Vascular endothelial growth factor (VEGF) inhibition for the treatment of cancer is reviewed. Items in blue bold link to New Medicine’s Oncology KnowledgeBASE (nm/OK) so subscribers may access the complete regularly updated records of all agents/targets/developers mentioned in this document.
Bevacizumab (Avastin; Genentech/Roche), a monoclonal antibody (MAb), is the only currently approved VEGF inhibitor that selectively targets VEGF-A, while 3 other approved oral drugs, pazopanib (Votrient; GlaxoSmithKline), sunitinib (Sutent; Pfizer) and sorafenib (Nexavar; Onyx Pharmaceuticals) are orally available multi-targeted receptor tyrosine kinase inhibitors that include VEGF receptors among their targets.
Worldwide sales of Avastin were $6.2 billion in 2010. The recent FDA decision to rescind approval for advanced breast cancer in combination with standard treatments threatens up to $1 billion in sales.
Potential adverse effects (AE) of Avastin have come under increased scrutiny and may, along with unfavorable cost benefit analyses, pose challenges to its growth potential and continued widespread use.
The clinical development program for Avastin provides a roadmap of the complexities and challenges of developing a drug with such wide ranging potential in cancer therapy; at least 1,000 clinical trials have been initiated, with about half of them ongoing.
Avastin is also under investigation in combination regimens in about 78 trials with approximately 38 novel agents, 33 of which target more than 37 unique molecular moieties (Exhibit 1).
Cancer drug developers are beginning to conduct trials with combinations of novel targeted agents. With over 600 distinct targeted agents having entered/completed clinical trials the possibilities are staggering.
Increased focus on targeted cancer drugs and the high cost of treatment associated with their use underscore the pressing need for new methods (e.g., predictive biomarkers) to select specific drugs for specific patients.
Most of the VEGF pathway inhibitors in clinical development are multitargeted, addressing several VEGF family members plus other targets (Exhibit 2); the most common targets are c-Kit, FLT3, and Met.
In addition to the VEGF family, many other molecules play a role in angiogenesis such as Tie2 receptor and its ligand angiopoeitin, neuropilin 1, metalloproteinase, heparinase, integrins, and ephrins, among others.