Ivosidenib and Azacitidine Combination Shows Significant Clinical Benefit in Patients with Newly Diagnosed IDH1-Mutated AML

In a phase III, AGILE study, ivosidenib and azacitidine significantly improved event-free survival (EFS), response, and overall survival (OS) as compared with placebo and azacitidine in patients with newly diagnosed IDH1-mutated acute myeloid leukaemia (AML) who were ineligible for induction chemotherapy. This clinical benefit is supported by favourable health-related quality of life, incidences of transfusion independence, and the expected constellation of adverse events associated with treatment for acute leukaemia. The study findings are published by AGILE investigators in 21st April 2022 issue of The New England Journal of Medicine.

The authors wrote in the study background that somatic mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) occur in 6-10% of patients with AML. Several studies have suggested that IDH1-mutated AML is associated with older age and a poorer prognosis, especially in the context of a normal karyotype.

Older patients and those unable to receive intensive induction chemotherapy (unfit patients) receive less intensive, non-curative regimens. Addition of venetoclax to azacitidine has been associated with a significant improvement in OS among unfit patients with mutation-agnostic AML. Despite this progress, unfit patients with AML have poor outcomes. One strategy to improve outcomes is to use new agents that target molecular alterations.

Ivosidenib is a first-in-class, oral, potent, targeted small-molecule inhibitor of mutated IDH1. It has shown clinical activity as a single agent in studies involving patients with haematologic malignancies and solid tumours. Data from a phase Ib study that involved 23 patients with newly diagnosed IDH1-mutated AML showed encouraging clinical activity with ivosidenib and azacitidine combination therapy. 

Ivosidenib monotherapy is approved in the US for adults with relapsed or refractory IDH1-mutated AML or patients with newly diagnosed IDH1-mutated AML who are 75 years of age or older or who have coexisting conditions that preclude intensive chemotherapy.

In the AGILE, phase III study, the investigators randomly assigned patients with newly diagnosed IDH1-mutated AML who were ineligible for intensive induction chemotherapy to receive oral ivosidenib and subcutaneous or intravenous azacitidine or to receive matched placebo and azacitidine. The primary endpoint was EFS, defined as the time from randomisation until treatment failure (e.g. the patient did not have complete remission by week 24), relapse from remission, or death from any cause, whichever occurred first.

The intention-to-treat population included 146 patients, 72 in the ivosidenib and azacitidine group and 74 in the placebo and azacitidine group.

At a median follow-up of 12.4 months, EFS was significantly longer in the ivosidenib and azacitidine group than in the placebo and azacitidine group (hazard ratio [HR] for treatment failure, relapse from remission, or death 0.33, 95% confidence interval [CI] 0.16 to 0.69; p = 0.002). The estimated probability that a patient would remain event-free at 12 months was 37% in the ivosidenib and azacitidine group and 12% in the placebo and azacitidine group.

The median OS was 24.0 months with ivosidenib and azacitidine and 7.9 months with placebo and azacitidine (HR for death 0.44, 95% CI 0.27 to 0.73; p = 0.001).

Common adverse events of grade 3 or higher included febrile neutropenia (28% with ivosidenib and azacitidine and 34% with placebo and azacitidine) and neutropenia (27% and 16%, respectively); the incidence of bleeding events of any grade was 41% and 29%, respectively. The incidence of infection of any grade was 28% with ivosidenib and azacitidine and 49% with placebo and azacitidine. Differentiation syndrome of any grade occurred in 14% of the patients receiving ivosidenib and azacitidine and 8% of those receiving placebo and azacitidine.

The authors commented that this phase III study showed that combination therapy with ivosidenib and azacitidine was associated with adverse events similar to those attributed to treatment for acute leukaemia and was effective in extending EFS, increasing the likelihood of complete remission, and prolonging OS among patients with IDH1-mutated AML who were older or otherwise ineligible for induction chemotherapy. Durable and deep responses, with frequent IDH1 mutation clearance, occurred in patients who received ivosidenib and azacitidine, a finding that highlights the benefit of targeting the mutated IDH1 protein.

Furthermore, favourable health-related quality of life and incidences of transfusion independence support the clinical benefit of ivosidenib and azacitidine. The performance of the control group is consistent with previous reports indicating poor outcomes with azacitidine in patients with IDH1-mutated AML. Overall, the combination of ivosidenib and azacitidine was associated with few treatment discontinuations due to toxic effects.

The study was supported by Agios Pharmaceuticals. Servier Pharmaceuticals has completed the acquisition of the Agios oncology business.


Montesinos P, Recher C, Vives S, et al. Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia. N Engl J Med 2022;386:1519-1531.