Targeting mTOR

Initial VEGFR-TKIs, sunitinib or sorafenib, will eventually fail in the majority of patients with aRCC1-4

  • VEGFR-TKIs, sunitinib or sorafenib, are frequently used in the first-line treatment of aRCC
    • VEGFR-TKIs primarily target blood vessel cells and inhibit tumor angiogenesis5,6
  • Most patients eventually develop resistance to an initial VEGFR-TKI,sunitinib or sorafenib, and experience disease progression1-4
  • It is evident that multiple factors drive disease progression in aRCC1-4,7

Target mTOR—An important factor driving progression in aRCC

  • mTOR is an important target with multiple biologic effects
  • An important target:
    • The mTOR pathway is upregulated in the majority of aRCC tumors8,9
  • Multiple biologic effects:
    • mTOR, an important intracellular regulator, contributes to RCC progression through cellular proliferation, growth, and metabolism10-12
    • Dual cell targets: inhibit mTOR in both and blood vessel cells11-13
  • mTOR inhibition directly reduces cell growth, proliferation, and metabolism, in addition to angiogenesis*10-12

Important Safety Information

AFINITOR® (everolimus) tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Non-infectious Pneumonitis: Non-infectious pneumonitis was reported in 11%-14% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) Grade 3 and 4 non-infectious pneumonitis was 1.6%-4.0% and 0.1%, respectively. Fatal outcomes have been observed. If symptoms are moderate, patients should be managed with dose interruption until symptoms improve. If symptoms are severe, AFINITOR therapy should be discontinued. Under both circumstances, corticosteroids may be indicated and AFINITOR may be reintroduced at 5 mg daily depending on the individual clinical circumstances. The development of pneumonitis has been reported even at a reduced dose.

Infections: AFINITOR has immunosuppressive properties and may predispose patients to localized or systemic bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Viral infections may include reactivation of hepatitis B infection. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of pre-existing invasive fungal infections should be completed prior to starting treatment. Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered. Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate treatment.

Oral Ulceration: Oral ulcerations (i.e., mouth ulcers, stomatitis, and oral mucositis) are the most frequently occurring adverse event and occur in approximately 70% of advanced PNET patients, 44% of advanced RCC patients, and 86% of SEGA patients, which were mostly Grade 1 or 2. Grade 3 or 4 stomatitis was reported in 6% of patients with neuroendocrine tumors. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed.

Renal Failure: Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR.

Laboratory Tests and Monitoring: Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Renal function, blood glucose, lipids, and hematologic parameters should be evaluated prior to treatment and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR.

Drug-drug Interactions: Avoid co-administration with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole). Use caution and reduce the AFINITOR dose to 2.5 mg daily if co-administration with a moderate CYP3A4 and/or PgP inhibitor is required (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). Avoid co-administration with strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if co-administration is required, increase the AFINITOR dose from 10 mg daily up to 20 mg daily, using 5 mg increments.

Hepatic Impairment: AFINITOR should not be used in patients with severe hepatic impairment. Exposure of everolimus was increased in patients with moderate hepatic impairment. AFINITOR dose should be reduced to 5 mg daily for patients with moderate hepatic impairment.

Vaccinations: The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR.

Use in Pregnancy: Fetal harm can occur if AFINITOR is administered to a pregnant woman. Women of childbearing potential should be advised to use an effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment.

Adverse Reactions: The most common adverse reactions (incidence ≥ 30%) were stomatitis (44%), infections (37%), asthenia (33%), fatigue (31%), cough (30%), and diarrhea (30%). The most common Grade 3/4 adverse reactions (incidence ≥ 5%) were infections (10%), dyspnea (7%), stomatitis (5%) and fatigue (5%). Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the AFINITOR arm.

Laboratory Abnormalities: The most common laboratory abnormalities (incidence ≥ 50%, all grades) were: decreased hemoglobin (92%) and lymphocytes (51%); increased cholesterol (77%), triglycerides (73%), glucose (57%) and creatinine (50%). The most common Grade 3/4 laboratory abnormalities (incidence ≥ 5%) were: decreased hemoglobin (13%), lymphocytes (18%), and phosphate (6%); and increased glucose (16%).

References: 1. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8:592-603. 2. Ebos JML, Lee CR, Kerbal RS. Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res. 2009;15:5020-5025. 3. Casanovas O, Hicklin J, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8:299-309. 4. Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol. 2009;10:992-1000. 5. Sutent [prescribing information]. New York, NY: Pfizer Inc; 2008. 6. Nexavar [prescribing information]. Wayne, NJ: Bayer Healthcare Pharmaceuticals Inc.; 2008. 7. Rapisarda A, Melillo G. Role of the hypoxic tumor microenvironment in the resistance to anti angiogenic therapies. Drug Resist Updat. 2009;12:74-80. 8. Pantuck AJ, Seligson DB, Klatte T, et al. Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy. Cancer. 2007;109:2257-2267. 9. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 2004;4:335-348. 10. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471-484. 11. Dancey JE. Inhibitors of the mammalian target of rapamycin. Expert Opin Investig Drugs. 2005;14:313-328. 12. Hartford CM, Ratain MJ. Rapamycin: something old, something new, sometimes borrowed and now renewed. Clin Pharmacol Ther. 2007;82:381-388. 13. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18:1926-1945.

*Inhibition of mTOR by AFINITOR has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.

AFI-1025219

 
Important Safety Information

There have been reports of non-infectious pneumonitis, infections and kidney failure (including acute renal failure) in patients taking AFINITOR® (everolimus) tablets, some with fatal outcomes. Oral ulceration is the most frequently occurring adverse event and occurs in approximately 44% of AFINITOR-treated patients, which were mostly Grade 1 or 2. Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have also been reported.