In the phase III AGILE trial reported in The New England Journal of Medicine, Montesinos et al found that the addition of ivosidenib to azacitidine in induction therapy significantly prolonged event-free survival in patients with newly diagnosed IDH1-mutated acute myeloid leukemia. An overall survival benefit was also observed.

In the double-blind trial, 146 patients from sites in 20 countries were randomly assigned between March 2018 and May 2021 to receive a minimum of six cycles of ivosidenib at 500 mg one daily and subcutaneous or intravenous azacitidine at 75 mg/m² for 7 days in 28-day cycles (n = 72) or placebo plus azacitidine (n = 74). The primary endpoint was event-free survival.

Event-Free Survival

Trial recruitment was stopped in May 2021, after the data monitoring committee observed a difference in the number of deaths favoring the combination group. At a median follow-up of 12.4 months, event-free survival was significantly longer in the combination vs control group (hazard ratio [HR] = 0.33, 95% confidence interval [CI] = 0.16–0.69, P = .002).

Since more than half of the patients in each group did not have complete remission by week 24, median event-free survival was the same in both groups (0.03 months [95% CI = 0.03–11.01 months] in the combination group vs 0.03 months [95% CI = could not be estimated] in the control group). However, the estimated event-free survival at 12 months was 37% vs 12%. Complete remission by 24 weeks was achieved in 38% vs 11% of patients.

Median overall survival was 24.0 months (95% CI = 11.3-34.1 months) in the combination group vs 7.9 months (95% CI = 4.1–11.3 months) in the control group (HR = 0.44, 95% CI = 0.27–0.73,  P = .001).

Adverse Events

Grade ≥ 3 adverse events occurred in 93% of the combination group vs 95% of the control group, with those occurring in > 15% of both groups consisting of febrile neutropenia (28% vs 34%), anemia (25% vs 26%), neutropenia (27% vs 16%), thrombocytopenia (24% vs 21%), and pneumonia (23% vs 29%). Infection of any grade occurred in 28% vs 49%. Bleeding events of any grade occurred in 41% vs 29%.  Differentiation syndrome of any grade occurred in 14% vs 8%. Adverse events led to death in 10 patients (14%) in the combination group vs 21 patients (29%) in the control group.

The investigators concluded: “Ivosidenib and azacitidine showed significant clinical benefit as compared with placebo and azacitidine in this difficult-to-treat population. Febrile neutropenia and infections were less frequent in the ivosidenib-and-azacitidine group than in the placebo-and-azacitidine group, whereas neutropenia and bleeding were more frequent in the ivosidenib-and-azacitidine group.”

Pau Montesinos, MD, PhD, of the Hematology Department, Hospital Universitari i Politecnic La Fe, Valencia, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by Agios Pharmaceuticals and Servier Pharmaceuticals. For full disclosures of the study authors, visit nejm.org.