In the phase III EVEREST trial, adjuvant everolimus improved median recurrence-free survival in patients with resected renal cell carcinoma (RCC), but this finding failed to be statistically significant in the total study population of 1,499 patients, according to a prespecified boundary. However, a statistically significant improvement in recurrence-free survival was observed in a subgroup of very high–risk patients with RCC. No benefit of everolimus was observed in the intermediate high–risk group. These findings were presented at the 2022 ASCO Annual Meeting.1
Across all patients in the study, everolimus achieved a 15% reduction in the risk of recurrence or death, which narrowly missed the boundary for statistical significance. In the very high–risk subgroup, the risk of recurrence-free survival was reduced by 21% (P = .011).
“Narrowly missing statistical significance limits the ability to recommend this [therapy] to others,” said lead author and SWOG investigator Christopher W. Ryan, MD, of Oregon Health and Science University Knight Cancer Institute. “These results should be taken into context and considered alongside the other positive and negative trial results when making treatment decisions for patients.”
Christopher W. Ryan, MD
The use of adjuvant therapy for RCC has been studied with older therapies, with no benefit being found. For many years, surveillance alone following surgery was considered standard management.
Dr. Ryan said there have been six randomized, double-blind trials of adjuvant therapy reported since new targeted therapies and immunotherapies became available to treat RCC in the early 2000’s. Five of these trials evaluated adjuvant tyrosine kinase inhibitor therapy. Only one of these trials showed a disease-free survival benefit for the tyrosine kinase inhibitor sunitinib—the S-TRAC trial.2 However, the uptake of adjuvant sunitinib has been mixed, Dr. Ryan noted. The KEYNOTE-564 trial also showed a disease-free survival benefit with adjuvant pembrolizumab.3
“Of note, overall survival has been a secondary endpoint of all these studies, and none, as of yet, has reported a significant survival benefit,” Dr. Ryan said.
EVEREST is the first study of an mTOR inhibitor as adjuvant therapy for RCC.
“The thing about EVEREST is that it is a cooperative group, real-world study done in community and academic centers across the country, and the results have taken a long time to mature,” Dr. Ryan said. “These findings are some of the longest follow-up data we have for adjuvant therapy, and the results were surprising in a favorable way.”
Study Details
EVEREST, conducted by the SWOG Cancer Research Network, enrolled 1,545 patients with treatment-naive, nonmetastatic, fully resected RCC at intermediate high–risk or very high–risk for recurrence. The study randomly assigned 1,499 eligible patients to receive oral everolimus (n = 755) at 10 mg/d or placebo (n = 744) beginning within 12 weeks of radical or partial nephrectomy and continuing for 54 weeks.
A total of 45% of patients had intermediate high–risk RCC, defined as a range from pT1b grade 3 to 4 with no metastases to pT3a grade 1 to 2 with no metastases. The remaining 55% of patients had very high–risk disease, defined as a range from pT3a grade 3 to 4 to pT4 of any grade with no metastases or those with any pT stage and grade with node positivity.
The study was designed to detect an 18% reduction in the risk of recurrence-free survival.
The median patient age was approximately 58, and most patients had clear cell RCC (83%), with 17% having non–clear cell histology. Surgical intervention was radical nephrectomy for 90% of patients, and 10% underwent partial nephrectomy. The majority of patients had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 (80%); 20% had an ECOG performance score of 1.
Benefit in Higher-Risk Patients
Median recurrence-free survival was not reached in either arm. The 6-year estimated recurrence-free survival was 64% with everolimus and 61% with placebo. The benefit of adjuvant everolimus was confined to the very high–risk group: a 21% improvement in recurrence-free survival (P = .011). The median recurrence-free survival was 5.3 years for the placebo group and was not reached for the everolimus group. No recurrence-free survival benefit of everolimus was seen in the intermediate high–risk group.
“At the current time, higher-risk patients are the ones considered to potentially benefit from adjuvant therapy, and our subgroup analysis supported that,” Dr. Ryan said.
“There’s a general consistent effect favoring everolimus in most subgroups tested. Of particular note was a robust hazard ratio favoring everolimus in African Americans, but this was a small group and resulted in a wide confidence interval,” he continued.
According to Dr. Ryan, overall survival benefit has not yet been demonstrated for any adjuvant therapy in RCC. The 5-year estimated overall survival was 87% with everolimus, compared with 85% for placebo.
At a median follow-up of 76 months, 55% of patients in the everolimus arm and 31% of patients in the placebo arm had discontinued therapy. The median time on treatment was 9.3 months with everolimus vs 12.6 months with placebo.
Treatment Discontinuation Rates
Dr. Ryan also noted that 45% of patients assigned to everolimus completed all 54 weeks of adjuvant therapy. Treatment discontinuation for reasons other than disease progression or death occurred in 47% of patients; 37% of patients on everolimus discontinued therapy due to adverse events compared with 5% of placebo patients. Treatment was discontinued due to disease recurrence in 8% of the everolimus arm compared with 14% of the placebo arm. Dose reductions were required for 37% of patients in the everolimus arm and for 7% in the placebo group.
“Dropout rates are high across all adjuvant oral [tyrosine kinase inhibitor] therapies,” Dr. Ryan said. He also questioned the optimal duration of adjuvant therapy, noting that 1 year of treatment is “completely arbitrary” and that the effect of everolimus was observed despite a large number of patients not completing the full 54 weeks of study treatment.”
Adverse events occurred in 96% of those treated with everolimus and in 81% of those in the placebo group, with grade 3 or greater adverse events observed in 46% and 11% of patients, respectively. Adverse events more common on the everolimus arm were consistent with what is known about this agent. Mucositis was the most common grade 3 or higher adverse event and occurred in 14% of patients on the everolimus arm. It should be noted that prophylactic dexamethasone mouthwash was not incorporated in the study.
Dr. Ryan’s interpretation of the study results was similar to a “glass half-full” attitude. He said that although the study was technically negative, there was a “very strong trend” toward a recurrence-free survival benefit with everolimus, with a potential effect in high-risk patients. “People should look at the data with an open mind and think about where this might fit into the adjuvant landscape,” Dr. Ryan said.
Expert Point of View
Leonard J. Appleman, MD, PhD
Invited discussant Leonard J. Appleman, MD, PhD, of the University of Pittsburgh Hillman Cancer Center, was in general agreement with Dr. Ryan.
“This was a large, well-designed and executed, and definitive study that did an outstanding job answering the question it set out to,” Dr. Appleman said. He added that the data are unlikely to be robust enough to earn the drug U.S. Food and Drug Administration approval in this setting.
Dr. Appleman said that although the results in highest-risk patients were provocative, the evidence does not justify recommending adjuvant everolimus in a molecularly unselected group of patients. Perhaps if predictive biomarkers are identified, in the future, it might be possible to identify a subset of patients who would derive significant benefit from adjuvant everolimus.
DISCLOSURE: Dr. Ryan has served as a consultant or advisor to Aveo, Bristol Myers Squibb, Daiichi Sankyo, Exelixis, Partner Therapuetics, and Synox; and has received institutional research funding from Ayala Pharmaceuticals, Bristol Myers Squibb, Daiichi Sankyo, Deciphera, Exelixis, Genentech, GlaxoSmithKline/Novartis, Karyopharm Therapeutics, Leducq, Merck, Nektar, Pfizer, and Xynomic Pharma. Dr. Appleman has received research funding from Acerta Pharma, Agensys, Astellas Pharma, Aveo, Bayer, Bristol Myers Squibb, Calithera Biosciences, Eisai, Exelixis, Genentech/Roche, Inovio Pharmaceuticals, Lilly, Merck, Novartis, Peloton Therapeutics, Pfizer, Seattle Genetics, and Tokai Pharmaceuticals.
REFERENCES
1. Ryan CW, Tangen C, Heath EI, et al: EVEREST: Everolimus for renal cancer ensuing surgical therapy–A phase III study (SWOGS0931, NCT01120249). 2022 ASCO Annual Meeting. Abstract LBA4500. Presented June 3, 2022.
2. Ravaud A, Motzer RJ, Pandha HS, et al: Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med 375:2246-2254, 2016.
3. Choueiri TK, Tomczak P, Park SH, et al: Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med 385:683-694, 2021.
