Ivosidenib and Azacitidine Yield Significant Clinical Benefit Vs Placebo in IDH1-Mutant AML


Patients with previously untreated IDH1-mutant acute myeloid leukemia experienced significant clinical benefit following treatment with ivosidenib and azacitidine compared with the placebo combination.

Treatment with the combination of ivosidenib (Tibsovo) and azacitidine (Onureg) resulted in a significant clinical benefit compared with a placebo combination in patients with previously untreated IDH1-mutant acute myeloid leukemia (AML), according to findings from the phase 3 AGILE study (NCT03173248).1

After a median follow-up of 12.4 months, the 12-month event-free survival (EFS) rate was 37% in the experimental arm compared with 12% in the placebo arm (HR, 0.33; 95% CI, 0.16-0.69; P = .002). Additionally, the probability of remaining event-free at 6 months was 40% vs 20% in the ivosidenib and placebo cohorts, respectively. Moreover, the median overall survival (OS) was 24.0 months vs 7.9 months in the 2 respective arms (HR, 0.44; 95% CI, 0.27-0.73; P = .001).

“Patients with IDH1-mutated AML have a poor prognosis and have few, if any, treatment options, especially for newly diagnosed patients who are not eligible for intensive chemotherapy,” Susan Pandya, MD, vice president of clinical development and head of Cancer Metabolism Global Development Oncology & Immuno-Oncology, Servier Pharmaceuticals, said in a press release.2 “The publication of the compelling phase 3 AGILE study data in [the New England Journal of Medicine], reinforces the clinical importance of these results and supports Servier's ongoing pursuit to serve patients with IDH1-mutated malignancies.”

The goal of the global, double-blind, randomized, placebo-controlled trial was to determine the safety and efficacy of ivosidenib and azacitidine in a population of patients with newly diagnosed, IDH1-mutant disease. Treatment included ivosidenib administered at a dose of 500 mg or a matched oral placebo once daily plus 75 mg of azacitidine either intravenously or subcutaneously for 7 days per 28-day cycle. Patients were randomized 1:1 and stratified based on geographic region and disease status.

Patients were required to be 18 years or older with centrally confirmed disease. Additionally, patients could not have previously received treatment with an IDH1 inhibitor or hypomethylating agent for myelodysplastic syndrome. An ECOG performance status of 0 to 2 and adequate renal and hepatic function were also required.

The primary end point of the trial was EFS, with secondary end points including complete remission (CR), OS, CR with partial hematologic recovery, objective response, safety, and health-related quality of life (HRQOL).

A total of 295 patients were screened for the study, of whom 146 were randomized to the ivosidenib cohort (n = 72) or placebo cohort (n = 74). The median ages in both respective groups were 76.0 years and 75.5 years.

At 24 weeks, 38% of patients in the ivosidenib arm had a CR compared with 11% of patients in the placebo group. Moreover, EFS among complete responders at 24 weeks was higher in the experimental arm than the placebo arm. The CR rate was 47% (95% CI, 35%-59%) and 15% (95% CI, 8%-25%) in both respective arms. When assessing the EFS among patients who didn’t achieve a CR, investigators reported a median of 22.9 months (95% CI, 7.5–not estimated) vs 4.1 months (95% CI, 2.7-6.8) in the ivosidenib and placebo arms, respectively. The median duration of CR was not reached in the ivosidenib cohort and was 11.2 months (95% CI, 3.2–not estimated) in the placebo cohort. The probability that patients would remain in CR at 12 months was 88% in the ivosidenib group compared with 36% in the placebo group. The median time to CR was 4.3 months vs 3.8 months, respectively.

CR or CR without complete hematologic recovery was reported in 53% of patients in the experimental arm and 18% of patients in the placebo arm (P <.001). Moreover, an objective response occurred in 62% of patients and 19% of patients, respectively. The median duration of response was 22.1 months in the ivosidenib cohort and 9.2 months in the placebo cohort.A total of 28 and 46 deaths were reported in the 2 cohorts, respectively.

In terms of HRQOL, baseline EORTC QLQ-C30 scores were available from the majority of patients in the experimental (96%) and placebo arms (89%). HRQOL assessment was not available after cycle 19, and the adherence rate was over 70%. Results from the HRQOL assessment favored the ivosidenib arm across all subscales.

In total, 93% of patients who were treated with the ivosidenib combination and 95% of patients in the placebo cohort had an adverse effect (AE) that was grade 3 or higher. The most common grade 3 or higher AE that occurred in 15% or more of patients in the ivosidenib and placebo cohorts, respectively, were febrile neutropenia (28% vs 34%), anemia (25% vs 26%), neutropenia (27% vs 16%), thrombocytopenia (24% vs 21%), and pneumonia (23% vs 29%). Additionally, infections of any grade were reported in 28% and 49% of patients, respectively. Death related to AEs occurred in 14% of those in the experimental arm vs 29% in the placebo arm.


  1. 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. doi:10.1056/NEJMoa2117344
  2. Phase 3 AGILE data of TIBSOVO® (ivosidenib tablets) in combination with azacitidine for patients with previously untreated IDH1-mutated acute myeloid leukemia published in the New England Journal of Medicine. News release. Cision. April 21, 2022. Accessed April 21, 2022. https://yhoo.it/37suQ1f
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