The US Food and Drug Administration (FDA) approved everolimus (Afinitor; Novartis Pharmaceuticals Corporation) for the treatment of postmenopausal women with advanced hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole. This approval was granted on July 20, 2012. For more information about the FDA approval, see http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm313008.htm.
Background Breast cancer is the most common cancer diagnosed in women in the United States. It is the second most common cause of cancer deaths among women; only lung cancer accounts for more cancer deaths. It is estimated that 39,620 women will die of breast cancer in 2013.1 The lifetime risk for a woman to develop breast cancer is 1 in 8. In 2008, it was estimated that 2.6 million women had a history of breast cancer. Approximately two-thirds of breast cancers are estrogen and/or progesterone positive; this is associated with a favorable prognosis.2 Breast cancer mortality in patients with early-stage disease has been dramatically reduced with the use of adjuvant endocrine, with hormone therapy as the cornerstone of treatment in advanced stages.3
Although most postmenopausal women with estrogen receptor–positive breast cancer benefit from an aromatase inhibitor as first-line endocrine treatment for metastatic disease, ~30% do not respond.4 In patients with breast cancer, resistance to endocrine therapy has been found to be associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway.5 Both in vitro and in vivo studies have shown that inhibition of mTOR by everolimus reduces cell proliferation, angiogenesis, and glucose uptake.6
In July 2012, the US Food and Drug Administration approved everolimus tablets for the treatment of advanced hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer in combination with exemestane, after treatment failure with letrozole or anastrozole, in postmenopausal women. Approval was based on a randomized, double-blind, multicenter, international trial conducted in 724 postmenopausal women who had estrogen receptor–positive, HER2-negative advanced breast cancer with recurrence or progression after previous treatment with letrozole or anastrozole. Patients were randomly allocated (2:1, in favor of the everolimus/exemestane group) to everolimus 10 mg/day plus exemestane 25 mg/day (n = 485) or to placebo plus exemestane 25 mg/day (n = 239). Crossover to everolimus at the time of disease progression was not permitted. The median progression-free survival (PFS) upon final PFS analysis was 7.8 and 3.2 months in the everolimus and placebo arms, respectively.7
Table 1
Table 2
Table 3
Serious adverse events (AEs) were reported among 23% of patients in the combination-therapy group (11% attributed to study treatment) and 12% in the exemestane-alone group (1% attributed to study treatment). A higher percentage of patients discontinued everolimus in the combination-therapy group than placebo in the control group because of AEs (19% vs 4%, respectively). In the combination-therapy group, 7 deaths were attributed to AEs during treatment or within 28 days after discontinuing treatment: 2 deaths from sepsis and 1 each from pneumonia, tumor hemorrhage, cerebrovascular incident, renal failure, and suicide. In the exemestane-alone group, 1 death from pneumonia was reported during treatment.5
The most common adverse reactions in patients receiving everolimus plus exemestane were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common (≥2%) grade 3 or 4 AEs were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. Additionally, the most common (≥3%) grade 3 or 4 laboratory abnormalities were lymphopenia, hyperglycemia, anemia, decreased potassium, increased aspartate aminotransferase, increased alanine aminotransferase, and thrombocytopenia. Fatal adverse reactions occurred in 2% of patients in the combination group compared with 0.4% of patients in the placebo group. Dose interruptions or reductions were necessary in 63% of the patients receiving everolimus compared with 14% of the placebo group.7
Management of Adverse Reactions Noninfectious Pneumonitis
Noninfectious pneumonitis is a class effect of rapamycin derivatives, including everolimus. It can occur with or without signs and symptoms (pleural effusion, hypoxia, cough, dyspnea, wheezing, shortness of breath, and chest pain). Patients taking everolimus should be educated about the importance of immediately reporting any new or worsening respiratory symptoms. Fatal outcomes have been observed. If symptoms are moderate, consider interrupting everolimus therapy until symptoms improve; steroids may be indicated. Everolimus may be reintroduced at 50% of the previous dose. If symptoms are severe, reinitiation should be based on individual clinical circumstances.8
Infections Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Viral infections may include reactivation of hepatitis B. Infections may be severe, and can even lead to death. Management includes watching for signs and symptoms of infection and treating promptly. Patients should tell their healthcare provider right away if they have a temperature of ≥100.5°F, chills, or do not feel well. If infection occurs, consider interruption or discontinuation of everolimus.8
Stomatitis Mouth ulcers, stomatitis, and oral mucositis occur in patients treated with everolimus, at an incidence ranging from 44% to 86%. Grade 3 or 4 stomatitis was reported in 4% to 9% of patients. In such cases, topical treatments such as mouthwashes or mouth gels are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided. Patients should be instructed on good oral hygiene. Unless a fungal infection has been diagnosed, antifungal agents should not be used.8
Laboratory Abnormalities Laboratory abnormalities have been reported with everolimus, including electrolyte imbalances and hematologic, renal function, and glucose and lipid abnormalities. Laboratory testing should be performed prior to the initiation of therapy and periodically thereafter, and should include renal function, fasting glucose and lipid panels, and complete blood cell count. Whenever possible, optimal glucose and lipid control should be achieved before a patient starts everolimus.8
Other Nursing Considerations Everolimus is available in 2.5-, 5-, 7.5-, and 10-mg tablets. It should be taken daily at the same time of day and consistently with or without food. The tablet cannot be crushed, chewed, or broken. It should be swallowed whole with a glass of water.
The recommended dose and schedule for everolimus for this indication is 10 mg orally daily. Patients with severe or intolerable adverse reactions may require dose reduction or interruption. A missed dose can be taken up to 6 hours later. If it is past the 6 hours, the dose should be skipped until the next day. Patients should not take 2 tablets to make up for the missed dose. Each tablet is packaged in a foil-wrapped blister pack to protect it from light. The tablets should be kept in the original container and opened with scissors before taking the medication.8 Decreased effectiveness was noted when pills were taken out of the blister pack and kept in a pillbox.
Patients taking everolimus should avoid live vaccines and close contact with those who have recently been vaccinated with a live vaccine.8
Agents that inhibit cytochrome P (CYP) 3A4 (Table 1) can increase everolimus blood concentrations, whereas CYP3A4 inducers (Table 2) can decrease blood concentrations. Patients should report all medications including dietary supplements and should not start any new medications without contacting their healthcare professionals. Coadministration with strong CYP3A4 inhibitors and inducers should be avoided. When coadministering with a moderate CYP3A4 inhibitor (Table 3), dose adjustments are recommended. Everolimus should be reduced to 2.5 mg daily if coadministration is required. If the moderate inhibitor is discontinued, a washout period of approximately 2 to 3 days should be allowed before the everolimus dose is increased. If the moderate inhibitor is discontinued, the everolimus dose should be returned to the dose used prior to initiation of the moderate CYP3A4 inhibitor. Grapefruit, grapefruit juice, and other foods that are known to inhibit CYP450 and P-glycoprotein activity may increase everolimus exposure and should be avoided during treatment. An increase in everolimus is recommended if use with a strong CYP3A4 inducer is required; it should be increased from 10 mg daily up to 20 mg daily, using 5-mg increments.8
Everolimus requires insurance verification and prior authorization. Novartis, the manufacturer of Afinitor (everolimus), offers Patient Assistance NOW oncology support programs that make prescribing easier and can help with patient education, insurance verification, assistance with denial and/or appeals, copays, and out-of-pocket costs. When everolimus is prescribed, a 14-day free supply can be shipped directly to patients so they can start treatment while waiting for insurance approval. This resource can be used with new prescriptions and also with changes in dosage.
Clinical Trials With Everolimus Everolimus combined with an aromatase inhibitor has been found to improve PFS in patients with hormone receptor–positive advanced breast cancer who were previously treated with a nonsteroidal aromatase inhibitor.5 Other clinical trials are ongoing, including a study adding everolimus with letrozole, tamoxifen, and trastuzumab, and another study using letrozole and everolimus in the neoadjuvant setting.
References 1. American Cancer Society. Cancer Facts & Figures 2013. http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/cancer-facts-figures-2013. Accessed April 1, 2013. 2. American Cancer Society. Breast Cancer Facts & Figures 2011-2012. http://www.cancer.org/research/can cerfactsfigures/breastcancerfactsfigures/breast-cancer-facts-and-figures-2011-2012. Accessed April 1, 2013. 3. Paplomata E, O’Regan R. New and emerging treatments for estrogen receptor-positive breast cancer: focus on everolimus. Ther Clin Risk Manag. 2013;9:27-36. 4. Zagouri F, Sergentanis TN, Chrysikos, et al. mTOR inhibitors in breast cancer: a systematic review. Gynecol Oncol. 2012;127(3):662-672. 5. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520-529. 6. CenterWatch. Afinitor (everolimus). http://www.cen terwatch.com/drug-information/fda-approvals/drug-de tails.aspx?DrugID=1199. Accessed April 26, 2013. 7. US Food and Drug Administration. Everolimus 2012. Updated July 23, 2012. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm313008.htm. Accessed April 1, 2013. 8. Afinitor [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2012.
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