Vascular endothelial growth factor is an important component in the angiogenesis process, the way in which a tumour embeds itself in the body’s blood supply. The tyrosine kinase increases vascular permeability while promoting the proliferation of endothelial cells, and there are several forms with slightly different activities. Blocking VEGF can thus have an impact on angiogenesis, and numerous drugs have already been developed that target VEGF receptors.
Another such drug, tivozanib, is being investigated by Aveo Therapeutics, under licence from Kyowa Hakko Kirin. The novel oral quinolone urea derivative targets three different VEGF receptors, and is showing promise in clinical trials.1 In one Phase II randomised discontinuation trial, 272 patients with advanced or metastatic renal cell carcinoma were given 1.5mg/day of open label tivozanib or placebo orally for 16 weeks in cycles of three treatment weeks, followed by a one-week break.2 After this, the 78 patients who had at least 25% tumour shrinkage continued to take tivozanib, while the remaining 118 were randomised once more to tivozanib or placebo.
After 16 weeks, the objective response rate was 18%, and significantly more of the tivozanib patients remained progression free after 12 weeks – 49% compared with 21%. The median progression free survival was 11.7 months overall, with the most common serious adverse event being hypertension.
It has also been compared with sorafenib in a randomised, open label trial. Patients with advanced renal cell carcinoma and prior nephrectomy were given tivozinib according to the same schedule as above or twice-daily doses of sorafenib continuously in a four-week cycle.3 A total of 517 patients were treatment naïve or had no more than one prior therapy that did not target VEGF or mTOR. The objective response rate for the tivozinib group was 33%, compared with 23% for those given sorafenib. Again, the most common adverse event with tivozanib was hypertension; hand-foot syndrome was the most significant with sorafenib. Tivozanib had a low incidence of common chemotherapy side-effects, including fatigue, diarrhoea, myelosuppression and hand-foot syndrome. Patient outcomes analysis is under way, and trials continue.
References
1. N. Guilbaud et al. Cancer Res. 2006, 66, 9134
2. D.A. Nosov et al. J. Clin. Oncol. 2012, 30, 1678
3. R.J. Motzer et al. J. Clin. Oncol. 2012, 30 (Suppl.), Abst. 4501