Enasidenib in mutant-IDH2 R/R AML

Recurrent mutations in the isocitrate dehydrogenase 2 (IDH2) gene occur in approximately 12% of Acute Myeloid Leukemia (AML) patients. Isocitrate Dehydrogenase (IDH) enzymes catalyze the conversion of isocitrate to α-Ketoglutarate (αKG). However, mutations in IDH1/2 lead to a reverse reaction of αKG to the oncometabolite 2-Hydroxyglutarate (2HG) which can induce hematopoietic differentiation block.

In a phase I/II dose escalation and expansion study (NCT01915498), the safety, clinical activity, Maximum Tolerated Dose (MTD), and pharmacodynamic profile of enasidenib (AG-221), a first in class, oral, selective inhibitor of mutations in IDH2, in patients with mutant IDH2 advanced hematologic malignancies including those with Relapsed or Refractory (R/R) AML was investigated by Eytan M. Stein, from the Memorial Sloan Kettering Cancer Center, and colleagues. The results of the study were published ahead of print in Blood on 6^th June 2017.¹

In total, 239 patients (median age = 70 years) with advanced hematologic malignancies and IDH2 mutation were enrolled in the study. 176 patients (median age = 67 years) had R/R AML.

The MTD of enasidenib was not reached at doses up to 650 mg daily. The dose escalation phase of this study was followed by an expansion phase comprising four cohorts including two cohorts with patients with R/R AML patients. The key results obtained from the cohorts of R/R AML patients were:

• Overall Response Rate (ORR) in all R/R AML patients (n = 176); 40.3%
• Complete Remission (CR) rate in all R/R AML patients; 34%
• Median Overall Survival (OS) in all R/R AML patients; 9.3 months
• Median OS in R/R AML patients that achieved Complete Remission and patients that did not achieve CR were 19.7 and 7.0 months respectively
• Grade 3–4 drug-related investigator reported AEs included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (7%)
• Analysis of bone marrow aspirates from responders to enasidenib showed reduced myeloblasts with an increase in mature myeloid forms with normal immunophenotype

Enasidenib was “well-tolerated, induced hematologic responses and was associated with a median survival of over 9 months” in mutant IDH2 R/R AML patients.

Conversely, the mechanisms of action of enasidenib in R/R AML patients was further investigated by Michael D. Amatangelo and colleagues. Samples of R/R AML patients treated in this phase I/II study were analyzed in other to identify response biomarkers to enasidenib targeted therapy.²

The key results were:

• Treatment with enasidenib was associated with a potent reduction of 2-HG in mutant IDH2 R/R AML patient samples (n = 125)
• Enasidenib treatment lead to a near normalization of the immature to mature cell population in patients in CR compared to non-responders
• Seventeen co-occurring mutations were observed in ≥ 5% of patients including NRAS, DNMT3A, ASXL1, RUNX1, SRSF2 and BCOR
• Patients who achieved a response to enasidenib had significantly fewer co-occurring mutation compared to non-responders; P < 0.001

In summation, enasidenib inhibits mIDH2, which can lead to leukemic cell differentiation. Additionally, co-occurring mutations are significantly associated with poor response rate to mutant IDH2 inhibition by enasidenib.

Amantangelo et al., noted that, “although, the enasidenib responses are durable, the genetic heterogeneity” observed in the R/R AML patients suggests that combination therapy “may be required to achieve long term disease remission in more patients”.

The results of this phase I/II study were presented at the recently concluded 2017 American Society of Clinical Oncology (ASCO) annual meeting.

The AML Global Portal interviewed Associate Professor Tapan M. Kadia, M.D  from The University of Texas MD Anderson Cancer Center, who commented on this study of enasidenib in R/R AML. He highlighted that the “responses seen with single agent enasidenib in R/R AML patients were durable, tolerable and evolve over time”.

Abstract

Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ~12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, leading to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human, phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients (N=239) and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML (n=176), from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50-650 mg daily. Enasidenib 100 mg daily was selected for the expansion phase based on pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3-4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (IDH-DS; 7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission was 19.7 months. Continuous daily enasidenib treatment was generally well-tolerated and induced hematologic responses in patients who had failed prior AML therapy. Inducing differentiation of myeloblasts, not cytotoxicity, appears to drive the clinical efficacy of enasidenib.