Enasidenib Does Not Improve OS Over Conventional Care in IDH2-Mutated AML

By Cecilia Brown - Last Updated: January 17, 2023

A phase III trial of enasidenib in patients with IDH2-mutated acute myeloid leukemia (AML) failed to meet its primary endpoint of improving overall survival (OS) over conventional care regimens, but provided “meaningful benefits” in other areas, according to the investigators.

Stéphane de Botton, MD, PhD, of the Gustave Roussy Institute in Paris, France, and colleagues conducted the open-label, randomized trial and published its results in Blood.

The study included 319 patients with late-stage IDH2-mutated AML who were at least 60 years old. The median patient age was 71 years. All patients were relapsed or refractory to two or three prior lines of AML-directed therapies. Patients were initially preselected to receive a conventional care regimen of azacitidine, intermediate-dose cytarabine, low-dose cytarabine, or supportive care. The researchers then randomized patients 1:1 to receive enasidenib 100 mg daily (n=158) or a conventional care regimen (n=161).

The median duration of enasidenib exposure was 142 days and the median duration of conventional care regimen exposure was 36 days. In the enasidenib arm of the study, one patient (0.6%) did not receive randomized treatment, while 20 patients (12%) in the conventional care regimen arm did not receive randomized treatment. Around one-third (30%) of patients randomized to receive enasidenib and 43% of those randomized to receive a conventional care regimen received a subsequent therapy for AML during follow-up.

The primary endpoint was OS, with secondary endpoints including event-free survival (EFS), time to treatment failure, overall response rate (ORR), hematologic improvement, and transfusion independence.

There was no significant difference in the median OS between patients receiving enasidenib (6.5 months) and those receiving conventional care regimens (6.2 months; P=.23). The one-year survival rate was 37.5% in patients receiving enasidenib, while it was 26.1% in those receiving conventional care regimens.

However, patients who received enasidenib had significant improvements in EFS, with a median EFS of 4.9 months, nearly double that of those receiving conventional care regimens (2.6 months; P=.008). The median time to treatment failure was also significantly longer in patients receiving enasidenib (4.9 months) compared with those receiving conventional care regimens (1.9 months; P<.001).

The ORR was also significantly higher in patients receiving enasidenib (40.5%) than in those receiving conventional care regimens (9.9%; P<.001). Hematologic improvement rates were 42.4% in patients receiving enasidenib, around four times higher than the rate of 11.2% in those receiving conventional care regimens. Red blood cell transfusion independence rates were also higher in those receiving enasidenib (31.7%) than in those receiving conventional care regimens (9.3%).

The safety profile of enasidenib safety was “consistent with prior reports,” according to the study’s authors.

“The primary study endpoint was not met, but OS was confounded by early dropout and subsequent AML-directed therapies,” Dr. de Botton and colleagues concluded. “Enasidenib provided meaningful benefits in EFS, [time to treatment failure], ORR, [hematologic improvement], and [red blood cell transfusion independence] in this heavily pretreated older mutant-IDH2 [relapsed/refractory] AML population.”


De Botton S, Montesinos P, Schuh AC, et al. Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial. Blood. 2023;141(2):156-167. doi:10.1182/blood.2021014901

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