The phase III BOLERO-2 trial enrolled 724 postmenopausal women with HR-positive metastatic breast cancer who had progressed on a nonsteroidal aromatase inhibitor (AI), such as anastrozole or letrozole. The median progression-free survival (PFS) was 11.0 months for patients receiving everolimus and exemestane compared to 4.1 months for those taking exemestane alone. The 4.1-month median PFS in this study was similar to other trials examining single-agent exemestane, notes Adam M. Brufsky, MD, PhD.

Everolimus targets the resistance mechanism that allows for progression on AIs, notes Denise A. Yardley, MD. However, despite the knowledge that the agent acts in the PI3K/AKT/mTOR pathway, a biomarker for response has yet to be discovered. When balancing side effects and benefits, the lack of a biomarker can make it difficult to select therapy, Yardley notes.

The results of the BOLERO-2 trial were surprising, since a similar study with the mTOR inhibitor temsirolimus in combination with letrozole was unsuccessful, notes Brufsky. This trial, labeled HORIZON, examined the combination as a first-line therapy. The particular mechanism that allows mTOR inhibition to be successful may not occur until resistance to a nonsteroidal AI is acquired, Mark D. Pegram, MD, suggests. To explore this further, the phase II BOLERO-4 trial is examining everolimus plus letrozole as first-line therapy in ER-positive, HER2-negative metastatic breast cancer, adds Hope S. Rugo, MD.

A leading concern with the administration of everolimus is stomatitis, which can occur in up to 40% of patients, notes Joyce A. O’Shaughnessy, MD. To treat this symptom, O’Shaughnessy recommends a steroid mouth rinse that includes 20 mg of hydrocortisone. To explore this approach further, a clinical trial will compared dexamethasone 0.5mg in 5 cc of mouthwash with 20-mg hydrocortisone in 10 cc of mouthwash for 6 to 8 weeks following the initiation of treatment with everolimus.