Ivosidenib and Azacitidine Combination Demonstrates Durable Activity in Newly Diagnosed AML

Ivosidenib, an inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, was well tolerated and associated with deep and durable responses in combination with azacitidine in patients with newly diagnosed acute myeloid leukemia (AML), according to findings published in the Journal of Clinical Oncology.

According to lead study author Courtney DiNardo, MD, of the University of Texas MD Anderson Cancer Center, the ivosidenib and azacitidine combination regimen studied in this small trial may be considered as an appropriate frontline combination approach for older patients with IDH1-mutated AML. This could be a welcome option for this population, considering that standard of care with intensive induction chemotherapy and subsequent consolidation chemotherapy or allogeneic hematopoietic cell transplantation is generally unsuitable for older patients and those with comorbidities.

This open-label, multicenter phase I/IIb trial evaluated the safety and efficacy of continuous oral ivosidenib 500 mg once daily with subcutaneous azacitidine 75 mg/m2 on days 1 through 7 in 28-day cycles. Trial participants had newly diagnosed IDH1-mutated AML and were deemed ineligible for intensive induction chemotherapy. Dr. DiNardo and coauthors reported findings from the phase Ib portion of the trial, which enrolled 7 patients in the dose-finding stage and 16 in the dose-expansion stage.

The median age of the 23 patients was 76 years (range = 61-88). Most patients presented with an Eastern Cooperative Oncology Group performance status score of 1 at baseline (61%). The IDH1 mutation types were R132C in 70% of patients, R132H in 17%, and R132L in 13%. Most participants (65%) were considered to have an intermediate cytogenetic risk status, as assessed by investigators.

During a median follow-up period of 16 months, patients remained on treatment for a median of 15.1 months (range = 0.3-32.2). As of data cutoff on February 19, 2019, 10 patients remained on treatment.

In the safety analysis, grade ≥3 treatment-related adverse events (AEs) that occurred in more than 10% of patients included neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). AEs of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥3 leukocytosis (9%). The researchers reported that the ivosidenib and azacitidine combination had a safety profile consistent with each agent as a monotherapy.

In the entire 23-patient cohort, the overall response rate was 78%, which included:

  • complete remission (CR) rate: 61%
  • CR with incomplete hematologic or platelet recovery (CRi/CRp) rate: 9%
  • morphologic leukemia-free state rate: 9%

The median time to CR was 3.7 months and ranged between 0.8 and 15.7 months. Among responders to ivosidenib and azacitidine, the median durations of CR, CRi/CRp, and overall response were not reached. The estimated 12-month survival rate was 82%.

Dr. DiNardo and co-authors noted that responses were deep and durable, with approximately 71% of patients who achieved a CR showing evidence of IDH1 mutation clearance in bone marrow mononuclear cells, as assessed by polymerase chain reaction.

Limitations of this study included the small sample size, as well as the lack of a randomized design and comparator arm. Dr. DiNardo added that the main question to be explored in future investigations is whether azacitidine plus ivosidenib or azacitidine plus venetoclax, or all three in a sequenced or triplet approach, results in the best outcomes for patients with IDH1-mutated AML.

Dr. DiNardo noted that, on the basis of these encouraging results, the large, phase III, randomized AGILE study comparing azacitidine plus ivosidenib versus azacitidine alone in patients with previously untreated IDH1-mutated AML, is underway outside the U.S.

The study authors report relationships with Agios Pharmaceuticals and Bristol Myers Squibb, both of which sponsored the study.


DiNardo CD, Stein AS, Stein EM, et al. Mutant isocitrate dehydrogenase 1 inhibitor ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2020 October 29. [Epub ahead of print]