Health & Medical Cancer & Oncology

Antiangiogenic Therapies in Glioblastoma Multiforme

Antiangiogenic Therapies in Glioblastoma Multiforme


Based on an impressive response rate compared with that of historical controls, bevacizumab (Avastin®; Genentech, CA, USA) received accelerated approval by the US FDA for recurrent GBM in May 2009. Bevacizumab is a recombinant humanized IgG1 monoclonal antibody that selectively binds with high affinity and sterically inhibits coupling of all biologically active isoforms of human VEGF to its receptors Flt1 (VEGFR-1) and KDR (VEGFR-2) on the surface of endothelial cells. Bevacizumab effectively inhibits downstream effects of activation of these receptors, including tyrosine autophosphorylation and subsequent induction of signal transduction pathways involved in mitogenesis and pro-survival activity within vascular endothelial cells.

The multicenter, randomized noncomparative Phase II BRAIN study evaluated bevacizumab with or without irinotecan in recurrent temozolomide-experienced GBM patients and reported objective response rates with bevacizumab alone or in combination with irinotecan as 28 and 38%, respectively, and the 6-month PFS and OS as 43 and 50%, and 9.2 and 8.7 months, respectively. Treatment with bevacizumab or bevacizumab plus irinotecan was generally well tolerated, and toxicity was limited to that expected for these agents. Steroid doses were stable or reduced in almost all patients. In the supporting, single-arm, single-center, Phase II, NCI 06-C-0064E trial of bevacizumab in patients with GBM that had recurred after radiotherapy and temozolomide (n = 48), the rate of PFS at 6 months was 29% and the overall response rate based on Macdonald criteria was 35%.

The addition of carboplatin and irinotecan to bevacizumab significantly increased toxicity but did not improve anti-tumor activity compared with that achieved with single-agent bevacizumab among bevacizumab-naive, recurrent GBM patients.

Bevacizumab has also been evaluated in combination with the EGF receptor tyrosine kinase inhibitor erlotinib in patients with recurrent malignant glioma. The regimen was associated with similar PFS benefit and radiographic response when compared with other bevacizumab-containing regimens.

A recent Phase II study of bevacizumab (10 mg/kg every 2 weeks) plus temozolomide during and after radiation therapy for patients with newly diagnosed GBM demonstrated improved PFS without improved OS when compared with the University of California, Los Angeles/Kaiser Permanente Los Angeles control group, a regimen that was well tolerated without unanticipated toxicities. Following enrolment of 70 patients and after a median follow-up time of 24.2 months, a median OS time of 21.1 months and median PFS of 13.6 months were reported. A Phase III registration trial, AVAglio, designed to examine the safety and efficacy of combining bevacizumab with standard radiotherapy and temozolomide in patients with newly diagnosed GBM, has been initiated and is currently recruiting patients.

Bevacizumab has also been evaluated with fractionated stereotactic radiotherapy (30 Gy in five fractions) in a series of 25 patients with recurrent GBM or anaplastic glioma. This treatment was deemed feasible but there were three grade 3 toxicities: gastrointestinal perforation, intratumoral hemorrhage and wound dehiscence.

Bevacizumab has been evaluated as salvage therapy following progression in 24 high-grade glioma patients who experienced disease progression following prior therapy with VEGF receptor tyrosine kinase inhibitors (R-TKis); (cediranib, sorafenib, pazopanib or sunitinib). Treatment with bevacizumab salvage therapy yielded a 21% partial response, a PFS at 6 months of 12.5% and a median time to progression of 8 weeks. Treatment was discontinued owing to bowel perforation (grade III) in two patients (8%) and pulmonary embolism (grade IV) in two patients (8%). One patient (4%) had avascular necrosis of the femoral head and thus had interrupted bevacizumab therapy. Three of the four patients who discontinued bevacizumab treatment owing to adverse events had stable disease at the time of discontinuation. The median OS from the start of R-TKi therapy was 9.2 months (range: 2.8–34.1+), whereas the median OS after bevacizumab was 5.2 months (range: 1.3–28.9+). Bevacizumab had modest activity in these patients who progressed on R-TKi, although durable tumor control was not achieved in most patients.

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