James J. Hsieh, MD, PhD: mTOR inhibition has been at the forefront of kidney cancer treatment for the past 10 years. As I alluded to earlier, there are 2 different major mechanisms that are involved. One is VEGF inhibitors and one is mTOR inhibitors. VEGF inhibitors mainly work on the blood vessels. It’s interesting because it’s not working on the tumor cells, but is working on the blood vessels. The mTOR inhibitors are mainly working on the tumor cells.

So, their mechanisms are a bit different. That’s why their combination is actually very synergistic. But in the past, when you used multiple TKIs, like sunitinib with everolimus, sunitinib plus everolimus is not very specific. So, the toxicity was huge. That’s why the combinations will never benefit. But later on, Avastin [bevacizumab] and everolimus were a very easy combination because Avastin is easy to tolerate. The reason I say everolimus mTOR inhibitors should always be a core part of the treatment scheme of kidney cancer is based on biology.

There is so much evidence that mTOR inhibition should not be forgotten for the disease of kidney cancer. In mouse models, the human trial data, and the biology, all 3 speak to the use of mTOR inhibitors, and we cannot just forget about that. We should learn how to use it in the right way instead of saying this is third-line or fourth-line—everybody wants to beat it. It’s almost similar to sunitinib—not everyone want to beat sunitinib.

Thomas Hutson, DO, PharmD, FACP: The role of temsirolimus as a frontline agent has been established early in the new era of targeted therapies for kidney cancer, based upon a compelling phase III study that Dr. Gary Hudes was the first author of during a plenary presentation in an ASCO Annual Meeting several years ago. It was in the New England Journal of Medicine, showing a survival advantage in the patients with the poorest of poor prognoses of kidney cancer. That agent has a special place in that setting. In my own practice, I utilize that for patients who have the highest-risk disease. Many of the current ongoing trials in the frontline setting tend to exploit their enrollment on the good and intermediate-risk patients. So, I think temsirolimus may always have a special place for that highly selected, high-risk patient moving forward.

Martin H. Voss, MD: There’s really no agent that has been studied more intensely in the second-line setting, using randomized trials, than everolimus. The pivotal trial that originally got the medication approved was the RECORD-1 study, which was a randomized phase III trial that was conducted in patients who had sunitinib, sorafenib, or both. So, these were second or third-line patients who were randomized, at the time, to receive either everolimus or placebo. Everolimus was far more efficient than placebo, the primary endpoint of progression-free survival was met, and the drug was approved. This happened, now, about 8 years ago. Since then, we have most recently had 3 randomized phase III studies that have challenged everolimus as a gold standard in the second-line and third-line setting, which adds to our understanding of how effective this medication is and how it compares to other drugs in this space.

The first trial, the CheckMate-025 study, which was published in The New England Journal of Medicine in 2015, was a randomized phase III study testing the novel therapeutic nivolumab, which was the targeted PD-1 inhibitor, against everolimus in patients who had either 1 or 2 TKIs plus a third agent that wasn’t an mTOR inhibitor. It met its primary endpoint of overall survival, and it also showed that nivolumab had a superior response rate versus everolimus. So, everolimus fell short on that trial.

The second study was the METEOR trial, a phase III registration trial of cabozantinib comparing that novel TKI to everolimus in patients who had had at least 1 prior line of therapy. So, a lot of second-line patients went on that trial. Cabozantinib beat everolimus on every efficacy endpoint tested—response rate, PFS, and OS. The third, and most recent approval, was based on the Eisai 205 trial, which was a randomized 3-arm trial comparing everolimus alone in the second-line setting to lenvatinib alone or the combination of lenvatinib plus everolimus at reduced doses. These were strictly second-line patients who went on this randomized phase II study, and the combination of lenvatinib plus everolimus—but also lenvatinib alone—was superior to everolimus. So, taking all of this into consideration, the best way to think about everolimus in the second-line space is that it really only has a role as part of the combination regimen with lenvatinib. As a monotherapy, it has proven less effective than 3 other approved regimens at this point and is unlikely to be used by physicians in the second-line space.

James J. Hsieh, MD, PhD: The combinations with mTOR inhibitors will mainly include anti-VEGF treatment. The good combinations with everolimus, with the least toxicity, will be with very pure VEGF inhibitors. So, I can think of 2. One combination is Avastin [bevacizumab] and everolimus—we have to use this for the non—clear cell trial—and the only other combination I can think of is axitinib plus everolimus, because axitinib is a very, very straight, easy to titrate and specific drug. In terms of the other 2 drugs, the other drug that we have experience with is lenvatinib. So, lenvatinib plus everolimus is tolerable, we know that, and the question is whether or not cabozantinib will be a good combination with everolimus. It’s not known.

Transcript Edited for Clarity