title: Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial.
abstract: BACKGROUND
  Patients with EGFR-mutant non-small-cell lung cancer generally have a progression-free survival of 9-13 months while being treated with the EGFR tyrosine-kinase inhibitors gefitinib or erlotinib. However, resistance inevitably develops, and more effective EGFR inhibitors are needed. Dacomitinib is a covalent pan-HER inhibitor that has shown clinical activity in patients previously treated with gefitinib or erlotinib. We did a trial of dacomitinib as initial systemic therapy in clinically and molecularly selected patients with advanced non-small-cell lung cancer.
  
  
  METHODS
  In this open-label, multicentre, phase 2 trial, we enrolled treatment-naive patients with advanced lung cancer who had clinical (never-smokers [<100 cigarettes per lifetime] or former light smokers [<10 pack-years per lifetime] and ≥15 years since last cigarette) or molecular (EGFR mutation, regardless of smoking status) characteristics associated with response to EGFR inhibitors. We gave dacomitinib orally once daily (45 mg or 30 mg) until progressive disease, unacceptable toxicity, or patient withdrawal. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.0) to investigate the activity of dacomitinib in all patients with a baseline scan and at least one post-treatment scan, with investigator assessment of response and progression. The primary endpoint was progression-free survival at 4 months in the as-enrolled population, with a null hypothesis of progression-free survival at 4 months of 50% or less. The study is registered with ClinicalTrials.gov, number NCT00818441, and is no longer accruing patients.
  
  
  RESULTS
  Between March 11, 2009, and April 1, 2011, we enrolled 89 patients from 25 centres, including 45 (51%) with EGFR-activating mutations in exon 19 (n=25) or exon 21 (n=20). Progression-free survival at 4 months was 76·8% (95% CI 66·4-84·4) in the as-enrolled population, and was 95·5% (95% CI 83·2-98·9) in the EGFR-mutant population. The most common all-grade treatment-related adverse events were diarrhoea in 83 (93%) patients, dermatitis acneiform in 69 (78%) patients, dry skin in 39 (44%) patients, and stomatitis in 36 (40%) patients. Two patients (2%) had grade 4 treatment-related events (one with hypokalaemia and one with dyspnoea). No grade 5 toxicities were recorded.
  
  
  CONCLUSIONS
  Dacomitinib had encouraging clinical activity as initial systemic treatment in clinically or molecularly selected patients with advanced non-small-cell lung cancer.
  
  
  BACKGROUND
  Pfizer.
authors.affiliation: Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, MA, USA; Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, MA, USA. Electronic address: pasi_janne@dfci.harvard.edu.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA, USA.
authors.forename: Sai-Hong I
authors.initials: SI
authors.lastname: Ou
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Oxnard
authors.affiliation: Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA.
authors.forename: Renato
authors.initials: R
authors.lastname: Martins
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.affiliation: Duke University Medical Center, Durham, NC, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Dunphy
authors.affiliation: Department of Thoracic Medical Oncology, Cancer Institute Hospital of JFCR, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nishio
authors.affiliation: Pfizer Oncology, New York, NY, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: O'Connell
authors.affiliation: Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Cloud
authors.initials: C
authors.lastname: Paweletz
authors.affiliation: Pfizer Oncology, Point Road, Groton, CT, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Taylor
authors.affiliation: Pfizer (China) Research & Development Co Ltd, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Pfizer Oncology, San Diego, CA, USA.
authors.forename: Zelanna
authors.initials: Z
authors.lastname: Goldberg
authors.affiliation: State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin NT, Hong Kong SAR, China.
authors.forename: Tony
authors.initials: T
authors.lastname: Mok
mesh_terms: D000328:Adult; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D052999:Quinazolinones / Q000627:therapeutic use*; D015996:Survival Rate
chemical_list: D052999:Quinazolinones; C525726:dacomitinib; C512478:EGFR protein, human; D066246:ErbB Receptors