The first clinical trial of the investigational drug enasidenib, which targets IDH2 mutations, suggests that it is safe and may improve survival in patients with relapsed or refractory acute myeloid leukemia. It induced responses in 40.3% of patients, yielding a median overall survival of 9.3 months.

Promising efficacy and safety data from the first phase I/II trial of enasidenib (Idhifa; Celgene/Agios) suggest that the drug could be an option for the 12% of patients with acute myeloid leukemia (AML) with IDH2 mutations.

IDH2 mutations spur the synthesis of 2-HG, a metabolite that prevents myeloid cells from differentiating and drives the development of the cancer. In preclinical studies, enasidenib reduced 2-HG levels by more than 90%, allowing leukemia cell differentiation.

The trial, performed by Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, and colleagues, included 176 patients who had relapsed or refractory AML or who were ineligible for chemotherapy. The researchers found that 40.3% of these individuals showed an objective response to enasidenib, and 19.3% experienced complete remissions. The median overall survival (OS) was 19.7 months for patients who had complete remissions and 14.4 months for patients with partial remissions; for the entire cohort, median OS was 9.3 months. Patients with relapsed or refractory AML typically live for only a few months, so this result “is a huge leap forward for these patients,” says Stein. A companion study from the same trial suggests that the drug promoted leukemia cell differentiation.

The researchers assessed enasidenib's safety in 239 patients, including the 176 patients in the efficacy portion of the trial, with either AML or myelodysplastic syndromes, which can progress to AML. The most common grade 3 or 4 treatment-related side effect was hyperbilirubinemia, the accumulation of bilirubin in the blood due to red blood cell breakdown. Although hyperbilirubinemia can signal liver toxicity, the patients did not show elevated levels of the liver enzymes ALT or AST, says Stein.

After hyperbilirubinemia, the most prevalent grade 3 or 4 adverse effect was IDH inhibitor–associated differentiation syndrome, a response to the differentiation of large numbers of immature cells that can cause fever, edema, and other problems. The syndrome occurred in 7% of the patients who had grade 3 or 4 adverse effects and may have triggered two deaths. Stein notes that only 5% of patients stopped treatment because of adverse effects.

“The results unequivocally support further exploration of the drug due to the very manageable side effect profile and auspicious efficacy data,” says Joshua Sasine, MD, of the University of California, Los Angeles, who wasn't connected to the research. “Enasidenib will be practice-changing for patients with IDH2-mutant AML and will have a large impact if it is approved,” adds Hetty Carraway, MD, of the Cleveland Clinic in Ohio.

One issue that requires exploration, notes Ravi Majeti, MD, PhD, of Stanford University in California, is why the amount of 2-HG reduction didn't correlate with the clinical response. “IDH2 mutations may be subclonal” or not present in every leukemia cell, he says.

Further trials of enasidenib are under way, and others are being planned. A phase III trial that will compare the drug to chemotherapy in patients with relapsed or refractory AML has started. A phase I and a phase II trial, both in development, will assess its potential as a first-line treatment. –Mitch Leslie