Yi-Long Wu1, Ying Cheng2, Xiangdong Zhou3, Ki Hyeong Lee4, Kazuhiko Nakagawa5, Seiji Niho6, Fumito Tsuji7, Rolf Linke8, Rafael Rosell9, Jesus Corral10, Maria Rita Migliorino11, Adam Pluzanski12, Eric I Sbar13, Tao Wang14, Jane Liang White14, Sashi Nadanaciva14, Rickard Sandin15, Tony S Mok16. 1. Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address: syylwu@live.cn. 2. Jilin Provincial Cancer Hospital, Changchun, China. 3. First Affiliated Hospital of Third Military Medical University, Chongqing, China. 4. Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, South Korea. 5. Kindai University Hospital, Osaka, Japan. 6. National Cancer Center Hospital East, Kashiwa, Japan. 7. SFJ Pharma Japan, Osaka, Japan. 8. SFJ Pharmaceuticals Group, Pleasanton, CA, USA. 9. Catalan Institute of Oncology, Barcelona, Spain. 10. Hospital Universitario Virgen del Rocio, Seville, Spain. 11. Pulmonary Oncology Unit, San Camillo-Forlanini Hospital, Rome, Italy. 12. The Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland. 13. Pfizer, Collegeville, PA, USA. 14. Pfizer, Groton, CT, USA. 15. Pfizer, Sollentuna, Sweden. 16. State Key Laboratory of South China, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, China.
Abstract
BACKGROUND:Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor. We compared its efficacy and safety with that of the reversible EGFR tyrosine kinase inhibitor gefitinib in the first-line treatment of patients with advanced EGFR-mutation-positive non-small-cell lung cancer (NSCLC). METHODS: In this international, multicentre, randomised, open-label, phase 3 study (ARCHER 1050), we enrolled adults (aged ≥18 years or ≥20 years in Japan and South Korea) with newly diagnosed advanced NSCLC and one EGFR mutation (exon 19 deletion or Leu858Arg) at 71 academic medical centres and university hospitals in seven countries or special administrative regions. We randomly assigned participants (1:1) to receive oral dacomitinib 45 mg/day (in 28-day cycles) or oral gefitinib 250 mg/day (in 28-day cycles) until disease progression or another discontinuation criterion was met. Randomisation, stratified by race and EGFR mutation type, was done with a computer-generated random code assigned by a central interactive web response system. The primary endpoint was progression-free survival assessed by masked independent review in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT01774721, and is ongoing but no longer recruiting patients. FINDINGS:Between May 9, 2013, and March 20, 2015, 452 eligible patients were randomly assigned to receive dacomitinib (n=227) or gefitinib (n=225). Median duration of follow-up for progression-free survival was 22·1 months (95% CI 20·3-23·9). Median progression-free survival according to masked independent review was 14·7 months (95% CI 11·1-16·6) in the dacomitinib group and 9·2 months (9·1-11·0) in the gefitinib group (hazard ratio 0·59, 95% CI 0·47-0·74; p<0·0001). The most common grade 3-4 adverse events were dermatitis acneiform (31 [14%] of 227 patients given dacomitinib vs none of 224 patients given gefitinib), diarrhoea (19 [8%] vs two [1%]), and raised alanine aminotransferase levels (two [1%] vs 19 [8%]). Treatment-related serious adverse events were reported in 21 (9%) patients given dacomitinib and in ten (4%) patients given gefitinib. Two treatment-related deaths occurred in the dacomitinib group (one related to untreated diarrhoea and one to untreated cholelithases/liver disease) and one in the gefitinib group (related to sigmoid colon diverticulitis/rupture complicated by pneumonia). INTERPRETATION:Dacomitinib significantly improved progression-free survival over gefitinib in first-line treatment of patients with EGFR-mutation-positive NSCLC and should be considered as a new treatment option for this population. FUNDING: SFJ Pharmaceuticals Group and Pfizer.
RCT Entities:
BACKGROUND:Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor. We compared its efficacy and safety with that of the reversible EGFR tyrosine kinase inhibitor gefitinib in the first-line treatment of patients with advanced EGFR-mutation-positive non-small-cell lung cancer (NSCLC). METHODS: In this international, multicentre, randomised, open-label, phase 3 study (ARCHER 1050), we enrolled adults (aged ≥18 years or ≥20 years in Japan and South Korea) with newly diagnosed advanced NSCLC and one EGFR mutation (exon 19 deletion or Leu858Arg) at 71 academic medical centres and university hospitals in seven countries or special administrative regions. We randomly assigned participants (1:1) to receive oral dacomitinib 45 mg/day (in 28-day cycles) or oral gefitinib 250 mg/day (in 28-day cycles) until disease progression or another discontinuation criterion was met. Randomisation, stratified by race and EGFR mutation type, was done with a computer-generated random code assigned by a central interactive web response system. The primary endpoint was progression-free survival assessed by masked independent review in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT01774721, and is ongoing but no longer recruiting patients. FINDINGS: Between May 9, 2013, and March 20, 2015, 452 eligible patients were randomly assigned to receive dacomitinib (n=227) or gefitinib (n=225). Median duration of follow-up for progression-free survival was 22·1 months (95% CI 20·3-23·9). Median progression-free survival according to masked independent review was 14·7 months (95% CI 11·1-16·6) in the dacomitinib group and 9·2 months (9·1-11·0) in the gefitinib group (hazard ratio 0·59, 95% CI 0·47-0·74; p<0·0001). The most common grade 3-4 adverse events were dermatitis acneiform (31 [14%] of 227 patients given dacomitinib vs none of 224 patients given gefitinib), diarrhoea (19 [8%] vs two [1%]), and raised alanine aminotransferase levels (two [1%] vs 19 [8%]). Treatment-related serious adverse events were reported in 21 (9%) patients given dacomitinib and in ten (4%) patients given gefitinib. Two treatment-related deaths occurred in the dacomitinib group (one related to untreated diarrhoea and one to untreated cholelithases/liver disease) and one in the gefitinib group (related to sigmoid colon diverticulitis/rupture complicated by pneumonia). INTERPRETATION:Dacomitinib significantly improved progression-free survival over gefitinib in first-line treatment of patients with EGFR-mutation-positive NSCLC and should be considered as a new treatment option for this population. FUNDING: SFJ Pharmaceuticals Group and Pfizer.
Authors: Tejas Patil; Rao Mushtaq; Sydney Marsh; Christine Azelby; Miheer Pujara; Kurtis D Davies; Dara L Aisner; William T Purcell; Erin L Schenk; Jose M Pacheco; Paul A Bunn; D Ross Camidge; Robert C Doebele Journal: Clin Lung Cancer Date: 2019-11-21 Impact factor: 4.785
Authors: Matthias Villalobos; Piotr Czapiewski; Niels Reinmuth; Jürgen R Fischer; Stefan Andreas; Cornelius Kortsik; Monika Serke; Martin Wolf; Petra Neuser; Alexander Reuss; Philipp A Schnabel; Michael Thomas Journal: Med Oncol Date: 2018-06-15 Impact factor: 3.064