Anti-Angiogenic Therapies in the Management of Glioblastoma

Jessica D. Schulte; Manish K. Aghi; Jennie W. Taylor


Chin Clin Oncol. 2021;10(4):37 

In This Article

Therapeutic Strategies Targeting Angiogenesis

Targeting angiogenesis through VEGF blockade and other mechanisms has been efficacious in other cancers. In addition to triggering tumor cell death via deprivation of oxygen and nutrients, targeting angiogenesis may lead to the transient normalization of the tumor vasculature and improved uptake of cytotoxic chemotherapy.[34] In addition to observations that GBM is a highly vascularized tumor, several studies correlated VEGF expression with glioma grade and prognosis.[16,35,36] Thus, angiogenesis became a prime target of therapy in GBM as well.

While there are many inhibitors targeting different parts of the angiogenesis cascade, the only approved treatment in the United States (US) is bevacizumab, a recombinant human monoclonal antibody that binds to and sequesters VEGF, preventing activation of its receptors. In 2004, it was first FDA-approved for treatment of advanced colorectal cancer, where it reduced microvascular density and blood perfusion.[37] The first clinical trials of bevacizumab in GBM were in recurrent disease in the "AVF3708g/BRAIN" and "NCI 06-C-0064E" phase II trials. In these trials, bevacizumab monotherapy or combination therapy with irinotecan, demonstrated objective response rates (28–40%) and progression-free survival at 6 months (PFS6) of 40–50% that were markedly improved compared to higher historical controls, but no improvement in overall survival (OS).[38–40] These studies led to conditional accelerated FDA approval of bevacizumab in recurrent GBM in 2009, approved as monotherapy given the added toxicity in the combination arm.[38,39] The phase III European Organization of Research and Treatment of Cancer (EORTC) 26101 trial in recurrent GBM investigated lomustine with or without bevacizumab, and combination therapy also demonstrated improvement in PFS (1.5 to 4.2 months) but no change in OS.[41] Both the AVF3708g and EORTC 26101 trials demonstrated reduced reliance on steroids. In EORTC 26101, more patients on bevacizumab were able to completely stop steroids than patients in the control arm (23% vs. 12%). Based on the results of this trial, bevacizumab received full approval for treatment of recurrent GBM in 2017.

Bevacizumab was also investigated in newly diagnosed GBM in two large randomized, double-blinded, phase III trials—Radiation Therapy Oncology Group (RTOG) 0825 and AVAglio. Both trials demonstrated an improvement in PFS by 3.4–4.4 months with addition of bevacizumab to standard temozolomide and radiation, but no improvement in OS.[42,43]

Aflibercept, also known as VEGF trap, is a recombinant fusion protein that binds to circulating VEGF-A and VEGF-B, as well as placenta growth factor (PGF), and inhibits binding to VEGF receptors and downstream signaling. A phase II trial in recurrent malignant glioma demonstrated PFS6 of 7.7% in GBM, however the study was notable for high dropout attributed to significant toxicities.[44]

Tyrosine kinase inhibitors (TKIs) are small molecules that target one or many tyrosine kinase receptors, including VEGFR, EGFR, PDGFR, and FGFR. Sunitinib and sorafenib both target VEGFR in addition to c-Kit and PDGFR, and are shown to improve survival in other cancers including metastatic renal and hepatic cell carcinoma.[45,46] However, a phase II trial looking at sunitinib monotherapy in bevacizumab-naïve and -resistant recurrent GBM demonstrated no improvement in PFS or OS.[47] Sorafenib was tested in a phase I trial of recurrent GBM with modest effect on outcomes (median PFS 7.9 months and OS 17.8 months), but several dose-limiting toxicities.[48] Phase III trial of cediranib, another inhibitor of VEGFR, c-Kit and PDGFR, versus lomustine versus combination failed to meet its primary endpoint of PFS in recurrent GBM.[49] Enzastaurin, which targets the protein kinase C and PI3K/AKT serine/threonine 1 pathways, also failed to meet its primary endpoint of improvement in PFS or OS in a phase III trial in recurrent GBM comparing enzastaurin versus lomustine.[50]

Unfortunately, targeting other components of angiogenesis has also demonstrated limited efficacy. Trebananib (AMG386), a peptide fused to the Fc immunoglobulin protein, inhibits ANG1 and ANG2 ligands from interacting with the TIE2 receptor. Phase II study of trebananib versus combination with bevacizumab in recurrent GBM showed no improvement compared to historical OS of bevacizumab monotherapy.[51] Cilengitide, an antagonist of integrins αvβ3 and αvβ5 that mediate vascular stability, did not improve PFS or OS in combination with standard therapy for newly diagnosed GBM.[52] In addition to the treatments discussed above, there are many additional clinical trials using medications targeted toward angiogenesis, in different phases of development (Table 1).