Enasidenib Approved for AML, but Best Uses Unclear

The FDA has approved enasidenib (Idhifa; Celgene/Agios) for patients who have relapsed or refractory acute myeloid leukemia (AML) and carry IDH2 mutations. The drug provides a new treatment option for the disease, researchers say, but the optimal way to use it and the reason it doesn't work in many eligible patients remain to be determined.

Enasidenib is the first targeted therapy for patients with refractory or relapsed AML, whose 5-year survival rate ranges from 5% to 10%. The phase I/II trial that led to the drug's approval reported objective responses in 40.3% of 176 patients and a median overall survival of 9.3 months. The single-arm study did not compare the drug to any other treatments. IDH2 mutations occur in about 12% of patients with AML; to identify these people, the FDA also approved a companion diagnostic, the RealTime IDH2 Assay (Abbott Laboratories).

Oncologists will be eager to prescribe the drug, says Mark Levis, MD, PhD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, MD. He enrolled patients in the enasidenib trial and says he's seen the drug produce remissions. “When it works, it's extraordinary,” he says, noting that it might allow some patients to avoid a bone marrow transplant.

Michael Savona, MD, of Vanderbilt University Medical Center in Nashville, TN, also finds the drug's performance impressive. “There's little doubt that this provides added benefit to patients with the marker.” He says that enasidenib offers “a quality of life improvement” because responding patients are less dependent on transfusions.

However, the FDA's decision surprised Elihu Estey, MD, of Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine in Seattle. “It's unprecedented for the FDA to approve a drug based just on an amount [of evidence] like this without a comparison [group],” he says. Estey notes that the trial found complete remissions in 19.3% of patients, but certain chemotherapy regimens can produce complete remissions in more than 60% of patients.

Savona acknowledges that the trial did not establish a survival benefit, but says that “signals of response may later translate to survival benefit in acute leukemia, and response often leads to hematologic improvement, and that is important.” He and Levis agree that the FDA approved the drug with less supporting evidence than usual, but both support the decision.

Enasidenib's clinical role is uncertain, however, because of questions about which patients will benefit. “Unfortunately, it only works in one in five patients, and we don't know why,” says Levis. He notes that researchers might pinpoint additional mutations to help identify likely responders.

Whether the drug could serve as a first-line treatment and whether it can be part of combination therapies are also open questions. “We need to learn how to use the drug and how to maximize its benefits,” says Levis. Some of that work has already begun. A trial is now testing the combination of enasidenib and a chemotherapy regimen as a first-line therapy for AML. –Mitch Leslie