Alterations to genes involved in cellular metabolism and regulation of gene expression have been implicated in the pathogenesis of myeloid malignancies. Recurrent mutations in isocitrate dehydrogenase 2 (mIDH2) genes are detected in approximately 12% of patients with acute myeloid leukemia (AML). Mutant IDH2 proteins catalyze formation of the metabolite 2-hydroxyglutarate, causing DNA and histone hypermethylation and blocked myeloid differentiation.
Enasidenib (AG-221), an oral, selective, small-molecule inhibitor of the mIDH2 protein, was evaluated in a phase 1/2 study conducted to assess maximum tolerated dose (MTD), pharmacokinetic (PK) and pharmacodynamic (PD) profiles, safety, and clinical activity in patients with mIDH2 myeloid malignancies. In the study, 239 patients received enasidenib. In the dose-escalation phase (n = 113), MTD was not reached at doses up to 650 mg daily. Median age was 67 years, and 51% of patients were male.
Enasidenib 100 mg once daily was chosen for the expansion phase (n = 126) based on efficacy and PK/PD profiles. The overall response rate was 40.3% (n = 71), including 19.3% (n = 34) with complete remissions (CRs). Response was associated with cellular differentiation; in most cases, there was no evidence of aplasia. Median overall survival (OS) was 9.3 months. For patients who attained CRs, OS was 19.7 months, compared with 13.7 months for those with non-CRs and 7.0 months for nonresponders. Median time to first response was 1.9 months, and researchers noted that responses deepened over time. Grade 3 and 4 adverse events occurring at a rate of more than 5% included hyperbilirubinemia (12%) and thrombocytopenia (6%).
The researchers concluded that enasidenib was well-tolerated, induced durable CRs, and improved OS in patients who had failed prior AML therapies. Unlike with cytotoxic chemotherapy, patients may require several cycles of treatment before responding to enasidenib, and responses can improve over time with continued treatment.
Stein EM, et al. ASCO Abstract 7004.