Phase II study of aflibercept in recurrent malignant glioma: a North American Brain Tumor Consortium study

Abstract

Purpose: 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.

Patients and methods: 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.

Results: 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.

Conclusion: Aflibercept monotherapy has moderate toxicity and minimal evidence of single-agent activity in unselected patients with recurrent malignant glioma.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Kaplan-Meier estimates of time to progression (TTP) and overall survival (OS) for patients with anaplastic glioma (A) and glioblastoma (B).

Fig 2.

Coronal (top) and axial (middle) T1-weighted post gadolinium (Gd) and fluid attenuated inversion recovery (FLAIR; bottom) magnetic resonance imaging of a patient with recurrent glioblastoma achieving a partial response to aflibercept.

Fig A1.

Heat map showing unsupervised gene clustering for patients with longer time to progression (TTP) on the basis of whole genome cDNA-mediated annealing, selection, extension, and ligation analysis of original tumor tissue. Red, bottom quartile; blue, top quartile; white, middle 50%; pink and gray, censored samples.

Fig A2.

Heat map showing unsupervised gene clustering for patients with shorter time to progression (TTP) on the basis of whole genome cDNA-mediated annealing, selection, extension, and ligation analysis of original tumor tissue. Red, bottom quartile; blue, top quartile; white, middle 50%; pink and gray, censored samples.