Everolimus after surgery can improve outcomes in those with high-risk kidney cancer

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Published: 4 Jun 2022
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Dr Christopher Ryan - OHSU Knight Cancer Institute, Portland, USA

Dr Christopher Ryan speaks to ecancer about the results of a phase III S0931 trial, also known as the EVEREST study, which indicated that patients with high-risk renal cell carcinoma, who took the drug everolimus daily for up to one year after surgery lived longer without their disease returning.

He explains that the trial enrolled patients, who had been diagnosed with intermediate high-risk or very high-risk renal cell carcinoma and who had had their cancer surgically removed by a partial or radical nephrectomy. The study randomised 1,545 of these patients to a year of either everolimus or a placebo, starting within 12 weeks of their surgery.

He continues to discuss the results of the trial that EVEREST patients with very high-risk disease (55 percent of those enrolled) who took everolimus saw a 21 percent improvement in RFS (HR: 0.79; 95 percent CI 0.65-0.97), whereas RFS was essentially unchanged for those in the intermediate high-risk group (HR: 0.99; 95 percent CI 0.73-1.35).

He concludes by discussing the next steps in the investigation, which involves further analysis, such as molecular profiling, to determine which patients may benefit most from the everolimus treatment method.

 

EVEREST was a big effort, asking the question of adjuvant therapy for renal cancer, and at the time the trial was designed in 2009 everolimus had just been approved as a treatment for renal cancer, one of the early waves of targeted treatment that started with the first approvals in 2005 and 2006 with tyrosine kinase inhibitors. So the question was asked, can this agent, an mTOR inhibitor, be an effective adjuvant therapy after surgery for patients with kidney cancer. At the time, there was no known effective adjuvant therapy - previous studies of cytokine therapies in decades past had all been negative. So we undertook this big effort, it was a placebo controlled study, because there was no standard therapy, and it kind of came on the heels of ECOG’s ASSURE study, which was one of the first of these new generation adjuvant studies looking at two different tyrosine kinase inhibitors, sorafenib and sunitinib. We really modelled the study off of our colleagues in ECOG - the same type of patient population, the same risk group. We accrued for the study over 1500 patients between 2011 and 2016 and it was like a fine wine, waiting for it to mature. 

Some of the surprising findings: the number of events, fortunately for patients, were not happening as fast as we had expected; fewer patients were relapsing. So we did a final analysis just in March of this year, we drew the line, there were fewer events than we had expected. We were pleasantly surprised to see there was a difference and patients who got the everolimus had fewer occurrences, fewer deaths, but it just missed statistical significance by 0.002, or 0.003, which was somewhat disappointing. When we drilled down into it more, it was patients with the very high-risk disease, those with stage 3 tumours, high grade stage 3 tumours, T3a, high grade tumours, all the way up through patients with positive nodes. When we looked at that subgroup there was a notable better outcome with everolimus, while the remainder of the patients with lower risk, what we call intermediate risk, there was no difference between placebo and everolimus. 

Those are certainly the patients where it seems to be potentially effective. It also overlaps with the current thinking of patients to consider for adjuvant therapy, so the other approved drugs, at least in the US, we have an approval of sunitinib for several years, which is really focusing on high-risk patients, so the uptake of that drug has not been as much because there was a number of other negative studies with TKIs. Also the approval for pembrolizumab, which just came last November, really focused on the high-risk patients. So this population is overlapping with those other studies that really focused on the high-risk patients. The problem of course is that we just missed statistical significance – what do you say about it? We can’t necessarily recommend it as treatment but I really think there is something going on here and we need to look at it further in the adjuvant landscape.

What are the next steps? 

Well, we’re going to do a lot of analyses on this, try to drill down on the population who are benefitting, and potentially some molecular profiling. We’re in the works of designing some correlative studies, as well as looking at the subgroups as well of who may benefit the most and we’ll see where we are from there. It’s an important consideration in design of the next adjuvant studies. We’re still waiting for the readout of some of the other… there’s a number of other checkpoint immunotherapy trials that are still maturing, and it will be interesting to see if there’s a consistent trend across all of those studies, or if the pembrolizumab study is the only one, so we’ll see. I think that will beg the next series of questions about can we pick adjuvant therapies based on certain characteristics that may benefit one patient group versus the next.

One of the issues with the trial was that people may focus on the side effect rate. So there is a large number of patients who stopped treatment early, mostly because of side effects, though the side effects were all well-known side effects of everolimus. But we see this across adjuvant studies in renal cell, and across cancer as well, that oral adjuvant therapies sometimes are just not, in clinical trials… don’t seem to be tolerated as well by patients, or are easier to stop. They just say, “I don’t want to take this pill” and they stop. 

So, despite the fact that a significant proportion of patients stop treatment early, we still saw this difference in recurrence free survival, which to me raises a question – how much adjuvant therapy is needed? We chose an arbitrary year of therapy, like most of the adjuvant studies have done, a very arbitrary period. We need to look at that further – perhaps there’s a shorter amount of time where we could deliver effective preventative therapy and reduce side effects and long-term effects for patients.