Bevacizumab

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Abstract
Bevacizumab (Avastin®) is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor (VEGF) that is used to inhibit VEGF function in vascular endothelial cells and thereby inhibit tumour angiogenesis, upon which solid tumours depend for growth and metastasis. The addition of bevacizumab to fluoropyrimidine-based chemotherapy, with or without irinotecan or oxaliplatin, in both the first- and second-line treatment of metastatic colorectal cancer, significantly increased median progression-free survival or time to disease progression in most randomized controlled trials. Bevacizumab was generally, but not always, associated with a survival advantage; in phase III trials, the increases in median overall survival attributable to bevacizumab were 4.7 months with first-line therapy and 2.1 months with second-line therapy. In some studies, patients experienced clinical improvement without an apparent overall survival benefit. Bevacizumab had acceptable tolerability, with the majority of adverse events being generally mild and clinically manageable. However, from the UK National Health Service perspective, bevacizumab was not considered to be cost effective in combination with bolus fluorouracil/folinic acid or irinotecan/bolus fluorouracil/folinic acid. Additional pharmaco-economic analyses from different perspectives and using clinical data for combinations with the more efficacious infusional fluorouracil/folinic acid plus oxaliplatin or irinotecan chemotherapy regimens are required. Although cost effectiveness may be a concern, the combination of bevacizumab and fluoropyrimidine-based chemotherapy has potential in the treatment of metastatic colorectal cancer. Bevacizumab, produced by incorporating six VEGF-binding residues from a murine anti-human VEGF monoclonal antibody into a human IgG framework, binds to soluble VEGF and prevents it from binding to its receptors, VEGFR-1 or VEGFR-2, predominantly on vascular endothelial cells. VEGF activates and promotes the growth of vascular endothelial cells and is a potent regulator of angiogenesis and vascular permeability. Bevacizumab and murine anti-VEGF monoclonal antibody had no effect on the growth of tumour cell lines in vitro, indicating that they do not act directly on tumour cells. Treatment of mice bearing human colorectal cancer cell lines with bevacizumab or murine anti-VEGF monoclonal antibody produced dose-dependent reductions in tumour volume, reduced tumour blood vessel density, vascular permeability and liver metastases, and paradoxically increased tumour perfusion; resulting in increased intratumoural concentrations of irinotecan. Bevacizumab similarly reduced tumour volume and normalized tumour vasculature in patients with colorectal carcinoma, but in humans, tumour perfusion was reduced. The pharmacokinetic profile of intravenous bevacizumab in patients with metastatic colorectal cancer was linear over the dose range 0.3–10 mg/kg, with some accumulation after multiple-dose administration of 10 mg/kg every 2 weeks. Steady-state levels of the drug were achieved after 100 days. The clearance of bevacizumab was low and varied with bodyweight, gender and tumour burden. Both the volume of distribution in the central compartment and clearance were higher in male than in female patients with metastatic colorectal cancer after correcting for bodyweight. The elimination half-life of bevacizumab is long (12–22 days), allowing administration once every 2–3 weeks. Bevacizumab did not affect, to any clinically relevant extent, the pharmacokinetics of common chemotherapy agents with which it might be administered. In randomized controlled trials, the addition of intravenous bevacizumab to chemotherapy with bolus fluorouracil/folinic acid (FU/FA), irinotecan/bolus fluorouracil/folinic acid (IFL), irinotecan/infusional fluorouracil/folinic acid (FOLFIRI), infusional fluorouracil/folinic acid/oxaliplatin (FOLFOX), capecitabine/oxaliplatin (XELOX) or bolus fluorouracil/folinic acid/oxaliplatin generally displayed efficacy in the first-line treatment of metastatic colorectal cancer. In a pivotal phase III trial, adding bevacizumab to IFL significantly improved overall survival, progression-free survival, objective tumour response rate and 1-year survival compared with IFL plus placebo. Similarly, a large phase III trial demonstrated that bevacizumab in combination with FOLFOX4 or XELOX significantly increased progression-free survival compared with FOLFOX4 or XELOX plus placebo, although bevacizumab had no effect on the objective response rate. Other controlled trials have generally demonstrated significantly improved progression-free survival, time to disease progression or response rates with the addition of bevacizumab compared with chemotherapy alone. The addition of bevacizumab to FOLFOX4 for the second-line treatment of metastatic colorectal cancer also significantly improved overall survival, progression-free survival and the objective response rate compared with FOLFOX4 alone in a large phase III trial. Controlled studies suggested that combining bevacizumab with cetuximab was practical and beneficial, but that combination with either panitumumab or erlotinib/XELOX was impractical due to reduced efficacy or an increase in severe adverse events. The tolerability of bevacizumab was generally acceptable in patients with metastatic colorectal cancer. Adverse events were common in controlled clinical trials with bevacizumab, but most were of mild or moderate severity and many were related to the concomitant chemotherapy. Haemorrhage (mostly epistaxis), hypertension and proteinuria were relatively common bevacizumab-related adverse events, but were seldom of grade 3 (severe) or 4 (life-threatening) severity and were generally clinically manageable. In placebo-controlled trials of first-line therapy, only hypertension and any grade 3/4 event occurred with a significantly higher...

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