Suresh S Ramalingam1, Pasi A Jänne2, Tony Mok3, Kenneth O'Byrne4, Michael J Boyer5, Joachim Von Pawel6, Adam Pluzanski7, Mikhail Shtivelband8, Lara Iglesias Docampo9, Jaafar Bennouna10, Hui Zhang11, Jane Q Liang12, Jim P Doherty13, Ian Taylor12, Cecile B Mather12, Zelanna Goldberg14, Joseph O'Connell13, Luis Paz-Ares15. 1. Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA, USA. Electronic address: ssramal@emory.edu. 2. Dana-Farber Cancer Institute, Boston, MA, USA. 3. State Key Laboratory of South China, Hong Kong Cancer Institute, Department of Clinical Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong, China. 4. Princess Alexandra Hospital, Woolloongabba, QLD, Australia. 5. Chris O'Brien Lifehouse/Royal Prince Alfred Hospital, Camperdown, Sydney, NSW, Australia. 6. Asklepios-Fachkliniken, Munchen-Gauting, Gauting, Munich, Germany. 7. Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland. 8. Ironwood Cancer and Research Centers, Chandler, AZ, USA. 9. Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain. 10. Institut de Cancerologie de I'Ouest, Nantes, France. 11. Pfizer (China) Research and Development, Shanghai, China. 12. Pfizer Oncology, Groton, CT, USA. 13. Pfizer Oncology, New York, NY, USA. 14. Pfizer Oncology, San Diego, CA, USA. 15. University Hospital Virgen del Rocio, Seville, Spain.
Abstract
BACKGROUND:Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib. We aimed to compare dacomitinib with erlotinib in a phase 3 study. METHODS: In a randomised, multicentre, double-blind phase 3 trial in 134 centres in 23 countries, we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer, progression after one or two previous regimens of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and presence of measurable disease. We randomly assigned patients in a 1:1 ratio to dacomitinib (45 mg/day) or erlotinib (150 mg/day) with matching placebo. Treatment allocation was masked to the investigator, patient, and study funder. Randomisation was stratified by histology (adenocarcinoma vs non-adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian sub-continent), performance status (0-1 vs 2), and smoking status (never-smoker vs ever-smoker). The coprimary endpoints were progression-free survival per independent review for all randomly assigned patients, and for all randomly assigned patients with KRAS wild-type tumours. The study has completed accrual and is registered with ClinicalTrials.gov, number NCT01360554. FINDINGS:Between June 22, 2011, and March 12, 2013, we enrolled 878 patients and randomly assigned 439 to dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) toerlotinib. Median progression-free survival was 2·6 months (95% CI 1·9-2·8) in both the dacomitinib group and the erlotinib group (stratified hazard ratio [HR] 0·941, 95% CI 0·802-1·104, one-sided log-rank p=0·229). For patients with wild-type KRAS, median progression-free survival was 2·6 months for dacomitinib (95% CI 1·9-2·9) and erlotinib (95% CI 1·9-3·0; stratified HR 1·022, 95% CI 0·834-1·253, one-sided p=0·587). In patients who received at least one dose of study drug, the most frequent grade 3-4 adverse events were diarrhoea (47 [11%] patients in the dacomitinib group vs ten [2%] patients in the erlotinib group), rash (29 [7%] vs 12 [3%]), and stomatitis (15 [3%] vs two [<1%]). Serious adverse events were reported in 52 (12%) patients receiving dacomitinib and 40 (9%) patients receiving erlotinib. INTERPRETATION: Irreversible EGFR inhibition with dacomitinib was not superior to erlotinib in an unselected patient population with advanced non-small-cell lung cancer or in patients with KRAS wild-type tumours. Further study of irreversible EGFR inhibitors should be restricted to patients with activating EGFR mutations. FUNDING: Pfizer.
RCT Entities:
BACKGROUND:Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib. We aimed to compare dacomitinib with erlotinib in a phase 3 study. METHODS: In a randomised, multicentre, double-blind phase 3 trial in 134 centres in 23 countries, we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer, progression after one or two previous regimens of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and presence of measurable disease. We randomly assigned patients in a 1:1 ratio to dacomitinib (45 mg/day) or erlotinib (150 mg/day) with matching placebo. Treatment allocation was masked to the investigator, patient, and study funder. Randomisation was stratified by histology (adenocarcinoma vs non-adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian sub-continent), performance status (0-1 vs 2), and smoking status (never-smoker vs ever-smoker). The coprimary endpoints were progression-free survival per independent review for all randomly assigned patients, and for all randomly assigned patients with KRAS wild-type tumours. The study has completed accrual and is registered with ClinicalTrials.gov, number NCT01360554. FINDINGS: Between June 22, 2011, and March 12, 2013, we enrolled 878 patients and randomly assigned 439 to dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib. Median progression-free survival was 2·6 months (95% CI 1·9-2·8) in both the dacomitinib group and the erlotinib group (stratified hazard ratio [HR] 0·941, 95% CI 0·802-1·104, one-sided log-rank p=0·229). For patients with wild-type KRAS, median progression-free survival was 2·6 months for dacomitinib (95% CI 1·9-2·9) and erlotinib (95% CI 1·9-3·0; stratified HR 1·022, 95% CI 0·834-1·253, one-sided p=0·587). In patients who received at least one dose of study drug, the most frequent grade 3-4 adverse events were diarrhoea (47 [11%] patients in the dacomitinib group vs ten [2%] patients in the erlotinib group), rash (29 [7%] vs 12 [3%]), and stomatitis (15 [3%] vs two [<1%]). Serious adverse events were reported in 52 (12%) patients receiving dacomitinib and 40 (9%) patients receiving erlotinib. INTERPRETATION: Irreversible EGFR inhibition with dacomitinib was not superior to erlotinib in an unselected patient population with advanced non-small-cell lung cancer or in patients with KRAS wild-type tumours. Further study of irreversible EGFR inhibitors should be restricted to patients with activating EGFR mutations. FUNDING: Pfizer.
Authors: Dong-Wan Kim; Edward B Garon; Aminah Jatoi; Dorothy M Keefe; Mario E Lacouture; Stephen Sonis; Diana Gernhardt; Tao Wang; Nagdeep Giri; Jim P Doherty; Sashi Nadanaciva; Joseph O'Connell; Eric Sbar; Byoung Chul Cho Journal: Lung Cancer Date: 2017-02-01 Impact factor: 5.705
Authors: Jelena Mirkovic; Lynette M Sholl; Elizabeth Garcia; Neal Lindeman; Laura MacConaill; Michelle Hirsch; Paola Dal Cin; Melissa Gorman; Justine A Barletta; Marisa R Nucci; W Glenn McCluggage; Brooke E Howitt Journal: Mod Pathol Date: 2015-09-04 Impact factor: 7.842