Progress in preventing kidney cancer recurrence

Cancer “adjuvant” therapies are treatments designed to reduce the chances of tumors coming back after surgery. But for decades, attempts to find adjuvant treatments for kidney cancer failed to show any benefit.

In a new study, people with kidney cancer who took the drug everolimus daily for up to one year after surgery were less likely to have a recurrence or die than those who did not take everolimus, although the results narrowly missed reaching statistical significance.

“Still, we were very excited to see this lower risk of recurrence or death,” said Christopher Ryan, M.D., a professor in the OHSU School of Medicine who led the phase 3 clinical trial, called EVEREST, conducted by SWOG Cancer Research Network and supported by the National Cancer Institute (study number S0931).

Photo: Christopher Ryan (OHSU/Kristyna Wentz-Graff)Ryan said the findings show that everolimus has potential as an adjuvant treatment, particularly for patients at high risk of recurrence. “It has activity in this setting, and its potential utility warrants continued study,” he said. Ryan presented the findings today at the American Society of Clinical Oncology Annual Meeting in Chicago.

About 70% of kidney cancer are diagnosed at a stage that can potentially be cured with surgery. But fatal cancers return after surgery in about a third of patients. Effective adjuvant treatments are urgently needed.

As it stands, there is only one widely accepted adjuvant therapy for kidney cancer, pembrolizumab, a high-priced immune therapy given by intravenous injection. It sells under the brand name Keytruda. The Food and Drug Administration approved the adjuvant use last November.

Everolimus, taken as a pill, has been on the market since 2009 and is now available as an affordable generic drug. If it holds up as an adjuvant therapy for kidney cancer, it would provide an option costing a fraction of the price of pembrolizumab.

The EVEREST trial enrolled more than 1,500 subjects. “It was a huge study,” Ryan said. “And it included a wide group of patients, lower risk all the way up to highest risk, such as those with affected lymph nodes at surgery. Patients were enrolled at nearly 400 sites across 48 states.  That means its findings are more translatable to everyday practice with patients.”

Subjects were randomly assigned to take everolimus or a placebo pill daily for one year. The primary endpoint measured was recurrence-free survival, the risk of cancer recurrence or death. Overall, subjects in the everolimus group had fewer recurrences and deaths, than those in the placebo group with a hazard ratio (HR) of 0.85. (The P value, a measure of statistical significance, was 0.025, below the trial’s pre-specified significance level of 0.022.)

High-risk patients, those with signs of cancer cells extending beyond the kidney or in their lymph nodes, saw the greatest risk reduction. Fifty-seven percent of high risk patients who took everolimus were alive and without cancer recurrence at 5 years as compared to 51% who received placebo, while there was no apparent benefit in patients with less-advanced tumors .

Less than half of subjects in the everolimus group continued taking the drug for all 54 weeks of the study, complicating interpretation of the findings. More than a third stopped treatment because of side effects they were experiencing.

“We had a high treatment discontinuation rate, and yet we still saw this signal of activity,” Ryan said. That raises the possibility that patients might not need to take the drug for an entire year to benefit from it, he said.

Ryan said he and his collaborators continue to explore the findings. It may be possible, for instance, to identify molecular signatures in tumors that are most likely to benefit from everolimus as an adjuvant therapy.

Further reading:

EVEREST: Everolimus for renal cancer ensuing surgical therapy—A phase III study, ASCO abstract

Everolimus after Surgery Can Improve Outcomes in Those with High-Risk Kidney Cancer, SWOG news release