After Second-Line RCC Approvals, Focus Shifts to Frontline

Chung-Han (Joe) Lee, MD

Three recent drug approvals have shifted the landscape in the second-line setting for renal cell carcinoma (RCC), and researchers are now setting their sights on transforming upfront care, according to Chung-Han (Joe) Lee, MD.

In the second-line setting, the PD-1 inhibitor nivolumab (Opdivo) was approved in November 2015, followed by the respective April 2016 and May 2016 approvals of cabozantinib (Cabometyx) and the combination of lenvatinib (Lenvima) and everolimus (Afinitor), creating promising additions to an already abundant landscape.

Frontline trials with these agents are already creating buzz. For example, in the phase II CABOSUN trial, frontline cabozantinib was found to reduce the risk of progression or death by 34% versus sunitinib (Sutent) for patients with metastatic RCC.

During the 2016 OncLive State of the Science Summit on Genitourinary Cancers, Lee, who is a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed current paradigms and future directions in RCC.

OncLive: What was the focus of your RCC discussion at the meeting?

In an interview at the meeting, Lee highlighted recent treatment approvals in RCC, current and emerging treatments and strategies, and the significance of clinical trial enrollment.Lee: Today, I briefly went over the new developments within kidney cancer. Over the course of the last 11 years, we have developed approximately 10 new regimens for the treatment of kidney cancer, with 3 of them approved within the last year or so. Then, we talked briefly about adjuvant therapy and some of the questions that have arisen from the studies that have come out, and some of the future directions to take.

How did these recent approvals shift the treatment landscape?

Where are we at currently with understanding resistance?

Within the last year or so, we had the FDA approval of 3 new regimens for the treatment of kidney cancer: cabozantinib, nivolumab, and our first combination therapy of everolimus and lenvatinib.Within the last year, we have really seen, in the second-line setting, a shift in the drugs that are being used at this moment. We have not only shown improvements in overall survival, but also we are starting to look more deeply at some of the resistance mechanisms of some of the first-line therapies.There is a lot more research that needs to be done with regard to how we can improve upon the treatments that we have. In addition to the targeted therapies that we currently use, a lot of what we are looking at right now is figuring out how to enhance those treatments in combinations that might be beneficial.

Down the line, what therapeutic approaches do you see occurring in kidney cancer?

With the plethora of agents available, sequencing must be a challenge.

What factors will you likely consider in choosing first-line therapy?

What is another area of importance right now in this field?

What advice can you give to practicing oncologists to help promote clinical trials with their patients?

Unfortunately, our ways of predicting resistance have been pretty limited. We have tried multiple approaches but, essentially, we aren’t able to really know who may or may not respond until after they start therapy.What we really want to see are improvements in therapy for which we can see more durable responses. As of right now, we think that immunotherapies are probably the way forward. How to combine these immunotherapies may be very important. Will it be dual immunotherapy? Is it going to be a combination of immunotherapy plus VEGF-targeted therapy? Or, there may be a development of new pathways that might be important, now that we better understand the genetics of kidney cancer.The sequencing for first-line therapy has really been established over the last 2 or 3 years. In the frontline setting, most patients are getting sunitinib or pazopanib (Votrient). However, in the next couple of years, first-line therapy is likely to change. There are multiple phase III trials currently out right now that are exploring whether or not we should be changing what we use as first-line therapy.It really is the way that the drugs work. Right now, there is a lot of interest in exploring whether using immunotherapies in combination upfront may actually improve upon the gains we have made in the past.We highly encourage people, if possible, to participate in a clinical trial. It is one of those things where it allows them access to medications that otherwise wouldn’t be available to them. Especially for first-line trials, there is often a lot of misinformation on whether it is a phase I, phase II, or phase III trial. It is our hope that this is something better than everything else that we already have.A lot of it is education. A lot of it is having people understand what it means to be part of a clinical trial. There was a recent study that, overall for the population, people have a negative impression of what it means to be on a trial, whether or not they are being experimented on or whatnot. It really is trying to offer someone additional treatment that might not otherwise be available. It shouldn’t be something where you’ve blown through all of the available medications, and now this is like a last-ditch “Hail Mary.”

Right now, we actually have quite a few first-line trials. The only reason they are first-line trials is because we hope and think that this might be better than everything we already have. These types of combinations may actually be practice changing in the near future.

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