The phase 2 expansion and phase 1b of the Beat AML Master Trial (phase 2/1b substudy) assessed the efficacy of enasidenib (ENA), a selective inhibitor of isocitrate dehydrogenase (IDH2), monotherapy (ENAm) in patients aged ≥60 years with newly diagnosed IDH2mut acute myeloid leukemia (AML), and subsequent response-driven addition of azacitidine (AZA) treatment.
This study began with a 3-outcome, 2-stage phase 2 design that enrolled patients for up to 5 cycles of ENAm. Patients were transferred to phase 1b, in which they received ENA + AZA if they achieved complete response (CR) or CR with incomplete hematologic recovery (CRi) following 5 cycles of ENAm, or exhibited disease progression or intolerance at any time. Patients were eligible for this study if they had newly diagnosed IDH2mut AML; were aged ≥60 years; and had an Eastern Cooperative Oncology Group performance status of 0 to 2. Patients received ENAm 100 mg daily in continuous 28-day cycles in phase 2 and ENA + AZA (75 mg/m2 on days 1-7 every 28 days) in phase 1b. The 2017 European LeukemiaNet AML criteria were used to assess response. The primary end point was CR/CRi rate.
At data cutoff on June 18, 2020, 60 patients were enrolled, had received ENAm, and were evaluable for the primary end point. The median age was 75 years (range, 60-89 years), and approximately half (52%) of patients were female. Median time receiving ENAm was 4.7 months. Twelve patients were still receiving ENAm treatment at data cutoff. The most common reasons for treatment discontinuation were treatment failure (no response to treatment, 38%), disease progression (loss of response to treatment, 12%) and adverse events (AEs; 10%). Five (8%) patients received an allogeneic stem-cell transplant (allo-SCT). A total of 28 patients achieved CR/CRi (47%; adjusted 95% confidence interval [CI], 34-60). Responses were higher in patients with IDH2R140 mutation (55%) than in those with IDH2R172 mutation (25%; P = .04). The median overall survival (mOS) was 24.4 months (95% CI, 10.6-not evaluable) after a median follow-up of 14.6 months. The median duration of response (DOR) was not reached, with a landmark 12-month DOR rate estimate of 57% (95% CI, 34-75). Overall, 20 treatment-related serious adverse events (SAEs) occurred in 15 patients, the most common being differentiation syndrome (21.7%). Two patients had tumor lysis syndrome. The most common AEs (in ≥20% of patients) of any grade were nausea (56.7%), anemia (51.7%), and low potassium (48.3%).
A total of 17 patients had inadequate response to ENAm and moved to phase 1b, in which they received ENA + AZA. Including ENAm, for these patients, the median time on treatment was 6.2 months. Median time on treatment after starting ENA + AZA was 2.1 months. The most common reasons for treatment discontinuation were treatment failure (29%), disease progression (12%), allo-SCT, death, and AEs (each 12%). The CR/CRi rate was 41% (exact 95% CI, 18-67). The mOS was 8.9 months after a median follow-up of 12.7 months from start of the ENA + AZA combination. Four ENA-related SAEs occurred in 3 patients, the most common being differentiation syndrome (16.7%). One dose-limiting toxicity (grade 3 nausea) related to both treatments was observed. The most common AEs (≥20% of patients) of any grade were anemia (43.8%), low albumin (37.5%), and vomiting (37.5%).
In conclusion, treatment with ENA among newly diagnosed patients with IDH2mut AML was associated with low early death rate and high CR/CRi rate and yielded durable remissions. Differentiation syndrome was the most common unique toxicity. A subset of patients who did not achieve CR/CRi with ENAm achieved CR/CRi with the addition of AZA. Monotherapy with ENA followed by the addition of AZA in patients with suboptimal response resulted in an mOS of more than 2 years.
Stein EM, Huang Y, Borate U, et al. Enasidenib (ENA) Monotherapy with Addition of Azacitidine in Non-Responders Is Effective in Older Patients with Newly Diagnosed IDH2 Mutated Acute Myeloid Leukemia (AML): A Completed Phase 2/1b Sub-Study of the Beat AML Master Trial. Presented at: 62nd American Society of Hematology Annual Meeting & Exposition, December 5-8, 2020. Abstract 635.