• Pasi A Jänne, Ou Sai-Hong I SI Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA, USA., Dong-Wan Kim, Geoffrey R Oxnard, Renato Martins, Mark G Kris, Frank Dunphy, Makoto Nishio, Joseph O'Connell, Cloud Paweletz, Ian Taylor, Hui Zhang, Zelanna Goldberg, and Tony Mok.
• 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.
• Lancet Oncol. 2014 Dec 1; 15 (13): 1433-1441.

BackgroundPatients 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.MethodsIn 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.FindingsBetween 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.InterpretationDacomitinib had encouraging clinical activity as initial systemic treatment in clinically or molecularly selected patients with advanced non-small-cell lung cancer.FundingPfizer.Copyright © 2014 Elsevier Ltd. All rights reserved.

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