Renal cell carcinoma sunitinib treatment

Everolimus (40 Afinitor Novartis, 2009), a rapamycin analog, is the 42-0-(2-hydroxyethyl) derivative of sirolimus (34), and is marketed as an immunosuppressant by Novartis under the tradename Afinitor for use in advanced renal cell carcinoma.In March 2009, the FDA approved everolimus (40) for use against advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. The drug works similarly to sirolimus as an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, downstream of the PI3K/AKT pathway. Everolimus (40) binds to an intracellular protein, EKBP-12, resulting in an inhibitory... 

Sunitinib (7),10 developed by Sugene/Pfizer, was approved in 2006 for the treatment of renal cell carcinoma (RCC). It is a VEGFR kinase inhibitor that slows down the angiogenesis of tumor endothelial cells, which provide nutrients and help tumor growth and metastasis. Sunitinib also blocks KIT, an oncogenic kinase that causes gastrointestinal stromal cell tumors. It was approved as a second-line anti-GSIT therapy for imatinib-resistant patients. 

In summary, sunitinib maleate (1) is a multitargeted receptor tyrosine kinase inhibitor with potent anti-angiogenic and antitumor activity. It is approved for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors, and is currently undergoing clinical trials for a number of additional malignancies. The discovery synthesis of 1 along with its process development approaches were described in this chapter. 

Goodman VL, Rock EP, Dagher R, et al. Approval summary Sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007 13(5) 1367-1373. 

Flaig TW, Costa LJ, Gustafson DL, Breaker K, Schultz MK, Crighton F, Kim FJ, Drabkin H. Safety and efficacy of the combination of erlotinib and sirolimus for the treatment of metastatic renal cell carcinoma after failure of sunitinib or sorafenib. Br J Cancer 2010 103(6) 796-801. 

Sunitinib (Sutent ) is also an orally available multi-targeted TKI. Especially in renal cell carcinoma and in gastrointestinal stroma tumors (GIST), sunitinib proved to be superior to earlier therapy strategies and is now established as first-line treatment. 

Sorafenib and sunitinib are both approved for the treatment of renal cell carcinoma. A clinical phase III trial studying sunitinib compared to sorafenib or placebo in treating patients with kidney cancer that has... 

Another Raf kinase inhibitor, sunitinib (Sutent), was approved in 2006 based on a multi-center, international randomized trial enrolling 750 patients with treatment-naive metastatic renal cell carcinoma (Motzer et al. 2007). In that study, patients were randomized to receive either Sutent or interferon-a (IFN-a). Common metastatic sites included lung, lymph nodes, bone, and liver. There were 96 events (25.6%) of progression/death on Sutent compared with 154 events (41.1%) on IFN-a. Median progression-free survival was 47.3 weeks for Sutent-treated patients and 22.0 weeks for patients treated with IFN. Objective response rate on the Sutent arm was 27.5 vs 5.3% on IFN-a arm. 

---