Martin H. Voss, MD: We know that different molecular processes can drive cancerous growth in the kidneys, and we know that the cardinal event that we have therapeutically targeted in kidney cancer is the functional loss of VHL and the upregulation of tumor angiogenesis. But, in addition to that, we know that VHL loss through upregulation of hypoxia-inducible factor can upregulate a number of downstream protein targets and cellular programs. Some of these can be targeted in parallel to targeting VEGF. So, what multi-tyrosine inhibitors do is not only block the VEGF receptor, which is their main target, but also inhibit various other molecular targets, such as the platelet-derived growth factor receptor, AXL, c-Met, and so forth. It’s really an approach to try to hit more than 1 target, recognizing that the cancer, most likely on the molecular level, is not only driven by 1 singular pathway.

Tyrosine kinase inhibitor therapy in the frontline treatment of advanced clear cell kidney cancer tends to be very effective, and we can see RECIST objective response rates in over 30% of our patients from most of the agents we commonly use in our clinic. We know that many of these patients can have extended periods of disease control. However, ultimately, the inevitable consequence of long-term use of these medications is the development of acquired molecular resistance—meaning that a patient who goes on TKI therapy ultimately, even if they have good response, will experience tumor growth on their scans. We are now starting to learn the molecular underpinnings of why that happens, and we can exploit that in the development of new therapy options.

It’s generally thought that using combination therapy makes it less likely for a tumor to break through the therapeutic approach and develop an acquired resistance. We have yet to learn whether or not the combinations that we are starting to use in clinical trials now will ultimately yield longer-term responses—longer-term control, really—of the underlying disease.

Thomas Hutson, DO, PharmD, FACP: The strategies that are being employed and developed in the frontline setting are combining new agents—predominantly immune-oncology class agents—with traditional TKIs. Unfortunately, not all TKIs are combinable in a manner that is safe and effective, and we’re seeing that with our staple first-line agents, sunitinib and pazopanib, being difficult with toxicity concerns when one combines them with a variety of PD-1 and PD-L1 inhibitors.

We’ve seen reports of a pazopanib combination with pembrolizumab, which had excessive hepatotoxicity, for example. So, a combination strategy would involve employing inhibition of VEGF pathways with immune-oncology approaches, which is going to be important, and we have phase I data that support that statement. Finding VEGF-targeted agents that are more combinable, with less toxicity, with immune-oncology agents is of importance.

Right now, from the phase I setting—and we’ve seen these reports at recent meetings—it appears that axitinib, or INLYTA, is a combinable agent. Lenvatinib also seems to be a combinable agent. Bevacizumab, or Avastin, is a combinable agent. And so, all 3 of those VEGF-targeted agents are being combined with a variety of different immune-oncology agents in the frontline setting. The hope is that one can, again, combine those at near maximal doses of the single agent to maintain efficacy and then hopefully provide synergy as we stimulate an immune response with the immune-oncology agent—at the same time, not compromising toxicity.

The role of sunitinib and pazopanib in the future is uncertain. As data mature from ongoing pivotal studies of combination strategies, the role of single-agent sunitinib and pazopanib becomes less clear. For instance, if one of the combination strategies shows that it is better than the current gold standard, which is sunitinib, then it will supplant sunitinib as frontline therapy. Whether or not a physician should choose sunitinib or pazopanib in a later line of therapy is uncertain, as there are minimal to no data supporting its use in that setting. Again, this past year we’ve seen 3 new agents with strong levels of activity in the second-line setting. We don’t have data that support the use of sunitinib and pazopanib in the same manner in that setting.

Transcript Edited for Clarity