Jean-Charles Soria1, Yuichiro Ohe1, Johan Vansteenkiste1, Thanyanan Reungwetwattana1, Busyamas Chewaskulyong1, Ki Hyeong Lee1, Arunee Dechaphunkul1, Fumio Imamura1, Naoyuki Nogami1, Takayasu Kurata1, Isamu Okamoto1, Caicun Zhou1, Byoung Chul Cho1, Ying Cheng1, Eun Kyung Cho1, Pei Jye Voon1, David Planchard1, Wu-Chou Su1, Jhanelle E Gray1, Siow-Ming Lee1, Rachel Hodge1, Marcelo Marotti1, Yuri Rukazenkov1, Suresh S Ramalingam1. 1. From Gustave Roussy Cancer Campus and University Paris-Sud, Orsay, France (J.-C.S., D.P.); the Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo (Y.O.), the Department of Thoracic Oncology, Osaka International Cancer Institute (F.I.), and the Department of Thoracic Oncology, Kansai Medical University Hospital (T.K.), Osaka, the Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama (N.N.), and the Research Institute for Diseases of the Chest, Graduate School of Medical Science, Kyushu University, Fukuoka (I.O.) - all in Japan; the Respiratory Oncology Unit, University Hospital KU Leuven, Leuven, Belgium (J.V.); Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok (T.R.), the Oncology Unit, Department of Medicine, Chiang Mai University, Chiang Mai (B.C.), and the Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai (A.D.) - all in Thailand; the Division of Medical Oncology, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheong-ju (K.H.L.), 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 Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon (E.K.C.) - all in South Korea; Pulmonary Hospital of Tongji University, Shanghai (C.Z.), and Jilin Provincial Cancer Hospital, Changchun (Y.C.) - both in China; Hospital Umum Sarawak, Kuching, Malaysia (P.J.V.); National Cheng Kung University, Tainan, Taiwan (W.-C.S.); the Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (J.E.G.); the Department of Oncology, University College London Hospitals Biomedical Research Centre, and the Cancer Research UK Lung Cancer Centre of Excellence, London (S.-M.L.), and AstraZeneca, Cambridge (R.H., M.M., Y.R.) - all in the United Kingdom; and Emory University School of Medicine, Winship Cancer Institute, Atlanta (S.S.R.).
Abstract
BACKGROUND: Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). METHODS: In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival. RESULTS: The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%). CONCLUSIONS: Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125 .).
BACKGROUND: Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). METHODS: In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival. RESULTS: The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%). CONCLUSIONS: Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125 .).
Authors: Michael Offin; Joseph M Chan; Megan Tenet; Hira A Rizvi; Ronglai Shen; Gregory J Riely; Natasha Rekhtman; Yahya Daneshbod; Alvaro Quintanal-Villalonga; Alexander Penson; Matthew D Hellmann; Maria E Arcila; Marc Ladanyi; Dana Pe'er; Mark G Kris; Charles M Rudin; Helena A Yu Journal: J Thorac Oncol Date: 2019-06-19 Impact factor: 15.609
Authors: Yong-Jin Kim; Mark Oremus; Helen H Chen; Thomas McFarlane; Danielle Fearon; Susan Horton Journal: Pharmacoeconomics Date: 2021-03-31 Impact factor: 4.981
Authors: Suresh S Ramalingam; Suzanne E Dahlberg; Chandra P Belani; Joel N Saltzman; Nathan A Pennell; Gopakumar S Nambudiri; John C McCann; Jerome D Winegarden; Mohammed A Kassem; Mohamed K Mohamed; Jan M Rothman; Alan P Lyss; Leora Horn; Thomas E Stinchcombe; Joan H Schiller Journal: J Clin Oncol Date: 2019-07-30 Impact factor: 44.544