Everolimus: An mTOR Inhibitor

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 a central 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 also been in development to treat cancer patients both as monotherapy and in combination with a number of other anticancer agents.

In 2008, an independent data monitoring committee stopped a major Phase III clinical trial of everolimus (RAD001) after interim results showed significantly better progression-free survival in patients with advanced kidney cancer who received everolimus compared to placebo after failure with VEGFR-TKI therapy. Everolimus continues to be studied in multiple tumor types.

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 is a class effect of rapamycin derivatives, including Afinitor. Fatal outcomes have been observed. If symptoms are moderate or severe, patients should be managed with dose interruption until symptoms improve or discontinuation, respectively. Corticosteroids may be indicated. Afinitor may be reintroduced at 5 mg daily depending on the individual clinical circumstances.

Afinitor has immunosuppressive properties and may predispose patients to infections. Localized and systemic infections (bacterial and invasive fungal infections) have occurred. Some of these infections have been severe or fatal. Complete treatment of pre-existing invasive fungal infections prior to starting treatment. If a diagnosis of invasive systemic fungal infection is made, discontinue Afinitor and treat with appropriate antifungal therapy.

Oral ulcerations have occurred in patients treated with Afinitor. 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.

Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes, neutrophils and platelets have been reported in clinical trials. Renal function, hematological parameters, blood glucose, and lipids 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.

Co-administration with strong or moderate inhibitors of CYP3A4 or PgP should be avoided. Increase in the Afinitor dose is recommended when co-administered with a strong CYP3A4 inducer.

Afinitor should not be used in patients with severe hepatic impairment.

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

Fetal harm can occur if Afinitor is administered to a pregnant woman.

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 ≥3%) were infections (9%), dyspnea (8%), fatigue (5%), stomatitis (4%), dehydration (4%), pneumonitis (4%), abdominal pain (3%), and asthenia (3%). The most common laboratory abnormalities (incidence ≥50%) were anemia (92%), hypercholesterolemia (77%), hypertriglyceridemia (73%), hyperglycemia (57%), lymphopenia (51%), and increased creatinine (50%). The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (18%), hyperglycemia (16%), anemia (13%), hypophosphatemia (6%), and hypercholesterolemia (4%). Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the Afinitor arm.

Full Prescribing Information about Afinitor.

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References
  • Hartford CM, Ratain MJ. Rapamycin: something old, something new, sometimes borrowed and now renewed. Clin Pharmacol Ther. 2007;82:381-388.
  • Everolimus (RAD001) Significantly Extends Progression-Free Survival In Advanced Kidney Cancer Patients After Failure Of Other Targeted Therapy. Feb 2008. http://www.medicalnewstoday.com/articles/98948.php. Accessed September 18, 2009.