Expert Discusses Targeted Combinations in RCC

David I. Quinn, PhD, MBBS

Over the past several decades, there has been significant improvement in the understanding of the biology of renal cell carcinoma (RCC), which has led to the development of multiple targeted agents that have changed clinical practice.

“We've developed significant activity over more than a decade in this area and now we’re capitalizing on it. We have our first real administrable combination and we have some new drugs that are coming that are going to be important,” said David I. Quinn, PhD, MBBS.

One of the targeted therapies that has seen promising for patients with RCC is cabozantinib (Cabometyx), which has been shown to have an advantage when compared to sunitinib (Sutent) in the frontline setting. Cabozantinib reduced the risk of progression or death by 34%, according to results from the phase II CABOSUN trial.

OncLive: Can you provide an overview of your talk on targeted therapies in RCC?

In an interview with OncLive, Quinn, an associate professor of Medicine, medical director of USC Norris Cancer Hospital, discusses the latest advances with targeted agents in RCC, including combination regimens with checkpoint inhibitors.Quinn: I covered the various targeted therapies that we've used for more than a decade with various iterations. I focused on some of the later data that we’ve had and that is chiefly the emergence of cabozantinib (Cabometyx). Level 1 evidence in the second-line versus everolimus (Afinitor) showed an improvement in overall survival (OS), response, and progression-free survival (PFS) compared to what had been a standard second-line drug for a period of years.

The other focus is an alliance-led cooperative group study, which compared cabozantinib and sunitinib in the first-line setting. This is a randomized phase II study with a very significant number of patients. It shows a PFS advantage for cabozantinib at this time, but with immature OS data.

There are some interesting aspects to the study. The toxicity of cabozantinib and sunitinib seem to be relatively comparable where we perhaps thought cabozantinib would be more toxic. This may be a viable option that changes the first-line setting. We're not sure how the FDA will deal with this data since certain things need to happen, such as review of the imaging studies that were done and more follow-up data to determine whether there is an OS advantage. We've had some movement in the targeted therapy area in that regard.

The other interesting development in targeted therapy has been the combination of the VEGF inhibitor, lenvatinib (Lenvima) with the mTOR inhibitor, everolimus. In randomized phase II data, the combination of the 2 drugs is better for PFS with a trend toward improvement in OS compared to either of the drugs alone. This was randomized phase II data which led to the FDA approving the combination of lenvatinib and everolimus.

It has been difficult for us to combine the VEGF receptor TKIs with everolimus. However, lenvatinib seems to do that tolerably well and has some activity against some other receptors that may be of interest. We now have that combination in the mix for targeted therapies, but clinicians are grappling with how to use that. It clearly has significant efficacy since we’re not using everolimus as a single-agent anymore because not only was it beaten in the lenvatinib plus everolimus study, it was beaten in the study where it was compared with cabozantinib and the study where it was compared with nivolumab (Opdivo).

Are there any other combinations that are in clinical trials right now?

People feel that the mTOR inhibitors have some positive activity since a select group of patients seemingly do extremely well with them and so they’ll opt to potentially combine with lenvatinib. We have some interesting combinations in RCC. Recently, at ASCO GU, we have seen the combination in the first-line setting of bevacizumab (Avastin) and atezolizumab (Tecentriq) showing quite significant activity, which seems to be greater in patients that express the PD-L1 marker via immunohistochemistry. We have a follow-up phase III study for that which will give us more ideas and definitive efficacy and safety data.

With these new agents being explored, where do you see the focus being in the next few years?

Then, we have a number of combinations with the PD-L1 or PD-1 agents that are combined with targeted agents, most particularly with axitinib (Inlyta). We also saw data for the PD-L1 inhibitor avelumab (Bavencio) and the PD-1 inhibitor pembrolizumab (Keytruda) in combinations with axitinib in phase I/II studies at ESMO 2016, which suggested very significant activity. In my opinion, we're going to have some other combinations and these are now being explored in phase III trials. I think it will depend on the first-line setting as to what happens with several phase III studies. We have a phase III study accruing with bevacizumab and atezolizumab compared to sunitinib. We have the CTLA-4 inhibitor ipilimumab (Yervoy) plus nivolumab in the first-line setting also compared to sunitinib. If either of those studies beat sunitinib, we'll have a new first-line therapy in that regard. However, we don't know how these therapies would stack up against cabozantinib as a single-agent or in combination. There are combination studies with cabozantinib that are ongoing at present.

What would you want the main takeaways to be from your talk?

A lot can change or we may end up with group selection based on markers like PD-L1. That will all impact what happens with subsequent therapies, so the outcomes will dictate a new sequence, but where we put some of the older drugs is going to be likely more art than science. We're not going to have trials to tell us that. I think targeted therapies are important and need to continue to be developed—it’s not all about immunotherapy. We need to pick the right drug for the right patient. We've developed significant activity over more than a decade in this area and now we’re capitalizing on it. We have our first real administrable combination and we have some new drugs that are coming that are going to be important.

Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial [published online November 14, 2016]. J Clin Oncol. doi:10.1200/JCO.2016.70.7398