Anticancer agent - axitinib

For a tumour to grow and thrive, it needs to develop a blood supply so that it gets the nutrients it needs. It does this by means of angiogenesis, and a number of protein growth factors are implicated in this process, including the tyrosine kinase vascular endothelial growth factor (VEGF), and small molecule drugs that target VEGF receptors are already available.

Another, axitinib, is under development at Pfizer in the US, and numerous clinical trials have been carried out in a variety of different cancer types. In one, a total of 52 treatment experienced patients with cytokine refractory metastatic renal cell carcinoma were given 5mg of axitinib twice a day for repeated four week cycles in a Phase II trial.¹ Of these, 24 achieved a partial response and a further 21 stable disease, the majority of which also experienced tumour shrinkage. Side-effects included hypertension, fatigue, nausea, diarrhoea and proteinurea.

A Phase II trial has also been carried out in patients with metastatic thyroid cancer that is either refractory to or not suitable for radioactive iodine therapy.² A total of 32 patients were given 5mg axitinib twice a day for between six and 469 days. The side effects observed included anorexia, nausea, vomiting, weight loss, proteinuria, fatigue, abdominal pain and stomatitis. Six of the subjects achieved a partial response, two of them lasting more than a year, and there was an unconfirmed partial response in five further patients. A total of 12 subjects discontinued treatment, including six because of disease progression and three as a result of adverse events.

It is also being looked at in combination with other anticancer agents. For example, in a Phase I/II trial it was given in combination with docetaxel to metastatic breast cancer patients as a first line therapy.³ Initially, in the Phase I part of the trial, six subjects were given 80mg/m² of docetaxel intravenously once every three weeks, and also 5mg doses of axitinib twice a day from the third day. Plasma pharmacokinetics showed no drug interactions, and serious adverse events included neutropoenia, anaemia, stomatitis and hypertension. Two of the patients had a partial response, three stable disease, and the disease progressed in the sixth. The stable disease and partial response were maintained after 14 weeks on axitinib alone after the completion of docetaxel treatment. The Phase II part of the trial is under way with docetaxel plus axitinib or placebo.

The drug is also being looked at in a number of other cancer types, including non-small cell lung cancer, acute myeloid leukaemia and myelodysplastic syndrome, melanoma and colorectal cancer.