AGILE Study: Addition of Ivosidenib to Azacitidine Triples Median Overall Survival in Difficult-to-Treat AML Population

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In patients with newly diagnosed acute myeloid leukemia (AML) with an IDH1 mutation who were ineligible for intensive chemotherapy, the addition of the IDH1 inhibitor ivosidenib to azacitidine significantly improved survival vs azacitidine alone, according to data presented at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition.1 Results of the phase III AGILE study showed that median overall survival was more than three times longer in those who received the combination therapy compared with those receiving azacitidine alone (24.0 months vs 7.9 months; hazard ratio [HR] = 0.44; P = .0005). The combination was also shown to be safe and tolerable, with fewer infections reported relative to placebo plus azacitidine, authors of the study reported.

“The combination of ivosidenib and azacitidine significantly improved event-free survival, overall survival, and clinical response compared with placebo plus azacitidine in all patients with newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy,” said Hartmut Döhner, MD, Professor of Medicine and Medical Director of the Department of Internal Medicine III at Ulm University and Deputy Director of the Comprehensive Cancer Center, Germany. “The clinical benefit of the combination was also supported by favorable health-related quality of life.”

Hartmut Döhner, MD

Hartmut Döhner, MD

Somatic mutations in the metabolic enzyme IDH1 (isocitrate dehydrogenase 1) occur in 6% to 10% of patients with AML and have been associated with a poor prognosis. Ivosidenib is an oral inhibitor of the mutant IDH1 enzyme and is approved by the U.S. Food and Drug Administration as monotherapy for patients with relapsed or refractory IDH1-mutated AML as well as for patients with newly diagnosed IDH1-mutated AML who are 75 years or older or have comorbidities precluding the use of intensive induction chemotherapy.

A phase Ib study of older, unfit patients with newly diagnosed IDH1-mutant AML showed a favorable safety profile and clinical activity for the combination of ivosidenib and azacitidine.

Study Methods

For this global, double-blind, placebo-controlled, phase III study, patients were randomly assigned to receive either ivosidenib (500 mg once daily) plus standard-dose azacitidine or placebo plus azacitidine. The primary endpoint was event-free survival. Key secondary endpoints included complete remission rate, overall survival, rate of complete remission plus complete remission with partial hematologic recovery, and objective response rate.

As of March 18, 2021, the data cutoff for this analysis, 146 patients were randomly assigned to the study. On May 12, the independent data monitoring committee recommended to hold further enrollment based on an order difference of clinical importance between the treatment groups that was not related to safety. After a difference in survival benefit favoring the combination arm was confirmed, the site and study teams were unblinded, and crossover to ivosidenib plus azacitidine was permitted for patients receiving placebo plus azacitidine.

Baseline demographic and disease characteristics were well balanced between the two treatment arms. The median patient age was 76 in the ivosidenib-plus-azacitidine arm and 75.5 in the placebo-plus-azacitidine arm.

Improved Outcomes With Combination

As Dr. Döhner reported, event-free survival based on the intention-to-treat population was statistically significant in favor of ivosidenib plus azacitidine (HR = 0.33). In addition, 37.5% of patients achieved complete remission by week 24 with ivosidenib plus azacitidine vs 10.8% with placebo plus azacitidine. (Patients who did not achieve complete remission by week 24 were considered to have treatment failure and therefore were counted as an event at day 1 of randomization.)

Overall survival was also statistically significant in favor of ivosidenib plus azacitidine. “Median overall survival with ivosidenib plus azacitidine was 24 months and three times longer than with placebo plus azacitidine at 7.9 months,” said Dr. Döhner. He noted that the overall survival benefit was consistent across clinical and disease subgroups.

The combination of ivosidenib plus azacitidine also significantly improved clinical responses. The complete remission rate with ivosidenib plus azacitidine was 47.2% vs 14.9% with placebo plus azacitidine, and the overall response rate was 62.5% vs 18.9%, respectively. The median treatment duration on ivosidenib plus azacitidine was 6 months vs 2.8 months with placebo plus azacitidine.

Quality-of-life results also favored ivosidenib plus azacitidine across all subscales, including clinically meaningful improvements in global health status and fatigue over time.

Safety Profile

The safety profile of ivosidenib plus azacitidine was favorable overall and consistent with observations from the recent phase Ib study in a similar population. Adverse events of special interest with ivosidenib plus azacitidine vs placebo plus azacitidine included grade 2 or greater differentiation syndrome in 14.1% vs 8.2% and grade 3 or greater QT prolongation in 9.9% vs 4.1% of patients. There were no reported grade 3 or greater leukocytosis in either treatment arm.

The frequency of febrile neutropenia was 28.2% with ivosidenib plus azacitidine and 34.2% with placebo plus azacitidine. Infections of any grade were less common with the combination therapy (28.2%) vs azacitidine monotherapy (49.3%).

There were no reported deaths related to treatment or differentiation syndrome. 

DISCLOSURE: Dr. Döhner reported financial relationships with Astellas, Celgene, AstraZeneca, Astex Pharmaceuticals, Amgen, Agios, AbbVie, Bristol Myers Squibb, Berlin-Chemie, Janssen, Jazz, Kronos Bio, Novartis, Oxford Biomedica, Roche, Gilead, Pfizer, and Syndax.


1. Montesinos P, Recher C, Vives S, et al: AGILE: A global, randomized, double-blind, phase 3 study of ivosidenib + azacitidine versus placebo + azacitidine in patients with newly diagnosed acute myeloid leukemia with an IDH1 mutation. 2021 ASH Annual Meeting & Exposition. Abstract 697. Presented December 13, 2021.

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