How Everolimus (Afinitor) Works

Everolimus (Afinitor, made by Novartis Pharmaceuticals) is an oral compound cancer treatment, and classified as a signal transduction inhibitor — specifically, an inhibitor of the mTOR protein that controls other proteins known to trigger tumor growth.  The drug is currently approved for the treatment of  certain types of breast cancer, pancreatic cancer, gastrointestinal cancer, lung cancer, renal cell carcinoma, subependymal giant cell astrocytoma, as well as transplant rejection (brand name, Zortress), and its use for other types of cancer is under investigation.

According to the National Cancer Institute (NCI)’s Drug Dictionary, everolimus is a “derivative of the natural macrocyclic lactone sirolimus with immunosuppressant and anti-angiogenic properties. In cells, everolimus binds to the immunophilin FK Binding Protein-12 (FKBP-12) to generate an immunosuppressive complex that binds to and inhibits the activation of the mammalian Target of Rapamycin (mTOR), a key regulatory kinase. Inhibition of mTOR activation results in the inhibition of T lymphocyte activation and proliferation associated with antigen and cytokine (IL-2, IL-4, and IL-15) stimulation and the inhibition of antibody production.” By inhibiting the protein mTOR’s activation, everolimus interferes with the process of division and reproduction of the cancer cells to stop or slow cancer growth.

Everolimus (Afinitor) for Breast Cancer

Everolimus was first approved by the U.S. Food and Drug Administration (FDA) in March 2009 for adult patients with advanced renal cell carcinoma (RCC), whose disease is resistant to sunitinib or sorafenib. On July 20, 2012, the FDA approved its use to also treat postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after a lack of response to treatment with letrozole or anastrozole. The recommended dosage is 10 mg orally each day, and everolimus is provided in the form of tablets.

The drug’s approval was based a randomized and double-blind, multicenter clinical trial in 724 postmenopausal women with estrogen receptor-positive, HER2-negative, advanced breast cancer. “The median progression-free survival (PFS) by investigator assessment at the time of the final PFS analysis was 7.8 months for patients receiving everolimus and 3.2 months for patients receiving placebo,” states the NCI. “The objective response rates were 12.6 percent in patients receiving everolimus and 1.7 percent in patients receiving placebo.” The same study also identified adverse reactions related to treatment with everolimus. At least 30% of the patients experienced stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. Other, less common, side effects included lymphopenia, hyperglycemia, anemia, decreased potassium, and thrombocytopenia.

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