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Adjuvant everolimus (Afinitor) failed to significantly improve recurrence-free survival (RFS) in patients with renal cell carcinoma (RCC) who were at high risk for recurrence after nephrectomy, according to results from a randomized phase III trial.

The so-called EVEREST study showed that among 1,545 patients with histologically confirmed RCC who had undergone a full surgical resection, the 5-year RFS rate was 67% with the mTOR inhibitor compared with 63% with placebo (stratified HR 0.85, 95% CI 0.72-1.00, P=0.051), reported Christopher W. Ryan, MD, of Oregon Health & Science University's Knight Cancer Institute in Portland, and colleagues.

This failed to meet the prespecified threshold for statistical significance of P=0.044, they noted in .

However, in an analysis by risk group, longer RFS was observed among patients with very high risk defined as tumor stage IIIa with grade 3 or 4; tumor stage IIIb, IIIc, or IV with any grade; or nodal metastases with any tumor stage and any grade (HR 0.79, 95% CI 0.65-0.97, P=0.022).

This was not the case for those with intermediate-high risk (HR 0.99, 95% CI 0.73-1.35, P=0.96), which was defined as no nodal metastases and tumor stage Ib with grade 3 or 4; tumor stage II with any grade; or tumor stage IIIa with grade 1 or 2.

Ryan and team noted that pembrolizumab (Keytruda) is currently used as adjuvant therapy in RCC after the KEYNOTE-564 trial showed that it significantly increased disease-free survival versus placebo (HR 0.68, 95% CI 0.53-0.87, P=0.001) in patients with high-risk clear cell RCC.

This led to the FDA approving the PD-1 inhibitor for the adjuvant treatment of patients who have an intermediate-high risk or high risk of recurrence following nephrectomy, or nephrectomy and resection of metastatic lesions.

"Although the [current] overall study did not reach statistical significance, improvement in recurrence-free survival with everolimus was observed in the subset of patients at very high risk of recurrence," Ryan and colleagues wrote. "These findings lend support to current recommendations for the use of adjuvant therapy in patients at the highest risk of recurrence after surgery."

As for overall survival (OS), of 290 deaths that occurred during the course of the trial, 18% were in the everolimus group and 20% were in the placebo group. Median OS was not reached in either arm, and the estimated rate of OS at 5 years was 87% in the everolimus arm and 85% in the placebo arm.

"Overall survival has been a secondary endpoint of all recent adjuvant renal cell carcinoma trials, and these studies might not be adequately powered to detect modest survival differences," Ryan and colleagues observed. "Given the continued improvement in outcomes for patients with metastatic renal cell carcinoma, detection of an overall survival benefit from adjuvant therapy might be delayed and continued survival follow-up for adjuvant studies is imperative."

In a Jens Bedke, MD, of the Stuttgart Cancer Center in Germany, and Axel Bex, MD, PhD, of University College London in England and the Netherlands Cancer Institute in Amsterdam, called the efficacy results for the very-high-risk group of patients "remarkable," considering everolimus had only shown modest clinical activity in the second-line setting in the , and had been outperformed by cabozantinib (Cabometyx) and nivolumab (Opdivo) in the second-line setting in other trials.

Questions remain regarding the benefit-harm ratio for the individual patient in the adjuvant setting, they added.

Patient selection is "key" in adjuvant therapy to balance that benefit-harm ratio, they wrote, adding that the results from the very-high-risk subgroup analysis in EVEREST support evidence from previous adjuvant trials that showed that patients at higher risk should be targeted for trial eligibility.

However, they also questioned the prognostic and predictive value of TNM staging in RCC, suggesting "it is premature to conclude that TNM predicts response to adjuvant therapy on the basis of the recurrence-free survival data in the very-high-risk subgroup in the EVEREST trial and data from patients at higher risk in other trials."

The was conducted from April 2011 to September 2016, enrolling 1,545 adults with histologically confirmed RCC at 398 academic and community institution centers in the U.S. After nephrectomy, patients were randomly assigned 1:1 to receive 10-mg oral everolimus daily or placebo for 54 weeks.

Of the included patients, 55% in each arm belonged to the very-high-risk subgroup. Median age was 58 years, and the majority of patients were white (91%) and male (70%), with 90% of patients undergoing radical as opposed to partial nephrectomy.

Grade 3 or higher adverse events occurred in 46% of patients who received everolimus and 11% who received placebo.

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