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N Engl J Med. 2017 Nov 16;377(20):1954-1963. doi: 10.1056/NEJMoa1707358.

Lomustine and Bevacizumab in Progressive Glioblastoma.

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From the University Medical Center and German Cancer Research Center, Heidelberg, Germany (W.W., M.B., F.S., I.H., A.D., M.P.); the European Organization for Research and Treatment of Cancer, Brussels (T.G., V.G.), and Leuven Cancer Institute-KU Leuven, Leuven (P.M.C.) - both in Belgium; Haaglanden Medical Center, The Hague (M.T.), Erasmus MC Cancer Institute, Rotterdam (W.T., J.C.B., M.J.B.), and VU University Medical Center, Amsterdam (M.K.) - all in the Netherlands; the Medical Oncology Department, Azienda Unità Sanitaria Locale di Bologna-IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy (A.A.B.); Institut Gustave Roussy, Villejuif (J.D.), Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, INSERM Unité 1127, Centre National de la Recherche Scientifique Unité Mixte de Recherche (UMR) 7225, Sorbonne Universités, University Pierre and Marie Curie 06 UMR S1127, and Institut du Cerveau et de la Moelle Épinière, Paris (A.I.), Institut de Cancerologie de l'Ouest-Centre Rene Gauducheau, Saint-Herblain (M.C.), Institut Régional du Cancer Montpellier, Montpellier (M.F.), and Centre Hospitalier Régional Universitaire de Lille, Lille (E.L.R., F.D.) - all in France; and the Departments of Oncology and Neurology, University Hospital and University of Zurich, Zurich, Switzerland (R.S., M.W.).



Bevacizumab is approved for the treatment of patients with progressive glioblastoma on the basis of uncontrolled data. Data from a phase 2 trial suggested that the addition of bevacizumab to lomustine might improve overall survival as compared with monotherapies. We sought to determine whether the combination would result in longer overall survival than lomustine alone among patients at first progression of glioblastoma.


We randomly assigned patients with progression after chemoradiation in a 2:1 ratio to receive lomustine plus bevacizumab (combination group, 288 patients) or lomustine alone (monotherapy group, 149 patients). The methylation status of the promoter of O6-methylguanine-DNA methyltransferase (MGMT) was assessed. Health-related quality of life and neurocognitive function were evaluated at baseline and every 12 weeks. The primary end point of the trial was overall survival.


A total of 437 patients underwent randomization. The median number of 6-week treatment cycles was three in the combination group and one in the monotherapy group. With 329 overall survival events (75.3%), the combination therapy did not provide a survival advantage; the median overall survival was 9.1 months (95% confidence interval [CI], 8.1 to 10.1) in the combination group and 8.6 months (95% CI, 7.6 to 10.4) in the monotherapy group (hazard ratio for death, 0.95; 95% CI, 0.74 to 1.21; P=0.65). Locally assessed progression-free survival was 2.7 months longer in the combination group than in the monotherapy group: 4.2 months versus 1.5 months (hazard ratio for disease progression or death, 0.49; 95% CI, 0.39 to 0.61; P<0.001). Grade 3 to 5 adverse events occurred in 63.6% of the patients in the combination group and 38.1% of the patients in the monotherapy group. The addition of bevacizumab to lomustine affected neither health-related quality of life nor neurocognitive function. The MGMT status was prognostic.


Despite somewhat prolonged progression-free survival, treatment with lomustine plus bevacizumab did not confer a survival advantage over treatment with lomustine alone in patients with progressive glioblastoma. (Funded by an unrestricted educational grant from F. Hoffmann-La Roche and by the EORTC Cancer Research Fund; EORTC 26101 number, NCT01290939 ; Eudra-CT number, 2010-023218-30 .).

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