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Expert Discusses Targeted Combinations in RCC

Danielle Bucco
Published: Friday, Mar 31, 2017

David I. Quinn, PhD, MBBS

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.

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.

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

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).

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. 

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

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.

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