HEALTH SYSTEMS EDITIONMTOR INHIBITORS FOR METASTATIC RENAL CELL CARCINOMATable 2Temsirolimus Phase III Study ResultsOutcome Temsirolimus Temsirolimus IFN-AMeasure Arm + IFN-A Arm ArmMedian OS 10.9 mo 8.4 mo 7.3 moMedian PFS 5.5 mo 4.7 mo 3.1 moClinical benefit a 32.1% 28.1% 15.5%aProportion of patients with objective response or stable disease for ≥24 wk.IFN-A: interferon-alpha; OS: overall survival; PFS: progression-free survival.Source: Reference 3.with strong inducers and inhibitors, so these medicationsshould be avoided. If coadministration is unavoidable,the dose of temsirolimus should be increased to 50 mgwhen given with a strong CYP450 3A4 inducer andreduced to 12.5 mg when given with a strong inhibitor. 2Grapefruit juice should be avoided because it may increasesirolimus levels. Use temsirolimus with caution in patientswith hypersensitivity to polysorbate 80. 10Phase I and II clinical trials determined that temsirolimus25 mg IV could be given safely on a weekly basisand had promising activity in RCC. Researchers alsofound that patients with treatment-refractory, poorprognosisRCC who were receiving temsirolimus had amedian overall survival of 8.2 months versus 4.9 monthsfor IFN-A. 7 Subsequently, Hudes and colleagues conducteda phase III trial comparing three treatment arms in 626patients with metastatic RCC: temsirolimus 25 mg IVweekly; temsirolimus 15 mg IV weekly with IFN-A at3 to 6 MU subcutaneously (SC) three times weekly; andIFN-A 3 to 18 MU SC three times weekly. Patients hadto be treatment-naïve and have at least three predictorsof short survival. 3 See TABLE 2 for results. 3Dose reductions and delays were least common in thetemsirolimus single-agent arm. 3 The FDA approvedtemsirolimus for metastatic RCC in May 2007. As aresult of the phase II and III trials, temsirolimus is nowfavored as first-line treatment for patients with poorprognosismetastatic RCC. 9EverolimusEverolimus, also known as RAD001, is an orally administeredmTOR kinase inhibitor. It forms a complex withthe intracellular protein FKBP-12 and inhibits the mTORkinase. Everolimus reduces cell proliferation, cell growth,angiogenesis, and glucose uptake, and it inhibits HIF-1expression and reduces VEGF expression. 7,8,11Everolimus is administered once daily as a 10-mgtablet, at the same time every day, with or without food.It is metabolized hepatically via CYP450 3A4. Druginteractions with CYP450 3A4 inducers and inhibitorsshould be avoided. If treatment with a strong CYP450inducer cannot be avoided, the dose of everolimus maybe increased from 10 mg to 20 mg in 5-mg increments.The dose of everolimus may also be reducedto 5 mg in the presence of moderate hepaticimpairment or severe adverse events. Themean half-life is about 30 hours. Thereare six main metabolites of everolimus;they are 100 times less potent than theparent compound. Grapefruit juice shouldbe avoided. 11Phase I and II studies established thesafety and efficacy of everolimus administeredon a daily oral dosing schedule.They also demonstrated disease stabilizationor tumor reduction in metastaticRCC. 4,7,9,12 Responding to the need for active cancermedications after traditional agents have failed, a phaseIII study investigated the role of everolimus in second- orthird-line dosing. 12Motzer and colleagues conducted a phase III trial in410 patients with metastatic clear cell RCC assigned ina 2-to-1 ratio to two treatment arms: oral everolimus 10mg daily plus best supportive care or placebo plus bestsupportive care. 12 Patients had to have progressed by orwithin 6 months of stopping sunitinib, sorafenib, or bothdrugs; previous therapy with bevacizumab, IL-2, or IFN-Awas allowed. At progression, placebo patients couldtransition to active open-label everolimus treatment forethical reasons. At the second interim safety analysis, thestudy was halted early because the prolongation in progression-freesurvival (PFS) was greater than expected.See TABLE 3 for results. 12,13 The crossover from placeboto everolimus at disease progression would likely confoundthe median overall survival data for the everolimus group;therefore, the endpoint was not reached. 12In a follow-up to the phase III everolimus study,researchers collected 4.5 months of additional blindeddata for a total of 416 patients. The results of this studydemonstrated persistence of PFS prolongation. 13In March 2009, the FDA approved everolimus forthe treatment of advanced RCC after failure of treatmentwith sunitinib or sorafenib. 11 The drug also is FDAapprovedas a medical device as a component of theeverolimus-eluting coronary stent system for coronaryartery disease. 14 Everolimus is approved in Europe as animmunosuppressant for the prevention of solid organtransplant rejection. 9Adverse EventsThe primary adverse-events profile of the mTOR inhibitorsincludes hyperglycemia, hypercholesterolemia, andhyperlipidemia. This reflects the blockade of mTOR, theprimary signaling conduit for insulin and insulin growthfactor. Other common adverse events for temsirolimusand everolimus include fatigue, stomatitis, diarrhea,hypophosphatemia, low red blood cells and platelets, andperipheral edema. These adverse events are commonlyreversible upon treatment discontinuation. Less commonHS-24U.S. <strong>Pharmacist</strong> • November 2009 • www.uspharmacist.com
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