• David Planchard, Pasi A Jänne, Ying Cheng, James C-H Yang, Noriko Yanagitani, Sang-We Kim, Shunichi Sugawara, Yan Yu, Yun Fan, Sarayut L Geater, Konstantin Laktionov, Chee K Lee, Natalia Valdiviezo, Samreen Ahmed, Jean-Marc Maurel, Igor Andrasina, Jonathan Goldman, Dana Ghiorghiu, Yuri Rukazenkov, Alex Todd, Kunihiko Kobayashi, and FLAURA2 Investigators.
• From the Department of Medical Oncology, Institut Gustave Roussy, Thoracic Group and International Center for Thoracic Cancers, Villejuif, and the Faculty of Medicine, Paris-Saclay University, Paris - both in France (D.P.); the Department of Medical Oncology, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston (P.A.J.); the Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun (Y.C.), the Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin (Y.Y.), and the Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou (Y.F.) - all in China; the Department of Oncology, National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei (J.C.-H.Y.); the Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo (N.Y.), the Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai (S.S.), and the Department of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka (K.K.) - all in Japan; the Department of Oncology, Asan Medical Center, Seoul, South Korea (S.-W.K.); the Department of Internal Medicine, Prince of Songkla University, Songkhla, Thailand (S.L.G.); the Federal State Budgetary Institution "N.N. Blokhin National Medical Research Center of Oncology" of the Ministry of Health of the Russian Federation, Moscow (K.L.); the Department of Medical Oncology, Cancer Care Centre, St. George Hospital, Kogarah, NSW, Australia (C.K.L.); the Department of Oncology, Instituto Nacional de Enfermedades Neoplásicas, Surquillo, Peru (N.V.); the Department of Medical Oncology, University Hospitals of Leicester, Leicester (S.A.), and Oncology Research and Development (D.G., Y.R.) and Oncology Biometrics (A.T.), AstraZeneca, Cambridge - both in the United Kingdom; the Department of Clinical Oncology, Rondebosch Oncology Centre, Cape Town, South Africa (J.-M.M.); the Department of Radiotherapy and Oncology, Východoslovenský Onkologický Ústav, Košice, Slovakia (I.A.); and the David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J.G.).
• N. Engl. J. Med. 2023 Nov 23; 389 (21): 193519481935-1948.

BackgroundOsimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and EGFR T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy.MethodsIn this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed.ResultsA total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy - a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents.ConclusionsFirst-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR-mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.).Copyright © 2023 Massachusetts Medical Society.

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