Article

Global ARCC Trial. Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma

Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
New England Journal of Medicine (Impact Factor: 55.87). 05/2007; 356(22):2271-81. DOI: 10.1056/NEJMoa066838
Source: PubMed

ABSTRACT

Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease.
In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group.
Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patients who received interferon alone. Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P=0.70). Median overall survival times in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group (P=0.02).
As compared with interferon alfa, temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis. The addition of temsirolimus to interferon did not improve survival. (ClinicalTrials.gov number, NCT00065468 [ClinicalTrials.gov].).

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Available from: Anil Kapoor, Feb 18, 2014
    • "Hyperglycaemia is well established as an important mechanismbased toxicity associated with mTORi, which has led to development of guidelines for its effective management (Busaidy et al, 2012). In patients treated with everolimus and temsirolimus in large phase III clinical trials, incidence of all-grade hyperglycaemia ranged between 12 and 50% with 4–22% of high-grade (G3–G4; Hudes et al, 2007; Motzer et al, 2008; Verges et al, 2014). A recent meta-analysis studying toxicities of allosteric mTORi showed an increased risk of hyperglycaemia, all-grade by 2.95-fold (95% CI, 2.14, 4.05) and high-grade by 5.25-fold (95% CI, 3.07, 9.00) (Sivendran et al, 2014). "
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    ABSTRACT: Background: PI3K-AKT-mTOR inhibitors (PAMi) are promising anticancer treatments. Hyperglycaemia is a mechanism-based toxicity of these agents and is becoming increasingly important with their use in larger numbers of patients. Methods: Retrospective case-control study comparing incidence and severity of hyperglycaemia (all grades) between a case group of 387 patients treated on 18 phase I clinical trials with PAMi (78 patients with PI3Ki, 138 with mTORi, 144 with AKTi and 27 with PI3K/mTORi) and a control group of 109 patients treated on 10 phase I clinical trials with agents not directly targeting the PAM pathway. Diabetic patients were excluded in both groups. Results: The incidence of hyperglycaemia was not significantly different between cases and controls (86.6% vs 80.7%, respectively, P=0.129). However, high grade (grade 3-4) hyperglycaemia was more frequent in the PAMi group than in controls (6.7% vs 0%, respectively, P=0.005). The incidence of grade 3-4 hyperglycaemia was greater with AKT and multikinase inhibitors compared with other PAMi (P<0.001). All patients with high-grade hyperglycaemia received antihyperglycemic treatment and none developed severe metabolic complications (diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic state). High-grade hyperglycaemia was the cause of permanent PAMi discontinuation in nine patients. Conclusions: PI3K-AKT-mTOR inhibitors are associated with small (6.7%) but statistically significant increased risk of high-grade hyperglycaemia compared with non-PAM targeting agents. However, PAMi-induced hyperglycaemia was not found to be associated with severe metabolic complications in this non-diabetic population of patients with advanced cancers.British Journal of Cancer advance online publication, 10 November 2015; doi:10.1038/bjc.2015.373 www.bjcancer.com.
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    • "). Over the past decade, the US Food and Drug Administration has approved several drugs targeting vascular endothelial growth factor and mammalian target of rapamycin pathways, including sorafenib (Escudier et al, 2007a), sunitinib (Motzer et al, 2007), bevacizumab (Escudier et al, 2007b), temsirolimus (Hudes et al, 2007), everolimus (Motzer et al, 2010), pazopanib (Sternberg et al, 2013), and axitinib (Motzer et al, 2013). These drugs have shown better clinical outcomes than the traditional therapies, but most cancers exhibit drug resistance within a year on drug and the drugs have significant side effects (Harada et al, 2013). "
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