Suresh S Ramalingam1, Johan Vansteenkiste1, David Planchard1, Byoung Chul Cho1, Jhanelle E Gray1, Yuichiro Ohe1, Caicun Zhou1, Thanyanan Reungwetwattana1, Ying Cheng1, Busyamas Chewaskulyong1, Riyaz Shah1, Manuel Cobo1, Ki Hyeong Lee1, Parneet Cheema1, Marcello Tiseo1, Thomas John1, Meng-Chih Lin1, Fumio Imamura1, Takayasu Kurata1, Alexander Todd1, Rachel Hodge1, Matilde Saggese1, Yuri Rukazenkov1, Jean-Charles Soria1. 1. From Winship Cancer Institute, Emory University School of Medicine, Atlanta (S.S.R.); the Respiratory Oncology Unit, Department of Respiratory Medicine, University Hospital KU Leuven, Leuven, Belgium (J.V.); the Thoracic Unit, Department of Medical Oncology, Institut Gustave Roussy, Villejuif (D.P., J.-C.S.), and University Paris Sud, Orsay (J.-C.S.) - both in France; the Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul (B.C.C.), and the Division of Medical Oncology, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheong-ju (K.H.L.) - both in South Korea; the Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (J.E.G.); the Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo (Y.O.), the Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka (F.I.), and the Department of Thoracic Oncology, Kansai Medical University Hospital, Osaka (T.K.) - all in Japan; Pulmonary Hospital of Tongji University, Shanghai (C.Z.), and Jilin Provincial Cancer Hospital, Changchun (Y.C.) - both in China; the Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok (T.R.), and the Oncology Unit, Department of Medicine, Chiang Mai University, Chiang Mai (B.C.) - both in Thailand; Kent Oncology Centre, Maidstone Hospital, and Tunbridge Wells NHS Trust, Maidstone (R.S.), and Late Oncology Statistics (A.T., R.H.) and Oncology Research and Development (M.S., Y.R.), AstraZeneca, Cambridge - both in the United Kingdom; Hospital Regional Universitario Málaga, Instituto de Investigación Biomédica de Málaga, Malaga, Spain (M.C.); William Osler Health System, University of Toronto, Toronto (P.C.); the Department of Medicine and Surgery, University of Parma and Medical Oncology Unit, University Hospital of Parma, Parma, Italy (M.T.); the Department of Medical Oncology, Austin Health, Melbourne, VIC, Australia (T.J.); the Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan (M.-C.L.); and Early Oncology Research and Development, AstraZeneca, Gaithersburg, MD (J.-C.S.).
Abstract
BACKGROUND: Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. A phase 3 trial compared first-line osimertinib with other EGFR-TKIs in patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). The trial showed longer progression-free survival with osimertinib than with the comparator EGFR-TKIs (hazard ratio for disease progression or death, 0.46). Data from the final analysis of overall survival have not been reported. METHODS: In this trial, we randomly assigned 556 patients with previously untreated advanced NSCLC with an EGFR mutation (exon 19 deletion or L858R allele) in a 1:1 ratio to receive either osimertinib (80 mg once daily) or one of two other EGFR-TKIs (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily, with patients receiving these drugs combined in a single comparator group). Overall survival was a secondary end point. RESULTS: The median overall survival was 38.6 months (95% confidence interval [CI], 34.5 to 41.8) in the osimertinib group and 31.8 months (95% CI, 26.6 to 36.0) in the comparator group (hazard ratio for death, 0.80; 95.05% CI, 0.64 to 1.00; P = 0.046). At 3 years, 79 of 279 patients (28%) in the osimertinib group and 26 of 277 (9%) in the comparator group were continuing to receive a trial regimen; the median exposure was 20.7 months and 11.5 months, respectively. Adverse events of grade 3 or higher were reported in 42% of the patients in the osimertinib group and in 47% of those in the comparator group. CONCLUSIONS: Among patients with previously untreated advanced NSCLC with an EGFR mutation, those who received osimertinib had longer overall survival than those who received a comparator EGFR-TKI. The safety profile for osimertinib was similar to that of the comparator EGFR-TKIs, despite a longer duration of exposure in the osimertinib group. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125.).
BACKGROUND: Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. A phase 3 trial compared first-line osimertinib with other EGFR-TKIs in patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). The trial showed longer progression-free survival with osimertinib than with the comparator EGFR-TKIs (hazard ratio for disease progression or death, 0.46). Data from the final analysis of overall survival have not been reported. METHODS: In this trial, we randomly assigned 556 patients with previously untreated advanced NSCLC with an EGFR mutation (exon 19 deletion or L858R allele) in a 1:1 ratio to receive either osimertinib (80 mg once daily) or one of two other EGFR-TKIs (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily, with patients receiving these drugs combined in a single comparator group). Overall survival was a secondary end point. RESULTS: The median overall survival was 38.6 months (95% confidence interval [CI], 34.5 to 41.8) in the osimertinib group and 31.8 months (95% CI, 26.6 to 36.0) in the comparator group (hazard ratio for death, 0.80; 95.05% CI, 0.64 to 1.00; P = 0.046). At 3 years, 79 of 279 patients (28%) in the osimertinib group and 26 of 277 (9%) in the comparator group were continuing to receive a trial regimen; the median exposure was 20.7 months and 11.5 months, respectively. Adverse events of grade 3 or higher were reported in 42% of the patients in the osimertinib group and in 47% of those in the comparator group. CONCLUSIONS: Among patients with previously untreated advanced NSCLC with an EGFR mutation, those who received osimertinib had longer overall survival than those who received a comparator EGFR-TKI. The safety profile for osimertinib was similar to that of the comparator EGFR-TKIs, despite a longer duration of exposure in the osimertinib group. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125.).