FDA Grants Priority Review to Ivosidenib Plus Azacitidine for IDH1-Mutant AML


The FDA has granted priority review to ivosidenib tablets as a potential treatment for patients with previously untreated IDH1-mutated acute myeloid leukemia.

The FDA has accepted and granted priority review to a supplemental new drug application (sNDA) for ivosidenib tablets (Tibsovo) as a potential treatment for patients with previously untreated IDH1-mutated acute myeloid leukemia (AML), according to an announcement by Servier.1

Supporting the sNDA are results from the phase 3, multicenter, double-blind, randomized, placebo-controlled AGILE study (NCT03173248) of ivosidenib plus azacitidine (Vidaza) versus placebo in combination with azacitidine in patients with previously untreated AML with an IDH1 mutation.

"On the heels of our recent FDA approval of Tibsovo in cholangiocarcinoma, we are pleased with this important step forward in the agency's consideration to expand its current indication to include the treatment of patients with previously untreated IDH1-mutated acute myeloid leukemia," said David K. Lee, chief executive officer, Servier Pharmaceuticals, in a press release. "We are thrilled with the positive momentum of this program as we continue to grow our leadership in oncology and deliver more life-changing medicines to patients living with difficult-to-treat cancers."

In the AGILE study, ivosidenib plus azacitidine demonstrated a statistically significant improvement in event-free survival (EFS) compared with the placebo control arm (HR, 0.33; 95% CI, 0.16-0.69; 1-sided P = .0011), the primary end point of the study. There was also a statistically significant improvement in a secondary end point, overall survival (OS), with ivosidenib/azacitidine compared with placebo azacitidine (HR, 0.44; 95% CI, 0.27-0.73; 1-sided P = .0005). The median OS was 24.0 months versus 7.9 months, respectively.1,2

Clinical response in the study favored the ivosidenib combination. The complete response rate observed 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), with a median time to response of 4.3 months versus 3.8 months, respectively. 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).2

At 24 weeks, the CR rate in the ivosidenib plus azacitidine arm compared with the placebo/azacitidine arm 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%) compared with 18.9% (95% CI, 10.7%, 29.7%) with placebo plus azacitidine (< .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%).

Grade 3 or higher AEs occurred in 93.0% of patients who received ivosidenib plus azacitidine compared with 94.5% of those treated with placebo plus azacitidine. The most common grade ≥3 AEs in the ivosidenib arm versus the placebo arm 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%).

The AGILE study randomized 146 patients who had a median age was 75.5 years (range, 70.0–80.0). Overall, there were 72 patients in the ivosidenib/azacitidine arm and 74 were in the control arm. The experimental population was made of up 54 patients with de novo AML compared with 18 with secondary AML. Further, 16 patients receiving ivosidenib plus azacitidine had poor-risk genetics compared with 20 patients in the placebo plus azacitidine arm.1,3

In addition to EFS and OS, secondary end points ongoing analyses in AGILE include 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 AEs, severe AEs, and AEs of special interest.3

The study is ongoing but no longer recruiting patients with previously untreated AML and IDH1 mutations.

Ivosidenib tablets are currently 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.1

"Tibsovo is the first therapy targeting cancer metabolism to demonstrate improved event-free survival and overall survival in combination with azacitidine in patients with previously untreated IDH1-mutated AML," said Susan Pandya, MD, vice president of clinical development, and head of cancer metabolism global development oncology & immuno-oncology, Servier Pharmaceuticals, in the press release. "With this FDA acceptance for priority review, we are closer to offering this critical treatment option to patients in the [United States] and we look forward to engaging with regulatory agencies around the world."


1. Servier Announces FDA filing acceptance and priority review for Tibsovo® (ivosidenib tablets) in combination with azacitidine for patients with previously untreated IDH1-mutated acute myeloid leukemia. News release. Servier. March 7, 2022. Accessed March 7, 2022. https://prn.to/3KlkMVt

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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