HEALTH SYSTEMS EDITIONMTOR INHIBITORS FOR METASTATIC RENAL CELL CARCINOMATable 3Everolimus Phase III Study Results aOutcome Everolimus + Best Placebo + BestMeasure Supportive Care Supportive CareMedian PFS 4.9 mo 1.9 moMedian OS Not reached 8.8 moPatients with PR 1% 0%Patients with stable disease 63% 32%Patients with progressive disease 19% 46%aIncluding 4.5-mo follow-up.OS: overall survival; PFS: progression-free survival; PR: partial response.Source: References 12, 13.symptoms are renal insufficiency, interstitial pneumonitis,and low white blood cells. 8Fatigue is experienced by more than 50% of patientstaking mTOR inhibitors. About 10% have dose-limitingfatigue to the degree of warranting dose reduction. 9Hyperglycemia is experienced by more than 50% oftreated patients. Owing to the rising incidence of obesityand metabolic syndrome, it is important to identify theseadverse events quickly. Up to 10% of patients developsevere symptoms and require medical intervention withan oral hypoglycemic agent or SC insulin. Regular monitoringof triglycerides is recommended, with early dietaryinterventions for minor elevations and initiation of alipid-lowering agent for levels exceeding 500 mg/dL.Severe hypertriglyceridemia is associated with acutepancreatitis. 9Impairment of renal function and interstitial pulmonaryfibrosis are rare but important events. Serum creatinineshould be monitored regularly. The pulmonaryfibrosis is often steroid-responsive and frequently fullyreversible. If symptoms of progressive dyspnea or lunginfiltrates are present, the dose may be reduced or thetreatment discontinued. 9Both temsirolimus and everolimus are classified aspregnancy category D. Men and women receivingtemsirolimus should use contraception while receivingactive treatment and for 3 months afterthe final dose. Women taking everolimusshould use contraception while receivingactive treatment and for 8 weeks afterthe final dose. 10,11Patients being treated with mTORinhibitors should not receive live vaccines.Patients should also avoid close contactwith individuals who have received livevaccines. 10,11Investigational Combination StudiesThe goal of combining different therapiesis to achieve greater efficacy. Strategiesoften involve combining agents withdifferent mechanisms of action and sideeffectprofiles. Investigational combinations in phase Iand II studies include bevacizumab with either everolimusor temsirolimus; other studies are examiningtemsirolimus with sorafenib or IFN-A. 4,8 Certain combinationsrequire up-front dose reductions, such astemsirolimus with sorafenib, or are not safe, such astemsirolimus with sunitinib. 15CostThe average wholesale price (AWP) of the temsirolimusinjection kit 25 mg IV weekly is $1,499, or $5,996 permonth. The respective monthly AWPs of everolimus 5mg and 10 mg orally daily are $6,400 and $6,700. Themanufacturers offer assistance programs for eligiblepatients. Prior authorization often is required for thesehigh-cost medications.SummaryThere are two recently approved novel mTOR inhibitorswith activity in metastatic RCC. Temsirolimus is FDAapprovedfor first-line treatment of metastatic RCC andis favored for poor-prognosis patients. Everolimus isFDA-approved for second-line treatment of metastaticRCC after sunitinib or sorafenib failure. These agentsprovide a valuable choice for providers and patients withlimited treatment options.REFERENCES1. American Cancer Society. Detailed Guide: Kidney Cancer.What are the key statistics for kidney cancer?www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_are_the_key_statistics_for_kidney_cancer_22.asp?sitearea=.Accessed July 25, 2009.2. Reeves DJ, Liu CY. Treatment of metastatic renal cell carcinoma.Cancer Chemother Pharmacol. 2009;64:11-25.3. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus,interferon alfa, or both for advanced renal-cell carcinoma. NEngl J Med. 2007;356:2271-2281.4. Basso M, Cassano A, Barone C. A survey of therapy foradvanced renal cell carcinoma. Urol Oncol. Epub July 6,2009. www.urologiconcology.org/article/S1078-1439(09)00142-2/abstract [registration required]. AccessedJuly 20, 2009.5. Nexavar (sorafenib) package insert. Wayne, NJ: BayerHealthCare Pharmaceuticals, Inc; February 2009.6. Sutent (sunitinib) package insert. New York, NY: PfizerLabs; July 2009.7. Wysocki P. mTOR in renal cell cancer: modulator oftumor biology and therapeutic target. Expert Rev Mol Diagn.2009;9:231-241.8. Hudes GR. Targeting mTOR in renal cell carcinoma.Cancer. 2009;115(suppl 10):2313-2320.9. Dasanu CA, Clark BA III, Alexandrescu DT. mTORblockingagents in advanced renal cancer: an emerging therapeuticoption. Expert Opin Investig Drugs. 2009;18(2):175-187.10. Torisel (temsirolimus) injection package insert. Philadelphia,PA: Wyeth Pharmaceuticals Inc; September 2008.11. Afinitor (everolimus) package insert. East Hanover, NJ:Novartis Pharmaceuticals Corp; March 2009.12. Motzer RJ, Escudier B, Oudard S, et al. Efficacy ofeverolimus in advanced renal cell carcinoma: a double-blind,randomised, placebo-controlled phase III trial. Lancet.2008;372:449-456.13. Kay A, Motzer R, Figlin R, et al. Updated data from aphase III randomized trial of everolimus (RAD001) versusPBO in metastatic renal cell carcinoma (mRCC). Proc AmSoc Clin Oncol. 2009. Abstract 278 [presented at 2009ASCO Genitourinary Cancers Symposium].14. FDA. XIENCE V everolimus eluting coronary stenton the over-the-wire (OTW) or rapid exchange (RX) stentdelivery systems–P070015.www.fda.gov/medicaldevices/productsandmedicalprocedures/deviceapprovalsandclearances/recently-approveddevices/ucm074025.htm. Accessed July 15, 2009.15. Sosman J, Puzanov I. Combination targeted therapy inadvanced renal cell carcinoma. Cancer. 2009;115(suppl10):2368-2375.HS-26U.S. <strong>Pharmacist</strong> • November 2009 • www.uspharmacist.com
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