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Everolimus Offers No Survival Benefit in Non–Clear Cell RCC

TOPLINE:
Adjuvant everolimus does not improve recurrence-free or overall survival in patients with papillary and chromophobe subtypes of non–clear cell renal cell carcinoma (RCC) and is associated with higher rates of severe adverse events compared with placebo.
METHODOLOGY:
Non–clear cell RCC accounts for approximately 25% of RCC cases and includes various distinct tumor types such as papillary and chromophobe RCC. A common design flaw in clinical trials has been applying treatments effective in clear cell RCC to non–clear cell RCC subtypes without a strong biological rationale. The broad approval of drugs for RCC without considering subtype differences complicates treatment decisions.
The EVEREST phase 3 randomized clinical trial evaluated everolimus in the adjuvant setting, enrolling patients with either clear cell (n = 1248) or non–clear cell (n = 208) RCC at a high risk for recurrence after resection. The patients were randomly assigned to receive either everolimus or placebo.
To assess the benefits of everolimus in patients with non–clear cell RCC, this analysis focused on the subgroup of 109 patients with papillary RCC (median age, 60 years) and 99 patients with chromophobe RCC (median age, 51 years).
The primary outcome was recurrence-free survival, and the secondary outcome was overall survival. The median follow-up was 76 months.
TAKEAWAY:
In the papillary RCC subgroup, the 5-year recurrence-free survival was lower among patients receiving everolimus vs placebo (62% vs 70%), but this difference was not significant (HR, 1.19; 95% CI, 0.61-2.33; P = .61).
In the chromophobe RCC subgroup, the 5-year recurrence-free survival was similar between the two groups — 79% for everolimus vs 77% for placebo (HR, 0.89; 95% CI, 0.37-2.13; P = .79).
Everolimus was also not associated with a significant overall survival benefit in patients with papillary RCC (HR, 1.47; 95% CI, 0.67-3.24; P = .34) or chromophobe RCC (HR, 0.93; 95% CI, 0.33-2.65; P = .89). In the papillary RCC subgroup, 5-year overall survival rates were slightly lower in the everolimus group than in the placebo group (76% vs 82%); however, in the chromophobe RCC subgroup, the rates were the same for both arms (89%).
Patients treated with everolimus reported an increased incidence of grade 3 or higher adverse events compared with those treated with placebo (48% vs 9%). No treatment-related deaths were reported, but a significant number of patients — 54% with papillary RCC and 51% with chromophobe RCC — discontinued treatment early due to adverse events.
IN PRACTICE:
This secondary analysis “found that patients with papillary or chromophobe RCC did not benefit from treatment with everolimus in the adjuvant setting,” the authors wrote. “Our study highlights an area of unmet need in the kidney cancer field. It thus serves to provide a foundational background for future randomized clinical trials to address specific subgroups of RCC for risk mitigation strategies in the adjuvant setting.”
SOURCE:
The study was led by Shuchi Gulati, MD, MSc, University of California Davis Comprehensive Cancer Center, Sacramento, California, and was published online on August 6, 2024, in JAMA Network Open, along with an accompanying editorial.
LIMITATIONS:
The subgroup analyses were underpowered to detect a significant difference. Additionally, the study lacked a central pathology review to confirm non–clear cell histologies.
DISCLOSURES:
The study was supported by awards from the National Institutes of Health, National Cancer Institute, and National Clinical Trials Network. Several authors reported receiving grants or personal fees from various sources outside the submitted work.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
 
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