Many receptor tyrosine kinase pathways are involved in cancer proliferation, and many drugs have been designed to affect one or more of them
Many receptor tyrosine kinase pathways are involved in cancer proliferation, and many drugs have been designed to affect one or more of them. Foretinib, designed by Exelixis and licensed to GlaxoSmithKline, acts on both c-Met and VEGFR-2.1 c-Met is a receptor tyrosine kinase that is vital in regulating cell growth and survival. It is activated by binding to the ligand hepatocyte growth factor, and in some forms of cancer the receptor is overexpressed or mutated.
VEGFR-2, meanwhile, is expressed on the surface of vascular endothelial cells. By targeting both of these, it cuts out the possibility of one pathway being upregulated to compensate for the blocking of the other. It also appears to act on at least two other kinases, RON and AxI.
In a first in human Phase I trial, 40 patients with histologically confirmed metastatic or unresectable solid tumours were given oral doses of the drug in eight dose cohorts for five consecutive days every 14 days, with doses escalated via a conventional 3+3 design.2 The maximum tolerated dose was 3.6mg/kg, with the maximum dose given being 4.5mg/kg. The dose-limiting toxicities observed included grade 3 elecations in aspartate aminotransferase and lipase; other adverse events included hypertension, diarrhoea, vomiting, fatigue, haematuria and proteinuria. Two patients with papillary renal cell cancer and one with medullary thyroid cancer had a response, with stable disease achieved by a further 22.
A Phase II trial has also been carried out in 14 patients with recurrent or metastatic squamous cell carcinoma of the head and neck.3 The drug was given as a single agent in oral doses of 240mg for five consecutive days in a 14 day cycle, with a maximum of 30 cycles being given. Half of the patients showed stable disease, six had tumour shrinkage, and two experienced disease stabilisation for at least 13 months. Fatigue, constipation and hypertension were the most common adverse events. Trials continue, including in renal cell carcinoma and breast cancer.
1. S.R. Wedge et al. Cancer Res. 2005, 65, 4389
2. J.P. Eder et al. Clin. Cancer Res. 2010, 16, 3507
3. T. Seiwert et al. Invest. New Drugs 2012