Anticancer agent bevacizumab

Just like organs, tumours need a blood supply to survive and thrive. Therefore, in the process of tumour angiogenesis, the tumour grows new blood vessels that dock into the body's blood supply to keep the tumour alive. The formation of the new blood vessels is stimulated by vascular endothelial growth factor, or VEGF, a protein that binds to specific receptors on nearby blood vessels in order to stimulate extensions to existing blood vessels, and is crucial in the maintenance of established tumour blood vessels.

VEGF is secreted from hypoxic cells, including those that are malignant or cancerous. As well as promoting tumour growth, VEGF is also implicated in the process of metastasis, where a malignant tumour spreads to other sites far away from the initial growth. VEGF was discovered by scientists at Genentech, and they subsequently developed a recombinant humanised monoclonal antibody, rhuMAb-VEGF, that is designed to prevent VEGF from binding to its receptors, and therefore, theoretically, inhibiting the tumour's growth and metastasis.

Now referred to as bevacizumab, and given the trade name Avastin, the monoclonal antibody is being investigated as a potential treatment for metastatic breast, colorectal and non-small cell lung cancers.

A Phase II trial looked at the efficacy and safety of a combination of bevacizumab with fluorouracil and leucovorin, compared with fluorouracil and leucovorin alone.¹ A total of 104 previously untreated patients with metastatic colorectal cancer were randomly given weekly doses of 500mg/m² of fluorouracil and 500mg/m² leucovorin alone, or in combination with either 5 or 10mg/kg of bevacizumab twice a week.

Those given the monoclonal antibody showed higher response rates, longer median time to disease progression and longer median survival. After crossover, two of 22 patients had a partial response to bevacizumab alone. The most significant adverse event was thrombosis, which was fatal in one case. Other side-effects included hypertension, proteinuria and nose bleed. Better results were seen with the lower dose of bevacizumab.

Another randomised, double-blind, placebo-controlled Phase II trial was carried out in patients suffering from metastatic renal cell carcinoma.² Subjects were given placebo, or bevacizumab at 3 or 10mg/kg every two weeks. Minimal toxic events were seen, with the main problems being hypertension and proteinuria.

After four months, 64% of those given the higher dose were progression free, compared with 39% with the lower dose and 20% for placebo. Results were similarly good after eight months: the respective figures are 30, 14 and 5%.

Phase III trials are being carried out on the antibody, and it could be a useful addition to the arsenal of therapeutic agents to treat metastatic cancers.