title: Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial.
abstract: BACKGROUND
  Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease.
  
  
  METHODS
  In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025.
  
  
  RESULTS
  Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6-29·6) for patients in the dacomitinib group and 24·4 months (11·5-38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months [95% CI 6·08-7·49] for dacomitinib vs 6·31 months [5·32-7·52] for placebo; hazard ratio [HR] 1·00 [95% CI 0·83-1·21]; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months [1·91-3·32] vs 1·38 months [0·99-1·74], respectively; HR 0·66 [95% CI 0·55-0·79]; p<0·0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 [7%] of 480 patients vs three [1%] of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR-mutation-positive tumours (HR 0·98, 95% CI 0·67-1·44) and EGFR wild-type tumours (0·93, 0·71-1·21; pinteraction=0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS-mutation-positive tumours (2·10, 1·05-4·22) and patients with KRAS wild-type tumours (0·79, 0·61-1·03; pinteraction=0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0·0001), dyspnoea (p=0·049), and pain (p=0·041). 185 (39%) of 477 patients who received dacomitinib and 86 (36%) of 239 patients who received placebo had serious adverse events. The most common grade 3-4 adverse events were diarrhoea (59 [12%] patients on dacomitinib vs no controls), acneiform rash (48 [10%] vs one [<1%]), oral mucositis (16 [3%] vs none), and fatigue (13 [3%] vs four [2%]).
  
  
  CONCLUSIONS
  Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor.
  
  
  BACKGROUND
  Canadian Cancer Society Research Institute and Pfizer.
authors.affiliation: Juravinski Cancer Centre, Hamilton, ON, Canada. Electronic address: Peter.Ellis@jcc.hhsc.ca.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Ellis
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.affiliation: University of Western Australia, Perth, WA, Australia; Australasian Lung Cancer Trials Group, Sydney, NSW, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Millward
authors.affiliation: Clinical Trials Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori-Fondazione G Pascale IRCCS, Napoli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Perrone
authors.affiliation: NCIC Clinical Trials Group, Queen's University, ON, Canada.
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.affiliation: British Columbia Cancer Agency, Vancouver Centre, Vancouver, BC, Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Sun
authors.affiliation: Yonsei Cancer Centre, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Cho
authors.affiliation: Thoraco-Pulmonary Medical Oncology, Istituto Nazionale Tumori "Fondazione G Pascale"-IRCCS, Napoli, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Morabito
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Natasha B
authors.initials: NB
authors.lastname: Leighl
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Stockler
authors.affiliation: British Columbia Cancer Agency, Fraser Valley Centre, Surrey, BC, Canada.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Lee
authors.affiliation: R S MacLaughlin Durham RegionalCancer Centre, Oshawa, ON, Canada.
authors.forename: Rafal
authors.initials: R
authors.lastname: Wierzbicki
authors.affiliation: Jewish General Hospital and Segal Cancer Centre, McGill University, Montreal, QC, Canada.
authors.forename: Victor
authors.initials: V
authors.lastname: Cohen
authors.affiliation: Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada.
authors.forename: Normand
authors.initials: N
authors.lastname: Blais
authors.affiliation: Cross Cancer Institute, Edmonton, AB, Canada.
authors.forename: Randeep S
authors.initials: RS
authors.lastname: Sangha
authors.affiliation: Istituto Oncologico Veneto, Padua, Italy.
authors.forename: Adolfo G
authors.initials: AG
authors.lastname: Favaretto
authors.affiliation: Seoul St Mary's Hospital, The Catholic University, Seoul, South Korea.
authors.forename: Jin Hyoung
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.affiliation: NCIC Clinical Trials Group, Queen's University, ON, Canada.
authors.forename: Carolyn F
authors.initials: CF
authors.lastname: Wilson
authors.affiliation: Pfizer Oncology, La Jolla, CA, USA.
authors.forename: Zelanna
authors.initials: Z
authors.lastname: Goldberg
authors.affiliation: NCIC Clinical Trials Group, Queen's University, ON, Canada.
authors.forename: Keyue
authors.initials: K
authors.lastname: Ding
authors.affiliation: Division of Medical Oncology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Glenwood D
authors.initials: GD
authors.lastname: Goss
authors.affiliation: NCIC Clinical Trials Group, Queen's University, ON, Canada.
authors.forename: Penelope Ann
authors.initials: PA
authors.lastname: Bradbury
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002170:Canada; 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; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D015990:Placebo Effect; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D052999:Quinazolinones / Q000008:administration & dosage* / Q000009:adverse effects; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D052999:Quinazolinones; C525726:dacomitinib; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins