EVEREST is the first reported study of an mTOR inhibitor as adjuvant treatment for renal cell carcinoma (RCC). Everolimus administered up to 1 year after surgery did not improve recurrence-free survival (RFS) compared with placebo in the overall study population. Subgroup analysis by risk group stratification suggested a RFS benefit with everolimus among patients with very high risk disease, but no benefit among those with intermediate-high risk disease.
Positive studies that led to the US Food and Drug Administration adjuvant indications for sunitinib and pembrolizumab limited inclusion to patients at higher risk compared with the broader population eligible for EVEREST. Consensus recommendations currently recognise that patients at the highest risk of recurrence, those with stage pT3–4 or node-positive disease, should be the focus of adjuvant studies. The findings of EVEREST lend further support to these recommendations according to Prof. Christopher W Ryan of the Oregon Health and Science University Knight Cancer Institute in Portland, OR, US and colleagues, who published the findings from the EVEREST study on 28 July 2023 in The Lancet.
The authors wrote in the background that prevention of metastatic disease remains a priority in the curative setting of early-stage RCC. Following the advent of effective tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) for metastatic RCC, numerous adjuvant studies were conducted with these agents. However, only one of five reported studies with TKI and one of four reported studies with ICI have reported a statistically significant, albeit modest, disease-free survival benefit when administered as adjuvant treatment.
Everolimus was approved for use in metastatic RCC in 2009 based on a placebo-controlled study that showed improved progression-free survival in the second-line setting. Given the activity of everolimus in advanced RCC and its distinct mechanism of action directed towards the tumour cell itself rather than the tumour microenvironment, the EVEREST investigators hypothesised that adjuvant treatment could reduce disease recurrence after nephrectomy. They performed this randomised, placebo-controlled study of everolimus after surgical resection, to determine the effect of treatment with this mTOR inhibitor on RFS.
In randomised, double-blind, phase III EVEREST study, adult patients with histologically confirmed RCC who had undergone a full surgical resection and were at intermediate-high or very high risk of recurrence were enrolled at 398 academic and community institutions in the US. After nephrectomy, patients were randomly assigned (1:1) to receive 10 mg oral everolimus daily or placebo for 54 weeks. The primary endpoint was RFS. Efficacy analyses included all eligible, randomly assigned patients and safety analysis included all patients who received treatment. This study is closed to new participants.
Between 1 April 2011 and 15 September 2016, a total of 1545 patients were randomly assigned, of whom 775 to receive everolimus and 770 to placebo; 755 patients assigned to everolimus and 744 assigned to placebo were eligible for inclusion in the efficacy analysis. With a median follow-up of 76 months, RFS was longer with everolimus than with placebo; 5-year RFS was 67% (95% confidence interval [CI] 63–70) versus 63% (95% CI 60–67) with stratified log-rank p = 0.050; stratified hazard ratio (HR) was 0.85 (95% CI 0.72–1.00; p = 0.051) but did not meet the prespecified p value for statistical significance of 0.044. RFS was longer with everolimus than with placebo in the very high risk group (HR 0.79, 95% CI 0.65–0.97; p = 0.022), but not in the intermediate-high risk group (HR 0.99, 0.73–1.35; p = 0.96).
Grade 3 or higher adverse events occurred in 343 of 740 patients (46%) who received everolimus and 79 of 723 patients (11%) who received placebo.
The authors concluded that up to 1 year of adjuvant everolimus did not improve RFS in the overall study population, but the EVEREST results warrant further study of mTOR inhibition in the adjuvant treatment of very high risk RCC. Patient selection and future studies for adjuvant treatment should be limited to those at highest risk of RCC recurrence and could employ recurrence models derived from recent adjuvant study data.
In an accompanied comment, Drs. Jens Bedke of the Department of Urology and Transplantation Surgery, Klinikum Stuttgart – Katharinenhospital and Stuttgart Cancer Center – Tumorzentrum Eva Mayr-Stihl in Stuttgart, Germany, and Axel Bex of The Royal Free London NHS Foundation Trust, and UCL Division of Surgery and Interventional Science, University College London in London, UK and Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital in Amsterdam, Netherlands wrote that the EVEREST study illustrates the shortcomings of patient eligibility based on TNM staging.
The exploratory subgroup results of the EVEREST study are surprising because the mechanism of mTOR inhibition in metastatic RCC is regarded as a weak mode of action. Perhaps the EVEREST revealed that the mode of action of adjuvant drugs is superimposed by the respective patient population selected for adjuvant therapy.
According to the editorialists, it should not be forgotten that surgery alone cures patients with non-metastatic RCC, and that a certain, yet to be defined, proportion of patients will never relapse. However, for as long as no molecular marker or gene signature is available, patient eligibility for adjuvant studies is still based on pathological TNM stage or clinical risk scores combining prognostic factors, such as grade, necrosis, and size of tumour, with TNM.
EVEREST study reminds that risk assessment must be refined beyond clinical tools. The molecular heterogeneity known in metastatic RCC is likely to be present in non-metastatic disease, determining the risk of relapse, especially given that RCC is heterogeneous in both the non-clear-cell and clear-cell subgroups. However, an association between responsive gene expression profiles in non-metastatic disease predictive for adjuvant treatment remains to be determined, as TNM-based risk classification does not appear sufficient. Future adjuvant studies should additionally target molecular classifications of RCC beyond TNM and the clear-cell and non-clear-cell subgroups.
The study was funded by the US National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation through the SWOG Trial Support programme.
