AGILE trial—Ivosidenib plus Azacitidine versus Azacitidine in IDH1 Mutated Acute Myeloid Leukemia

Dr. Aditi Sharma & Dr. Abhishek Mangaonkar - about phase III ASCEMBL Trial

Dr. Aditi Sharma of Barbara Ann Karmanos Cancer Institute

& Dr. Abhishek Mangaonkar of Mayo Clinic


In the phase III AGILE trial reported in the New England Journal of Medicine, Pau Montesinos, M.D., Ph.D., and colleagues found that the combination of ivosidenib and azacitidine showed significantly longer event-free survival (EFS) compared to placebo and azacitidine in newly diagnosed IDH1-mutated acute myeloid leukemia (AML) patients unfit to receive intensive chemotherapy.


Older patients who are ineligible to receive intensive chemotherapy have poor outcomes and represent a difficult-to-treat population. Targeted IDH1 inhibitor, ivosidenib, has been approved as a single agent in relapsed refractory IDH1-mutated AML or for older adults with newly diagnosed IDH1-mutated AML.


In this global, double-blind, placebo-controlled, intention-to-treat phase III trial, 146 participants were randomized 1:1 to receive either ivosidenib (500 mg) orally, once daily, plus azacitidine 75 mg/m2 subcutaneous or intravenously (N=72) or matching placebo combined with azacitidine (N=74). The primary endpoint was EFS, defined as the time from randomization to treatment failure, relapse, or death due to any cause. Secondary endpoints were complete remission, overall survival, complete remission or complete remission with partial blood count recovery, objective response, safety, and health-related quality of life. The patients were followed for a median of 12.4 months. EFS was significantly longer in the ivosidenib plus azacitidine group compared to the placebo plus azacitidine group (hazard ratio [HR] 0.33; 95% confidence interval [CI], 0.16 to 0.69; P 0.002). Although the median EFS was similar in both groups, the probability of EFS at 12 months was 37% vs. 12% in the ivosidenib plus azacitidine group and placebo plus azacitidine group, respectively. The median overall survival was 24 months with ivosidenib plus azacitidine and 7.9 months with placebo plus azacitidine (HR for death, 0.44; 95% CI, 0.27 to 0.73; P 0.001). Complete remission or complete remission with partial hematologic recovery and objective response were also higher in the ivosidenib and azacitidine group compared to placebo and azacitidine (47% vs. 15%, 53% vs. 18%, and 62% vs. 19% respectively and P<0.001 for all). Health-related quality of life measures using the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire also favored ivosidenib plus azacitidine.


More than 90% of participants experienced some form of grade 3 or higher adverse events, including febrile neutropenia (28% with ivosidenib plus azacitidine vs. 34% with placebo plus azacitidine), neutropenia (27% vs. 16%, respectively) and infections (21% vs. 30%, respectively). The incidence of differentiation syndrome was 14% in the ivosidenib plus azacitidine arm and 8% in those receiving a placebo and azacitidine.


It would be interesting to see how ivosidenib plus azacitidine performs when compared or combined with venetoclax-based regimens, and single-agent ivosidenib. A phase Ib trial studying the combination of ivosidenib and venetoclax with or without azacitidine in IDH1 mutated hematologic malignancies has demonstrated efficacy and a tolerable safety profile. Participants are currently being recruited for the phase II study.



  1. Montesinos P, Recher C, Vives S, Zarzycka E, Wang J, Bertani G, et al. Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia. N Engl J Med. 2022 Apr 21;386(16):1519–31.
  2. Lachowiez CA, Garcia JS, Borthakur G, Loghavi S, Zeng Z, Tippett GD, et al. A phase Ib/II study of ivosidenib with venetoclax +/- azacitidine in IDH1-mutated hematologic malignancies. J Clin Oncol. 2022 Jun 1;40(16_suppl):7018–7018.



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