On July 20, 2012, the U.S. Food and Drug Administration approved everolimus tablets (Afinitor, Novartis Pharmaceuticals Corporation) for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole.

 The approval was based on a randomized, double-blind, multicenter trial conducted in 724 postmenopausal women with estrogen receptor-positive, HER2-negative, advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole.

Patients were randomly allocated (2:1) to everolimus 10 mg/day plus exemestane 25 mg/day (n=485) or to placebo plus exemestane 25 mg/day (n=239). Patients were not permitted to cross over to everolimus at the time of disease progression. 

The median progression-free survival (PFS) by investigator assessment at the time of the final PFS analysis was 7.8 and 3.2 months in the everolimus and placebo arms, respectively [HR 0.45 (95% CI: 0.38, 0.54), p < 0.0001].

The results of the PFS analysis based on independent central radiological assessment were consistent with the investigator assessment. PFS results were also consistent across the subgroups of age, race, presence and extent of visceral metastases, and sensitivity to prior hormonal therapy. 

The objective response rates were 12.6% and 1.7% in the everolimus and placebo arms, respectively. An interim analysis of overall survival (OS) conducted at 46% of expected events was not statistically significant [HR=0.77 (95% CI: 0.57, 1.04)]. The final analysis of OS is expected to occur in June 2014. 

Safety was evaluated in 720 patients enrolled in the randomized trial. The most common grade 1-4 adverse reactions (incidence ≥ 30%) in patients receiving everolimus plus exemestane were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3-4 adverse reactions (≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common grade 3-4 laboratory abnormalities (≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia.

Fatal adverse reactions occurred in 2% of patients on the everolimus arm compared to 0.4% of patients on the placebo arm. Adverse reactions resulting in permanent discontinuation occurred in 24% and 5% of patients in the everolimus and placebo arms, respectively. Dose interruptions or reductions were necessary in 63% of patients on the everolimus arm compared to 14% on the placebo arm.

Forty percent of patients on the everolimus arm were ≥ 65 years of age and 15% were ≥ 75 years of age. No overall differences in effectiveness were observed between elderly and younger patients. The incidence of deaths due to any cause within 28 days of the last everolimus dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% of patients < 65 years of age.

The recommended dose and schedule for everolimus for this indication is 10 mg orally each day. Patients with severe or intolerable adverse reactions may require dose reduction or interruption.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022334s016lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Source: FDA