Post-Nephrectomy Everolimus for Patients With Renal Cell Carcinoma: Findings From the EVEREST Trial

Christopher Ryan, MD, Oregon Health & Science University, Knight Cancer Institute, Portland, discusses findings from the phase 3, double-blind, placebo-controlled EVEREST trial, which investigated the effect of adjuvant treatment, everolimus, an mTOR inhibitor, on recurrence-free survival (RFS) in patients receiving nephrectomy for renal cell carcinoma (RCC).

These findings were presented at the 2022 ASCO Annual Meeting.

Transcript:

I'm Christopher Ryan. I'm a professor of medicine at Oregon Health & Sciences University Knight Cancer Institute, and an investigator with a SWOG Cancer Research Network. At ASCO, I reported on results of a phase 3 adjuvant trial in renal carcinoma called the EVEREST trial, which looked at the utility of everolimus after surgery in patients with high-risk renal cancer.

When this trial was designed, it was 2009. We had gotten through the first waves of approvals of new effective targeted agents for advanced renal cancer. One study had already completed accrual looking at the question of adjuvant therapy, and that was ECOG's ASSURE study, which looked at 2 TKIs, sorafenib or sunitinib. In 2009, everolimus, an mTOR inhibitor, had just been approved for treatment of metastatic renal cancer. We asked the question, "Can this different class of agents, different mechanism of action, be an effective adjuvant therapy?"

At the time, there was no effective adjuvant therapies known. Many studies in the past looked at cytokines and we had all these new agents. A number of studies were launched trying to find an effective adjuvant agent.

We enrolled a total of 1545 patients between 2011 to 2016. This was a placebo-controlled trial. Patients were randomized to everolimus or placebo. One of the issues is that a lot of patients discontinued everolimus. Only 45% of patients on the everolimus arm completed all treatment, as opposed to 69% on the placebo arm. This was main mainly due to side effects. And this is a common issue when we look at oral adjuvant therapies in renal cancer, but across other cancers as well. There tends to be a relatively high discontinuation rate, a kind of lack of acceptance of the side effects in the adjuvant population.

The primary end point of our study was recurrence-free survival. Overall survival was a secondary endpoint, and it's also important that we included a relatively broad range of patients, everyone who had stage 1B high grade cancers all the way up through patients who had node positive cancers that had been completely surgically removed. Regarding patient characteristics, they were well balanced between both arms. About 55% of patients were what we considered very high risk for recurrence. And these included patients that were T3A high-grade up through node-positive disease. When we looked at how much treatment was actually delivered, median time on treatment was 9.3 months with everolimus and 12.6 months with placebo. 37% of patients on the everolimus arm underwent a dose reduction, and 37% discontinued due to adverse events.

The adverse events that occurred were typical for those of everolimus. There really weren't any surprises. The most common adverse events were gastrointestinal and cutaneous. 46% of patients who received everolimus had a grade 3 or higher adverse event, as compared with 11% on the placebo arm. And the most common grade three adverse event was mucositis, which occurred in 14% of patients.

We also saw other common side effects of everolimus that were higher in the everolimus arm, including hyperlipidemia, anemia, and hyperglycemia. So regarding the primary endpoint, we found that patients who received everolimus had better recurrence free survival than those who had placebo. The Kaplan–Meier curves separated and stay separated for the duration of the follow up, which the medium follow up was 6.3 years. It was quite a long follow up with the study. However, we just unfortunately missed statistical significance. The hazard ratio was 0.85 favoring everolimus, but the upper bound of the confidence interval hit 1 exactly.

Regarding P-values, the one-sided P-value was 0.025, while the significance level was set at 0.022. It just missed statistical significance by 0.003. When we looked at patients in the very high-risk group on a subgroup analysis, the randomization was stratified on whether they were in this very high-risk group or the lower-risk group, which we termed intermediate high-risk, but patients in the very high-risk group, that's pretty much where all the effect was seen. When we looked at the patients in that group, again, 55% of patients on the trial, the median recurrence-free survival was 5.3 years on the placebo arm, and the median had not been reached on the everolimus arm. That hazard ratio was 0.79 and that one sided P-value was 0.011.

There was no difference at all in the recurrence-free survival for the intermediate high-risk group, those patients with T1B high grade through T3A low grade disease. All the benefit was seen in those with T3A high grade or higher. And secondary endpoint was overall survival. Like all the other adjuvant trials to date, we have not, at least of yet, seen any overall survival benefit. The hazard ratio of 0.9 slightly favored everolimus, but this was a secondary endpoint and no benefit has been seen. We need to follow these patients, obviously, going forward. To summarize, we saw a recurrence-free survival favoring everolimus, but it just missed statistical significance. It was really in the patients in the very high risk group where the benefit was seen.

Again, we designed this study in 2009, and the first patient was enrolled in 2011. Since that time, a number of adjunct trials have read out there have been five studies of tyrosine kinase inhibitors, all of which were negative except for one study of sunitinib that actually led to FDA approval for that use in the adjuvant setting, although it's uptake has been very mixed because of the other negative studies and side effects. And then last year at the ASCO meeting, we had the presentation of the first study of adjuvant checkpoint immunotherapy with pembrolizumab, and that was granted approval for adjuvant use last fall.

Now we have these data on everolimus, and although not meeting statistical significance, this being the only study of an mTOR inhibitor, it is very intriguing, and certainly think we should continue to investigate the role of everolimus in the adjuvant landscape. And as we dive into these data more, we will think about future studies to better refine our adjuvant treatment decisions.

Source:

Ryan CW, Tangen C, Heath EI, et al. EVEREST: Everolimus for renal cancer ensuing surgical therapy—A phase III study (SWOG S0931, NCT01120249). Presented at: ASCO Annual Meeting; June 3-7, 2022. Chicago, IL, and virtual. Abstract LBA4500.