Triplet Combination Therapies Under Study for IDH-Mutated AML
Posted: Friday, October 1, 2021
Courtney D. DiNardo, MD, of The University of Texas MD Anderson Cancer Center, Houston, explored several combination therapies that experts hope may improve clinical efficacy beyond that of monotherapy with the IDH inhibitors ivosidenib and enasidenib in patients with acute myeloid leukemia (AML), during the 2021 Society of Hematologic Oncology (SOHO) Annual Meeting (EXABS-175-AML). Dr. DiNardo concluded that the use of “well-tolerated and rational combinations” can improve the durability of responses and patient outcomes.
The first combination trial enrolled patients with AML and IDH1 mutations who were administered ivosidenib and azacitidine. This phase Ib trial yielded a complete remission/complete remission with a partial hematologic recovery rate of 70%, a complete remission rate of 61%, and a 12-month overall survival rate of 82%. Another phase II trial focused on newly diagnosed individuals with IDH2-mutated AML who were administered azacitidine with or without enasidenib. The combination therapy generated an overall response rate of 71%, with similarly impressive complete remission/complete remission with incomplete hematologic recovery and complete remission rates (63% vs. 24%, 53% vs. 12%).
A recent phase I study of 151 newly diagnosed patients administered standard 7+3 therapy with either enasidenib or ivosidenib. Of the 60 patients with IDH1 mutations, the 12-month overall survival rate was 78%, and the complete remission/complete remission with incomplete hematologic recovery rate was 77%; 91 patients with IDH2 mutations had an overall survival of 25.6 months and a complete remission/complete remission with an incomplete hematologic recovery rate of 74%.
The BCL2 inhibitor venetoclax is currently being combined with ivosidenib in a clinical trial, along with azacitidine, in patients with IDH1-mutated AML. So far, according to Dr. DiNardo, this trial has yielded a composite complete remission rate of 84% and a 1-year overall survival rate of 68%. Updated results from this study, with increased duration of follow-up, are expected to determine whether this triplet combination can avoid various pathways of resistance.
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