TY - JOUR
T1 - Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776)
T2 - A North Central Cancer Treatment Group Trial
AU - Galanis, Evanthia
AU - Anderson, S. Keith
AU - Lafky, Jackie M.
AU - Uhm, Joon H.
AU - Giannini, Caterina
AU - Kumar, Shaji K.
AU - Kimlinger, Teresa K.
AU - Northfelt, Donald W.
AU - Flynn, Patrick J.
AU - Jaeckle, Kurt A.
AU - Kaufmann, Timothy J.
AU - Buckner, Jan C.
PY - 2013/9/1
Y1 - 2013/9/1
N2 - Purpose: We hypothesized that vertical blockade of VEGF signaling by combining bevacizumab with sorafenib in patients with recurrent glioblastoma would result in a synergistic therapeutic effect. We also investigated whether VEGF, VEGFR2 and hypoxia-inducible factor-1α single-nucleotide polymorphisms (SNP), circulating biomarkers of angiogenesis, and MRI markers such as apparent diffusion coefficient (ADC) are correlated with treatment efficacy and/or toxicity. Experimental Design: Patients received bevacizumab (5 mg/kg every 2 weeks) with sorafenib (200 mg twice a day, weekly, days 1-5; group A). Due to toxicity, the starting sorafenib dose was subsequently modified to 200 mg every day (group B). Results: Fifty-four 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 months (range 0.5-24.1 months). Six-month progression-free survival (PFS6) was 20.4% (11/54), and median overall survival (OS) was 5.6 months [95% confidence interval (CI), 4.7-8.2]; outcome was similar between the two dose groups. We identified SNPs 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). Circulating endothelial cells decreased during treatment with subsequent increase at disease progression (P = 0.022). Imaging analysis showed a trend associating ADC-L with poor outcome. Conclusions: The bevacizumab/sorafenib combination did not improve outcome of patients with recurrent glioblastoma versus historic bevacizumab-treated controls. Biologic markers of response and resistance to bevacizumab in gliomas were identified which merit prospective validation.
AB - Purpose: We hypothesized that vertical blockade of VEGF signaling by combining bevacizumab with sorafenib in patients with recurrent glioblastoma would result in a synergistic therapeutic effect. We also investigated whether VEGF, VEGFR2 and hypoxia-inducible factor-1α single-nucleotide polymorphisms (SNP), circulating biomarkers of angiogenesis, and MRI markers such as apparent diffusion coefficient (ADC) are correlated with treatment efficacy and/or toxicity. Experimental Design: Patients received bevacizumab (5 mg/kg every 2 weeks) with sorafenib (200 mg twice a day, weekly, days 1-5; group A). Due to toxicity, the starting sorafenib dose was subsequently modified to 200 mg every day (group B). Results: Fifty-four 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 months (range 0.5-24.1 months). Six-month progression-free survival (PFS6) was 20.4% (11/54), and median overall survival (OS) was 5.6 months [95% confidence interval (CI), 4.7-8.2]; outcome was similar between the two dose groups. We identified SNPs 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). Circulating endothelial cells decreased during treatment with subsequent increase at disease progression (P = 0.022). Imaging analysis showed a trend associating ADC-L with poor outcome. Conclusions: The bevacizumab/sorafenib combination did not improve outcome of patients with recurrent glioblastoma versus historic bevacizumab-treated controls. Biologic markers of response and resistance to bevacizumab in gliomas were identified which merit prospective validation.
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U2 - 10.1158/1078-0432.CCR-13-0708
DO - 10.1158/1078-0432.CCR-13-0708
M3 - Article
C2 - 23833308
AN - SCOPUS:84883474833
SN - 1078-0432
VL - 19
SP - 4816
EP - 4823
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -