An oral abstract at the ASH Annual Meeting & Exposition presented the first interim outcomes from a randomized, phase 2 portion of an ongoing, open-label, phase 1/2 study of enasidenib (ENA) + azacitidine (AZA) vs AZA monotherapy (AZA-only) in patients with isocitrate dehydrogenase 2 (mIDH2) newly diagnosed acute myeloid leukemia (ND-AML) who are not candidates for intensive chemotherapy (IC) (NCT02677922).

Mutations in IDH2 occur in 8%-19% of patients with AML. ENA (AG-221) is an oral, small-molecule inhibitor of mIDH2 that promotes myeloid cell differentiation. ENA is approved in the United States for use in adult patients with relapsed/refractory mIDH2 AML. AZA is a hypomethylating agent that prolongs survival vs conventional care regimens in older unfit patients with ND AML. AZA promotes DNA hypomethylation by inhibiting DNA methyltransferases. ENA indirectly reduces DNA methylation by suppressing the oncometabolite, 2-hydroxyglutarate (2-HG), thereby restoring function to α-ketoglutarate-dependent TET family enzymes, among other substrates. In vitro, combination ENA + AZA enhances cell differentiation.

For the study, adult patients with mIDH2 ND-AML who were ineligible to receive IC and had ECOG PS scores ≤2 were randomized in a 2:1 ratio to receive ENA + AZA or AZA-only in repeated 28-day cycles. All patients receive SC AZA 75 mg/m2/day for the first 7 days of each treatment (Tx) cycle; patients randomized to ENA + AZA also receive continuous ENA 100 mg QD.

The primary endpoint is overall response rate (ORR), which includes complete remission (CR), CR with incomplete blood or platelet count recovery (CRi/CRp), partial remission (PR), and morphologic leukemia-free state (MLFS), per modified IWG 2003 AML response criteria. P values for response comparisons between Tx arms were derived using chi-square test. Duration of response (DOR) was estimated by Kaplan-Meier method. mIDH2 variant allele frequencies (VAF) in bone marrow mononuclear cells (BMMCs) were assessed by digital PCR.

Between October. 2016 and August 2018, 101 patients were randomized to receive ENA + AZA (n=68) or AZA-only (n=33). Median ages of patients were 74 years (range 62–85) in the ENA + AZA arm and 75 years (57–85) in the AZA-only arm. 

Among patients with available data, 78% in the ENA + AZA arm (43/55) and 90% (19/21) in the AZA-only arm had intermediate-risk cytogenetics, respectively, and 18% and 10% had poor-risk cytogenetics. At data cutoff (February 2019), 39 patients were still receiving their randomized Tx. Most common reasons for study discontinuation in the ENA + AZA and AZA-only arms were death (31% and 27%, respectively) and patient decision (4% and 12%). Two patients in the ENA + AZA arm and 1 pt in the AZA-only arm proceeded to transplant. Median number of Tx cycles was 8 (range 1–24) in the ENA + AZA arm and 6 (1–22) in the AZA-only arm; 27% and 19% of patients, respectively, received ≥12 Tx cycles.

Response rates were significantly higher with combination treatment vs AZA alone: ORRs were 68% vs 42%, respectively (P=.0155), and CR rates were 50% vs 12% (P=.0002). Median DOR was not reached with ENA + AZA and was 10.2 months in the AZA-only arm (P=.13). Maximal mIDH2 VAF suppression from baseline was significantly greater with ENA + AZA vs AZA-only (median –69.3% vs –14.1%, respectively; P=.0004).

In summary, presenters found that ENA + AZA was associated with significantly improved CR and ORRs and significant mIDH2 VAF reductions compared with AZA-only. Combination Tx was generally well tolerated, with a safety profile similar to that reported for either monotherapy. —Amanda Del Signore

DiNardo CD, Schuh AC, Stein EM, et al. Enasidenib Plus Azacitidine Significantly Improves Complete Remission and Overall Response Compared with Azacitidine Alone in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) with Isocitrate Dehydrogenase 2 (IDH2) Mutations: Interim Phase II Results from an Ongoing, Randomized Study. Presented at: the 2019 ASH Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 643.