Anticancer agent - sunitinib malate
In malignant diseases, signalling via receptor tyrosine kinases (RTKs) is often disrupted. These kinases are transmembrane proteins that have extracellular binding domains, and a number of type III split kinase domain RTKs are expressed on tumour cells.
In malignant diseases, signalling via receptor tyrosine kinases (RTKs) is often disrupted. These kinases are transmembrane proteins that have extracellular binding domains, and a number of type III split kinase domain RTKs are expressed on tumour cells.
Kinases such as vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) play a role in the proliferation of tumour cells and tumour angiogenesis. Pfizer has developed sunitinib, an extremely potent orally available compound that inhibits the receptors for both VEGF and PDGF, plus other RTKs such as Kit and Flt3.1
Many trials have been carried out in patients with various cancers. In a Phase II trial in patients with metastatic renal cell cancer sunitinib was given as second line therapy.2 In all, 63 patients were given repeat cycles of 50mg doses daily for four weeks, followed by a two-week rest period. A partial response was experienced by 15 patients, while 29 achieved stable disease. Its toxicity profile was acceptable.
It has also been tested in patients with gastrointestinal stromal tumours (GIST) - a group of mesenchymal neoplasms that is characterised by the expression of mutant Kit in more than 85% of sufferers. In a Phase I study 32 patients with GIST that was resistant to imatinib were given 25, 50 or 75mg of sunitinib daily for 14 days, followed by a 14-day rest period.3 Ten of the 12 patients given 50mg experienced a decrease in tumour-associated metabolic activity, with five of these also experiencing a decrease in tumour size on CT scans.
Another study in 75 patients with metastatic GIST who were refractory or intolerant to imatinib gave 50mg daily doses for either two weeks with two weeks" rest, four weeks with two weeks" rest or two weeks with one week rest.4 Of patients treated for at least six months 54% experienced clinical benefit (either an objective response or prolonged progression-free survival).
A placebo-controlled Phase III trial was started in patients with GIST resistant to imatinib. It showed efficacy and safety early on in the trial, and as a result was stopped seven months ahead of schedule. Further trials are being carried out in other cancers, including metastatic breast cancer, neuroendocrine cancer and non-small cell lung cancer.