Everolimus (Afinitor)

General information

Class/mechanism: mTOR kinase inhibitor; mTOR (mammalian target of rapamycin) is a serine-threonine kinase downstream of the PI3K/AKT pathway. In vitro, everolimus has been found to reduce cell proliferation, angiogenesis, and glucose uptake. Everolimus forms inhibitory complexes with mTORC1 by binding to the intracellular protein FKBP-12. Reduces activity of downstream effectors of mTOR that are involved in protein synthesis, S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E binding protein (4E-BP1). Reduces expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF-1).
Route: PO
Extravasation: n/a

• Anecdotally, taking the pill in a small amount of whipped/sour cream or putting the pill in a marshmallow may decrease the likelihood of developing stomatitis/mucositis.

For conciseness and simplicity, HemOnc.org currently will focus on treatment regimens and not list information such as: renal/hepatic dose adjustments, metabolism (including CYP450), excretion, monitoring parameters (although this will be considered for checklists), or manufacturer. Instead, for the most current information, please refer to your preferred pharmacopeias such as Micromedex, Lexicomp, UpToDate (courtesy of Lexicomp), or the prescribing information.

Diseases for which it is established (work in progress)

• Renal cell carcinoma
  • Non-clear cell renal cell carcinoma
• Subependymal giant cell astrocytoma

Diseases for which it is used

• B-cell acute lymphoblastic leukemia
• HR+ Breast cancer
• Diffuse large B-cell lymphoma
• Hodgkin lymphoma
• Mantle cell lymphoma
• Neuroendocrine tumor
• Pancreatic NET
• Peripheral T-cell lymphoma
• Thymoma
• Waldenström macroglobulinemia

Patient drug information

• Everolimus (Afinitor) package insert
• Everolimus (Afinitor) patient drug information (Chemocare)
• Everolimus (Afinitor) patient drug information (UpToDate)

History of changes in FDA indication

HR+ Breast cancer

• 2012-07-20: Approval expanded to include postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole. (Based on BOLERO-2)

Neuroendocrine tumor

• 2016-02-26: Approval expanded for the treatment of adult patients with progressive, well-differentiated non-functional, neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease. (Based on RADIANT-4)

Pancreatic NET

• 2011-05-05: Approval expanded to include progressive neuroendocrine tumors of pancreatic origin (PNET) that is unresectable, locally advanced or metastatic. (Based on RADIANT-3)

Renal cell carcinoma

• 2009-03-30: Initial approval for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. (Based on RECORD-1)

Tuberous sclerosis complex-associated renal angiomyolipoma

• 2012-04-26: Accelerated approval for adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. (Based on EXIST-2)
  • 2016-02-18: Converted to regular approval

Tuberous sclerosis complex-associated subependymal giant cell astrocytoma

• 2010-10-29: Accelerated approval for subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) who require therapeutic intervention but are not candidates for curative surgical resection. (Based on CCHMC 06-07-50)
  • 2016-01-29: Converted to regular approval for subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) who require therapeutic intervention but are not candidates for curative surgical resection. (Based on EXIST-1)

History of changes in EMA indication

• 2009-08-02: Initial marketing authorization as Afinitor.

History of changes in Health Canada indication

• 2011-06-30: Initial notice of compliance with conditions
• 2016-09-23: Conditions were met

History of changes in PMDA indication

• 2016-08-26: revised indication from "pancreatic neuroendocrine tumor" to "neuroendocrine tumor."

Also known as

• Code names: RAD001, RAD-001
• Brand names: Advacan, Afinitor, Afinitor Disperz, Certican, Everecan, EverGraf, Evermil, Evertor, Rapact, Rolimus, Votubia, Zortress