General Information

Afinitor is specifically indicated for the treatment of advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.

Afinitor is supplied as a 5 mg or 10 mg tablet designed for oral administration. The recommended initial dose of the drug is 10 mg, to be taken once daily at the same time every day, either with or without food. Afinitor tablets should be swallowed whole with a glass of water; they should not be chewed or crushed.

Clinical Results

FDA Approval
FDA approval of Afinitor was based on the results of a clinical trial. This international, multicenter, randomized, double-blind study enrolled 416 subjects with metastatic renal cell carcinoma whose disease had progressed despite prior treatment with sunitinib, sorafenib, or both sequentially. The subjects received Afinitor 10 mg once daily or placebo, both in conjunction with best cupportive care. After documented radiological progression, subjects could be unblinded by the investigator: those randomized to placebo were then able to receive open-label Afinitor 10 mg daily. The primary endpoint was progression-free survival (PFS), documented using RECIST criteria. The median progression-free survival was 4.9 months for Afinitor versus 1.9 months for placebo (p<0.0001).

Ongoing Study Commitments

Novartis has agreed to conduct a trial in patients with severe hepatic impairment (Child Pugh Class C). This trial need not be conducted in patients with cancer and a single dose evaluation will be appropriate.
Final Protocol Submission: May 14, 2009
Trial Start Date: October 14, 2009
Final Report Submission: April 14, 2011

Novartis has agreed to submit the final, per-protocol overall survival analysis of protocol C2240 which was to be conducted 2 years after randomization of the last patient.
Protocol Submission: July 27, 2006
Trial Start Date: December 6, 2006
Final Report Submission: June 2010

Mechanism of Action

Afinitor is an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation and inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4E-BP), downstream effectors of mTOR, involved in protein synthesis. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.

Literature References

Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008 Aug 9;372(9637):449-56

Amato RJ, Jac J, Giessinger S, Saxena S, Willis JP A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer 2009 Mar 20

O'Donnell A, Faivre S, Burris HA 3rd, Rea D, Papadimitrakopoulou V, Shand N, Lane HA, Hazell K, Zoellner U, Kovarik JM, Brock C, Jones S, Raymond E, Judson I Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008 Apr 1;26(10):1588-95