In a subgroup analysis of the EVEREST trial reported in JAMA Network Open, Gulati et al found that adjuvant everolimus did not improve recurrence-free survival vs placebo in patients with localized papillary or chromophobe non–clear cell renal cell carcinoma (RCC).
Study Details
In the trial, patients with fully resected RCC at intermediate high risk (pT1 grade 3-4, N0 to pT3a grade 1-2, N0) or very high risk (pT3a grade 3-4 to pT4 any grade or N+) for recurrence were randomly assigned between April 2011 and September 2016 to receive everolimus at 10 mg daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival.
Among the total of 1,545 randomized patients, 109 had papillary RCC, including 57 in the everolimus group and 52 in the placebo group, and 99 had chromophobe RCC, including 53 in the everolimus group and 46 in the placebo group.
Key Findings
The target 54 weeks of everolimus was completed by 26 (46%) of 57 patients with papillary RCC and 26 (49%) of 53 with chromophobe RCC.
Median follow-up was 76 months (interquartile range = 61–96 months). Recurrence-free survival at 5 years was 62% in the everolimus group vs 70% in the placebo group for those with papillary RCC (hazard ratio [HR] = 1.19, 95% confidence interval [CI] = 0.61–2.33, P = .61) and 79% vs 77% among patients with chromophobe RCC (HR = 0.89, 95% CI = 0.37–2.13, P = .79).
Overall, 26 patients (24%) in the papillary RCC cohort and 14 patients (14%) in the chromophobe RCC cohort died. Median overall survival was not reached in either treatment group in either cohort; hazard ratios for everolimus vs placebo were 1.47 (95% CI = 0.67–3.24, P = .34) in the papillary RCC cohort and 0.93 (95% CI = 0.33–2.65, P = .89) in the chromophobe RCC cohort. Estimated 5-year overall survival was 76% vs 82% in the papillary RCC cohort and 89% vs 89% in the chromophobe RCC cohort.
In the combined papillary and chromophobe RCC population, grade ≥ 3 adverse events occurred in 48% of the everolimus group vs 9% of the placebo group; the most common events in the everolimus group were hypertriglyceridemia (14%), mucositis (13%), fatigue (6%), and hyperglycemia (5%). No treatment-related deaths were reported.
The investigators concluded, “In this clinical trial assessing the use of adjuvant everolimus, postoperative everolimus did not show evidence of improved recurrence-free survival among patients with papillary or chromophobe RCC, and results from the study do not support adjuvant everolimus for this cohort. However, since the [lower bound of the 95% confidence interval was 0.61 in the papillary RCC comparison, and the hazard ratio was 0.89 with a lower confidence interval bound of 0.37 in the chromophobe RCC comparison], potential treatment benefit in these subgroups cannot be ruled out.”
Shuchi Gulati, MD, MSc, of the University of California Davis Comprehensive Cancer Center, Sacramento, and Sumanta K. Pal, MD, of City of Hope Comprehensive Cancer Center, Duarte, CA, are the corresponding authors for the JAMA Network Open article.
Disclosure: The study was supported by the National Cancer Institute and Novartis Pharmaceuticals. For full disclosures of the study authors, visit jamanetwork.com.
