Adjuvant everolimus nonsignificantly improved recurrence-free survival in renal cancer
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CHICAGO — In renal cell carcinoma, adjuvant everolimus improved recurrence-free survival after nephrectomy but narrowly missed the benchmark for statistical significance, according to final results from the phase 3 EVEREST study.
“Up to one-third of patients who undergo curative-intent nephrectomy will end up developing metastatic recurrence, and for many years, surveillance alone remained standard management for these patients, with no benefit of adjuvant cytokine therapy being seen in early trials,” Christopher W. Ryan, MD, from the Oregon Health & Science University Knight Cancer Institute, said during a presentation at ASCO Annual Meeting. “But with the advent of targeted therapies, and subsequently checkpoint immunotherapies, a new generation of adjuvant trials was launched over 15 years ago.”
Study design, concerns
To test the effectiveness of everolimus as adjuvant therapy, Ryan and colleagues randomly assigned patients with fully resected renal cell carcinoma (RCC) within 12 weeks of radical or partial nephrectomy who had high-risk RCC, defined as T1b high-grade through node-positive disease, clear or nonclear cell histology and no evidence of metastases to 54 weeks of everolimus 10 mg daily or matching placebo.
The trial’s primary objective was recurrence-free survival (RFS), which was defined as time from randomization to first documentation of metastatic or local RCC recurrence or death due to any cause. Secondary endpoints included OS, toxicity assessment and investigation of steady state everolimus trough levels and associations with adverse events.
Patients were also stratified according to risk. The researchers considered those with T1b high-grade tumors through T3a low-grade tumors to be at intermediate-high risk for recurrence and those with T3a high-grade tumors through node-positive disease to have very high risk for recurrence.
Ryan noted that the researchers originally designed the study with a sample size of 1,170 patients using a modified intention-to-treat analysis plan that included only eligible patients and stratified log-rank testing. However, in 2015, the data and safety monitoring committee raised concerns regarding an excess number of early treatment discontinuations. The researchers addressed this issue by increasing the sample size to 1,464 patients, which yielded 80% power to detect an 18% reduction in HR at a one-sided significance level of 2.5%, corresponding to an increase in the median expected RFS of 4.9 years in the placebo group and 6 years in the everolimus group.
The study design also included four prespecified interim analyses for futility and efficacy at a set number of expected events within the placebo arm, with the final analysis to occur after 804 total events occurred across both arms. In 2020, however, the number of events needed for the fourth interim analysis had not yet occurred. The analysis timeline was, therefore, revised and the final analysis was conducted in March 2022 after 556 RFS events.
Efficacy, safety data
From 2011 to 2016, the researchers randomly assigned 1,545 patients to treatment, of whom 1,499 were included in the efficacy analysis and 1,463 were included in the safety analysis. Of note, only 45% of patients assigned everolimus, as compared with 69% of those assigned placebo, completed all prescribed study treatment. Further, more patients in the everolimus arm discontinued treatment due to adverse events than in the placebo arm, whereas more patients in the placebo arm discontinued due to disease recurrence than in the placebo arm.
Median follow-up at the time of the final analysis was 6.3 years. The median time on treatment was 9.3 months in the everolimus arm and 12.6 months in the placebo arm, with 37% of patients in the everolimus arm undergoing a dose reduction. Forty-seven percent of patients treated with everolimus also discontinued due to a reason other than progression or death, as compared with 17% of those treated with placebo.
Baseline patient characteristics were well balanced between the two study arms, Ryan noted. The median age was approximately 58 years, most were men (around 70%) and white (around 90%), 55% had very high risk for recurrence, the vast majority had undergone radical (around 90%) as opposed to partial (around 10%) nephrectomy and 17% had non-clear cell histology.
In terms of the primary endpoint, RFS was not reached in either study arm, with 5-year RFS estimates of 67% in the everolimus arm and 63% in the placebo arm, Ryan reported. Kaplan Meier curves separated early and remained separated, favoring everolimus with a HR of 0.85 but a one-sided P value of 0.025, which narrowly missed the prespecified boundary for statistical significance of 0.22 that accounted for the interim analyses.
In the very-high-risk group, the median RFS was 5.3 years with placebo and was not reached in the everolimus arm, with a 5-year estimate of 57% with everolimus vs. 51% with placebo (HR = 0.79; 95% CI, 0.65-0.97). In the intermediate-high-risk group, there was no difference in RFS between the everolimus and placebo arms (HR = 0.99; 95% CI, 0.73-1.35).
Results demonstrated a general consistent effect favoring everolimus across most subgroups, with a particularly robust HR favoring everolimus for African Americans. However, the number of patients in this group was small, Ryan noted.
The researchers also observed no significant difference in OS, the study’s secondary endpoint, with a HR of 0.9 slightly favoring everolimus.
Adverse events were reported more frequently in the everolimus arm than in the placebo arm, with grade 3 or higher adverse events occurring in 46% of patients assigned everolimus vs. 11% of those assigned placebo. Adverse events that were more common in the everolimus arm were those well known to be associated with the drug and were primarily gastrointestinal and cutaneous in nature, Ryan noted. The most common grade 3 or higher adverse event was mucositis, occurring in 14% of patients receiving everolimus. Pneumonitis was also detected in 13% of patients on everolimus, but only 1% of events were deemed grade 3 or higher.
Similarly, laboratory abnormalities that were more common among patients receiving everolimus, including hyperlipidemia, anemia and hyperglycemia, were those well known to be associated with the drug, according to Ryan.
Further investigation necessary
These results raise some questions, Ryan noted.
“Adjuvant everolimus improved RFS in RCC patients after nephrectomy, but the nominal significance level was narrowly missed. The effect of everolimus was especially pronounced in those with high-risk disease, a patient population for whom adjuvant therapy is currently recommended,” Ryan said.
The adverse events were consistent with the known safety profile of everolimus, but Ryan highlighted the high discontinuation rate in this adjuvant population.
“I will point out that despite the early discontinuation rate, the fact that we detected the RFS benefit does bring into question the duration of adjuvant therapy that may be needed,” Ryan said. “Finally, these compelling results warrant further investigation into the role of everolimus in the current adjuvant landscape and subsets that may benefit most.”
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Ryan CW, et al. Abstract LBA4500. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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