Bevacizumab Plus Irinotecan Versus Temozolomide in Newly Diagnosed O6-Methylguanine–DNA Methyltransferase Nonmethylated Glioblastoma: The Randomized GLARIUS Trial

Herrlinger, Ulrich ; Schäfer, Niklas ; Steinbach, Joachim P.

; Weyerbrock, Astrid ; Hau, Peter ; Goldbrunner, Roland ; Friedrich, Franziska ; Rohde, Veit ; Ringel, Florian ; Schlegel, Uwe ; Sabel, Michael ; Ronellenfitsch, Michael W.

; Uhl, Martin ; Maciaczyk, Jaroslaw ; Grau, Stefan ; Schnell, Oliver ; Hänel, Mathias ; Krex, Dietmar ; Vajkoczy, Peter ; Gerlach, Rüdiger ; Kortmann, Rolf-Dieter ; Mehdorn, Maximilian ; Tüttenberg, Jochen ; Mayer-Steinacker, Regine ; Fietkau, Rainer ; Brehmer, Stefanie ; Mack, Frederic ; Stuplich, Moritz ; Kebir, Sied ; Kohnen, Ralf ; Dunkl, Elmar ; Leutgeb, Barbara ; Proescholdt, Martin ; Pietsch, Torsten ; Urbach, Horst ; Belka, Claus ; Stummer, Walter ; Glas, Martin

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Purpose In patients with newly diagnosed glioblastoma that harbors a nonmethylated O-6-methylguanine-DNA methyltransferase promotor, standard temozolomide (TMZ) has, at best, limited efficacy. The GLARIUS trial thus explored bevacizumab plus irinotecan (BEV+IRI) as an alternative to TMZ. Patients and Methods In this phase II, unblinded trial 182 patients in 22 centers were randomly assigned 2: 1 to BEV (10mg/kg every 2 weeks) during radiotherapy (RT) followed by maintenance BEV (10mg/kg every 2 weeks) plus IRI(125 mg/m(2) every 2 weeks) or to daily TMZ (75 mg/m(2)) during RT followed by six courses of TMZ (150-200 mg/m(2)/d for 5 days every 4 weeks). The primary end point was the progression-free survival rate after 6 months (PFS-6). Results In the modified intention-to-treat (ITT) population, PFS-6 was increased from 42.6% with TMZ(95% CI, 29.4% to 55.8%) to 79.3% with BEV+IRI (95% CI, 71.9% to 86.7%; P < .001). PFS was prolonged from a median of 5.99 months (95% CI, 2.7 to 7.3 months) to 9.7 months (95% CI, 8.7 to 10.8 months; P < .001). At progression, crossover BEV therapy was given to 81.8% of all patients who received any sort of second-line therapy in the TMZ arm. Overall survival (OS) was not different in the two arms: the median OS was 16.6 months (95% CI, 15.4 to 18.4 months) with BEV+IRI and was 17.5 months (95% CI, 15.1 to 20.5 months) with TMZ. The time course of quality of life (QOL) in six selected domains of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (QLQ)-C30 and QLQ-BN20 (which included cognitive functioning), of the Karnofsky performance score, and of the Mini Mental State Examination score was not different between the treatment arms. Conclusion BEV+IRI resulted in a superior PFS-6 rate and median PFS compared with TMZ. However, BEV+IRI did not improve OS, potentially because of the high crossover rate. BEV+IRI did not alter QOL compared with TMZ. (C) 2016 by American Society of Clinical Oncology

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