Savolitinib Hepatocyte growth factor receptor (HGFR, MET, c-Met) inhibitor Cancer therapy

摘要

Mesenchymal-epithelial transition factor (c-Met), a tyrosine kinase, is a proto-oncogene encoding the high-affinity receptor for hepatocyte growth factor (HGF). Under pathological conditions c-Met activation may confer proliferative, survival and invasive/metastatic abilities to cancer cells. Indeed, c-Met is overexpressed in a wide array of carcinomas including lung, breast, ovary, kidney, colon, thyroid, liver and gastric carcinomas. Savolitinib (AZD-6094) is a potent and selective small-molecule c-Met kinase inhibitor with IC50 values in the low nanomolar range in enzyme assays which has been found to inhibit c-Met autophosphorylation and HGF-induced proliferation in human lung cancer cell lines. In a phase II clinical study in MET-driven papillary renal cell carcinoma (PRCC), patients receiving orally administered savolitinib displayed a partial response rate of 18% and a progression-free survival of 6.2 months in comparison with 1.4 months in MET-independent patients. Currently, a phase III clinical trial (SAVOIR) is ongoing to study the efficacy of savolitinib in comparison with sunitinib in patients with MET-driven PRCC.