Everolimus (brand name Afinitor, formerly RAD001)

Everolimus (brand name Afinitor, formerly RAD001) from Novartis is an orally available derivative of the compound rapamycin, found over 30 years ago in soil bacteria from Easter Island (called Rapa Nui in the native language). First tried as an antifungal, it was later approved as an immunosuppressant for organ transplants, blocking the proliferation of cells that cause rejection. Later, rapamycin was found to inhibit an important kinase that was named mTOR (mammalian Target Of Rapamycin), a signal transduction molecule downstream from the KIT kinase pathway. The mTOR pathway plays a role in normal cellular growth, proliferation and survival. The hope is that some cancers dependent on an overactive mTOR pathway might respond to a safe inhibitor.

NCI drug dictionary definition:  everolimus  – A derivative of the natural macrocyclic lactone sirolimus withimmunosuppressant and anti-angiogenic properties. In cells, everolimus binds to the immunophilin FK Binding Protein-12 (FKBP-12) to generate an immunosuppressive complex that binds to and inhibits the activation of the mammalian Target of Rapamycin (mTOR), a key regulatory kinase. Inhibition of mTOR activation results in the inhibition of T lymphocyte activation and proliferation associated with antigen and cytokine (IL-2, IL-4, and IL-15) stimulation and the inhibition of antibody production.
Information at manufacturer website: Novartis – Afinitor 
More recently, for Gastrointestinal Stromal Tumor (GIST) resistant to the KIT inhibitor Gleevec, the idea of trying Gleevec in combination with RAD001 to further block of the downstream mTOR kinase pathway was proposed for clinical trial investigation.


Available results using everolimus against GIST

Everolimus in combination with Gleevec for advanced GIST patients was studied in a small clinical trial in Belgium by Dr. Allan van Oosterom. Initial Phase I data were presented at the 2004 ASCO Annual Meeting.

Initial results did not show significant effectiveness; however, shortly after the 2004 ASCO meeting Dr. Charles Blanke responded: “Dr. Allan van Oosterom presented data on RAD001, which theoretically is a very attractive drug that plays well with imatinib preclinically. He only presented Phase I data, and, as you would expect from a Phase I trial, there were no response data. But we also believe that the drug was not given in the most optimal fashion, and that if it were given daily, there would be more of an angiogenic effect. I do hope to see a benefit in the Phase II portion of the studies. All we can say right now is that it remains a promising drug but there is no way to say if it will work yet.”

Schöffski P, Reichardt P, Blay JY, Dumez H, Morgan JA, Ray-Coquard I, Hollaender N, Jappe A, Demetri GD.
A phase I-II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors.
Ann Oncol. 2010 Oct;21(10):1990-8. PubMed PMID:

In patients who had shown progression on imatinib and on sunitinib or another TKI, the combination of everolimus 2.5 mg/day plus imatinib 600 mg/day, results showed 2% had partial response, 43% stable disease, and 32% progressive disease (remaining 23% unevaluable).
Pantaleo MA, Nicoletti G, Nanni C, Gnocchi C, Landuzzi L, Quarta C, Boschi S,  Nannini M, Di Battista M, Castellucci P, Fanti S, Lollini PL, Bellan E, Castelli M, Rubello D, Biasco G.
Preclinical evaluation of KIT/PDGFRA and mTOR inhibitors in gastrointestinal stromal tumors using small animal FDG PET.
J Exp Clin Cancer Res. 2010 Dec 30;29:173. PubMed PMID: 21192792; PubMed Central PMCID: PMC3022678.  free access


Clinical Trials with everolimus

U.S. Clinical Trials information for other (currently, non-GIST) everolimus trials may be found at: