FATAL AEs WITH mTOR INHIBITORS 

NEW YORK (Reuters Health) May 20 - The risk of fatal adverse events (FAEs) is slightly but significantly elevated in patients treated with mammalian target of rapamycin (mTOR) inhibitors, a new meta-analysis shows.
"As this class of drugs gains greater clinical use, practitioners must be aware of the risks associated with their use and provide rigorous continuous monitoring, especially since the initial recognition of serious adverse events can occur several years after a drug receives FDA approval," Dr. Toni K. Choueiri of the Dana-Farber Cancer Institute in Boston and colleagues state in their report.
Nevertheless, they add, the clinical benefits of these drugs when given to patients with "clear FDA-approved indications" outweigh the risk of FAEs.
At present there are two FDA-approved drugs that selectively target mTOR, according to the authors; those are everolimus (Afinitor, Novartis) and temsirolimus (Torisel, Pfizer). As Dr. Choueiri and colleagues noted in a paper online May 8th in Annals of Oncology, side effects linked to the drugs include metabolic changes, gastrointestinal disturbances, and pneumonitis.
To investigate the risk of FAEs associated with the drugs, the researchers looked at eight randomized controlled trials including 3,293 patients (2,236 from everolimus studies and 957 from temsirolimus trials).
The collective risk of FAEs in the mTOR inhibitor arms was 3.2%, vs 1.2% for the placebo/control arms. Overall, compared to the control group, the mTOR inhibitor group had a relative risk of FAEs of 2.20 (p=0.006).
There was no difference between everolimus and temsirolimus in FAE rate, nor was there a difference in FAEs based on tumor type.
Three studies did not include details on the cause of death in suspected FAEs, and these deaths accounted for 61.4% of FAEs included in the meta-analysis. The leading reported causes of deaths were sepsis or infection (15.7%). Acute renal failure accounted for 5.7% of deaths, while 3% were attributed to cardiac arrest or myocardial infarction.
"In this study, the large percentage of reported FAEs that were not assigned a specific cause raise concern," Dr. Choueiri and colleagues note.
"The way that adverse events are reported in clinical trials is I would say fairly non-uniform, and particularly with assigning a patient death on a study there is some subjectivity there," Dr. Benjamin Gartrell, director of genitourinary oncology at the Montefiore Einstein Center for Cancer Care in New York City, told Reuters Health. Dr. Gartrell did not participate in the new study.

And, he added, the causes of FAEs that were reported did not correspond well with the "well-described and understood side effect profile of mTOR inhibitors."
The lack of information on cause of death limits the ability of physicians to act on the findings, Dr. Gartrell said, but the results underscore the importance of carefully following patients treated with relatively new drugs.
"These drugs that we've become comfortable with do have toxicities that we need to be closely monitoring for," he said. "We need to be paying attention to the side effects and trying to minimize their impact on the patient's well being."
SOURCE: http://bit.ly/12NFPFm
Ann Oncol 2013.