Everolimus — Drug Monograph

Brand names: Afinitor, Zortress

Drug class: Other

Mechanism of Action

Orally bioavailable rapamycin analog (rapalog) and mTORC1 (mechanistic target of rapamycin complex 1) inhibitor. Everolimus binds the intracellular receptor FKBP12 (FK506 binding protein 12); the resulting FKBP12-everolimus complex allosterically inhibits mTORC1 kinase activity, impairing phosphorylation of downstream effectors S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1). This blocks mRNA translation of cell cycle regulators, inhibits cell proliferation, induces autophagy, suppresses HIF-1α and VEGF expression (anti-angiogenic effect), and disrupts…

FDA Indications

• Advanced renal cell carcinoma (RCC) after failure of sunitinib or sorafenib — FDA approved March 2009 (RECORD-1 trial)
• Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) requiring intervention but not amenable to surgery — FDA approved October 2010
• Progressive, well-differentiated, non-functional neuroendocrine tumors of pancreatic origin (pNETs) — FDA approved May 2011 (RADIANT-3: PFS HR 0.35)
• Postmenopausal women with advanced hormone receptor-positive (HR+), HER2-negative breast cancer in combination with exemestane, after failure of letrozole or anastrozole — FDA approved July 2012 (BOLERO-2: PFS HR 0.43)
• Renal angiomyolipoma associated with TSC not requiring immediate surgery — FDA approved April 2012
• Progressive, well-differentiated, non-functional gastrointestinal or lung neuroendocrine tumors (GI-NETs, lung-NETs) — FDA approved February 2016
• Pulmonary lymphangioleiomyomatosis (LAM)

Common Side Effects

• Stomatitis/mouth sores (mTOR inhibitor stomatitis — aphthous-like ulcers, approximately 44–67%)
• Infections (upper respiratory, urinary tract)
• Fatigue
• Diarrhea
• Edema (peripheral)
• Decreased appetite/anorexia
• Nausea
• Rash
• Pneumonitis (non-infectious, ~14%)
• Hyperglycemia
• Hyperlipidemia (hypercholesterolemia, hypertriglyceridemia)
• Myelosuppression (anemia, leukopenia, thrombocytopenia)
• Elevated creatinine

Clinical Pearl

Non-infectious pneumonitis is the most clinically important and potentially underdiagnosed toxicity of everolimus (~14%) — it can occur as early as 2–3 months after initiation, is often asymptomatic on CT, and can be life-threatening if missed. Baseline and serial CT chest imaging (or prompt imaging with any new respiratory symptoms) is key. The treatment for mTOR inhibitor stomatitis is unique: dexamethasone 0.5 mg/5 mL oral rinse (swish-and-spit, NOT swallow) significantly reduces severity…

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