A secondary analysis from the phase III SWOG S0931 EVEREST trial found that adjuvant everolimus given to patients with clear cell renal cell carcinoma at very high risk of recurrence after nephrectomy produced a statistically significant improvement in recurrence-free survival compared with placebo after surgery. “The results may inform the design and development of future adjuvant clinical trials in patients with high-risk disease,” said Primo N. Lara, Jr, MD, and colleagues. The study findings were presented by Dr. Lara during the European Society for Medical Oncology (ESMO) Congress 2023.1 Dr. Lara is Distinguished Professor Medicine and Executive Associate Dean for Cancer Programs at the University of California Davis School of Medicine, Director of the UC Davis Comprehensive Cancer Center, and Co-Chair-Elect of the SWOG Cancer Research Network.
Primo N. Lara, Jr, MD
The trial’s primary results were published earlier this year in The Lancet.2 The investigators found that although recurrence-free survival was longer for patients randomly assigned to receive adjuvant everolimus, the difference narrowly missed meeting the criterion for statistical significance. In this secondary analysis, the researchers reported on their findings in a subset of patients with renal cell carcinoma with clear cell histology who were considered to have a very high risk of disease recurrence.
Study Methodology and Results
The researchers identified patients with any clear cell component at very high risk for disease recurrence after nephrectomy. They defined high risk as patients with pT3a (grade 3–4), pT3b–c (any grade), T4 (any grade), or node-positive disease. Patients’ characteristics, treatment, and adverse event data were summarized. A Cox regression model stratified by performance status was used to evaluate recurrence-free and overall survival.
Of the nearly 1,500 patients enrolled in the study, 717 had both clear cell and very high–risk disease; 699 patients were eligible for this analysis: 348 in the everolimus arm and 351 in the placebo arm. A total of 163 of the 348 patients (47%) receiving everolimus completed all treatment as planned, whereas more patients completed planned treatment with placebo (225 of the 351 patients [64%]).
Among the 699 eligible patients in this subgroup, those on the everolimus arm had a 20% lower risk of disease recurrence or death than those on the placebo arm (hazard ratio = 0.80; 95% confidence interval = 0.65–0.99; two-sided P value = .04). The researchers found that grade 3+ adverse events were more frequent with everolimus (42%) vs placebo (8%).
“EVEREST remains the only phase III adjuvant renal cell carcinoma trial of an mTOR inhibitor. In patients with clear cell renal cell carcinoma at very high risk for recurrence, adjuvant everolimus was associated with significantly improved recurrence-free survival vs placebo in a subset of patients comparable to those in [placebo-controlled phase III trials of sunitinib] S-TRAC and [pembrolizumab] KN546,” concluded the study authors.
“The focus on patients with clear cell renal cell carcinoma at very high risk for recurrence allows researchers to better interpret the results of EVEREST in the context of the modestly positive S-TRAC and KN546 trials,” said Dr. Lara, in a statement.
DISCLOSURE: Funding for this study was provided by the National Institutes of Health, the National Cancer Institute, and Novartis. Dr. Lara reported no conflicts of interest.
REFERENCES
1. Lara PN, Pal SK, Puzanov I, et al: Adjuvant everolimus in patients with completely resected very high-risk renal cell cancer and clear cell histology: Results from the phase III SWOG S0931 (EVEREST) trial. ESMO Congress 2023. Abstract 1887P. Presented October 23, 2023.
2. Ryan CW, Tangen CM, Heath EI, et al: Adjuvant everolimus after surgery for renal cell carcinoma (EVEREST). Lancet 402:1043-1051, 2023.
