Enasidenib Shows Strong Activity in AML

Eytan M. Stein, MD

Results from a phase I/II study demonstrated that enasidenib (AG-221) is well-tolerated and associated with a median overall survival (OS) of more than 9 months in patients with IDH2-mutated relapsed/refractory acute myeloid leukemia (AML).

For 176 patients receiving 50 mg to 650 mg daily of enasidenib, the overall response rate (ORR) was 40.3% (95% CI, 33-48), with a 19.3% (95% CI, 13.8-25.9) rate of complete remission (CR). The CR with incomplete hematologic recovery (CRi) rate was 6.8%. Response was associated with cellular differentiation, typically with no evidence of aplasia. Median OS was 9.3 months overall, and 19.7 months for patients who had attained a CR.

“Enasidenib induces durable complete remissions. It’s associated with a median overall survival of slightly over 9 months in this patient population with relapsed and refractory AML, the majority of whom have very poor-risk disease,” said Eytan M. Stein, MD, a hematologic oncologist with Memorial Sloan-Kettering Cancer Center. He presented results from the 2-part study (dose escalation and dose expansion) during the 2017 ASCO Annual Meeting.

IDH2 proteins synthesize an oncometabolite, 2-hydroxyglutarate (2HG), causing DNA and histone hypermethylation and blocked myeloid differentiation. Enasidenib is an oral, selective, small-molecule inhibitor of the mutated IDH2 protein.

Stein presented data for 176 relapsed/refractory patients (median age, 67) who were enrolled in either the dose escalation phase or 1 of the 2 relapsed/refractory cohorts from the dose expansion phase. Overall, the dose expansion phase consisted of 4 cohorts: relapsed/refractory AML patients aged ≥60, or any age if relapsed after bone marrow transplant (BMT); relapsed/refractory AML patients aged <60, excluding patients who relapsed after BMT; treatment-naïve patients with AML aged ≥60; patients with any hematologic malignancy who did not qualify for the first 3 arms.

Among a subgroup of patients who received enasidenib at 100 mg daily (n = 109), the ORR was 38.5% (95% CI, 29.4-48.3), with a 20.2% CR rate (95% CI, 13.1-28.9). The rate of CRi was 6.4%.

The median time to first response across all doses was 1.9 months. The median time to CR was 3.8 months and the median duration of response was 5.8 months. Stein said physicians need patience when treating individuals with enasidenib.

“For a patient that one might have on the drug, it is important to keep them on the drug for a prolonged period of time so that they have the opportunity to have that response,” Stein said. “Unlike cytotoxic chemotherapy, responses to enasidenib may require several treatment cycles and responses can improve over time with continued treatment.”

Grade 3/4 drug-related adverse events occurring in ≥5% of patients included hyperbilirubinemia (12%), thrombocytopenia (6%), and anemia (5%).

Earlier results from this study were presented at the 2015 ASH Annual Meeting and used to support a new drug application (NDA) for enasidenib. At the time, enasidenib was associated with a 41% ORR in patients with relapsed or refractory IDH2-mutant AML. CR rate was 18% and 1.6% of patients had a CR with incomplete platelet recovery or CRi. Additionally, 6% of patients had a marrow CR.

The FDA granted a priority review for the NDA earlier this year, meaning the agency will issue a ruling in 6 months rather than the customary 10. Under the Prescription Drug User Fee Act, the FDA is scheduled to decide by August 30.

An ongoing phase II study, which has now been completely accrued, is examining enasidenib at 100 mg daily in patients with relapsed/refractory AML.

Steyn EM, Dinardo DC, Pollyea DA, et al. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia (R/R AML): Results of a phase I dose-escalation and expansion study. J Clin Oncol 35, 2017 (suppl; abstr 7004).