From the Guidelines
Everolimus is not the preferred treatment option for advanced renal cell carcinoma (RCC) patients who have failed prior treatments with VEGF-targeted therapies like sunitinib or sorafenib, as nivolumab has shown improved overall survival compared to everolimus in the CheckMate 025 study 1. The standard treatment for advanced RCC has evolved, and immunotherapy has become a crucial component.
- Nivolumab, a PD-1 inhibitor, has demonstrated improved overall survival compared to everolimus in patients with advanced RCC who have failed prior treatments with VEGF-targeted therapies 1.
- The CheckMate 025 study showed that nivolumab had a median overall survival of 25.0 months, compared to 19.6 months for everolimus, with a hazard ratio of 0.73 1.
- Common side effects of nivolumab include fatigue, rash, and diarrhea, which should be monitored regularly.
- Dose adjustments may be necessary if severe adverse effects occur, and patients should avoid grapefruit juice and St. John's wort during treatment as they can affect drug metabolism.
- Drug interactions with strong CYP3A4 inhibitors or inducers should be carefully managed, often requiring dose adjustments.
- Everolimus, an mTOR inhibitor, is still considered a useful option in certain circumstances, but its use should be individualized based on patient-specific factors, such as performance status and prior treatment history 1.
From the Research
Everolimus for Renal Cell Carcinoma (RCC)
- Everolimus is an mTOR serine/threonine kinase inhibitor that represents a therapeutic option for the treatment of advanced RCC 2.
- It was approved for second- and third-line therapy in patients with advanced RCC according to the results of a Phase III pivotal trial that demonstrated a benefit in median progression-free survival of ~2 months compared to placebo after failure of previous lines of therapy 2, 3.
- The role of everolimus in first-line setting has been investigated in Phase II trials, with no significant clinical benefit, even in combination with bevacizumab 2.
- Everolimus activity in non-clear cell RCC is supported by two randomized Phase II trials that confirmed the benefit in second-line setting but not in first line 2.
- Recently, two randomized Phase III trials (METEOR and CheckMate 025) demonstrated the inferiority of everolimus in second-line setting compared to the TKI cabozantinib and to the immune checkpoint inhibitor nivolumab, respectively 2.
Efficacy and Safety
- Median progression-free survival was significantly longer with everolimus 10 mg once daily than with placebo in both second interim (4.0 vs 1.9 months) and updated (4.9 vs 1.9 months) analyses of a randomized, double-blind, placebo-controlled, multicentre, phase III trial in patients with metastatic renal cell carcinoma that had progressed while receiving sunitinib and/or sorafenib treatment 3.
- The tolerability profile of everolimus was largely manageable in the phase III trial, with most treatment-related adverse events being of grade 1 or 2 severity 3, 4.
- The safety profile of the drug is favorable, with a good cost-effectiveness compared to second-line sorafenib or axitinib, and no significant impact on the quality of life of treated patients has been found 2.
Comparison with Other Therapies
- A randomized phase 2 trial compared sunitinib and everolimus in non-clear cell RCC, and found that everolimus was not superior to sunitinib, with both agents demonstrating modest efficacy 5.
- Genomic profiling of a chromophobe RCC from a patient with a PR to first-line everolimus revealed a somatic TSC2 mutation, highlighting the potential for targeted therapy in non-clear cell RCC 5.
- Everolimus still represents a current standard of treatment for RCC progressive to previous treatment lines with VEGFR-TKI, although its use may shift to the third-line setting and subsequent lines of treatment due to the emergence of new therapies such as cabozantinib and nivolumab 2.