Everolimus, combined with exemestane, is a targeted therapy for a specific form of advanced breast cancer. This treatment is for postmenopausal women with hormone receptor-positive (HR+), HER2-negative cancer that has progressed despite initial hormonal treatments. The drug combination aims to overcome resistance to hormonal therapies, extending the time before the disease worsens and offering patients more time.
Mechanism of Combined Action
This treatment leverages two drugs that work on different cellular pathways to fight cancer growth. Exemestane is an aromatase inhibitor, a type of hormone therapy. In postmenopausal women, estrogen that fuels HR+ breast cancer comes from the conversion of androgens by the aromatase enzyme. Exemestane works by inactivating this enzyme, which lowers estrogen levels and starves cancer cells of the hormone they need to grow.
Over time, cancer cells can become resistant to hormone therapy by activating other signaling routes. One of these is the PI3K/AKT/mTOR pathway, which regulates cell growth and survival. When this pathway becomes overactive, it can allow cancer cells to bypass the blockade created by aromatase inhibitors.
Everolimus is an mTOR inhibitor that targets and blocks the mTOR protein, a central component of this escape pathway. By inhibiting mTOR, everolimus shuts down this alternate growth signal and can re-sensitize cancer cells to exemestane. This dual action of starving cells of estrogen while blocking their escape route makes the combination more effective than exemestane alone.
Treatment Administration and Patient Monitoring
Everolimus and exemestane are oral medications taken at home. The standard dosage for everolimus is a 10 mg tablet taken once daily, while exemestane is a 25 mg tablet also taken once per day. Everolimus should be taken at the same time each day, with or without food, but high-fat meals should be avoided. Exemestane should be taken after a meal to aid its absorption.
If a dose of everolimus is missed, it can be taken up to 6 hours after the usual time; otherwise, the dose should be skipped and the regular schedule resumed the next day. Patients should not stop or alter their dosage without consulting their healthcare provider. This regimen continues until the disease progresses or side effects become unmanageable.
Regular medical supervision is part of the treatment plan to manage side effects. Follow-up appointments are scheduled within the first few weeks of starting therapy and may occur every four weeks for the first few months. These appointments include routine blood tests to monitor health indicators like blood counts for anemia or low platelets. Kidney, liver function, blood glucose, and cholesterol levels are also monitored.
Side Effects and Their Management
One of the most frequently reported side effects is stomatitis, which involves inflammation and sores in the mouth. This condition often appears within the first month of treatment. To manage this, patients may be advised to use a steroid-based, alcohol-free mouthwash at the start of their treatment to reduce the incidence and severity of mouth sores.
A less common but more serious side effect is non-infectious pneumonitis, an inflammation of the lungs. Patients should report any new or worsening respiratory symptoms, such as a persistent cough or shortness of breath, to their doctor immediately. If pneumonitis is suspected, treatment may be paused, and the everolimus dose may be reduced or discontinued.
Hyperglycemia, or high blood sugar, is another potential side effect because the mTOR pathway is involved in glucose metabolism. Blood sugar levels are monitored regularly, and management may include dietary adjustments or oral medications to lower blood sugar.
Other common side effects can include:
- Fatigue
- Skin rash, which can be helped with moisturizers and avoiding sun exposure
- Diarrhea, which can be managed with anti-diarrheal medications
- An increased risk of infections, so any signs like fever should be reported promptly
Clinical Efficacy
The effectiveness of adding everolimus to exemestane was established in the BOLERO-2 clinical trial. The study’s goal was to measure if the combination could extend Progression-Free Survival (PFS), the time patients lived with the disease without it worsening. The trial assigned participants to receive either everolimus with exemestane or a placebo with exemestane.
The results showed a significant benefit for the combination. Based on central radiology review, the median PFS for patients taking everolimus and exemestane was 11.0 months, compared to 4.1 months for those taking exemestane alone. This nearly seven-month improvement provided the evidence to support using this combination therapy.