FDA Approves Ivosidenib Plus Azacitidine for Previously Untreated IDH1-Mutated AML


The FDA has granted approval for ivosidenib tablets as treatment for patients with previously untreated IDH1-mutated acute myeloid leukemia.

The FDA has granted approval for ivosidenib tablets (Tibsovo) in combination with azacitidine (Vidaza) as a treatment option for patients with previously untreated IDH1-mutated acute myeloid leukemia (AML) aged 75 years or older or who have comorbidities that preclude use of intesive induction chemotherapy, according to an announcement by Servier.1

The approval is supported by the results of the phase 3, multicenter, double-blind, randomized, placebo-controlled AGILE study (NCT03173248) which examined ivosidenib plus azacitidine (Vidaza) versus placebo in combination with azacitidine in patients with previously untreated AML with an IDH1 mutation.

"People living with acute myeloid leukemia, especially those who are newly diagnosed and are not eligible for intensive chemotherapy, have had few treatment options," said Susan Pandya, MD vice president Clinical Development and head of Cancer Metabolism Global Development Oncology & Immuno-Oncology, Servier, in a press release. "Today's approval of Tibsovo in combination with azacitidine represents a major advancement for patients with newly diagnosed IDH1-mutated acute myeloid leukemia in the United States, and we look forward to continuing our engagement with regulatory authorities worldwide."

Ivosidenib tablets were previously FDA approved as a single-agent for the treatment of adults with IDH1-mutant relapsed or refractory AML, and for adults with newly diagnosed IDH1-mutant AML who are ≥ 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy.2

Back in March 2022, the FDA granted priority review to ivosidenib plus azacitidine as a potential treatment for this patient population as the AGILE study showed ivosidenib plus azacitidine to demonstrate a statistically significant improvement in event-free survival (EFS) compared with the placebo control arm (HR, 0.35; 95% CI, 0.17-0.72], 2-sided P =0.0038)

meeting the primary end point of the study.

A total of 146 patients were randomized in the AGILE study with a median age was 75.5 years (range, 70.0–80.0). The ivosidenib/azacitidine arm consisted of 72 patients, the control arm had 74 patients, and the experimental population was made of up 54 patients with de novo AML compared with 18 with secondary AML. Additionally, 16 patients receiving ivosidenib plus azacitidine had poor-risk genetics compared with 20 patients in the placebo plus azacitidine arm.3

Primary end points of the study included EFS and OS, with secondary end points including CR rate, CRh rate, ORR, duration of response, time to response, percentage of patient with abnormal performance status, percentage of patient with abnormalities in n 12-lead electrocardiograms, percentage of patients with abnormalities in echocardiogram or multi-gated acquisition for left ventricular ejection fraction, the number of patients with laboratory abnormalities, and the percentage of patients with adverse events (AEs), severe AEs, and AEs of special interest.

Findings revealed a statistically significant improvement in the secondary end point of overall survival (OS) with ivosidenib/azacitidine compared with placebo azacitidine (HR, 0.44; 95% CI, 0.27-0.73; 1-sided P = .0005) and the median OS to be 24.0 months versus 7.9 months, respectively.2

Clinical response in the study favored the ivosidenib combination. With a median time to response of 4.3 months versus 3.8 months, the complete response rate with ivosidenib/azacitidine was 47.2% (95% CI, 35.3%-59.3%) compared with 14.9% (95% CI, 7.7%-25.0%) with placebo/azacitidine (P < .0001). The rate of complete response (CR) plus CR with partial hematologic recovery (CRh) observed with the ivosidenib combination was 52.8% (95% CI, 40.7%-64.7%) compared with 17.6% (95% CI, 9.7%-28.2%) with placebo plus azacytidine (P < .0001).

The CR rate in the ivosidenib plus azacitidine arm compared with the placebo/azacitidine arm at 24 weeks was 37.5% versus 10.8%, respectively. The overall response rate (ORR) observed with the experimental combination was 62.5% (95% CI, 50.3%-73.6%) versus 18.9% (95% CI, 10.7%, 29.7%) with placebo plus azacitidine (P < .0001).

In terms of safety, the most common adverse events (AEs) in the ivosidenib group versus the placebo group were nausea (42.3% vs 38.4%, respectively), vomiting (40.8% vs 26.0%), diarrhea (35.2% vs 35.6%), pyrexia (33.8% vs 39.7%), anemia (31.0% vs 28.8%), febrile neutropenia (28.2% vs 34.2%), thrombocytopenia (28.2% vs 20.5%), constipation (26.8% vs 52.1%), and pneumonia (23.9% vs 31.5%).

A total of 93.0% of patients who received ivosidenib plus azacitidine reported grade 3 or higher AEs compared with 94.5% of those treated with placebo plus azacitidine. In the ivosidenib arm versus the placebo arm, the most common grade ≥3 AEs were febrile neutropenia (28.2% vs 34.2%, respectively), anemia (25.4% vs 26.0%), thrombocytopenia (23.9% vs 20.5%), and pneumonia (22.5% vs 28.8%).

"Acute myeloid leukemia is a rapidly progressing, difficult-to-treat blood cancer with a poor prognosis," said Eytan M. Stein, MD, director, Program for Drug Development in Leukemia, Leukemia Service, Department of Medicine at Memorial Sloan Kettering Cancer Center, in a press release.1 "In addition to a favorable safety profile, Tibsovo is the first therapy targeting cancer metabolism to demonstrate an impressive, significant benefit in event-free survival and overall survival in combination with azacitidine, underscoring its importance as part of a new combination regimen for patients with newly diagnosed IDH1-mutated acute myeloid leukemia who are not candidates for intensive induction chemotherapy."


1. Servier announces FDA approval of Tibsovo® (ivosidenib tablets) in combination with azacitidine for patients with newly diagnosed idh1-mutated acute myeloid leukemia. News release. Servier. May 25, 2022. Accessed May 25, 2022. https://prn.to/3sWKYzu

2. Montesinos P, Recher C, Vives S, et al. 697 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. Presented at: 2021 American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 3722.

3. Study of AG-120 (Ivosidenib) vs. placebo in combination with azacitidine in patients with previously untreated acute myeloid leukemia with an IDH1 mutation (AGILE). Clinicaltrials.gov. Accessed March 7, 2022. https://bit.ly/3vIi8oE

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