New multitargeted treatments with antiangiogenic and antitumor activity: focus on sunitinib

Tumor growth and survival requires both proliferative and angiogenic signals, involving many molecular pathways. There is increasing preclinical and clinical evidence that agents targeting more than one pathway or receptor may be more efficacious in inducing tumor regression and disrupting tumor vasculature than those directed at a single target. This review considers several multitargeted agents recently approved or currently in clinical development for various solid tumors. These include sunitinib malate, an oral multitargeted receptor tyrosine kinase inhibitor conditionally approved in the EU in July 2006 for the treatment of patients with advanced renal cell carcinoma (RCC) after failure of cytokine-based therapy and patients with gastrointestinal stromal tumors ( GIST) whose disease has progressed or who are unable to tolerate imatinib mesylate. Also reviewed are the multitargeted inhibitors sorafenib ( also recently approved for the treatment of advanced RCC after failure of cytokine-based therapy); lapatinib ( in clinical development for several solid tumors, with promising activity in advanced breast cancer); and dasatinib ( preliminary indications of activity in GIST and other solid tumors). These agents have demonstrated activity against a range of tumor types and show promise in settings for which few ( if any) alternative treatments are available. The present challenge is to optimize the way in which these drugs are used in the clinic. This will require further evaluation of dosing schedules, combination regimens ( with chemotherapy and/or other targeted agents), and patient populations likely to derive greatest clinical benefit.