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Everolimus Tablets (Afinitor®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.
Everolimus is the newest oral kinase inhibitor approved for the treatment of advanced renal cell carcinoma. It is a rapamycin derivative but unlike temsirolimus it is not converted to rapamycin after oral administration. Everolimus is marketed by Novartis Pharmaceuticals Corporation as Afinitor®.
Everolimus is indicated for the treatment of advanced renal cell carcinoma after treatment failure with sunitinib or sorafenib.1
The recommended dose is 10 mg once daily taken without regard for meals. The dose should be reduced to 5 mg in patients with hepatic impairment. For patients on a strong CYP3A4 inducer the dose should be increased at 5 mg increments to a maximum of 20 mg daily.1
Everolimus is available as 5 mg and 10 mg tablets.
In patients with metastatic renal cell carcinoma whose disease had progressed on prior treatment with sunitinib, sorafenib, or both sequentially, everolimus increased median survival time to 4.9 months compared to 1.9 months for placebo.1
Most frequently reported adverse events (≥ 25%) were: stomatitis (44%), infection/infestation (37%), diarrhea (30%), asthenia (33%), fatigue (31%), cough (30%), nausea (26%), peripheral edema (25%), rash (29%), and anorexia (25%).1 Strong and moderate inhibitors of CYP3A4 or P-glycoprotein should be avoided as well as strong inducers of CYP3A4.
Everolimus is an inhibitor of mTOR, a serine-threonine kinase. This pathway is dysregulated in several human cancers.1 Inhibition of this pathway inhibits cell growth and angiogenesis.2 The success of mTOR inhibition was demonstrated by improved survival with temsirolimus. Efficacy of everolimus was shown in an international, randomized, double-blind study in patients with metastatic renal cell carcinoma who had progressed despite treatment with sunitinib, sorentinib, or sequential therapy.1 Prior therapy with bevacizumab, interleukin-2, or interferon was permitted. Patients were randomized (2:1 ratio) to everolimus (n = 277) or placebo (n = 137) and stratified based on prognostic score and prior therapy. Study endpoint was based on progression-free survival based on radiographic assessment using Response Evaluation Criteria in Solid Tumor (RECIST). The median times for progression-free survival were 4.9 (4.0-5.5) months for everolimus compared to 1.9 (1.8-1.9) for placebo. Objective response rate was 2% compared to 0% for placebo. Most common adverse events were stomatitis, infections, asthenia, fatigue, cough, and diarrhea.
Treatment options for renal cell carcinoma have expanded recently with the approval of sunitinib, sorentinib, and temsirolimus. First-line treatment options for patients with good or intermediate-risk disease include sunitinib or bevacizumab and interferon alpha and temsirolimus for those with poor-risk.3 A recent, indirect, meta-analysis of sunitinib, sorentinib, bevacizumab/ interferon, and temsirolimus concluded that sunitinib was superior to sorentinib and bevacizumab/interferon in terms of progression-free survival (PFS) when interferon alpha was used as the comparator. However, when placebo was used, no statistical difference was found. Temsirolimus showed significant PFS in patients with poor prognosis.4 Everolimus provides another treatment option for patients whose disease has progressed with sunitinib and/or sorentinib.
1. Afinitor Product Information. East Hanover, NJ: Novartis Pharmaceutical Corporation; March 2009.
2. Amato RJ, et al. A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer 2009 Mar 20; Epub ahead of print.
3. Porta C, Szczylik C. Tolerability of first-line therapy for metastatic renal cell carcinoma. Cancer Treat Rev 2009;35:297-307.
4. Hudes G, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271-2281.