Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment.
Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. Sorafenib, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile. Further characterization showed that sorafenib suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, sorafenib demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, sorafenib showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral sorafenib as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of sorafenib in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for sorafenib and 0% for placebo. Stable disease was observed in 78% and 55% of patients on sorafenib and placebo, respectively. Sorafenib significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of sorafenib by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated.
Strumberg
Dirk
D
Department of Hematology and Medical Oncology, Marienhospital Herne, University of Bochum, Herne, Germany. dirk.strumberg@marienhospital-herne.de
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy; D008113:Liver Neoplasms / Q000188:drug therapy; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D012509:Sarcoma / Q000188:drug therapy; D000077157:Sorafenib
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D040262:Receptors, Vascular Endothelial Growth Factor