Pharmacology Update

Temsirolimus Injection (Torisel™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.

The FDA has approved the first mTOR inhibitor for the treatment of advance renal cancer. Temsirolimus is a more water soluble ester of sirolimus and the latter is the principal active metabolite. It is marketed by Wyeth Pharmaceuticals, Inc. as Torisel.

Indications

Temsirolimus is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma.1

Dosage

The recommended dose is 25 mg infused over 30-60 minutes once a week until disease progression or unacceptable toxicity. Due to the potential for hypersensitivity reactions, pre-treatment with an intravenous histamine-1 receptor antagonist (eg, diphenhydramine 25 to 50 mg) given approximately 30 minutes before the drug administration is recommended. Dosage adjustment or interruption of therapy is recommended if the absolute neutrophil count is less than 1,000 mm3, platelet count less than 75,000/mm3 or NCI Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or greater adverse reactions.1

Temsirolimus is supplied as a 25 mg/ml vial with a diluent vial.

Potential Advantages

Temsirolimus has been shown to be more effective than interferon alfa in improving overall survival.1,2 Median overall survival times and progressive-free survival were longer for temsirolimus compared to interferon alfa. In addition there were fewer serious adverse events in those treated with temsirolimus compared to interferon alfa.

Potential Disadvantages

Common adverse events (30% or higher) include rash, peripheral edema, asthenia, mucositis, nausea, anorexia, anemia, thrombocytopenia, neutropenia, hypophosphatemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, and elevated AST, serum creatinine, and alkaline phosphatase.1,2 Serious adverse events include interstitial lung disease, bowel perforation, renal failure, and intracerebral hemorrhage in patients with CNS tumors. Due to risk of abnormal healing, perioperative use of temsirolimus should be undertaken with caution. Strong CYP3A4/5 inducers and inhibitors of CYP3A4 may affect the plasma concentration of the metabolite of temsirolimus.1

Comments

Both temsirolimus and its principle metabolite, sirolimus, are inhibitors of the mammalian target of rapamycin (mTOR) kinase. The drugs are believed to act by binding to an intracellular protein (FKBP-12) that interferes with mTOR signaling, resulting in inhibition of cell growth and angiogenesis.3 Temsirolimus' efficacy was shown in an international, phase III, clinical trial of 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma.1,2 Subjects were randomized to temsirolimus (25 mg weekly), interferon alfa (3 million units three times weekly up to 18 million units three times weekly), or a combination of interferon (6 million units three times a week) and temsirolimus (15 mg weekly). Overall survival was the primary endpoint and progression free survival and overall response rate were the secondary endpoints. Median overall survivals were 10.9 months, 7.9 months, and 8.4 months respectively. The hazard ratio was 0.73 (95% CI; 0.58 to 0.92) compared to interferon alone. Combination therapy offered no benefit and may be related to greater frequency of dose delays and reductions due to higher frequency of grade 3 or 4 adverse events.2 Median progression-free survival was 5.5 months for temsirolimus compared to 3.1 months for interferon (hazard ratio, 0.66 [0.53, 0.81]). Overall response rates (8.6% and 4.8%) were not statistically different. Adverse events can be problematic as 66% of patients required one or more delays and 23% required one or more dose reductions. The cost of temsirolimus is $1441 per dose.

Clinical Implications

There are an estimated 51,190 new cases of renal cell carcinoma annually with 12,850 deaths.4 Surgical resection is the mainstay of therapy. Pharmacologic treatment (eg, interleukin-2 and interferon alfa) has resulted in limited success particularly in more advanced disease. Temsirolimus has demonstrated moderate efficacy in patients with at least three of the six predictors of short survival—serum lactate dehydrogenase level of more than 1.5 times the upper limit of normal, hemoglobin level below the lower limit of the normal range, corrected serum calcium level of more than 10 mg/dL, time from initial diagnosis to randomization of less than 1 year, Karnofsky performance score of 60 or 70, or metastases in multiple organs. Typically these patients have a median survival of 4 to 8 months. Comparative studies with other small molecules such as sunitinib and sorafenib are needed as well as the efficacy of temsirolimus in less extensive disease. Combination use with sunitinib has resulted in dose-limiting toxicity. The role of temsirolimus needs to be defined with further study. The mTOR pathway is a potential treatment option for other cancers such as non-Hodgkin's lymphoma, breast cancer, and glioblastoma multiforme.

References

1. Torisel™ Product Information. Wyeth Pharmaceuticals, Inc. May 2007.

2. Hudes G, et al. N Engl J Med. 2007;356:2271-2281.

3. Tsang CK, et al. Drug Discovery Today. 2007;12:112-124.

4. http://www.cancer.gov/cancertopics/types/kidney accessed 7/12/07.