Temsirolimus: A Review of its Use in the Treatment of Advanced Renal Cell Carcinoma

Abstract

Abstract:The mTOR (mammalian target of rapamycin) signaling pathway was discovered during studies of the immunosuppressive agent rapamycin. This pathway regulates cell growth, protein synthesis and angiogenesis in response to environmental factors. The mTOR complex-1 inhibitor temsirolimus was derived from rapamycin to have less immunosuppressive and improved solubility characteristics. The safety, tolerability and effi cacy of temsirolimus have been well established in clinical trials. Drug related toxicity included rash, mucositis, asthenia, nausea, hyperglycemia, hypophosphatemia, anemia, and hypertriglyceridemia. An active and well-tolerated single agent dose is 25 mg i.v. weekly. A large Phase III trial in poor-prognosis patients with metastatic renal cancer compared i.v weekly temsirolimus administration to subcutaneous interferon alpha (IFNα), or a combination of temsirolimus plus IFNα. This study established that median overall survival was improved to 10.9 months in the temsirolimus group compared to 7.3 months in IFNα-treated group (0.73 hazard ratio for death; 95% confi dence interval [CI], 0.58 to 0.92; P = 0.008). A modest objective response rate of 8.6%, 4.8%, and 8.1%, respectively was observed in the three groups, associated with a median time to treatment failure of 3.8 months for temsirolimus alone, 1.9 months for IFNα, and 2.5 months for the combination. These results led to approval of temsirolimus for the treatment of renal cancer in the United States. Temsirolimus is clearly indicated for fi rst-line therapy of Motzer "poor risk" renal cancer and aggressive non-clear cell renal cancer. Temsirolimus may be useful after failure of VEGF tyrosine kinase inhibitors. Clinical activity in other tumor types, such as endometrial cancer has been observed. Temsirolimus is therefore an important new agent for cancer treatment.

PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond

“…Temsirolimus (CCI-779) is the first generation of mTOR inhibitors created by Wyeth Pharmaceuticals that bind to FKBP12 to prevent mTORC1 activity. It was approved by the FDA in May 2007 for the treatment of renal cell carcinoma [218]. Currently, it is being tested in phase I trials for advanced solid tumors and GC [219].…”