From Australian Prescriber:
Temsirolimus
Torisel (Wyeth)
vials containing 25 mg/mL concentrate
Approved indication: advanced renal cell carcinoma
Australian Medicines Handbook section 14.2.3About 30% of patients with renal cell carcinoma have advanced or metastatic disease at the time of diagnosis. Chemotherapy is generally ineffective and nephrectomy is the mainstay of treatment for disease confined to the kidney. Treatment with drugs such as interferon alfa, interleukin-2 and the tyrosine kinase inhibitors sunitinib and sorafenib may benefit some patients.1
Temsirolimus is a kinase inhibitor derived from sirolimus (rapamycin) (see Aust Prescr 2002;25:97-9). It works by inhibiting the action of an enzyme called ‘mammalian target of rapamycin’ or mTOR. Inhibition prevents the division of cancerous cells, slowing the growth and spread of the cancer.
Following intravenous administration, temsirolimus is extensively metabolised by CYP3A4, with the main metabolite being sirolimus. The half-life is 17 hours for temsirolimus and 55 hours for sirolimus. Metabolites are primarily eliminated in the faeces.
The efficacy of temsirolimus in advanced renal cell carcinoma was first assessed in a dose escalation trial of 111 previously treated patients. After a weekly dose of 25, 75 or 250 mg (for a median of 5.6 months), 7% of the patients had a complete or partial response to temsirolimus, but this was not dose-dependent.2 In a larger trial of 626 previously untreated patients, median overall survival was longer in patients treated with temsirolimus (25 mg each week) than those treated with interferon alfa (10.9 months vs 7.3 months). Adding interferon alfa to temsirolimus did not improve the overall survival time and was associated with more serious adverse events than temsirolimus alone.3
In the trials, rash, fatigue, mucositis, nausea, oedema, anaemia and anorexia were common adverse events in patients receiving temsirolimus. The most frequent laboratory test abnormalities were hyperglycaemia, hypercholesterolaemia, hyperlipidaemia, hypophosphataemia, thrombocytopenia, leucopenia and elevated alkaline phosphatase, serum creatinine and aspartate aminotransferase.2,3
Approximately 5% of the participants in the larger trial had a hypersensitivity reaction to temsirolimus so patients should be given intravenous antihistamine approximately 30 minutes before temsirolimus is administered. If a hypersensitivity reaction develops, the temsirolimus infusion should be stopped.
Cases of interstitial lung disease have occurred in patients taking temsirolimus and patients should be advised to seek medical attention if they develop worsening respiratory symptoms. Other rare but serious adverse events that have been reported include fatal bowel perforation and renal failure. Patients with central nervous system tumours and/or taking anticoagulants may have an increased risk of intracerebral bleeding.
Immunosuppression may occur with temsirolimus, so be vigilant for infections. Also, live vaccines and contact with people who have recently had them should be avoided. Temsirolimus may delay wound healing and should not be given to patients in the peri-surgical period.
Drugs that induce or inhibit the CYP3A4 enzyme should be avoided in patients taking temsirolimus. Concomitant use of sunitinib can result in dose-limiting toxicities such as serious maculopapular rash and gout or cellulitis requiring hospitalisation. Angioneurotic oedema-type reactions have been observed in patients who were receiving temsirolimus concomitantly with an angiotensin converting enzyme inhibitor. Some patients on temsirolimus and interferon alfa have developed cataracts.
Temsirolimus provides another option for patients with advanced renal cell carcinoma. However, its relative efficacy compared to tyrosine kinase inhibitors is not known.
manufacturer provided clinical evaluation
References*†
1. Pavlakis N. Drug treatment of renal cancer. Aust Prescr 2006;29:151-3.
2. Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004;22:909-18.
3. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271-81.
Source: Australian Prescriber. New drugs: temsirolimus. Volume 31 Number 4- August 2008