Therapeutic Targeting Against Abnormal Tumor Vasculature

Transcript:

Mark Socinski, MD: Understanding the process of angiogenesis has created a number of therapeutic targets for us. We know that the dominant initial factor, and the factor that’s present mainly throughout the lifecycle of the cancer, is vascular endothelial growth factor (VEGF). That’s the ligand for the VEGF receptor. There are three known receptors; primarily VEGF receptor 2 (VEGFR2), that’s the driving pro-angiogenic receptor on endothelial cells. Tumors will secrete VEGF to induce angiogenesis, so one target of anti-angiogenic therapy is the VEGF ligand which is the target of bevacizumab.

Bevacizumab is a monoclonal antibody that binds to various isoforms of the VEGF ligand and prevents ligand—receptor interaction, thereby decreasing or inhibiting angiogenesis. Another strategy is to direct the monoclonal antibody to VEGFR2, and, in fact, that’s been a successful strategy with ramucirumab, where we saw in the REVEL trial that the addition of ramucirumab to docetaxel improved response rate and progression-free survival, as well as overall survival. This led to the FDA approval of ramucirumab in the second-line setting of metastatic lung cancer in combination with docetaxel.

One of the areas a decade or so ago that was of great interest was the use of vascular endothelial receptor tyrosine kinase inhibitors, all the ‘ib’ drugs as I refer to them: sunitinib, pazopanib, sorafenib, and that class of drugs. These are orally administered small molecules. They inhibit the kinase domain of VEGF. Although they’re not specific, they do have other targets such as PDGF, RET in certain cases, and others. So they’re a bit more promiscuous than the monoclonal antibodies which have a much higher degree of specificity. And even though in this class of drugs almost all of them have been tested in lung cancer, all of them have some low level of activity. However, not all have yet passed the phase III test where they’ve led to improved survival outcomes. Therefore, we don’t typically use them nowadays because we don’t have any FDA approvals for these drugs, despite the fact that they do have a level of activity in this setting.

Transcript Edited for Clarity