Adjuvant everolimus did not benefit high-risk renal cell carcinoma 

In patients with renal cell carcinoma (RCC), adjuvant everolimus after nephrectomy did not provide a statistically significant benefit over placebo in terms of recurrence-free survival (RFS). However, the observed numerical benefit, especially in the very high-risk subgroup of patients, warrants further investigation into the role that everolimus may play in the adjuvant treatment of patients with RCC after nephrectomy. 

“Approximately one-third of the patients with RCC relapses after nephrectomy,” explained Dr Christopher W. Ryan (Oregon Health & Science University, OR, USA) [1]. Since 2006, a new generation of adjuvant trials has emerged to improve the standard-of-care for these patients, which was ‘surveillance alone’. Everolimus is a mechanistic target of rapamycin (mTOR) inhibitor, approved for the treatment of metastatic RCC [2]. The phase 3 EVEREST trial (NCT01120249) randomised patients with RCC who underwent nephrectomy and have high risk of recurrence to everolimus (n=775) or placebo (n=770). The primary endpoint was RFS and Dr Ryan presented the final analysis of the trial [1].

After a median follow-up of 6.3 years, the primary endpoint narrowly missed the prespecified P-value for statistical significance of 0.022 (HR 0.85; P_1-sided=0.025). Notably, the numerical benefit of everolimus over placebo appeared to be more pronounced in the very high-risk patient population (HR 0.79; P_1-sided=0.011) compared with the intermediate high-risk population (HR 0.99; P_1-sided=0.48), although no significant interaction effect of risk stratification on treatment outcome was reported (P_interaction=0.20). Furthermore, the results of the trial did not favour everolimus over placebo with respect to overall survival (HR 0.90; P_1-sided=0.178).

Adverse events (AEs) of all grades were more frequently observed in patients on everolimus (96%) than in patients on placebo (81%), predominantly due to a higher rate of gastrointestinal or cutaneous AEs. Similarly, grade 3 or higher AEs were noted in 46% of the patients in the experimental arm and in 11% of the patients in the placebo arm. In total, 14% of the patients on everolimus experienced oral mucositis of grade 3 or higher, compared with 0% in the placebo group. Also, diarrhoea (33% vs 15%), nausea (24% vs 17%), maculo-papular rash (31% vs 8%), acneiform rash (29% vs 5%), and pruritus (18% vs 8%) of any grade were more common in patients receiving everolimus than placebo. As a result, the percentage of the discontinuation rate not due to progression or death was higher in the experimental arm than in the placebo arm (47% vs 17%).

“The effect of everolimus was especially pronounced in patients with very high-risk disease. Further analyses are needed to establish which subgroups of patients may benefit the most from adjuvant treatment with everolimus,” argued Dr Ryan. “In addition, the high discontinuation rate in the everolimus group puts the therapy duration into question.”

1. Ryan CW, et al. Everolimus for Renal Cancer Ensuing Surgical Therapy—A Phase III Study. LBA 4500, ASCO 2022 Annual Meeting, 3–7 June, Chicago, IL, USA.
2. https://www.ema.europa.eu/en/medicines/human/EPAR/afinitor

Copyright ©2022 Medicom Medical Publishers



Posted on 5 August 2022