title: Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial.
abstract: BACKGROUND
  Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib. We aimed to compare dacomitinib with erlotinib in a phase 3 study.
  
  
  METHODS
  In a randomised, multicentre, double-blind phase 3 trial in 134 centres in 23 countries, we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer, progression after one or two previous regimens of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and presence of measurable disease. We randomly assigned patients in a 1:1 ratio to dacomitinib (45 mg/day) or erlotinib (150 mg/day) with matching placebo. Treatment allocation was masked to the investigator, patient, and study funder. Randomisation was stratified by histology (adenocarcinoma vs non-adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian sub-continent), performance status (0-1 vs 2), and smoking status (never-smoker vs ever-smoker). The coprimary endpoints were progression-free survival per independent review for all randomly assigned patients, and for all randomly assigned patients with KRAS wild-type tumours. The study has completed accrual and is registered with ClinicalTrials.gov, number NCT01360554.
  
  
  RESULTS
  Between June 22, 2011, and March 12, 2013, we enrolled 878 patients and randomly assigned 439 to dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib. Median progression-free survival was 2·6 months (95% CI 1·9-2·8) in both the dacomitinib group and the erlotinib group (stratified hazard ratio [HR] 0·941, 95% CI 0·802-1·104, one-sided log-rank p=0·229). For patients with wild-type KRAS, median progression-free survival was 2·6 months for dacomitinib (95% CI 1·9-2·9) and erlotinib (95% CI 1·9-3·0; stratified HR 1·022, 95% CI 0·834-1·253, one-sided p=0·587). In patients who received at least one dose of study drug, the most frequent grade 3-4 adverse events were diarrhoea (47 [11%] patients in the dacomitinib group vs ten [2%] patients in the erlotinib group), rash (29 [7%] vs 12 [3%]), and stomatitis (15 [3%] vs two [<1%]). Serious adverse events were reported in 52 (12%) patients receiving dacomitinib and 40 (9%) patients receiving erlotinib.
  
  
  CONCLUSIONS
  Irreversible EGFR inhibition with dacomitinib was not superior to erlotinib in an unselected patient population with advanced non-small-cell lung cancer or in patients with KRAS wild-type tumours. Further study of irreversible EGFR inhibitors should be restricted to patients with activating EGFR mutations.
  
  
  BACKGROUND
  Pfizer.
authors.affiliation: Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA, USA. Electronic address: ssramal@emory.edu.
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: State Key Laboratory of South China, Hong Kong Cancer Institute, Department of Clinical Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Tony
authors.initials: T
authors.lastname: Mok
authors.affiliation: Princess Alexandra Hospital, Woolloongabba, QLD, Australia.
authors.forename: Kenneth
authors.initials: K
authors.lastname: O'Byrne
authors.affiliation: Chris O'Brien Lifehouse/Royal Prince Alfred Hospital, Camperdown, Sydney, NSW, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Boyer
authors.affiliation: Asklepios-Fachkliniken, Munchen-Gauting, Gauting, Munich, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Von Pawel
authors.affiliation: Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Pluzanski
authors.affiliation: Ironwood Cancer and Research Centers, Chandler, AZ, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Shtivelband
authors.affiliation: Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Lara Iglesias
authors.initials: LI
authors.lastname: Docampo
authors.affiliation: Institut de Cancerologie de I'Ouest, Nantes, France.
authors.forename: Jaafar
authors.initials: J
authors.lastname: Bennouna
authors.affiliation: Pfizer (China) Research and Development, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Pfizer Oncology, Groton, CT, USA.
authors.forename: Jane Q
authors.initials: JQ
authors.lastname: Liang
authors.affiliation: Pfizer Oncology, New York, NY, USA.
authors.forename: Jim P
authors.initials: JP
authors.lastname: Doherty
authors.affiliation: Pfizer Oncology, Groton, CT, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Taylor
authors.affiliation: Pfizer Oncology, Groton, CT, USA.
authors.forename: Cecile B
authors.initials: CB
authors.lastname: Mather
authors.affiliation: Pfizer Oncology, San Diego, CA, USA.
authors.forename: Zelanna
authors.initials: Z
authors.lastname: Goldberg
authors.affiliation: Pfizer Oncology, New York, NY, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: O'Connell
authors.affiliation: University Hospital Virgen del Rocio, Seville, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Paz-Ares
mesh_terms: D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D004311:Double-Blind Method; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000008:administration & dosage*; D052999:Quinazolinones / Q000008:administration & dosage*; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D052999:Quinazolinones; C525726:dacomitinib; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins