Better outcomes adding enasidenib to azacitidine in mIDH2-AML

Updated results from the randomised phase 2 portion of the AG-221-AML-005 study showed that the combination of enasidenib and azacitidine had better outcomes than azacitidine alone in IDH2-mutant, newly diagnosed acute myeloid leukaemia (AML) patients who were not eligible for intensive chemotherapy.

Dr Courtney Di Nardo (MD Anderson Cancer Centre, USA) presented the results. Enasidenib is a small-molecule inhibitor of the mutant IDH2 protein, present in a subset of AMLs, and it has been hypothesised that it might be synergistic with azacitidine.

A total of 101 patients (median age, 75 years) were enrolled and randomised to combination therapy (n=68) or azacitidine monotherapy (n=33). All patients received azacitidine subcutaneously at 75 mg/m² for 7 days of each 28-day cycle. Patients in the combination therapy arm received oral enasidenib at 100 mg once daily throughout the study. The median number of treatment cycles was 10 (range 1-26) in the combination therapy arm and 6 (range 1-28) in the azacitidine monotherapy arm. A total of 7 patients in the azacitidine monotherapy arm crossed-over to receive subsequent treatment with enasidenib. The primary endpoint of this portion of the trial was overall response rate (ORR). Key secondary endpoints included duration of response (DOR), overall survival (OS), and event-free survival (EFS).

The primary endpoint was met; ORR was 48% in the combination therapy arm compared with 14% with azacitidine monotherapy. However, the secondary endpoint of median OS was not met; both of the treatment arms had a median OS of 22 months (HR 0.99; 95% CI 0.52-1.87; P=0.97), which may be attributable to the fact that most patients from the azacitidine monotherapy arm received enasidinib after they left the study. Despite a numerical difference, median EFS was also not met: 17.2 months in the combination arm versus 10.8 months for azacitidine monotherapy (HR 0.59; 95% CI 0.30-1.17; P=0.13).

The most common treatment-related grade 3-4 adverse events (AEs) with enasidenib plus azacitidine were thrombocytopenia (37% vs 19% with azacitidine monotherapy), neutropenia (35% vs 22%, respectively), anaemia (19% vs 22%, respectively), and febrile neutropenia (15% vs 16%, respectively). Grade 3-4 infections were reported in 18% and 31% of patients in each arm, respectively. The most common reason for treatment discontinuation was disease progression.

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   1. DiNardo C, et al. Enasidenib plus azacitidine significantly improves complete remission and overall response rates versus azacitidine monotherapy in mutant-IDH2 newly diagnosed acute myeloid leukemia (ND-AML). EHA25 Virtual, 11-21 June 2020, Abstract S139.

Posted on 9 September 202023 February 2021