TY - JOUR
T1 - Adjuvant everolimus after surgery for renal cell carcinoma (EVEREST)
T2 - a double-blind, placebo-controlled, randomised, phase 3 trial
AU - Ryan, Christopher W.
AU - Tangen, Catherine M.
AU - Heath, Elisabeth I.
AU - Stein, Mark N.
AU - Meng, Maxwell V.
AU - Alva, Ajjai S.
AU - Pal, Sumanta K.
AU - Puzanov, Igor
AU - Clark, Joseph I.
AU - Choueiri, Toni K.
AU - Agarwal, Neeraj
AU - Uzzo, Robert G.
AU - Haas, Naomi B.
AU - Synold, Timothy W.
AU - Plets, Melissa
AU - Vaishampayan, Ulka N.
AU - Shuch, Brian M.
AU - Thompson, Ian M.
AU - Lara, Primo N.
N1 - Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023/9/23
Y1 - 2023/9/23
N2 - Background: Patients undergoing resection of renal cell carcinoma are at risk of disease relapse. We evaluated the effectiveness of the mammalian target of rapamycin inhibitor everolimus administered after surgery. Methods: In this randomised, double-blind, phase 3 trial, we enrolled adults with histologically confirmed renal cell carcinoma who had undergone a full surgical resection and were at intermediate-high or very high risk of recurrence at 398 academic and community institution centres in the USA. After nephrectomy, patients were randomly assigned (1:1) via a central web-based application using a dynamic balancing algorithm to receive 10 mg oral everolimus daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival. Efficacy analyses included all eligible, randomly assigned patients; safety analysis included all patients who received treatment. This trial is registered with ClinicalTrials.gov, NCT01120249 and is closed to new participants. Findings: Between April 1, 2011, and Sept 15, 2016, a total of 1545 patients were randomly assigned to receive everolimus (n=775) or placebo (n=770), of whom 755 assigned to everolimus and 744 assigned to placebo were eligible for inclusion in the efficacy analysis. With a median follow-up of 76 months (IQR 61–92), recurrence-free survival was longer with everolimus than with placebo (5-year recurrence-free survival 67% [95% CI 63–70] vs 63% [60–67]; stratified log-rank p=0·050; stratified hazard ratio [HR] 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. Recurrence-free survival 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 (0·99, 0·73–1·35; p=0·96). Grade 3 or higher adverse events occurred in 343 (46%) of 740 patients who received everolimus and 79 (11%) of 723 who received placebo. Interpretation: 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. Funding: US National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation.
AB - Background: Patients undergoing resection of renal cell carcinoma are at risk of disease relapse. We evaluated the effectiveness of the mammalian target of rapamycin inhibitor everolimus administered after surgery. Methods: In this randomised, double-blind, phase 3 trial, we enrolled adults with histologically confirmed renal cell carcinoma who had undergone a full surgical resection and were at intermediate-high or very high risk of recurrence at 398 academic and community institution centres in the USA. After nephrectomy, patients were randomly assigned (1:1) via a central web-based application using a dynamic balancing algorithm to receive 10 mg oral everolimus daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival. Efficacy analyses included all eligible, randomly assigned patients; safety analysis included all patients who received treatment. This trial is registered with ClinicalTrials.gov, NCT01120249 and is closed to new participants. Findings: Between April 1, 2011, and Sept 15, 2016, a total of 1545 patients were randomly assigned to receive everolimus (n=775) or placebo (n=770), of whom 755 assigned to everolimus and 744 assigned to placebo were eligible for inclusion in the efficacy analysis. With a median follow-up of 76 months (IQR 61–92), recurrence-free survival was longer with everolimus than with placebo (5-year recurrence-free survival 67% [95% CI 63–70] vs 63% [60–67]; stratified log-rank p=0·050; stratified hazard ratio [HR] 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. Recurrence-free survival 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 (0·99, 0·73–1·35; p=0·96). Grade 3 or higher adverse events occurred in 343 (46%) of 740 patients who received everolimus and 79 (11%) of 723 who received placebo. Interpretation: 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. Funding: US National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation.
KW - Adjuvants, Immunologic/therapeutic use
KW - Adult
KW - Carcinoma, Renal Cell/drug therapy
KW - Everolimus/therapeutic use
KW - Humans
KW - Kidney Neoplasms/drug therapy
KW - Neoplasm Recurrence, Local/drug therapy
KW - Sirolimus/therapeutic use
KW - United States
UR - http://www.scopus.com/inward/record.url?scp=85169070062&partnerID=8YFLogxK
UR - https://doi.org/10.1016/S0140-6736(23)00913-3
U2 - 10.1016/S0140-6736(23)00913-3
DO - 10.1016/S0140-6736(23)00913-3
M3 - Article
C2 - 37524096
SN - 0140-6736
VL - 402
SP - 1043
EP - 1051
JO - The Lancet
JF - The Lancet
IS - 10407
ER -