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

• Published in: The lancet oncology 2014-11, Vol.15 (12), p.1379-1388
• Main Authors: Ellis, Peter M, Dr, Shepherd, Frances A, Prof, Millward, Michael, Prof, Perrone, Francesco, PhD, Seymour, Lesley, Prof, Liu, Geoffrey, MD, Sun, Sophie, MD, Cho, Byoung Chul, MD, Morabito, Alessandro, MD, Leighl, Natasha B, MD, Stockler, Martin R, Prof, Lee, Christopher W, MD, Wierzbicki, Rafal, MD, Cohen, Victor, MD, Blais, Normand, MSc, Sangha, Randeep S, MD, Favaretto, Adolfo G, MD, Kang, Jin Hyoung, MD, Tsao, Ming-Sound, Prof, Wilson, Carolyn F, MSc, Goldberg, Zelanna, MD, Ding, Keyue, PhD, Goss, Glenwood D, Prof, Bradbury, Penelope Ann, MBBCh
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Canada; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Chemotherapy; Disease; Disease-Free Survival; Double-Blind Method; Female; Hematology, Oncology and Palliative Medicine; Humans; Lung cancer; Male; Metastasis; Middle Aged; Mutation; Neoplasm Metastasis; Pharmaceutical industry; Placebo Effect; Protein Kinase Inhibitors - administration & dosage; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); Quality of life; Quinazolinones - administration & dosage; Quinazolinones - adverse effects; ras Proteins - genetics; Receptor, Epidermal Growth Factor - antagonists & inhibitors
• ISSN: 1470-2045; 1474-5488
• DOI: 10.1016/S1470-2045(14)70472-3

Summary 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. Findings 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