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N Engl J Med. 2017 Feb 16;376(7):629-640. doi: 10.1056/NEJMoa1612674. Epub 2016 Dec 6.

Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer.

Collaborators (154)

John T, Hasani A, Lee C, Dear R, O'Byrne K, Wheatley-Price P, Shepherd F, Chu Q, Laskin J, Blais N, Morzycki W, Zhou Q, Zhang L, Wang J, Zhou C, Lu S, Han B, Zhou J, Cheng Y, Zhou X, Zhang W, Chen G, Shi Y, He Y, Zhuang C, Zhao Y, Shan L, Jiang L, Li K, Cadranel J, Merle P, Quoix E, Planchard D, Barlesi F, Dansin E, Mazieres J, Coudert B, Schuler M, Deschler-Baier B, Griesinger F, Schulz C, Sebastian M, Kimmich M, Mok T, Ho J, Chan OSH, Lee VHF, Li YC, Ostoros G, Delmonte A, Novello S, Tonini G, Garassino M, Gridelli C, Ikeda N, Sakai H, Sekine A, Takahashi T, Fujisaka Y, Akamatsu H, Yoshioka H, Shimokawaji T, Tanaka H, Hida T, Kasahara K, Imamura F, Atagi S, Takeda K, Katakami N, Satouchi M, Nogami N, Okamoto I, Koyama R, Nakagawa K, Yokoi T, Kiura K, Maemondo M, Murakami S, Kim YH, Alatorre Alexander J, Hernández Hernández C, Engelsman-Theelen W, de Langen A, Groen H, Bulavina I, Poltoratskiy A, Laktionov K, Statsenko G, South SO, Ahn M-J, Kang JH, Lee JS, Kim HR, Han J-Y, Kim S-W, Cho EK, Min YJ, Lee KH, Choi J-H, Lee G-W, Lee SS, Kim J-S, Felip Font E, Isla Casado D, Corral Jaime J, Ponce Aix S, Garrido López P, Cobo Dols M, Öhman R, Bergman B, Kölbeck K-G, Yang C-H, Su W-C, Hsia T-C, Tsai C-M, Chang G-C, Yang C-T, Wang C-C, Ho M-L, Lai R-S, Wei Y-F, Ko J-C, Blackhall F, Dangoor A, Koh P, Steele N, Price A, Nicolson M, Arkenau H-T, Newsom-Davis T, Potter V, Greystoke A, Brown N, Gold K, Rizvi N, Ramalingam S, Ou S-H, Cosgriff T, Frank R, Hanna N, Dragnev K, Mekhail T, Menon S, Charu V, Kaye F, Wrangle J, Smith F, Agrawal A, Anderson I, Hirsch R, Gill N, Harris M, Sui X, Belani C.

Author information

1
From the State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong (T.S.M.), the Division of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou (Y.-L.W.), and the Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing (Y.H.) - all in China; the Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, (M.-J.A.), and the Yonsei Cancer Center, Department of Internal Medicine, Division of Medical Oncology, Yonsei University College of Medicine (H.R.K.), Seoul, South Korea; the Thoracic Oncology Unit, Medical Oncology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan (M.C.G.); the Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta (S.S.R.); the Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, Toronto (F.A.S.); the Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan (H.A.); the Department of Thoracic Oncology, the Netherlands Cancer Institute, Plesmanlaan, Amsterdam (W.S.M.E.T.); the Clinical Research Unit, Division of Cancer Services, St. George Hospital, Kogarah, NSW, Australia (C.K.L.); the Department of Hematology-Oncology, Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany (M.S.); AstraZeneca, Cambridge, United Kingdom (A.T., H.M., M.M., S.G.); and the Department of Thoracic-Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston (V.A.P.).

Abstract

BACKGROUND:

Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown.

METHODS:

In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first-line EGFR-TKI therapy. The primary end point was investigator-assessed progression-free survival.

RESULTS:

The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%).

CONCLUSIONS:

Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced non-small-cell lung cancer (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy. (Funded by AstraZeneca; AURA3 ClinicalTrials.gov number, NCT02151981 .).

PMID:
27959700
DOI:
10.1056/NEJMoa1612674
[Indexed for MEDLINE]
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