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.
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).
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.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.