EVEREST is a phase 3 trial in patients with renal cell cancer (RCC) at intermediate-high or very high risk of recurrence after nephrectomy who were randomized to receive adjuvant everolimus or placebo. Longer recurrence-free survival (RFS) was observed with everolimus (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.72-1.00; p = 0.051), but the nominal significance level (p = 0.044) was not reached. To contextualize these results with positive phase 3 trials of adjuvant sunitinib and pembrolizumab, we conducted a secondary analysis in a similar population of EVEREST patients with very high-risk disease and clear cell histology.
Postnephrectomy patients with any clear cell component and very high-risk disease, defined as pT3a (grade 3-4), pT3b-c (any grade), T4 (any grade), or node-positive status (N+), were identified. A Cox regression model stratified by performance status was used to compare RFS and overall survival (OS) between the treatment arms.
Of 1499 patients, 717 had clear cell histology and very high-risk disease; 699 met the eligibility criteria, of whom 348 were randomized to everolimus arm, and 351 to the placebo arm. Patient characteristics were similar between the arms. Only 163/348 (47%) patients in the everolimus arm completed all treatment as planned, versus 225/351 (64%) in the placebo arm. Adjuvant everolimus resulted in a statistically significant improvement in RFS (HR 0.80; 95%CI 0.65-0.99, p = 0.041). Evidence of a survival benefit was not seen (HR 0.85; 95%CI 0.64-1.14, p = 0.3) CONCLUSIONS AND CLINICAL IMPLICATIONS: In patients with clear cell RCC at very high-risk for recurrence, adjuvant everolimus resulted in significantly improved RFS compared to placebo but resulted in a high discontinuation rate due to adverse events. Although the treatment HR for OS was consistent with RFS findings, it did not reach statistical significance. With a focus on risk stratification tools and/or biomarkers to minimize toxicity risk in those not likely to benefit, this information can help inform the design of future adjuvant trials in high-risk RCC PATIENT SUMMARY: We assessed treatment with everolimus in comparison to placebo after complete surgical removal of clear-cell kidney cancer at very high risk of recurrence. We found that survival outcomes were better for patients treated with everolimus, although these patients had a higher rate of side effects.
European urology. 2024 May 28 [Epub ahead of print]
Primo N Lara, Catherine Tangen, Elisabeth I Heath, Shuchi Gulati, Mark N Stein, Maxwell Meng, Ajjai Shivaram Alva, Sumanta K Pal, Igor Puzanov, Joseph I Clark, Toni K Choueiri, Neeraj Agarwal, Robert Uzzo, Naomi B Haas, Timothy W Synold, Melissa Plets, Ulka N Vaishampayan, Brian M Shuch, Seth Lerner, Ian M Thompson, Christopher W Ryan
University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA. Electronic address: ., SWOG Statistical Center, Seattle, WA, USA., Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA., University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA., Columbia University, New York, NY, USA., UC San Francisco Diller Comprehensive Cancer Center, San Francisco, CA, USA., University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA., City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Loyola University Medical Center, Chicago, IL, USA., Dana Farber Cancer Institute, Boston, MA, USA., Huntsman Cancer Institute, Salt Lake City, UT, USA., Fox Chase Comprehensive Cancer Center, Philadelphia, PA, USA., Abramson Comprehensive Cancer Center, University of Pennsylvania, Philadelphia, PA, USA., UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA., Baylor College of Medicine, Houston, TX, USA., Christus Santa Rosa Health System San Antonio, TX Health, San Antonio, TX, USA., Oregon Health and Science University, Portland OR, USA.