In the phase III EVEREST trial reported in The Lancet, Christopher W. Ryan, MD, and colleagues found that adjuvant everolimus was not associated with a significant improvement in event-free survival vs placebo in patients at high risk of disease recurrence following surgery for renal cell carcinoma.
Christopher W. Ryan, MD
Study Details
In the U.S. multicenter double-blind trial, 1,545 patients who had undergone nephrectomy and were at an intermediate-high or very high risk of recurrence were randomly assigned between April 2011 and September 2016 to receive everolimus at 10 mg (n = 775) or placebo (n = 770) once daily for 54 weeks. A total of 755 patients in the everolimus group and 744 in the placebo group were eligible for inclusion in an efficacy analysis. The primary endpoint was recurrence-free survival.
Recurrence-Free Survival
Median follow-up was 76 months (interquartile range = 61–92 months). Recurrence-free survival at 5 years was 67% (95% confidence interval [CI] = 63%–70%) in the everolimus group vs 63% (95% CI = 60%–67%) in the placebo group (hazard ratio [HR] = 0.85, 95% CI = 0.72–1.00, P = .051; prespecified threshold for statistical significance, P = .044).
Among 919 patents with very-high-risk disease, 5-year recurrence free survival was 57% (95% CI = 52%–62%) in the everolimus group vs 51% (95% CI = 46%–56%) in the placebo group (HR = 0.79, 95% CI = 0.65–0.97, P = .022). Among 680 patients in the intermediate-high–risk group, 5-year rates were 80% (95% CI = 75%–84%) with everolimus vs 78% (95% CI = 73%–83%) with placebo (HR = 0.99, 95% CI = 0.73–1.35, P = .96).
Rates of 5-year overall survival were 87% (95% CI = 84%–89%) in the everolimus group and 85% (95% CI = 82%–87%) in the placebo group (HR = 0.90, 95% CI = 0.71–1.13, P = .36).
KEY POINTS
- Adjuvant everolimus did not significantly improve recurrence-free survival.
- Benefit of everolimus was observed among patients at very high risk of recurrence.
Adverse Events
Grade ≥ 3 adverse events occurred in 46% of patients in the everolimus group vs 11% of the placebo group; the most common in the everolimus group were mucositis (14%), hypertriglyceridemia (11%), and hyperglycemia (5%). The most common adverse events of any grade in the everolimus group were oral mucositis (64%), fatigue (56%), diarrhea (33%), and maculopapular rash (31%). No treatment-related deaths were observed in the everolimus group.
The investigators concluded, “Postoperative everolimus did not improve recurrence-free survival compared with placebo among patients with renal cell carcinoma at high risk of recurrence after nephrectomy. These results do not support the adjuvant use of everolimus for renal cell carcinoma after surgery.”
Dr. Ryan, of Oregon Health & Science University Knight Cancer Institute, Portland, is the corresponding author for The Lancet article.
Disclosure: The study was funded by the National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation. For full disclosures of the study authors, visit thelancet.com.
