Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: An international randomized phase III trial

被引:319
作者
Omuro, Antonio [1 ,2 ]
Brandes, Alba A. [3 ,27 ,28 ]
Carpentier, Antoine F. [4 ]
Idbaih, Ahmed [5 ]
Reardon, David A. [6 ]
Cloughesy, Timothy [7 ]
Sumrall, Ashley [8 ]
Baehring, Joachim [1 ]
van den Bent, Martin [9 ]
Bahr, Oliver [10 ]
Lombardi, Giuseppe [11 ]
Mulholland, Paul [12 ]
Tabatabai, Ghazaleh [13 ]
Lassen, Ulrik [14 ]
Sepulveda, Juan Manuel [15 ]
Khasraw, Mustafa [16 ]
Vauleon, Elodie [17 ]
Muragaki, Yoshihiro [18 ]
Di Giacomo, Anna Maria [19 ]
Butowski, Nicholas [20 ]
Roth, Patrick [21 ,22 ,23 ]
Qian, Xiaozhong [24 ]
Fu, Alex Z. [24 ]
Liu, Yanfang [24 ]
Potter, Von [24 ]
Chalamandaris, Alexandros-Georgios [25 ]
Tatsuoka, Kay [24 ]
Lim, Michael [26 ]
Weller, Michael [21 ,22 ,23 ]
机构
[1] Yale Sch Med, Dept Neurol, New Haven, CT USA
[2] Mem Sloan Kettering Canc Ctr, Dept Neurol, 1275 York Ave, New York, NY 10021 USA
[3] AUSL IRCCS Inst Neurol Sci, Bologna, Italy
[4] Univ Paris, Hop St Louis, Assistance Publ Hop Paris AP HP, Serv Neurol, Paris, France
[5] Sorbonne Univ, Hop Univ La Pitie Salpetfiere, AP HP, Inst Cerveau Paris Brain Inst ICM,Inserm,CNRS,DMU, Paris, France
[6] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA
[7] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA
[8] Levine Canc Inst, Charlotte, NC USA
[9] Erasmus MC Canc Inst, Brain Tumor Ctr, Rotterdam, Netherlands
[10] Goethe Univ Hosp, Dr Senckenberg Inst Neurooncol, Frankfurt, Germany
[11] Veneto Inst Oncol IOV IRCCS, Dept Oncol, Oncol 1, Padua, Italy
[12] Univ Coll London Hosp, London, England
[13] Eberhard Karls Univ Tubingen, Dept Neurol & Interdisciplinary Neurooncol, Hertie Inst Clin Brain Res,Univ Hosp Tuebingen, Ctr Neurooncol,Comprehens Canc Ctr Tubingen Stutt, Tubingen, Germany
[14] Rigshosp, Dept Oncol, Copenhagen, Denmark
[15] Hosp Univ 12 Octubre, Madrid, Spain
[16] Univ Sydney, Sydney, NSW, Australia
[17] Ctr Eugene Marquis, Rennes, France
[18] Tokyo Womens Med Univ Hosp, Tokyo, Japan
[19] Univ Hosp Siena, Ctr Immunooncol, Siena, Italy
[20] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA
[21] Univ Hosp, Dept Neurol, Zurich, Switzerland
[22] Univ Hosp, Brain Tumor Ctr, Zurich, Switzerland
[23] Univ Zurich, Zurich, Switzerland
[24] Bristol Myers Squibb, Princeton, NJ USA
[25] Bristol Myers Squibb, Braine Lalleud, Belgium
[26] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA
[27] IRCCS Ist Sci Neurol, Bologna, Italy
[28] Nervous Syst Med Oncol Dept, Bologna, Italy
关键词
newly diagnosed glioblastoma; nivolumab; radiotherapy; temozolomide; unmethylated MGMT; ADJUVANT TEMOZOLOMIDE; METHYLATION; EXPRESSION; SURVIVAL; GLIOMAS; TUMOR; CONCOMITANT; REPAIR;
D O I
10.1093/neuonc/noac099
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in patients with glioblastoma (GBM), but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase III CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO) + RT compared with TMZ + RT in newly diagnosed GBM with unmethylated MGMT promoter. Methods Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240 mg every 2 weeks for eight cycles, then 480 mg every 4 weeks) or RT + TMZ (75 mg/m(2) daily during RT and 150-200 mg/m(2)/day 5/28 days during maintenance). The primary endpoint was OS. Results A total of 560 patients were randomized, 280 to each arm. Median OS (mOS) was 13.4 months (95% CI, 12.6 to 14.3) with NIVO + RT and 14.9 months (95% CI, 13.3 to 16.1) with TMZ + RT (hazard ratio [HR], 1.31; 95% CI, 1.09 to 1.58; P = .0037). Median progression-free survival was 6.0 months (95% CI, 5.7 to 6.2) with NIVO + RT and 6.2 months (95% CI, 5.9 to 6.7) with TMZ + RT (HR, 1.38; 95% CI, 1.15 to 1.65). Response rates were 7.8% (9/116) with NIVO + RT and 7.2% (8/111) with TMZ + RT; grade 3/4 treatment-related adverse event (TRAE) rates were 21.9% and 25.1%, and any-grade serious TRAE rates were 17.3% and 7.6%, respectively. Conclusions The study did not meet the primary endpoint of improved OS; TMZ + RT demonstrated a longer mOS than NIVO + RT. No new safety signals were detected with NIVO in this study. The difference between the study treatment arms is consistent with the use of TMZ + RT as the standard of care for GBM. ClinicalTrials.gov NCT02617589
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页码:123 / 134
页数:12
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