Everolimus is a phosphatidylinositol 3-kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR) inhibitor. Upregulation of the PI3K-mTOR pathway has been found to be a mechanism of resistance to endocrine therapies for women with estrogen-positive breast cancer. Evidence for an interaction between the mTOR pathway and estrogen-receptor signaling has been shown.
Impetus for the large-scale BOLERO-2 trial came from results of two phase II trials—a neoadjuvant trial that showed a high response rate and a hormone-receptor–positive HER2-negative trial published in the Journal of Clinical Oncology.[1,2]
The 12-month results of the BOLERO-2 phase III trial (published in the New England Journal of Medicine in February), showed a median progression-free survival of 10.6 months for the experimental group compared to 4.1 months for the placebo group (P < .001). No overall survival results were reported at the time.
In a subanalysis of patients older than 65, the combination of everolimus plus exemestane(Drug information on exemestane) improved progression-free survival in this patient population (hazard ration = 0.56). Elderly patients did not have more frequent high-grade adverse events compared with the general population.
“Overall, tolerance was fairly similar to the younger [patient] population—particularly in terms of risk of stomatitis,” said Dr. Rugo.
“The addition of everolimus to exemestane improved bone turnover and delayed progression specifically in bone,” said Dr. Rugo. As bone metastases are frequent in advanced breast cancer, the BOLERO-2 trial also analyzed differences in bone metastasis frequency, finding that disease progression in the bone was lower for the everolimus arm compared to the placebo arm, 3.03% vs 6.16%, respectively. This trend continued longer than 6 months. The authors conclude that everolimus is beneficial for deterring bone metastasis in this breast cancer patient population.
“I believe that the use of everolimus in combination with exemestane will become more common now that the drug is approved by the FDA, and as clinicians become more comfortable with using the drug and managing toxicity,” said Dr. Rugo, who added that if toxicity is well managed, the value of the improved progression-free survival can be substantial.
Everolimus is also being investigated for other breast cancer populations—advanced HER2-positive disease in combination with trastuzumab(Drug information on trastuzumab) and chemotherapy, and for hormone-receptor positive disease, including as adjuvant and post-neoadjuvant treatment.
A major goal for investigators is to identify biomarkers that will predict which patients will respond to therapy with mTOR inhibitors and other agents that target the PI3K pathway. “Combinations of inhibitors of this and related pathways are under intense study,” Dr. Rugo emphasized.
1. Baselga, et al. Phase II Randomized Study of Neoadjuvant Everolimus Plus Letrozole(Drug information on letrozole) Compared With Placebo Plus Letrozole in Patients With Estrogen Receptor–Positive Breast Cancer. J Clin Oncol. 2009;27:2630-2637.
2. Bachelot, et al. Randomized Phase II Trial of Everolimus in Combination With Tamoxifen(Drug information on tamoxifen) in Patients With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer With Prior Exposure to Aromatase Inhibitors: A GINECO Study. J Clin Oncol. 2012;30: 2718-2724.