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Temsirolimus: gateway into a new era
Agent first to affect survival in patients with poor-prognosis metastatic renal cell carcinoma.
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For the past two decades, significant progress in our understanding of the molecular basis of cancer has introduced several novel anticancer agents to clinical practice. From such efforts, temsirolimus emerged, rapidly gaining regulatory approval for the management of advanced renal cell carcinoma.
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Temsirolimus (Torisel, Wyeth) belongs to a novel drug class known as mTOR (mammalian target of rapamycin) inhibitors. mTOR kinase is a key component in the intracellular signaling pathways leading to cell proliferation and survival. Inhibition of mTOR can lead to cell cycle arrest, apoptosis and anti-angiogenesis. Temsirolimus is the first mTOR inhibitor approved by the FDA for cancer therapy. More importantly, it is the first molecularly targeted agent to affect survival in patients with metastatic RCC with poor prognostic features.
Recognizing the role mTOR plays in cellular proliferation, survival and angiogenesis, mTOR inhibitors have been investigated in oncology for many years. Rapamycin, the prototype of this class, has long been investigated without clinical success due to its poor solubility and short stability. It was not until the 1990s that structural modifications of rapamycin launched a series of analogs with more favorable features. Temsirolimus is an ester analogue of rapamycin with comparable potency and specificity for mTOR but with a longer stability and increased solubility.
Temsirolimus is progressively converted into rapamycin after IV administration. Thus, its antitumor activity is actually a combined effect of the parent drug and its active metabolite, rapamycin. These compounds exert their action by first binding to the cytoplasmic protein, FK506 binding protein-12 (FKBP 12), forming a drug-protein complex. The resulting complex interacts with mTOR and inhibits its functions.
Temsirolimus has demonstrated broad-spectrum antitumor activity against various malignancies such as prostate cancer, endometrial cancer, breast cancer and mantle cell lymphoma. To date, the most promising role of this agent lies in the treatment of advanced RCC.
Management of advanced RCC has changed dramatically in the last several years. Other recently approved targeted agents do improve quality of life and prolong time to progression, but none have yet to positively affect survival.
Early phase-2 data in advanced RCC suggest that temsirolimus is most effective in the subset of patients with unfavorable prognostic characteristics. As a result, a landmark phase-3 trial was conducted in untreated patients with RCC and three or more poor-risk features. Of note, both clear cell and nonclear cell histology were included.
In this study, 626 patients with poor-risk, advanced RCC were randomly assigned in a 1:1:1 ratio to three arms: 1) IFN
up to 18 million units subcutaneously three times weekly, 2) temsirolimus 25 mg IV weekly and 3) IFN 6 million units three times weekly plus temsirolimus 15 mg IV weekly. The primary outcome was median overall survival with either temsirolimus-containing regimens compared with interferon alone.
Single agent temsirolimus was shown to significantly improve median survival when compared with IFN alone (10.9 months vs. 7.3 months; P=.008). The combination arm failed to show a survival advantage when compared with IFN alone (8.4 months vs. 7.3 months, P=.7). Grade-3 or grade-4 adverse events occurred in 67% of patients in the temsirolimus group, 78% in the IFN group and 87% of patients in the combination group. Dose reductions were least common in the single-agent temsirolimus arm.
Pharmacokinetics and dosing
Temsirolimus exhibits nonlinear pharmacokinetics and has a large volume of distribution with extensive and saturable partitioning into red blood cells that contain abundant FKBP 12. Conversion of the parent compound to rapamycin occurs shortly after drug infusion via enzymatic hydrolysis. The mean half-life of temsirolimus is 17 hours, and the mean half-life of rapamycin is 55 hours. Temsirolimus is predominantly excreted in feces. The renal route accounts for only 4% of drug elimination.
Both temsirolimus and rapamycin are metabolized primarily by cytochrome P450 3A4 (CYP3A4). Because temsirolimus is primarily hydrolyzed to rapamycin, CYP3A4 inhibitors and inducers have little effect on the area under the concentration vs. the time curve (AUC) of the parent drug, temsirolimus. Strong CYP3A4 inducers or inhibitors do affect rapamycin AUC (Table 1). In human liver microsomes, temsirolimus inhibits CYP2D6 and CYP3A4, but no clinically significant drug interactions have been observed as a result of this inhibition.
Dose escalation trials with temsirolimus in patients with solid tumors identified a wide range of safe and effective doses for temsirolimus extending from 15 mg/m2 to 220 mg/m2 weekly. Further pharmacokinetic simulation models using body surface area–normalized dosing demonstrated negligible variability in systemic exposure. Therefore, a fixed-dose strategy was employed for subsequent studies.
Temsirolimus is commercially available as an IV formulation while its oral dosage form is still being investigated. The recommended dose for advanced renal cell carcinoma is 25 mg IV for 30 minutes to 60 minutes once a week until disease progression or intolerable adverse effects.
Premedication with an H1-antagonist is necessary to prevent infusion-related hypersensitivity reactions. Commonly, a single dose of diphenhydramine 25 mg to 50 mg IV is used as premedication.
Dosage adjustments
Temsirolimus should be held for grade-3 or higher nonhematologic toxicities or if the absolute neutrophil count is less than 1,000/mm3 or platelet count less than 75,000/mm3. Future dosing can be reduced as indicated by an increment of 5 mg per week to the minimum effective dose of 15 mg weekly.
It is recommended to empirically adjust temsirolimus dosage when used concomitantly with strong CYP3A4 inducers or inhibitors (Table 1). In the presence of enzyme inducers, temsirolimus dose should be increased to 50 mg/week. On the other hand, temsirolimus dose should be reduced to 12.5 mg/week when given with strong CYP3A4 inhibitors. However, this recommendation is based solely on pharmacokinetic studies and has not been validated in clinical trials. Individual circumstances should be evaluated independently and dosages chosen based on best clinical judgment.
Results from pharmacokinetic studies suggest the need for dose adjustment in patients with mild to moderate liver dysfunction. However, specific guidelines for dose adjustment are not available due to the lack of significant clinical data in this patient population. No dosage modification is necessary in renal dysfunction. However, temsirolimus has not been studied in patients on dialysis.
Adverse events
Nausea, mucositis, maculopapular rash, asthenia, myelosuppression, elevated serum creatinine and abnormal liver function tests are among the most common toxicities seen with temsirolimus (Table 2). Metabolic disturbances such as hyperlipidemia, hyperglycemia and hypertriglyceridemia are also prevalent, confirming mTOR roles in glucose and lipid regulation. Fortunately, these adverse effects are transient and reversible with drug interruption or supportive treatments.
Hypersensitivity reactions, manifested as dyspnea, flushing, chest pain and anaphylaxis, occurred in about 10% of patients despite standard premedication with diphenhydramine. This adverse effect is attributed to polysorbate-80 and/or propylene glycol, the vehicles used to solubilize temsirolimus. Prior to initiating temsirolimus infusion, it is crucial to have an anaphylactic kit available at the bedside for timely administration according to an established anaphylactic management protocol. If the patient does have a hypersensitivity reaction with the first infusion, prolonging the infusion time to 60 minutes and adding an H2 receptor antagonist to the premedication regimen are recommended with subsequent infusions.
Rashes, usually maculopapular in appearance, generally occur within the first few weeks of treatment and present as 5-cm to 10-cm lesions on the face and neck. An acne-like rash with an erythematous base has also been seen and appears most commonly on the face and upper trunk region. Although no specific preventative or management strategies have proven beneficial, topical steroids have been used with variable effectiveness.
Life-threatening interstitial lung disease has rarely been reported. The course of this complication can be unpredictable, however. Some patients were asymptomatic while others presented with progressive symptoms requiring drug discontinuation and/or the use of steroids and empiric antibiotics.
Temsirolimus is a promising addition to the anticancer drug armamentarium. Indeed, it is the first molecularly targeted agent to show significant survival benefit for advanced renal cell carcinoma patients with poor prognostic characteristics. The next challenge will be defining the role of temsirolimus in other clinical subsets and in combination therapy. With its broad spectrum of antitumor activity and favorable safety profile, it will provide a fertile ground for clinical trials in other malignancies as well. Continued investigation identifying molecular markers predicting resistance to mTOR inhibitors is another area of important research.
For more information:
- Thanh-Tam Bui, PharmD, is a clinical pharmacist and Laura Boehnke Michaud, PharmD, is a manager of clinical pharmacy services at The University of Texas M.D. Anderson Cancer Center.
- Cho D, Signoretti S, Regan M, et al. The role of mammalian target of rapamycin inhibitors in the treatment of advanced renal cancer. Clin Cancer Res. 2007;13:758s-763s.
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- Atkins MB, Hidalgo M, Stadler WM, 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;22:909-918.
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