Phase II Study of Bevacizumab in Combination with Sorafenib in Recurrent Glioblastoma (N0776): A North Central Cancer Treatment Group Trial
Mené sur 54 patients atteints d'un glioblastome récidivant, cet essai de phase II évalue l'efficacité et la toxicité d'un traitement combinant bevacizumab et sorafenib
Purpose: We hypothesized that vertical blockade of VEGF signaling by combining bevacizumab with sorafenib in recurrent glioblastoma (rGBM) patients would result in a synergistic therapeutic effect. We also investigated whether VEGF, VEGFR2, and HIF-1α single nucleotide polymorphisms (SNPs), circulating biomarkers of angiogenesis and Magnetic Resonance (MR) imaging markers, such as apparent diffusion coefficient (ADC), correlated with treatment efficacy and/or toxicity. Patients/Methods: Patients received bevacizumab (5 mg/kg every 2 weeks) with sorafenib (200 mg bid, weekly, days 1-5) (Group A), but due to toxicity, the starting sorafenib dose was subsequently modified to 200 mg qd (Group B). Results: 54 patients were enrolled: 19 patients in Group A and 35 in Group B. Objective response rate was 18.5% with median duration of 6.7 mo (range 0.5-24.1 mo). Six-month progression free survival (PFS6) was 20.4% (11/54), and median OS was 5.6 months (95% CI 4.7 - 8.2); outcome was similar between the two dose groups. We identified single nucleotide polymorphisms in the VEGF and VEGFR2 promoter regions which were associated with PFS6 (p<0.022). Among molecular markers of angiogenesis, a higher log2 baseline level of stromal cell derived factor-1 was associated with PFS6 success (p=0.04). The circulating endothelial cell log2-fold decreased during treatment with subsequent increase at disease progression (p=0.022). Imaging analysis demonstrated a trend associating ADC-L with poor outcome. Conclusions: The bevacizumab/sorafenib combination did not improve outcome of recurrent GBM patients versus historic bevacizumab treated controls. Biologic markers of response and resistance to bevacizumab in gliomas were identified which merit prospective validation.