Enasidenib (ENA) is a selective inhibitor of isocitrate dehydrogenase (IDH2). The efficacy of ENA monotherapy (ENAm) in patients aged ≥60 years with newly diagnosed IDH2mut acute myeloid leukemia (AML) and subsequent response-driven addition of azacitidine (AZA) treatment was assessed in the phase 2 expansion and phase 1b of the Beat AML Master Trial.
This study was initiated with a 3-outcome, 2-stage, phase 2 design that enrolled patients for ≤5 cycles of ENAm. Patients not achieving complete response (CR) or CR with incomplete hematologic recovery (CRi) following 5 cycles of ENAm, or exhibiting disease progression, or intolerance at any time were transferred to phase 1b and received ENA + AZA. Patients included in this study had newly diagnosed IDH2mut AML, were aged ≥60 years, and had an Eastern Cooperative Oncology Group performance status of 0 to 2. In phase 2, patients were administered ENAm 100 mg daily in continuous 28-day cycles. In phase 1b, patients were administered ENA + AZA (75 mg/m2 on days 1-7 every 28 days). Response was assessed using the 2017 European LeukemiaNet AML criteria. The primary end point was CR/CRi rate.
A total of 60 patients were enrolled, treated with ENAm, and evaluable for the primary end point at data cutoff on June 18, 2020. The median age was 75 years (range, 60-89 years), and 52% were female. The median time receiving ENAm was 4.7 months. At data cutoff, 12 patients were still receiving treatment with ENAm. The most common reasons for treatment discontinuation were treatment failure (38%), disease progression (12%), and adverse events (AEs) (10%). Five (8%) patients moved on to allogeneic stem-cell transplantation (allo-SCT). A total of 28 (47%) patients achieved CR/CRi (adjusted 95% confidence interval [CI], 34-60). Higher response rates were observed among patients with IDH2R140 mutation (55%) compared with patients with IDH2R172 mutation (25%; P = .04). After a median follow-up of 14.6 months, the median overall survival (mOS) was 24.4 months (95% CI, 10.6-not evaluable). The median duration of response (DOR) was not reached, with a landmark 12-month DOR rate estimate of 57% (95% CI, 34-75). A total of 20 treatment-related serious adverse events (SAEs) were reported in 15 patients. The most common SAE was differentiation syndrome (21.7%) and 2 patients had tumor lysis syndrome. The most common AEs (occurring in ≥20% of patients) of any grade were nausea, anemia, and low potassium (56.7%, 51.7%, and 48.3%, respectively).
A total of 17 patients had inadequate response to ENAm and were transferred to phase 1b and received ENA + AZA. The median time on treatment (including ENAm) was 6.2 months. After starting ENA + AZA, the median time on treatment was 2.1 months. Treatment failure (29%), disease progression (12%), allo-SCT, death, and AEs (each 12%) were the most common reasons for discontinuing treatment. The CR/CRi rate was 41% (exact 95% CI, 18-67). After a median follow-up of 12.7 months from the start of the ENA + AZA combination, the mOS was 8.9 months. Four SAEs determined to be related to ENA occurred in 3 patients. The most common was 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, low albumin, and vomiting (43.8%, 37.5%, and 37.5%, respectively).
Among newly diagnosed patients with IDH2mut AML, treatment with ENA was associated with a low early death rate, a high CR/CRi rate, and yielded durable remissions. The most common ENA-related toxicity reported was differentiation syndrome. In patients not achieving CR/CRi with ENAm, a subset attained CR/CRi with the addition of AZA. For patients with a suboptimal response to ENAm, the addition of AZA resulted in an mOS of >2 years.
Reference
Abstract 635. ASH 2020. December 7, 2020. 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.