Abstract
A meta-analysis of 8 randomized clinical trials shows that patients taking mTOR inhibitors have more than twice the risk of dying of those who don't take the drugs. However, researchers say that, for the right patients, the benefits of taking an mTOR inhibitor outweigh the risks.
A meta-analysis of 8 randomized phase II and III clinical trials comparing mTOR (mammalian target of rapamycin) inhibitors to controls, involving a total of 2,990 patients, shows that patients taking mTOR inhibitors have more than twice the risk of dying of those who don't take the drugs. The analysis included both everolimus (Afinitor; Novartis) and temsirolimus (Torisel; Wyeth).
The U.S. Food and Drug Administration first approved mTOR inhibitors to treat end-stage renal cancer in 2007. Since then, they have been approved for use in patients with advanced hormone-receptor positive, HER2-negative breast cancer, neuroendocrine tumors of pancreatic origin, and other malignancies.
“In general, the benefit of getting an mTOR inhibitor outweighs the risk. However, in patients who are very sick or suffering from uncontrolled medical conditions, problems can happen,” says Toni Choueiri, MD, director of the kidney cancer center at Dana-Farber Cancer Institute (DFCI) in Boston, MA. He presented the results of his analysis at the 2013 American Society of Clinical Oncology Genitourinary Cancers Symposium held in Orlando, FL, in February.
The most common cause of death specified for patients in these trials is infection, accounting for 16% of fatalities. This finding led Choueiri to partner with DFCI's Marina Kaymackalan, PharmD, to characterize the risk of infection with mTOR inhibitors versus controls using the same 8 studies that Choueiri analyzed.
Kaymackalan found that patients had nearly twice the risk of all-grade infections and a 2.6-fold increase in high-grade infections with treatment with mTOR inhibitors. She also presented her findings at the Symposium.
Based on these findings, which echo black box warnings on everolimus about infection risks, Choueiri cautions against using mTOR inhibitors to treat patients who have an active, uncontrolled infection. He also suggests that patients taking mTOR inhibitors be screened carefully for infections and seen frequently to allow immediate intervention if an infection flares up.
Choueiri likens these considerations to those used when choosing to take baby aspirin to prevent heart attacks. “It helps people in general, but if you have an active ulcer, taking baby aspirin could be the worst thing,” he says. “Read the label.”
Choueiri's study raises questions about what other risks to consider before using mTOR inhibitors. One of the difficulties, he says, is that the cause of death is unspecified for nearly two thirds of fatal adverse events.
In 2012, Choueiri performed a similar meta-analysis investigating the risks of vascular endothelial growth factor (VEGF) inhibitors. He found that patients taking these drugs had twice the risk of dying of those not taking them. “Yes, VEGF and mTOR inhibitors are more targeted than cytotoxic chemotherapy,” he says. “But they also interfere with normal physiologic processes, so people must be careful to use them in the right clinical context.”
