Risk of serious infection with mTOR inhibitors everolimus and temsirolimus in the treatment of cancer: A meta-analysis of randomized controlled trials.

2604 Background: Everolimus and temsirolimus are inhibitors of mammalian target of rapamycin (mTOR), and utilized in the treatment of a variety of cancers. The use of mTOR inhibitors is associated with serious infections. This meta-analysis of randomized controlled trials (RCTs) was conducted to determine the overall risk of infection with mTOR inhibitors in cancer patients. Methods: Databases from PubMed and abstracts presented at the American Society of Clinical Oncology annual meetings up to October 2013 were searched for relevant studies. Eligible studies included randomized controlled clinical trials in which everolimus or temsirolimus was compared to controls in cancer patients. Data on all-grade and high-grade (grade 3 and 4) infections were extracted from the safety profiles of each clinical trial. Incidence and relative risk (RR) were calculated using random- or fixed-effects models. Results: A total of 10 RCTs with 3,535 patients (mTOR 1,911, controls 1,624) of various tumors were included in the analysis. The incidence of all-grade and high-grade infections were 21.0% (95% CI 15.0-28.9%) and 4.0% (95% CI: 2.2-7.0%), respectively. In comparison with controls, mTOR inhibitors significantly increased the risk for developing all-grade (RR: 1.82, 95% CI: 1.08-3.08, P=0.03), and high-grade infections (RR: 2.86, 95% CI: P<0.001). The increased risk of high-grade infection was observed for both everolimus (RR: 3.91, 95% CI: 1.67- 9.13, P=0.002) and temsirolimus (RR: 2.42, 95% CI: 1.30-4.50, P=0.005). However, the increased risk did not vary significantly with different mTOR inhibitors (everolimus vs temsirolimus: P=0.37) and among different tumor types (P=0.47). There was also no significant difference between mTOR inhibitors alone and their combination with other agents (P=0.68). Conclusions: The mTOR inhibitors everolimus and temsirolimus are associated with a significantly increased risk of high-grade infections in cancer patients. Further studies are needed to identify the risk factors for high-grade infection.