Everolimus: An mTOR Inhibitor

Please see Important Safety Information.

Everolimus is the only oral inhibitor of mTOR, approved by the FDA, for the treatment of patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. In kidney cancer cells, everolimus inhibits mTOR,* a protein that acts as an important regulator of tumor cell division, cell metabolism and blood vessel growth. Due to these potential positive properties, it should be considered as a treatment option after VEGFR-TKI therapy treatments fail.

In the 1970s a bacterial strain, Streptomyces hygroscopicus, was isolated from a soil sample from Easter Island (known as Rapa Nui in the local language). This bacteria was found to produce an antifungal metabolite. The purified metabolite was a macrocyclic lactone, named rapamycin in honor of its place of discovery.1

Further research into rapamycin characterized its immunosuppressive properties and its ability to inhibit proliferation of mammalian cells. These discoveries prompted investigation of the mode of action of rapamycin.1

This led to discovery of the target of rapamycin (TOR), which was originally identified by its mutations, TOR1-1 and TOR2-1. These confer resistance to the growth inhibitory properties of rapamycin.1

Since November 2002, everolimus has been in development to treat cancer patients.

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

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Reference
  • Hartford CM, Ratain MJ. Rapamycin: something old, something new, sometimes borrowed and now renewed. Clin Pharmacol Ther. 2007;82:381-388.

AFINITOR is indicated for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.

Important Safety Information

AFINITOR 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%).

Please see full Prescribing Information for AFINITOR.