Bevacizumab

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Avastin (Roche)
100 mg/4 mL and 400 mg/16 mL in single-dose vials
Approved indication: metastatic colorectal cancer
Australian Medicines Handbook section 14.3.4

Many patients with colorectal cancer will develop metastatic disease. This is difficult to treat and has a very poor prognosis, so new therapies are being studied. One approach is to inhibit the new vessels the tumours need to grow. This can be attempted by inhibiting vascular endothelial growth factor, which is increased in metastatic disease.

Bevacizumab is a genetically engineered humanised monoclonal antibody against vascular endothelial growth factor. By binding to the growth factor, bevacizumab prevents it from binding to endothelial receptors.

In a study of 104 untreated patients with metastatic colorectal cancer bevacizumab was used in combination with fluorouracil and folinic acid. High and low doses of bevacizumab were tested in this regimen. The response rate, as judged by changes in tumour size, was 24% with the high dose regimen and 40% with the low dose regimen. This gave the low dose regimen a statistically significant advantage over the 17% response rate seen in a control group of patients who received fluorouracil and folinic acid alone. Compared to the control group, patients given the combination containing the low dose of bevacizumab also had a significantly longer median time before their cancers progressed (9 versus 5.2 months). Their median survival was 21.5 months compared to 13.8 months in the control group.¹

Following this trial, the low dose of bevacizumab (5 mg/kg) was studied in addition to a regimen containing irinotecan, fluorouracil and folinic acid. The four drugs were given to 402 patients with previously untreated metastatic disease and the results were compared with those of 411 patients given the three-drug regimen plus a placebo. Overall the response rate was 44.8% in the bevacizumab group and 34.8% in the control group. The progression-free survival was 10.6 months with bevacizumab compared with 6.2 months. There was also a significant difference in median survival time; 20.3 months in the bevacizumab group versus 15.6 months in the control group.²

Bevacizumab has to be diluted and given as a slow intravenous infusion once every 14 days. The antibody has a half-life of approximately 20 days.

Although bevacizumab improves survival by a few months it increases the risks of adverse effects. In the phase 3 trial there were significantly more serious adverse events in the patients taking the bevacizumab regimen than in those taking irinotecan, fluorouracil and folinic acid (84.9% versus 74%). Bevacizumab was associated with increased leucopenia, diarrhoea and hypertension.² Although there is a risk of venous and arterial thrombosis, including stroke and myocardial infarction, there is also a risk of fatal haemorrhage in patients taking regimens that include bevacizumab. The gut perforations which can occur with bevacizumab² may also be fatal. As wound healing may be affected, treatment should not begin until at least a month after surgery. Proteinuria is another problem and if the nephrotic syndrome develops treatment should be stopped. Congestive cardiac failure has also been reported.

Bevacizumab is approved for use with fluorouracil and folinic acid, or with fluorouracil, folinic acid and irinotecan.

Further studies are investigating the addition of bevacizumab to regimens containing oxaliplatin. Although genetic engineering is increasing treatment options, the best regimen is not yet clear.

Manufacturer provided the clinical evaluation

The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.