Multi-targeted kinase inhibitor sorafenib and its future

Sorafenib is an oral, small-molecule receptor, tyrosine kinase inhibitor with antiproliferative as well as antiangiogenic properties. The multiple cellular targets of sorafenib include serine/threonine kinase Raf, vascular endothelial growth factor receptors 1, 2, 3, platelet-derived growth factor-b, Flt-3, and c-Kit. Sorafenib has demonstrated preclinical activity against several tumor types and has been approved for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma, and iodine-refractory thyroid carcinoma. In this review we summarize the clinical antitumor activity of sorafenib in solid tumors, with focus on breast, ovarian, and glioblastoma cancers. We review available data from multiple phase Ib and phase II trials with sorafenib alone or in combination with other agents, and highlight the most encouraging clinical data which will guide the future directions of research. We also discuss biomarker research and the need for better predictive markers for response to sorafenib. Although sorafenib is relatively well tolerated, there are multiple toxicities that can result in dose reductions and discontinuations that are especially evident in combination therapy trials. In the next several years new data from large phase III trials will become available, which might broaden the clinical indication of sorafenib to adjuvant settings and/or other malignancies. Better understanding of its mechanism of action and clinical activity will assist in clinical management of patients.