mTOR—an important factor driving aRCC progression1-7


Cell growth and proliferation and mTOR

  • mTOR controls the cell's translational machinery (eg, ribosomes) and the production of proteins8,13:
    • Necessary for progress through the cell cycle
    • Essential for cell growth

Metabolism and mTOR

  • Many cancer cells rely on glycolysis—not oxidative phosphorylation—for energy14,15
  • Activated mTOR increases production of the enzymes necessary for glycolysis and controls the uptake of glucose and other nutrients9,15,16
  • Increased glucose uptake and metabolism helps fulfill the energy needs for mTOR-driven cell growth and proliferation9,16

Angiogenesis and mTOR

  • Activated mTOR stimulates HIF and VEGF7,8,12,17
  • Activated mTOR also stimulates VEGF-independent angiogenic processes
    • The proliferation of blood vessel cells8
    • The proliferation of pericytes that help stabilize tumor blood vessels8
    • The production of the proangiogenic factor FGF (fibroblast growth factor)18-20

Inhibit mTOR—An important target with multiple biologic effects

  • mTOR inhibition limits a tumor's ability to grow and spread by reducing*7-13,18-20:
    • Cell growth and proliferation
    • Cell metabolism
    • Both VEGF-dependent and VEGF-independent tumor angiogenesis
    • Dual cell targets: inhibit mTOR in both tumor and blood vessel cells12

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. Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol. 2009;10:992-1000. 2. Yuan R, Kay A, Berg W, Lebwohl D. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. J Hematol Oncol. 2009;2:45. 3. Zacchia M, Vilasi A, Capasso A, et al. Genomic and proteomic approaches to renal cell carcinoma. J Nephrol. 2011;24:155-164. 4. Hudes GR. Targeting mTOR in renal cell carcinoma. Cancer. 2009;115:2313-2320. 5. Kapoor A, Figlin RA. Targeted inhibition of mammalian target of rapamycin for the treatment of advanced renal cell carcinoma. Cancer. 2009;115:3618-3630. 6. 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. 7. Schmidinger M, Bellmunt J. Plethora of agents, plethora of targets, plethora of side effects in metastatic renal cell carcinoma. Cancer Treat Rev. 2010;36:416-424. 8. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 2004;4:335-348. 9. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471-484. 10. Hartford CM, Ratain MJ. Rapamycin: something old, something new, sometimes borrowed and now renewed. Clin Pharmacol Ther. 2007;82:381-388. 11. Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol. 2004;24:200-216. 12. Dancey JE. Inhibitors of the mammalian target of rapamycin. Expert Opin Investig Drugs. 2005;14:313-328. 13. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18:1926-1945. 14. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4:891-899. 15. Shaw RJ. Glucose metabolism and cancer. Curr Opin Cell Biol. 2006;18:598-608. 16. Brahimi-Horn MC, Pouysségur J. HIF at a glance. J Cell Sci. 2009;122:1055-1057. 17. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006;5:671-688. 18. Hsu T, Adereth Y, Kose N, Dammai V. Endocytic function of von Hippel-Lindau tumor suppressor protein regulates surface localization of fibroblast growth factor receptor 1 and cell motility. J Biol Chem. 2006;281:12069-12080. 19. Champion KL, Guinea M, Dammai V, Hsu T. Endothelial function of von Hippel-Lindau tumor suppressor gene: control of fibroblast growth factor receptor signaling. Cancer Res. 2008;68:4649-4657. 20. Acevedo VD, Ittmann M, Spencer DM. Paths of FGFR-driven tumorigenesis. Cell Cycle. 2009;8:580-588.

*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.