Combination Approaches for Metastatic Renal Cell Carcinoma - Episode 6

Antiangiogenic Resistance in mRCC


Thomas E. Hutson, DO, PharmD: Since the paradigm change of 2005, when we saw the first-in-class approvals of VEGF TKIs, sorafenib and sunitinib, we have been plagued with ultimate VEGF refractoriness. Once a VEGF inhibitor is started in a patient, it appears to be only a matter of time before resistance develops. We also have been plagued by the recognition that there has always been a population of patients who appear to be primarily refractory no matter what we do or what we give them. With traditional VEGF inhibitors, such as sunitinib, the likelihood would be around 20%.

We have 2 types of resistance that we focus on. We focus on the primary refractory type, where a patient who is started on a VEGF inhibitor seems to have no benefit whatsoever. The first imaging studies show progression. The second, more common group are those patients who ultimately develop recurrence. This latter group is actually a group of many different flavors. There are patients who have initial control and then rapid development of resistance. There are patients who have resistance that develops in multiple new sites, as well as those who have resistance that is indicated by slow growth of existing disease. So, as you can see, there are many different categories that ultimately suggest that different biologies are at play.

We have spent many years trying to understand this concept of angiogenic resistance, and a lot of research has looked at escape mechanisms. FGF, c-MET, and AXL are just 3 examples of factors of proteins that may be upregulated at the time of angiogenic escape. There’s also a belief that these same factors may be upregulated in those who have de novo primary resistance. Having multitargeted agents that target these factors, either at initial presentation, when you start therapy in the frontline setting, or at the time of resistance, when these agents are used as second-line or refractory therapy, is important. That’s the theory. There’s basic science that supports that. The proof is in the clinical trials. Several clinical trials have looked at this—for reference, the lenvatinib/everolimus combination trial versus everolimus, and the cabozantinib versus everolimus trial—demonstrating that this theory translates into absolute efficacy in clinical study.

Chung-Han Lee, MD, PhD: Currently, there are not very clear biomarkers to guide us in terms of how resistance develops—predictive biomarkers that predict resistance. However, what we do know about the TKIs—multikinase inhibitors and the targeting of multiple different kinases. In some ways, even though we’re using 1 drug, if you think about it from a target perspective, you’re actually using combination therapy of sorts. When we think about combination therapy and hitting multiple different kinase targets, this becomes critical in order to achieve better responses. Some of the pathways that have been critical as antiangiogenesis include both the c-MET pathway and the FGF pathway, which later-developed TKIs tend to address.

Transcript Edited for Clarity