Combination Approaches for Metastatic Renal Cell Carcinoma - Episode 3

Cabozantinib in mRCC


Thomas E. Hutson, DO, PharmD: There are obviously multiple combination therapies that deserve study as treatment for metastatic renal cell carcinoma. Looking particularly at VEGF-targeted agents, there are numerous ones that could potentially be combined with an immunologic agent. Some of interest include the traditional VEGF inhibitors, and we have looked at things like Inlyta (axitinib). We’ve looked at Sutent (sunitinib) and Votrient (pazopanib) and have found that these VEGF inhibitors are not all the same in their ability to be combined to immunologic therapy. Some of them produce toxicities that are not going to allow for further development. It seems that the types of pure VEGF inhibitors that can be combined with immunologic approaches are going to be the more pure VEGF inhibitors, such as axitinib, tivozanib, lenvatinib, and a multitargeted drug named cabozantinib.

Lenvatinib and cabozantinib not only are VEGF inhibitors, but they also target other factors that we now know are important in the pathogenesis of this disease. For instance, lenvatinib is not only a VEGF inhibitor. It inhibits FGF. Cabozantinib is a VEGF inhibitor, but it inhibits c-MET and AXL. The story of cabozantinib is quite interesting. It was initially developed in the refractory setting with an understanding of this concept of angiogenic escape, or resistance mechanisms that may happen to frontline VEGF inhibition via increased expression of AXL and MET. Having a drug that could target those as well as continue to inhibit VEGF seemed plausible and rational. And the phase III METEOR trial proved its efficacy.

Moving that into the frontline setting, in the CABOSUN trial, compared with sunitinib, showed us that this agent, which targets 3 important pathways, could provide value over what was the gold standard treatment. Taking a strong agent like cabozantinib, which has a trifecta of targets, and combining it with an immunologic-stimulator drug, whether that be a PD-L1 or PD-1 agent, is important. And now we see a trial that we call the CaboNivo trial. We are anxiously looking forward to those results. That trial is open at my own site, and we are accruing patients onto that trial very easily.

Transcript Edited for Clarity