Phase II Study of Aflibercept in Recurrent Malignant Glioma: A North American Brain Tumor Consortium Study

The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 05/2011; 29(19):2689-95. DOI: 10.1200/JCO.2010.34.1636
Source: PubMed


Antivascular endothelial growth factor (anti-VEGF) therapy is a promising treatment approach for patients with recurrent glioblastoma. This single-arm phase II study evaluated the efficacy of aflibercept (VEGF Trap), a recombinantly produced fusion protein that scavenges both VEGF and placental growth factor in patients with recurrent malignant glioma.
Forty-two patients with glioblastoma and 16 patients with anaplastic glioma who had received concurrent radiation and temozolomide and adjuvant temozolomide were enrolled at first relapse. Aflibercept 4 mg/kg was administered intravenously on day 1 of every 2-week cycle.
The 6-month progression-free survival rate was 7.7% for the glioblastoma cohort and 25% for patients with anaplastic glioma. Overall radiographic response rate was 24% (18% for glioblastoma and 44% for anaplastic glioma). The median progression-free survival was 24 weeks for patients with anaplastic glioma (95% CI, 5 to 31 weeks) and 12 weeks for patients with glioblastoma (95% CI, 8 to 16 weeks). A total of 14 patients (25%) were removed from the study for toxicity, on average less than 2 months from treatment initiation. The main treatment-related National Cancer Institute Common Terminology Criteria grades 3 and 4 adverse events (38 total) included fatigue, hypertension, and lymphopenia. Two grade 4 CNS ischemias and one grade 4 systemic hemorrhage were reported. Aflibercept rapidly decreases permeability on dynamic contrast enhanced magnetic resonance imaging, and molecular analysis of baseline tumor tissue identified tumor-associated markers of response and resistance.
Aflibercept monotherapy has moderate toxicity and minimal evidence of single-agent activity in unselected patients with recurrent malignant glioma.

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    • "Aflibercept is a novel agent that targets VEGF with a soluble decoy VEGFR fused to an immunoglobulin constant region and also binds placental growth factor [2]. However, a phase II trial of aflibercept monotherapy in recurrent malignant glioma showed minimal evidence of single-agent activity with PFS-6 of 7.7% and median PFS of 12 weeks for GBM patients and PFS-6 of 25% and median PFS of 24 weeks for anaplastic glioma patients [44]. Additionally, long-term treatment with aflibercept seemed to result in acquisition of an invasive phenotype of glioma, which seemed to coincide with preliminary data in GBM patients treated with bevacizumab [45]. "
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    • "Another challenge with response criteria is related to assessment variability of contrast-enhancing tumor. On the basis of their mechanisms of action, agents that target VEGF-A or its receptor (ie, bevacizumab, aflibercept, and cediranib) affect vascular permeability [26, 28, 29], which, in turn, influences both the leakage of gadolinium into the brain and the extent of contrast enhancement on imaging. Furthermore, many tumor-extrinsic factors also modulate vascular permeability [30–34], and the effects of radiation (or chemoradiation) are of particular relevance in the setting of newly diagnosed glioblastoma. "
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