assess the efficacy and safety of afatinib compared with methotrexate as second-line treatment in patients with recurrent or metastatic HNSCC progressing on or after platinum-based therapy.
  
  
  METHODS
  In this open-label, phase 3, randomised controlled trial conducted in 101 centres in 19 countries, we enrolled patients aged 18 years or older with histologically or cytologically confirmed HNSCC that was recurrent, metastatic, or both who had progressed on or after first-line platinum-based therapy, were not amenable for salvage surgery or radiotherapy, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Previous treatment with more than one systemic regimen in this setting was not allowed; previous treatment with EGFR-targeted antibody therapy (but not EGFR-targeted tyrosine-kinase inhibitors) was allowed. We randomly assigned eligible patients in a 2:1 ratio to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m(2) per week), stratified by ECOG performance status and previous EGFR-targeted antibody therapy for recurrent or metastatic disease. Randomisation was done centrally with an interactive voice or web-based response system. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. The primary endpoint was progression-free survival as assessed by an independent, central imaging review committee. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01345682.
  
  
  RESULTS
  Between Jan 10, 2012, and Dec 12, 2013, we enrolled 483 patients and randomly assigned 322 to afatinib and 161 to methotrexate. After a median follow-up of 6·7 months (IQR 3·1-9·0), progression-free survival was longer in the afatinib group than in the methotrexate group (median 2·6 months [95% CI 2·0-2·7] for the afatinib group vs 1·7 months [1·5-2·4] for the methotrexate group; hazard ratio [HR] 0·80 [95% CI 0·65-0·98], p=0·030). The most frequent grade 3 or 4 drug-related adverse events were rash or acne (31 [10%] of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group), diarrhoea (30 [9%] vs three [2%]), stomatitis (20 [6%] vs 13 [8%]), fatigue (18 [6%] vs five [3%]), and neutropenia (1 [<1%] vs 11 [7%]); serious adverse events occurred in 44 (14%) of afatinib-treated patients and 18 (11%) of methotrexate-treated patients.
  
  
  CONCLUSIONS
  Afatinib was associated with significant improvements in progression-free survival and had a manageable safety profile. These findings provide important new insights into the treatment of this patient population and support further investigations with irreversible ERBB family blockers in HNSCC.
  
  
  BACKGROUND
  Boehringer Ingelheim.
authors.affiliation: Institut Roi Albert II, Service d'Oncologie Médicale, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Brussels. Electronic address: jean-pascal.machiels@uclouvain.be.
authors.forename: Jean-Pascal H
authors.initials: JP
authors.lastname: Machiels
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School and Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Haddad
authors.affiliation: Léon Bérard Center and Hospices Civils de Lyon, University of Lyon, Lyon, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Fayette
authors.affiliation: Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Licitra
authors.affiliation: National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tahara
authors.affiliation: Antwerp University Hospital, Edegem, Belgium.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Vermorken
authors.affiliation: Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Clement
authors.affiliation: West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gauler
authors.affiliation: Institut du Cancer de Montpellier Val d'Aurelle, Montpellier, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Cupissol
authors.affiliation: Hospital Clínic de Barcelona, University of Barcelona, Spain.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Grau
authors.affiliation: Gustave Roussy, Villejuif and Centre Antoine Lacassagne, Nice, France.
authors.forename: Joël
authors.initials: J
authors.lastname: Guigay
authors.affiliation: Division of Head and Neck Medical Oncology, Istituto Nazionale Tumori "Fondazione G Pascale"-IRCCS, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Caponigro
authors.affiliation: Instituto do Câncer do Estado de São Paulo, Brazil.
authors.forename: Gilberto
authors.initials: G
authors.lastname: de Castro
authors.affiliation: Hospital de Câncer de Barretos, São Paulo, Brazil.
authors.forename: Luciano
authors.initials: L
authors.lastname: de Souza Viana
authors.affiliation: Charité Comprehensive Cancer Center, Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keilholz
authors.affiliation: Medical Oncology Department, Hospital Universitario Vall D'Hebron, Barcelona, Spain.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Del Campo
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA.
authors.forename: Xiuyu Julie
authors.initials: XJ
authors.lastname: Cong
authors.affiliation: Boehringer Ingelheim, Danmark A/S, Denmark.
authors.forename: Eva
authors.initials: E
authors.lastname: Ehrnrooth
authors.affiliation: University of California San Diego Moores Cancer Center, La Jolla, CA, USA.
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D018572:Disease-Free Survival; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D010984:Platinum / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage*; D000077195:Squamous Cell Carcinoma of Head and Neck; D016896:Treatment Outcome
chemical_list: D011799:Quinazolines; D000077716:Afatinib; D010984:Platinum; D008727:Methotrexate